WO2021147909A1 - 5ht2a receptor antagonist and medical application thereof - Google Patents

5ht2a receptor antagonist and medical application thereof Download PDF

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Publication number
WO2021147909A1
WO2021147909A1 PCT/CN2021/072899 CN2021072899W WO2021147909A1 WO 2021147909 A1 WO2021147909 A1 WO 2021147909A1 CN 2021072899 W CN2021072899 W CN 2021072899W WO 2021147909 A1 WO2021147909 A1 WO 2021147909A1
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compound
ring
pharmaceutically acceptable
disease
formula
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PCT/CN2021/072899
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French (fr)
Chinese (zh)
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邢洪涛
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行远医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and relates to a 5-HT2A receptor antagonist or inverse agonist with a central nervous system disease treatment effect and applications thereof.
  • the compounds can be used to treat certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism, etc.) and degenerative diseases of the central nervous system (such as Alzheimer’s disease, Parkinson’s disease, etc.) Disease, Huntington’s disease, Lewy body dementia, etc.) related or concurrent mental disorders.
  • Serotonin or 5-hydroxytryptamine plays an extremely important role in the physiological functions of the human body.
  • 5-HT is an important neurotransmitter and neuromodulator, which regulates a variety of behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure, and pathological states (such as anxiety, Mania, schizophrenia, obesity, drug addiction, migraine and hypertension) play an extremely important role (Alenina N, et al., (2009) ProcNatl Acad Sci USA, 106, 10332-10337; Filip M, et al., (2005) Pharmacol Rep, 57, 685-700; Greek AR, (2006) Br J Pharmacol, 147, Suppl 1: S145-S152).
  • 5-HT acts through its receptors. According to the structure (amino acid sequence), biochemical (post-receptor mechanism of signal transduction) and pharmacological differences, 5-HT receptors are divided into 7 families (5-HT1 ⁇ 5- HT7) and at least 15 different subtypes (Barnes NM, et al., (1999) Neuropharmacology, 38, 1083-1152; Hannon J, et al., (2008) Behav Brain Res, 195, 198-213; Hoyer D , Et al., (2002) Pharmacol Biochem Behav, 71, 533-554; Pauwels PJ. (2003) Tocris Reviews, No. 25). The distribution, ligand preference and related functions of different subtypes of receptors are different.
  • the 5-HT2A subtype receptors are widely and discretely expressed in the central nervous system, and are highest in the cerebral cortex, limbus, hippocampus, hypothalamus and basal ganglia that are involved in the regulation of higher cognitive and emotional functions. 5-HT2A receptors are expressed on dopamine, GABA, glutamate and Ach neurons and act as dendritic heterogeneous receptors (Buhot MC, (1997) Curr Opin Neurobiol, 7, 243-254; Leysen JE , (2004) Curr Drug Targets CNS Neuro Disord, 3, 11-26).
  • 5-HT2A receptors are G-protein coupled receptors, which complete signal transduction by activating guanine nucleotide binding protein (G protein), resulting in second messenger molecules such as loops.
  • G protein guanine nucleotide binding protein
  • cAMP adenylate
  • inositol phosphates adenylate
  • diacylglycerol adenylate
  • These second messenger molecules regulate the functions of a variety of intracellular enzymes (such as kinases and ion channels), and ultimately affect cell excitability and cell function.
  • 5-HT2A receptors are involved in the molecular mechanism of atypical antipsychotics such as clozapine, olanzapine, and risperidone (Gonzalez -Maeso J, et al., (2009) Trends Neurosci, 32: 225-232; Fricios M, et al., (2011) Cell, 147: 1011-1023; Kurita M, et al., (2012) Nat Neurosci , 15: 1245-1254); 5-HT2A receptor antagonists are very important for the treatment of negative symptoms of schizophrenia (such as affective disorders, language loss, etc.) (Blier P, et al., (2005) J Clin Psychiatry 66, Suppl 8, 30-40; Richt and NM, et al., (2008) Prog Brain Res, 172, 141-153; Meltzer, HY (2013) Annu Rev Med 64, 393-406); other studies have confirmed that cortical cones The 5-HT2A receptor regulation pathway of somatic neurons
  • the drugs used to treat mental illness are divided into two categories.
  • "Typical” antipsychotic drugs or the previous generation drugs have little clinical application due to the side effects of motor functions (extrapyramidal side effects, Parkinson's disease, etc.) caused by the previous generation of drugs.
  • Current drugs focus more on “atypical” antipsychotics.
  • Psychiatric drugs Principal Cre Companion J Clin Psychiatry. (2007) 9(6): 444-54).
  • the second-generation antipsychotic drugs all have broad-spectrum receptor activity. These compounds act as agonists, competitive antagonists or inverse agonists to modulate a variety of monoaminergic receptors such as 5-HT, dopaminergic, Adrenergic, muscarinic, or histaminergic receptors.
  • the present invention provides a compound with 5-HT2A receptor antagonistic activity, and a pharmaceutical composition containing the compound for the treatment of central nervous system diseases, and further provides a method for the treatment of central nervous system diseases.
  • the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • n and m are respectively selected from integers from 0 to 4, which limit the number of alkylene units of the alkylene chain,
  • X is a heteroatom or a carbon atom, and the heteroatom is selected from O, N, and S atoms, preferably a N atom;
  • Ring X is the ring where the X atom is located, and is connected to the main structure of the compound through a ring carbon atom or a ring N atom,
  • the ring B group is selected from the group containing 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aromatic ring group or 5-8 membered heteroaromatic ring group, and the ring is fused with a benzene ring; preferably Ring B is 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl;
  • R 1 is one or more substituents, located at any substitution position of the ring system where R 1 is located, and R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
  • R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
  • X is a heteroatom, selected from O, N, S atoms; preferably N atom;
  • the ring system formed by ring B and benzene ring is selected from the following structural groups:
  • Y is selected from O, N, S atoms; preferably O atom.
  • X is a heteroatom, selected from O, N, and S atoms, preferably N atom;
  • Y is selected from O, N, S atoms; preferably O atom;
  • R 1 is one or more substituents, located at any substitution position of the ring system where R 1 is located, and R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
  • R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
  • R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  • ring X is connected to the main structure of the compound through a ring carbon atom; preferably, R 3 is substituted at the X position.
  • ring X is azetidinyl, pyrrolidinyl, or piperidinyl; and Y is an O atom.
  • alkyl refers to saturated hydrocarbon groups, including straight chain alkyl groups and branched chain alkyl groups.
  • halogen refers to F, Cl, Br or I.
  • alkylene refers to a divalent alkyl group.
  • Alkylene chain is polymethylene, ie -(CH 2 )x-, where x is a positive integer.
  • cycloalkyl refers to a monocyclic hydrocarbon group that is saturated or contains one or more unsaturated units but is not aromatic.
  • the ring is a 3-20 membered ring, which has a single point of attachment to the rest of the compound .
  • heterocycloalkyl refers to a monocyclic group containing 1 to 5 independently selected from heteroatoms such as N, S, O, etc.
  • the heterocycloalkyl group may be a saturated ring or an unsaturated ring, so The ring is a 3-20 membered ring, including piperidine, pyrrolidine, tetrahydrofuran and the like.
  • aryl refers to a single ring, and the system has 5 to 10 (preferably 5, 6 or 9) ring members in total, and the ring members are ring carbon atoms; (4n+2) ⁇ electrons (where n is a positive integer) are shared in the ring system to comply with Huckel's rule.
  • heteroaryl and “heteroaryl ring” refer to having 5 to 10 ring atoms, preferably 5, 6, or 9; ring atoms have (4n+2) ⁇ electrons (where n is a positive integer) to conform Huckel's rule; and in addition to carbon atoms, it also has 1 to 5 heteroatoms selected from nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen .
  • arbitrary substitution position in the ring and “arbitrary substitution position in the ring system” mean that the substituent is located at any position in the ring or ring system that can be substituted, including ring carbon atoms, ring nitrogen, ring sulfur atoms, etc. Site.
  • the substitution position is the ortho, meta, and/or para position relative to the substitution position of the main chain, or 2, 3, 4, 5 or 6 (relative to the benzene ring connected to the main chain).
  • Position when the ring is a nitrogen-containing 5-membered or 6-membered ring, the substitution position may be the ring N position, or the ortho, inter or para position of the ring nitrogen position, or the 2, 3, 4, or 5 position.
  • pharmaceutically acceptable salts includes those derived from suitable inorganic acids and bases and organic acids and bases.
  • pharmaceutically acceptable non-toxic acid addition salts are amino acids with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, etc., or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, lemon Acid, succinic acid or malonic acid, etc., or salts formed by using other methods in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cypionate, gluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate , Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate,
  • the present invention further protects the following specific compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:
  • the present invention also protects a method for preparing the compound of formula I, which is characterized in that:
  • Step 1 The isocyanate compound of formula A and the amino compound of formula B are reacted according to the following reaction formula to synthesize the compound of formula I.
  • Step 2 If necessary, according to the needs of the target product, functional group modification is performed on the compound of formula I to convert it into a target product with the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
  • the preparation method is also applicable to the preparation of the compound of formula IA.
  • the compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has 5HT2A receptor inhibitory activity or inverse agonist activity, and can be used for 5HT2A receptor activity-mediated Treatment of related diseases.
  • the inhibitory activity of the compound of the present invention on 5HT2A is tested by using a Flp-In-CHO-5HT2A stable cell line and completed by the IP-One experiment.
  • the IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2 labeled IP1. If the compound exhibits EC 50 ⁇ 1 ⁇ M, the compound tested in the above analysis is considered to have 5HT2A receptor inhibitory activity.
  • Preferred compounds of the present invention have EC 50 ⁇ 150 nM, more preferred compounds have EC 50 ⁇ 50 nM, and most preferred compounds have EC 50 ⁇ 30 nM.
  • the compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has good 5HT2A receptor antagonistic activity. Furthermore, the compounds of the present invention also have good selectivity, especially selectivity to 5HT2B and/or 5HT2C, reduced cardiotoxicity, and/or improved metabolic stability.
  • the present invention provides the use of a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a medicine for treating related diseases mediated by 5HT2A receptor activity.
  • the related diseases mediated by the 5HT2A receptor activity include, but are not limited to, central nervous system diseases.
  • the central nervous system disease includes but is not limited to: mental disease, central nervous system degenerative disease, central nervous system degenerative disease related or concurrent mental disorder symptoms, and negative symptoms of mental disease.
  • the mental illness includes, but is not limited to: depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism, etc.
  • the degenerative diseases of the central nervous system include but are not limited to: Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia and the like.
  • the mental disorder symptoms related to or concurrent with degenerative diseases of the central nervous system, and negative symptoms of mental diseases include, but are not limited to: affective disorders, language dysfunction, hallucinations, loss of interest, and the like.
  • the present invention provides a pharmaceutical composition characterized by comprising a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the pharmaceutical composition can be used to treat related diseases mediated by 5HT2A receptor activity.
  • the definition of the related diseases mediated by the 5HT2A receptor activity is as described above.
  • the pharmaceutical composition further contains a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is various auxiliary materials commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc. .
  • the diluent examples include lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol and the like.
  • the binder is, for example, starch, gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone and the like.
  • the antioxidants are, for example, vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole and the like.
  • the pH adjusting agent includes, for example, hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like.
  • the preservatives include, for example, methyl paraben, ethyl paraben, m-cresol, benzalkonium chloride and the like.
  • the lubricants are, for example, magnesium stearate, micronized silica gel, talc and the like.
  • the disintegrant is for example: starch, methyl cellulose, xanthan gum, croscarmellose sodium and the like.
  • the pharmaceutical composition contains a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount of 0.1-1000 mg, preferably 1-500 mg, more preferably 5-100 mg .
  • the compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer in the pharmaceutical composition accounts for 10%-90% by mass of the pharmaceutical composition, preferably 20%-80 %, more preferably 30%-70%.
  • the dosage form of the pharmaceutical composition can be an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; it can also be an injection dosage form, such as injections, powder injections, etc. , Administered by intravenous, intraperitoneal, subcutaneous or intramuscular route injection. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.
  • the administration route of the pharmaceutical composition includes, but is not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous and intradermal , Intramuscular, intravenous; by implanting reservoirs or reservoirs.
  • the dosage of the compound of formula I, the compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer will depend on the age, health and weight of the recipient, the type of combined drug, the frequency of treatment, and the Drug route, etc.
  • the drug can be administered in a single daily dose, once a day, once every two days, once every three days, once every four days, or the total daily dose is administered in divided doses of two, three, or four times a day .
  • the dosage can be administered once or multiple times, and the administration time can be from a single day to several months or longer.
  • the dosage of the compound of formula I, the compound of formula IA or a pharmaceutically acceptable salt, solvate, or stereoisomer is 0.01-100 mg/kg/day, preferably 0.1-10 mg/kg/day, such as 0.5 mg /kg/day, 1mg/kg/day, 2mg/kg/day, 5mg/kg/day, etc.
  • the pharmaceutical composition can be used in combination with other drugs for treating related diseases mediated by 5HT2A receptor activity.
  • the pharmaceutical composition may further contain a second therapeutic agent, and the second therapeutic agent is another drug for treating related diseases mediated by 5HT2A receptor activity.
  • the present invention provides a method for treating related diseases mediated by 5HT2A receptor activity, which is characterized by administering a therapeutically effective amount of a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt thereof, and a solvent to a patient in need Compounds, or stereoisomers.
  • the administration route of the compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer includes, but is not limited to: oral; buccal; sublingual; transdermal; Pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial; by implanting reservoirs or reservoirs.
  • the method further includes administering other drugs for treating related diseases mediated by 5HT2A receptor activity to patients in need.
  • drugs for the treatment of related diseases mediated by 5HT2A receptor activity include but are not limited to: drugs for mental illness, drugs for degenerative diseases of the central nervous system, and the like.
  • the mental illness treatment drugs include but are not limited to: benzodiazepine Class (e.g. methyltriazepam, chlorazide Clonazepam, diazepam, sulvalin, fluazepam, midazolam, etc.); barbiturates (e.g., phenobarbital, pentobarbital, etc.); chloral hydrate; buspicyclic Ketones; phenothiazines (for example: chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthenes (for example: Thioxanthene); butyrylbenzenes (for example: haloperidol) ; Clozapine; risperidone; tricyclic antidepressants (for example: imipramine, doxepin, nortriptyline, amitriptyline, etc.); heterocyclic antidepressants (for example: Amo Sapine, maprotiline, trazodone,
  • fluoxetine paroxetine, sertraline, citalopram, Fluvoxamine, etc.
  • monoamine oxidase inhibitors for example: phenelzine, moclobemide, etc.
  • ketamine mirtazapine.
  • the drugs for the treatment of degenerative diseases of the central nervous system include but are not limited to: levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and ureteride.
  • DIEA N,N-diisopropylethylamine
  • Pd(PPh 3 ) 4 Tetra(triphenylphosphine) palladium
  • Triphosgene Triphosgene
  • Et ethyl
  • Ac acetyl
  • EtOAc is ethyl acetate or ethyl acetate
  • ETOH is ethanol.
  • N-(2,4-Difluorobenzyl)-1-methylpiperidin-4-amine (H002-069): The synthesis method is similar to (45-2). A brown oily intermediate (H002-069) (0.8 g, yield 38%) was obtained with 1-methylpiperidin-4-ylamine (8.8 mmol). LCMS: [M+1] + 241.3.
  • the ER10152 used is the positive control, and the structural formula is:
  • the IP-One experiment was selected to complete the test.
  • the following experiments were done using Flp-In-CHO-5HT2A stable cell line.
  • the IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2-labeled IP1.
  • the IP1 produced by the cells and the IP1 labeled with d2 provided in the kit compete for the antigen binding site of the anti-IP1 antibody.
  • the Chinese hamster ovary cell transformed cell line (Flp-In TM -CHO cell line) (purchased from invitrogen, R75807) was produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp- In TM -CHO cell line.
  • Flp-In TM -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone)+1 ⁇ Penicilin-Streptomycin (15140-122, Gibco), and then with human HTR2A gene ( Human HTR2A, GeneBank, NM_000621) was stably transfected to obtain Flp-In-CHO-5HT2A cells.
  • the stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1 x Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B (ant-hg-5, Invivogen).
  • the Flp-In-CHO-5HT2A stable cell line was cultured in a 384-well plate (7.5K) for 20 hours at 37°C and 5% CO 2.
  • the compounds were diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100 ⁇ l/well overnight. After the cells were treated with the compound for 30 minutes, 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding lysis detection buffer, IP1-d2 and IP1-Ab, incubate for 1 hour at room temperature and read the plate on Envision (HTRF module).
  • HTRF module plate on Envision
  • the IP-One experiment was selected to complete the test.
  • the following experiments were performed using Flp-In-CHO-5HT2B/2C VGV stable cell line.
  • the IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2 labeled IP1.
  • the IP1 produced by the cells and the IP1 labeled with d2 provided in the kit compete for the antigen binding site of the anti-IP1 antibody.
  • the Chinese Hamster Ovary Cell Transformed Cell Line (Flp-In TM -CHOcell line) (purchased from invitrogen, R75807) was produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp-In TM- CHO cell line.
  • Flp-In TM -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco)+1 ⁇ Penicilin-Streptomycin (15140122, Gibco), and then human HTR2B/2C VGV gene (Human HTR2B, GeneBank, NM 000867; Human HTR2C (5-HT2C VGV ), GeneBank, NM 000868) were stably transfected to obtain Flp-In-CHO-5HT2B/2C VGV cells.
  • the stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco) + 1 x Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B (ant-hg-5, Invivogen).
  • FBS Gibco
  • Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B anti-hg-5, Invivogen.
  • the Flp-In-CHO-5HT2B/2C VGV stable cell line was cultured in a 384-well plate (5K, 7.5K) for 20 hours at 37 degrees Celsius and 5% CO 2.
  • the compound was diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100 ⁇ l/well for overnight culture.
  • the cells were treated with compound for 30 minutes and 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding the lysis detection buffer, IP1-d2 and IP1-Ab, incubating for 1 hour at room temperature, the plate was read on Envision (HTRF module), and the inhibition rate of the compound on the 5-HT2B/2C VGV receptor of the cells was calculated.
  • HTRF module Envision
  • the hERG membrane protein specific binding experiment was selected to complete the detection.
  • the experiment used the HEK293 cell line stably expressing hERG (human Ether-a-go-go Related Gene) encoding potassium channel to complete the experiment.
  • the potassium channel encoded by hERG mediates a delayed rectifier potassium current (IKr), and Ikr inhibition is the most important mechanism for the prolongation of the QT interval caused by drugs.
  • IKr delayed rectifier potassium current
  • hERG's lack of function or drug inhibition will affect the repolarization process of cardiac action potentials and cause the QT interval to prolong. At the same time, it may induce torsade de pointes ventricular tachycardia and lead to arrhythmia.
  • hERG membrane protein, detection compound and a fixed concentration of radioligand are mixed, so that the detection compound and radioligand can competitively bind to hERG membrane protein.
  • vacuum filtration is used to remove no binding to membrane protein.
  • CPM isotope signal
  • ID hERG binding rate (%, when the compound is 10 ⁇ M) ER10152 91 ER10058 66 ER10217 53
  • the liver is the main organ for the metabolism of endogenous matrix and exogenous drugs.
  • in vitro tools that can help researchers study the metabolism of candidate drugs, including isolated fresh or cryopreserved liver cells, liver slices, and subcellular components such as liver microparticles and S9 components. These subcellular components are prepared from the liver through a series of homogenization and ultracentrifugation methods.
  • the S9 fraction produced by the initial low-speed centrifugation of 10,000g liver homogenate is the fraction in the supernatant obtained by this centrifugation method.
  • the S9 component contains all phase I and phase II enzymes, and the S9 component is further centrifuged at 100,000 g to obtain endoplasmic reticulum-derived microparticles.
  • Microsomes are rich in cytochrome P450 (CYP) and flavin monooxygenase (FMO).
  • CYP cytochrome P450
  • FMO flavin monooxygenase
  • phase II enzymes such as certain glycoside glucuronyltransferase UGT subtypes and cyclohydrolase EH are also present in the microsomes.
  • Microsomes can be used to study the activity of UGT, however, the microsomal membrane restricts the entry of UGT matrix and/or cofactors.
  • the best UGT activity can be achieved by adding MgCl 2 and pore-forming antibiotics (such as propylmethacin). These components allow the glucuronic acid product and the cofactor UDPGA in the microsomal network to be efficiently transported.
  • Individual or combined donor liver microsomes can be used for metabolism-related research. The combined donors can represent population averages or specific research factors such as age, BMI, or the limiting capacity of specific CYP subtypes. The purpose of this study is to evaluate the metabolic stability of the compound in human liver microsomes.
  • the human liver microsomes used in this test system were purchased from Corning (Cat No. 452117) and stored in a refrigerator below -60°C before use.
  • Coenzymes are NADPH (Chem-impex international, Cat. No. 00616) and UDPGA (Sigma, Cat. No. U6751) cofactors.
  • NADPH Chem-impex international, Cat. No. 00616
  • UDPGA Sigma, Cat. No. U6751
  • CL int(mic) 0.693/T 1/2 /microsomal protein content (microsomal protein concentration mg/mL during incubation)
  • CL int(liver) CL int(mic) ⁇ the amount of microsomal protein in the liver (mg/g) ⁇ liver weight-to-weight ratio
  • the intrinsic liver clearance rate and liver clearance rate can be converted by the following formula:

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Abstract

Provided is a compound of a structure of formula (I) having a central nervous system disease treatment effect, which has the activity of a 5-HT2A receptor antagonist or an inverse agonist, has high 5-HT2A receptor selectivity, low cardiotoxicity, and good metabolic stability, and can be applied to treat some mental diseases (such as depression, anxiety disorders, psychiatric disorders, schizophrenia, insomnia, and autism) and central nervous system degenerative disorder (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and dementia with Lewy bodies)-related or complicated mental disorders.

Description

5HT2A受体拮抗剂及其医疗应用5HT2A receptor antagonist and its medical application
本申请要求2020年1月21日向中国国家知识产权局提交的专利申请号为202010068325.9，发明名称为“5HT2A受体拮抗剂及其医疗应用”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申请中。This application claims the priority of the prior application whose patent application number is 202010068325.9 and the invention title is "5HT2A receptor antagonist and its medical application" filed with the State Intellectual Property Office of China on January 21, 2020. The full text of the prior application is incorporated into this application by reference.
技术领域Technical field
本发明属于医药技术领域，涉及一种具有中枢神经系统疾病治疗作用的5-HT2A受体拮抗剂或反向激动剂及其应用。所述化合物可以用于治疗某些精神疾病(如抑郁症，焦虑症，精神病，精神分裂症，失眠，自闭症等)及与中枢神经系统退行性疾病(如阿尔兹海默症，帕金森病，亨廷顿病，路易小体痴呆症等)相关或者并发的精神紊乱症状。The invention belongs to the technical field of medicine, and relates to a 5-HT2A receptor antagonist or inverse agonist with a central nervous system disease treatment effect and applications thereof. The compounds can be used to treat certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism, etc.) and degenerative diseases of the central nervous system (such as Alzheimer’s disease, Parkinson’s disease, etc.) Disease, Huntington’s disease, Lewy body dementia, etc.) related or concurrent mental disorders.
背景技术Background technique
血清素或5-羟色胺(5-HT)在人体生理功能中发挥着极为重要的作用。在中枢神经系统中，5-HT是一种重要的神经递质和神经调节剂，它在调控多种行为如睡眠、饮食、活动、学习和记忆、机体体温、血压以及病理状态(如焦虑、躁狂、精神分裂、肥胖、药物成瘾、偏头痛和高血压)方面发挥着极为重要的作用(Alenina N，et al.，(2009)ProcNatl Acad Sci USA，106，10332-10337；Filip M，et al.，(2005)Pharmacol Rep，57，685-700；Greek AR，(2006)Br J Pharmacol，147，Suppl 1：S145-S152)。5-HT通过其受体发挥作用，根据结构(氨基酸序列)、生化(信号转导的后受体机制)和药理学差异将5-HT受体分为7个家族(5-HT1～5-HT7)以及至少15个不同亚型(Barnes NM，et al.，(1999)Neuropharmacology，38，1083-1152；Hannon J，et al.，(2008)Behav Brain Res，195，198-213；Hoyer D，et al.，(2002)Pharmacol Biochem Behav，71，533-554；Pauwels PJ.(2003)Tocris Reviews，No.25)。不同亚型受体的分布、配体偏好以及相关功能各不相同。Serotonin or 5-hydroxytryptamine (5-HT) plays an extremely important role in the physiological functions of the human body. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator, which regulates a variety of behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure, and pathological states (such as anxiety, Mania, schizophrenia, obesity, drug addiction, migraine and hypertension) play an extremely important role (Alenina N, et al., (2009) ProcNatl Acad Sci USA, 106, 10332-10337; Filip M, et al., (2005) Pharmacol Rep, 57, 685-700; Greek AR, (2006) Br J Pharmacol, 147, Suppl 1: S145-S152). 5-HT acts through its receptors. According to the structure (amino acid sequence), biochemical (post-receptor mechanism of signal transduction) and pharmacological differences, 5-HT receptors are divided into 7 families (5-HT1～5- HT7) and at least 15 different subtypes (Barnes NM, et al., (1999) Neuropharmacology, 38, 1083-1152; Hannon J, et al., (2008) Behav Brain Res, 195, 198-213; Hoyer D , Et al., (2002) Pharmacol Biochem Behav, 71, 533-554; Pauwels PJ. (2003) Tocris Reviews, No. 25). The distribution, ligand preference and related functions of different subtypes of receptors are different.
5-HT2A亚型受体在中枢神经系统呈现广泛而离散的表达，在参与调节高级认知和情感功能的大脑皮质、边缘、海马、下丘脑和基底神经节中表达最高。5-HT2A受体在多巴胺、GABA、谷氨酸和Ach神经元上表达并起着树突状异质受体 的作用(Buhot MC，(1997)Curr Opin Neurobiol，7，243-254；Leysen JE，(2004)Curr Drug Targets CNS Neuro Disord，3，11-26)。和大多数5-HT受体一样，5-HT2A受体为G-蛋白偶联受体，它通过激活鸟嘌呤核苷酸结合蛋白(G蛋白)完成信号转导，导致第二信使分子如环腺苷酸(cAMP)、肌醇磷酸酯(inositol phosphates)以及二酰甘油(diacylglycerol)水平升高或降低。这些第二信使分子调节多种胞内酶的功能(如激酶和离子通道)，最终影响细胞兴奋性和细胞功能。The 5-HT2A subtype receptors are widely and discretely expressed in the central nervous system, and are highest in the cerebral cortex, limbus, hippocampus, hypothalamus and basal ganglia that are involved in the regulation of higher cognitive and emotional functions. 5-HT2A receptors are expressed on dopamine, GABA, glutamate and Ach neurons and act as dendritic heterogeneous receptors (Buhot MC, (1997) Curr Opin Neurobiol, 7, 243-254; Leysen JE , (2004) Curr Drug Targets CNS Neuro Disord, 3, 11-26). Like most 5-HT receptors, 5-HT2A receptors are G-protein coupled receptors, which complete signal transduction by activating guanine nucleotide binding protein (G protein), resulting in second messenger molecules such as loops. The levels of adenylate (cAMP), inositol phosphates, and diacylglycerol increase or decrease. These second messenger molecules regulate the functions of a variety of intracellular enzymes (such as kinases and ion channels), and ultimately affect cell excitability and cell function.
5-HT传递异常与多种精神疾病的发病机制相关，如精神疾病(抑郁、惊恐发作、精神分裂症、自杀倾向等)以及神经系统退行性疾病(阿尔兹海默症、亨廷顿舞蹈症、帕金森病等)(Fioravanti et al.，(1992)Brain Cogn.18，116-124；Sinopoli VM，et al.，(2017)Neurosci Biobehav Rev，80：372-381)。近年来研究发现，5-HT2A受体与神经精神疾病的病理状态密切相关，5-HT2A受体参与了非典型抗精神病药物如氯氮平、奥氮平、利培酮的分子作用机制(Gonzalez-Maeso J，et al.，(2009)Trends Neurosci，32：225-232；Fribourg M，et al.，(2011)Cell，147：1011-1023；Kurita M，et al.，(2012)Nat Neurosci，15：1245-1254)；5-HT2A受体拮抗剂对于治疗精神分裂症阴性症状(如情感障碍、语言功能减退等)十分重要(Blier P，et al.，(2005)J Clin Psychiatry 66，Suppl 8，30-40；Richtand NM，et al.，(2008)Prog Brain Res，172，141-153；Meltzer，H.Y.(2013)Annu Rev Med 64，393-406)；另有研究证实，皮质锥体神经元的5-HT2A受体调节通路对介导致幻剂引发的信号转导和行为反应至关重要(Gonzalez-Maeso J，et al.，(2009)Trends Neurosci，32：225-232)，提示5-HT2A受体在治疗多种神经退行性疾病幻觉症状方面的作用。Abnormal transmission of 5-HT is related to the pathogenesis of a variety of mental diseases, such as mental diseases (depression, panic attacks, schizophrenia, suicidal tendencies, etc.) and neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, Pa Jinsen disease, etc.) (Fioravanti et al., (1992) Brain Cogn. 18, 116-124; Sinopoli VM, et al., (2017) Neurosci Biobehav Rev, 80: 372-381). In recent years, studies have found that 5-HT2A receptors are closely related to the pathological state of neuropsychiatric diseases. 5-HT2A receptors are involved in the molecular mechanism of atypical antipsychotics such as clozapine, olanzapine, and risperidone (Gonzalez -Maeso J, et al., (2009) Trends Neurosci, 32: 225-232; Fribourg M, et al., (2011) Cell, 147: 1011-1023; Kurita M, et al., (2012) Nat Neurosci , 15: 1245-1254); 5-HT2A receptor antagonists are very important for the treatment of negative symptoms of schizophrenia (such as affective disorders, language loss, etc.) (Blier P, et al., (2005) J Clin Psychiatry 66, Suppl 8, 30-40; Richt and NM, et al., (2008) Prog Brain Res, 172, 141-153; Meltzer, HY (2013) Annu Rev Med 64, 393-406); other studies have confirmed that cortical cones The 5-HT2A receptor regulation pathway of somatic neurons is essential to mediate signal transduction and behavioral responses triggered by hallucinogens (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32: 225-232), It suggests the role of 5-HT2A receptors in the treatment of hallucinations in a variety of neurodegenerative diseases.
用于治疗精神疾病的药物，即抗精神病药物分为两大类。“典型”抗精神病药物或上一代药物由于对人体造成的机动功能副作用(锥体外系副反应、类帕金森病证等)在临床已很少应用，现行药物更多着眼于“非典型”抗精神病药物(Prim Cre Companion J Clin Psychiatry.(2007)9(6)：444-54)。但是该第二代抗精神病药物皆有广谱受体活性，这些化合物作为激动剂、竞争性拮抗剂或反向激动剂等方式调节多种单胺能受体如5-HT能、多巴胺能、肾上腺素能、毒蕈碱或组胺能受体，这种广谱调节很有可能是造成镇静异常、运动机能异常、II型糖尿病等副作用的原因。大多数抗精神病药物都具有多巴胺D2受体拮抗作用，现已证明与锥体外系副作用相关(Strange PG.(2001)Pharmacol Rev，53(1)：119-33；Tuppurainen H，et al.，(2010)Nord J Psychiatry，64(4)：233-8；Sykes DA，et al.，(2017)Nat Commun，8(1)：763)。因此，开发选择性5-HT2A受体拮抗剂或反向激动剂，尤其是具有选择性高的，和/或无多巴胺D2受体结合活性等特性，对于推动抗神经精神疾病药物发展有至关重要的作 用，这类化合物在治疗疾病同时能够避免由于无选择性受体相互作用导致的诸多副作用。The drugs used to treat mental illness, namely antipsychotics, are divided into two categories. "Typical" antipsychotic drugs or the previous generation drugs have little clinical application due to the side effects of motor functions (extrapyramidal side effects, Parkinson's disease, etc.) caused by the previous generation of drugs. Current drugs focus more on "atypical" antipsychotics. Psychiatric drugs (Prim Cre Companion J Clin Psychiatry. (2007) 9(6): 444-54). However, the second-generation antipsychotic drugs all have broad-spectrum receptor activity. These compounds act as agonists, competitive antagonists or inverse agonists to modulate a variety of monoaminergic receptors such as 5-HT, dopaminergic, Adrenergic, muscarinic, or histaminergic receptors. This broad-spectrum regulation is likely to cause side effects such as abnormal sedation, abnormal motor function, and type II diabetes. Most antipsychotic drugs have dopamine D2 receptor antagonism, which has been proved to be related to extrapyramidal side effects (Strange PG. (2001) Pharmacol Rev, 53(1): 119-33; Tuppurainen H, et al., ( 2010) Nord J Psychiatry, 64(4): 233-8; Sykes DA, et al., (2017) Nat Commun, 8(1): 763). Therefore, the development of selective 5-HT2A receptor antagonists or inverse agonists, especially those with high selectivity and/or no dopamine D2 receptor binding activity, is crucial for promoting the development of anti-neuropsychiatric drugs. An important role, these compounds can avoid many side effects caused by non-selective receptor interactions while treating diseases.
发明内容Summary of the invention
本发明提供一种具有5-HT2A受体拮抗活性的化合物，及含有该化合物的用于治疗中枢神经系统疾病的药物组合物，并进一步提供中枢神经系统疾病的治疗方法。The present invention provides a compound with 5-HT2A receptor antagonistic activity, and a pharmaceutical composition containing the compound for the treatment of central nervous system diseases, and further provides a method for the treatment of central nervous system diseases.
具体而言，本发明提供一种具有式I结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：Specifically, the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure PCTCN2021072899-appb-000001
Figure PCTCN2021072899-appb-000001
其中，in,
n、m分别选自0-4的整数，限定所述亚烷基链的亚烷基单元数量，n and m are respectively selected from integers from 0 to 4, which limit the number of alkylene units of the alkylene chain,
X为杂原子或碳原子，所述杂原子选自O，N，S原子，优选为N原子；X is a heteroatom or a carbon atom, and the heteroatom is selected from O, N, and S atoms, preferably a N atom;
环X即X原子所在环，通过环碳原子或者环N原子与化合物主体结构连接，Ring X is the ring where the X atom is located, and is connected to the main structure of the compound through a ring carbon atom or a ring N atom,
环B基团选自含4-8元环烷基、4-8元杂环烷基、5-8元芳环基或5-8元杂芳环基，该环与苯环稠合；优选环B为4-8元环烷基或4-8元杂环烷基；The ring B group is selected from the group containing 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aromatic ring group or 5-8 membered heteroaromatic ring group, and the ring is fused with a benzene ring; preferably Ring B is 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl;
R 1为1或多个取代基，位于所在环系的任意取代位置，R 1彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 1 is one or more substituents, located at any substitution position of the ring system where R 1 is located, and R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
进一步，所述式I结构化合物，Further, the compound of formula I,
其中，n为1，2或3；m为0，1或2；Wherein, n is 1, 2 or 3; m is 0, 1 or 2;
X为杂原子，选自O，N，S原子；优选为N原子；X is a heteroatom, selected from O, N, S atoms; preferably N atom;
环B与苯环形成的环系选自以下结构基团：The ring system formed by ring B and benzene ring is selected from the following structural groups:
Figure PCTCN2021072899-appb-000002
Figure PCTCN2021072899-appb-000002
其中，Y选自O，N，S原子；优选为O原子。Among them, Y is selected from O, N, S atoms; preferably O atom.
更进一步，一种具有式IA结构化合物，或其药物可接受的盐，溶剂化物，或立体异构体：Furthermore, a compound having the structure of Formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure PCTCN2021072899-appb-000003
Figure PCTCN2021072899-appb-000003
其中，in,
n为1，2或3；m为0，1或2，n is 1, 2 or 3; m is 0, 1 or 2,
X为杂原子，选自O，N，S原子，优选为N原子；X is a heteroatom, selected from O, N, and S atoms, preferably N atom;
Y选自O，N，S原子；优选为O原子；Y is selected from O, N, S atoms; preferably O atom;
R 1为1或多个取代基，位于所在环系的任意取代位置，R 1彼此独立选自H、 卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 1 is one or more substituents, located at any substitution position of the ring system where R 1 is located, and R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
优选，式I或式IA化合物中，环X通过环碳原子与化合物主体结构连接；优选R 3在X位置取代。 Preferably, in the compound of formula I or formula IA, ring X is connected to the main structure of the compound through a ring carbon atom; preferably, R 3 is substituted at the X position.
进一步优选，式I或式IA化合物中，环X为吖丁啶基，吡咯烷基，或哌啶基；Y为O原子。More preferably, in the compound of formula I or formula IA, ring X is azetidinyl, pyrrolidinyl, or piperidinyl; and Y is an O atom.
术语“烷基”是指饱和的烃基，包括直链烷基、分支链烷基。The term "alkyl" refers to saturated hydrocarbon groups, including straight chain alkyl groups and branched chain alkyl groups.
术语“卤素”指F、Cl、Br或I。The term "halogen" refers to F, Cl, Br or I.
术语“亚烷基”是指二价烷基。“亚烷基链”是聚亚甲基，即-(CH 2)x-，其中x为正整数。 The term "alkylene" refers to a divalent alkyl group. "Alkylene chain" is polymethylene, ie -(CH 2 )x-, where x is a positive integer.
术语“环烷基”，是指饱和或含有一个或一个以上不饱和单元但非芳香族的单环烃基，所述环为3-20元环，其具有单个连接点与化合物的其余部分相连接。The term "cycloalkyl" refers to a monocyclic hydrocarbon group that is saturated or contains one or more unsaturated units but is not aromatic. The ring is a 3-20 membered ring, which has a single point of attachment to the rest of the compound .
术语“杂环烷基”为含有1个到5个、独立的选自N，S，O等杂原子的单环状基团，所述杂环烷基可以是饱和环或不饱和环，所述环为3-20元环，包括哌啶，吡咯烷，四氢呋喃等。The term "heterocycloalkyl" refers to a monocyclic group containing 1 to 5 independently selected from heteroatoms such as N, S, O, etc. The heterocycloalkyl group may be a saturated ring or an unsaturated ring, so The ring is a 3-20 membered ring, including piperidine, pyrrolidine, tetrahydrofuran and the like.
术语“芳基”、“芳环基”或“芳香环基”，指单环，所述系统共具有5至10个(优选5、6或9个)环成员，环成员为环碳原子；环系中共享(4n+2)个π电子(其中n是正整数)以符合休克尔规则。The term "aryl", "aromatic ring group" or "aromatic ring group" refers to a single ring, and the system has 5 to 10 (preferably 5, 6 or 9) ring members in total, and the ring members are ring carbon atoms; (4n+2) π electrons (where n is a positive integer) are shared in the ring system to comply with Huckel's rule.
术语“杂芳基”和“杂芳环基”是指具有5到10个环原子，优选5、6或9个；环原子具有(4n+2)个π电子(其中n是正整数)以符合休克尔规则；并且除碳原子外，还具有1到5个杂原子，所述杂原子选自氮、氧或硫，并包括氮或硫的任何氧化形式和碱性氮的任何季铵化形式。The terms "heteroaryl" and "heteroaryl ring" refer to having 5 to 10 ring atoms, preferably 5, 6, or 9; ring atoms have (4n+2) π electrons (where n is a positive integer) to conform Huckel's rule; and in addition to carbon atoms, it also has 1 to 5 heteroatoms selected from nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen .
术语“彼此独立”在本申请中表示，所述取代彼此独立，不互为关联。The term "independent of each other" in this application means that the substitutions are independent of each other and not related to each other.
术语“所在环任意取代位置”、“位于所在环系任意取代位置”表示，取代基团位于环或环系中任意的可被取代的位置，包括环碳原子、环氮、环硫原子等取代位点。可举例为：所述环为苯环时，取代位置为相对于主链取代位置的邻、间和/或对位，或2，3，4，5或6位(相对于苯环连接主链位置)；所述环为含氮5元或6元环时，取代位置可能为环N位置，或环氮位置的邻、间或对位，或2，3，4或5位等。The terms "arbitrary substitution position in the ring" and "arbitrary substitution position in the ring system" mean that the substituent is located at any position in the ring or ring system that can be substituted, including ring carbon atoms, ring nitrogen, ring sulfur atoms, etc. Site. For example: when the ring is a benzene ring, the substitution position is the ortho, meta, and/or para position relative to the substitution position of the main chain, or 2, 3, 4, 5 or 6 (relative to the benzene ring connected to the main chain). Position); when the ring is a nitrogen-containing 5-membered or 6-membered ring, the substitution position may be the ring N position, or the ortho, inter or para position of the ring nitrogen position, or the 2, 3, 4, or 5 position.
术语“药学上可接受的盐”包括从适合的无机酸和碱以及有机酸和碱衍生而来的那些盐。药学上可接受的无毒性酸加成盐的实例是氨基与无机酸如盐酸，氢溴酸，磷酸，硫酸和高氯酸等，或者与有机酸如乙酸，草酸，马来酸、酒石酸，柠檬酸，琥珀酸或丙二酸等形成的盐，或者通过使用诸如离子交换等本领域的其他方法形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。The term "pharmaceutically acceptable salts" includes those derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino acids with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, etc., or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, lemon Acid, succinic acid or malonic acid, etc., or salts formed by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cypionate, gluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate , Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate , Valerate, etc.
本发明还进一步保护如下具体化合物，或其药学可接受的盐，溶剂化物，或立体异构体：The present invention further protects the following specific compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:
3-(色烷-6-基甲基)-1-(4-氟-苯甲基)-1-(1-甲基哌啶-4-基)-脲，3-(Chroman-6-ylmethyl)-1-(4-fluoro-benzyl)-1-(1-methylpiperidin-4-yl)-urea,
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea,
(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲，3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea,
(R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea ,
(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，或，(S)-3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea ,or,
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲。3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea.
本发明还保护一种制备式I化合物的方法，其特征在于：The present invention also protects a method for preparing the compound of formula I, which is characterized in that:
步骤1、式A结构的异氰酸化合物与式B氨基化合物按如下反应式反应，合成得到式I化合物，Step 1. The isocyanate compound of formula A and the amino compound of formula B are reacted according to the following reaction formula to synthesize the compound of formula I.
Figure PCTCN2021072899-appb-000004
Figure PCTCN2021072899-appb-000004
步骤2、如果需要，再根据目标产物的需要，对式I化合物进行官能团修饰，转化为具有式I结构的目标产物，或者转化为所述化合物的药学可接受的盐，或前体化合物。Step 2. If necessary, according to the needs of the target product, functional group modification is performed on the compound of formula I to convert it into a target product with the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
所述制备方法同样适用于式IA化合物的制备。The preparation method is also applicable to the preparation of the compound of formula IA.
本发明的式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体具有5HT2A受体抑制活性或反向激动活性，可以用于5HT2A受体活性介导的相关疾病的治疗。The compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has 5HT2A receptor inhibitory activity or inverse agonist activity, and can be used for 5HT2A receptor activity-mediated Treatment of related diseases.
本发明化合物对5HT2A的抑制活性是采用Flp-In-CHO-5HT2A稳定细胞系，通过IP-One实验完成检测。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。如果化合物表现出EC 50≤1μM，认为在以上分析中测试的化合物具有5HT2A受体抑制活性。本发明优选的化合物具有EC 50≤150nM，更优选的化合物具有EC 50≤50nM，最优选化合物具有EC 50≤30nM。 The inhibitory activity of the compound of the present invention on 5HT2A is tested by using a Flp-In-CHO-5HT2A stable cell line and completed by the IP-One experiment. The IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2 labeled IP1. If the compound exhibits EC 50 ≤ 1 μM, the compound tested in the above analysis is considered to have 5HT2A receptor inhibitory activity. Preferred compounds of the present invention have EC 50 ≤ 150 nM, more preferred compounds have EC 50 ≤ 50 nM, and most preferred compounds have EC 50 ≤ 30 nM.
本发明的式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体，具有好的5HT2A受体的拮抗活性。进一步的，本发明化合物还具有好的选择性，尤其是对5HT2B和/或5HT2C的选择性，降低的心脏毒性，和/或，提高的代谢稳定性。The compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has good 5HT2A receptor antagonistic activity. Furthermore, the compounds of the present invention also have good selectivity, especially selectivity to 5HT2B and/or 5HT2C, reduced cardiotoxicity, and/or improved metabolic stability.
本发明提供式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗5HT2A受体活性介导的相关疾病的药物中的用途。The present invention provides the use of a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a medicine for treating related diseases mediated by 5HT2A receptor activity.
所述5HT2A受体活性介导的相关疾病包括但不限于中枢神经系统疾病。The related diseases mediated by the 5HT2A receptor activity include, but are not limited to, central nervous system diseases.
所述中枢神经系统疾病包括但不限于：精神疾病、中枢神经系统退行性疾病、中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状。The central nervous system disease includes but is not limited to: mental disease, central nervous system degenerative disease, central nervous system degenerative disease related or concurrent mental disorder symptoms, and negative symptoms of mental disease.
所述精神疾病包括但不限于：抑郁症、焦虑症、躁狂症、精神分裂症、情感性分裂症、双相精神障碍、失眠、自闭症等。The mental illness includes, but is not limited to: depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism, etc.
所述中枢神经系统退行性疾病包括但不限于：阿尔兹海默症、帕金森病、亨廷 顿病、路易小体痴呆症等。The degenerative diseases of the central nervous system include but are not limited to: Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia and the like.
所述中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状包括但不限于：情感障碍、语言功能减退、幻觉、兴趣缺失等。The mental disorder symptoms related to or concurrent with degenerative diseases of the central nervous system, and negative symptoms of mental diseases include, but are not limited to: affective disorders, language dysfunction, hallucinations, loss of interest, and the like.
本发明提供一种药物组合物，其特征在于包括式I化合物、式IA化合物或其药学上可接受的盐，溶剂化物，或立体异构体。The present invention provides a pharmaceutical composition characterized by comprising a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
所述药物组合物可以用于治疗5HT2A受体活性介导的相关疾病。所述5HT2A受体活性介导的相关疾病的定义如前文所述。The pharmaceutical composition can be used to treat related diseases mediated by 5HT2A receptor activity. The definition of the related diseases mediated by the 5HT2A receptor activity is as described above.
所述药物组合物进一步含有药学上可接受的载体。The pharmaceutical composition further contains a pharmaceutically acceptable carrier.
所述药学上可接受的载体是制药领域中常用或已知的各种辅料，包括但不限于：稀释剂、粘合剂、抗氧化剂、pH调节剂、防腐剂、润滑剂、崩解剂等。The pharmaceutically acceptable carrier is various auxiliary materials commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc. .
所述稀释剂例如：乳糖、淀粉、纤维素衍生物、无机钙盐、山梨醇等。所述粘合剂例如：淀粉、明胶、羧甲基纤维素钠、聚乙烯吡咯烷酮等。所述抗氧化剂例如：维生素E、亚硫酸氢钠、亚硫酸钠、丁羟基茴香醚等。所述pH调节剂例如：盐酸、氢氧化钠、柠檬酸、酒石酸、Tris、乙酸、磷酸二氢钠、磷酸氢二钠等。所述防腐剂例如：对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、间甲酚、苯扎氯铵等。所述润滑剂例如：硬脂酸镁、微粉硅胶、滑石粉等。所述崩解剂例如：淀粉、甲基纤维素、黄原胶、交联羧甲基纤维素钠等。Examples of the diluent include lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol and the like. The binder is, for example, starch, gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone and the like. The antioxidants are, for example, vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole and the like. The pH adjusting agent includes, for example, hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like. The preservatives include, for example, methyl paraben, ethyl paraben, m-cresol, benzalkonium chloride and the like. The lubricants are, for example, magnesium stearate, micronized silica gel, talc and the like. The disintegrant is for example: starch, methyl cellulose, xanthan gum, croscarmellose sodium and the like.
所述药物组合物中含有式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的量为0.1-1000mg，优选1-500mg，更优选为5-100mg。The pharmaceutical composition contains a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount of 0.1-1000 mg, preferably 1-500 mg, more preferably 5-100 mg .
所述药物组合物中式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体占药物组合物的质量百分比为10％-90％，优选为20％-80％，更优选为30％-70％。The compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer in the pharmaceutical composition accounts for 10%-90% by mass of the pharmaceutical composition, preferably 20%-80 %, more preferably 30%-70%.
所述药物组合物的剂型可以是口服剂的形式，例如片剂、胶囊、丸剂、粉剂、颗粒剂、悬浮剂、糖浆剂等；也可以是注射给药的剂型，例如注射液、粉针剂等，通过静脉内、腹膜内、皮下或肌肉内的途径注射给药。所有使用的剂型形式都是药学领域普通技术人员所熟知的。The dosage form of the pharmaceutical composition can be an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; it can also be an injection dosage form, such as injections, powder injections, etc. , Administered by intravenous, intraperitoneal, subcutaneous or intramuscular route injection. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.
所述药物组合物的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；肺的；直肠的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的；通过植入储库或储液器。The administration route of the pharmaceutical composition includes, but is not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous and intradermal , Intramuscular, intravenous; by implanting reservoirs or reservoirs.
式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天 给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物、式IA化合物或其药学上可接受的盐，溶剂化物，或立体异构体的用药量为0.01-100mg/kg/天，优选为0.1-10mg/kg/天，例如为0.5mg/kg/天，1mg/kg/天、2mg/kg/天、5mg/kg/天等等。The dosage of the compound of formula I, the compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer will depend on the age, health and weight of the recipient, the type of combined drug, the frequency of treatment, and the Drug route, etc. The drug can be administered in a single daily dose, once a day, once every two days, once every three days, once every four days, or the total daily dose is administered in divided doses of two, three, or four times a day . The dosage can be administered once or multiple times, and the administration time can be from a single day to several months or longer. The dosage of the compound of formula I, the compound of formula IA or a pharmaceutically acceptable salt, solvate, or stereoisomer is 0.01-100 mg/kg/day, preferably 0.1-10 mg/kg/day, such as 0.5 mg /kg/day, 1mg/kg/day, 2mg/kg/day, 5mg/kg/day, etc.
所述药物组合物可以和其他的治疗5HT2A受体活性介导的相关疾病的药物联合应用。The pharmaceutical composition can be used in combination with other drugs for treating related diseases mediated by 5HT2A receptor activity.
所述药物组合物可以进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗5HT2A受体活性介导的相关疾病的药物。The pharmaceutical composition may further contain a second therapeutic agent, and the second therapeutic agent is another drug for treating related diseases mediated by 5HT2A receptor activity.
本发明提供一种治疗5HT2A受体活性介导的相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体。The present invention provides a method for treating related diseases mediated by 5HT2A receptor activity, which is characterized by administering a therapeutically effective amount of a compound of formula I, a compound of formula IA, or a pharmaceutically acceptable salt thereof, and a solvent to a patient in need Compounds, or stereoisomers.
所述式I化合物、式IA化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；肺的；直肠的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的；通过植入储库或储液器。The administration route of the compound of formula I, compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer includes, but is not limited to: oral; buccal; sublingual; transdermal; Pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial; by implanting reservoirs or reservoirs.
所述方法进一步包括，对有需要的患者给予其他的治疗5HT2A受体活性介导的相关疾病的药物。The method further includes administering other drugs for treating related diseases mediated by 5HT2A receptor activity to patients in need.
其他的治疗5HT2A受体活性介导的相关疾病的药物包括但不限于：精神疾病治疗药物、中枢神经系统退行性疾病治疗药物等。Other drugs for the treatment of related diseases mediated by 5HT2A receptor activity include but are not limited to: drugs for mental illness, drugs for degenerative diseases of the central nervous system, and the like.
所述精神疾病治疗药物包括但不限于：苯二氮
Figure PCTCN2021072899-appb-000005
类(例如：甲基三唑西泮、氯氮
Figure PCTCN2021072899-appb-000006
氯硝西泮、地西泮、舒乐安定、氟西泮、咪达唑仑等)；巴比妥类(例如：苯巴比妥、戊巴比妥等)；水合氯醛；丁螺环酮；吩噻嗪类(例如：氯丙嗪、硫利达嗪、氟奋乃静等)；硫杂蒽类(例如：替沃噻吨)；丁酰苯类(例如：氟哌啶醇)；氯氮平；利哌利酮；三环类抗抑郁药(例如：丙咪嗪、多塞平、去甲替林、阿米替林等)；杂环类抗抑郁药(例如：阿莫沙平、马普替林、曲唑酮、安非他酮、文法拉辛等)；选择性5-HT重摄取抑制剂(例如：氟西汀、帕罗西汀、舍曲林、西酞普兰、氟伏沙明等)；单胺氧化酶抑制剂(例如：苯乙肼、吗氯贝胺等)；氯胺酮；米氮平等。 The mental illness treatment drugs include but are not limited to: benzodiazepine
Figure PCTCN2021072899-appb-000005
Class (e.g. methyltriazepam, chlorazide
Figure PCTCN2021072899-appb-000006
Clonazepam, diazepam, sulvalin, fluazepam, midazolam, etc.); barbiturates (e.g., phenobarbital, pentobarbital, etc.); chloral hydrate; buspicyclic Ketones; phenothiazines (for example: chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthenes (for example: Thioxanthene); butyrylbenzenes (for example: haloperidol) ; Clozapine; risperidone; tricyclic antidepressants (for example: imipramine, doxepin, nortriptyline, amitriptyline, etc.); heterocyclic antidepressants (for example: Amo Sapine, maprotiline, trazodone, bupropion, venfalasine, etc.); selective 5-HT reuptake inhibitors (e.g. fluoxetine, paroxetine, sertraline, citalopram, Fluvoxamine, etc.); monoamine oxidase inhibitors (for example: phenelzine, moclobemide, etc.); ketamine; mirtazapine.
所述中枢神经系统退行性疾病治疗药物包括但不限于：左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺、利血平等。The drugs for the treatment of degenerative diseases of the central nervous system include but are not limited to: levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and ureteride.
具体实施方案Specific implementation plan
实施例中使用的化学试剂均为市售化合物，其中The chemical reagents used in the examples are all commercially available compounds, where
DMF：N，N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
DIEA：N，N-二异丙基乙胺；DIEA: N,N-diisopropylethylamine;
Et3N：三乙基胺Et3N: Triethylamine
DCM：二氯甲烷DCM: Dichloromethane
THF：四氢呋喃THF: Tetrahydrofuran
Acetone：丙酮Acetone: Acetone
Pyridine：吡啶Pyridine: Pyridine
Pd(PPh 3) 4：四(三苯基膦)钯 Pd(PPh 3 ) 4 : Tetra(triphenylphosphine) palladium
FTA：三氟乙酸FTA: Trifluoroacetic acid
Triphosgene：三光气Triphosgene: Triphosgene
Et：乙基，Ac：乙酰基；如EtOAc为乙酸乙酯或醋酸乙酯，ETOH为乙醇。Et: ethyl, Ac: acetyl; for example, EtOAc is ethyl acetate or ethyl acetate, and ETOH is ethanol.
中间体化合物制备Intermediate compound preparation
Figure PCTCN2021072899-appb-000007
Figure PCTCN2021072899-appb-000007
N-(4-氟苯甲基)-1-(1-甲基吖丁啶-3-基)甲胺(H001-057)，用5.5mmol(1-甲基吖丁啶-3-基)甲胺得到棕色油状中间体(H001-057)(500mg，44％产率)。LCMS：[M+1] +209.2。 N-(4-fluorobenzyl)-1-(1-methylazetidine-3-yl)methylamine (H001-057), use 5.5mmol(1-methylazetidine-3-yl) Methylamine gave the intermediate (H001-057) (500 mg, 44% yield) as a brown oil. LCMS: [M+1] + 209.2.
Figure PCTCN2021072899-appb-000008
Figure PCTCN2021072899-appb-000008
(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)，用8.5mmol(S)-(1-甲基吡咯烷-2-基)甲胺得到棕色油状中间体(H001-058)(720mg，38％产率)。LCMS：[M+1] +223.2。 (S)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-058), use 8.5mmol(S)-(1-methylpyrrole) Alk-2-yl)methylamine gave the intermediate (H001-058) (720 mg, 38% yield) as a brown oil. LCMS: [M+1] + 223.2.
Figure PCTCN2021072899-appb-000009
Figure PCTCN2021072899-appb-000009
(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)，用8.5mmol(R)-(1-甲基吡咯烷-2-基)甲胺得到棕色油状中间体(H001-059)(750mg，40％产率)。LCMS：[M+1] +223.2。 (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-059), use 8.5mmol(R)-(1-methylpyrrole) Alk-2-yl)methylamine gave the intermediate (H001-059) (750 mg, 40% yield) as a brown oil. LCMS: [M+1] + 223.2.
Figure PCTCN2021072899-appb-000010
Figure PCTCN2021072899-appb-000010
N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)，用8.8mmol(1-甲基哌啶-4-基)甲胺得到棕色油状中间体(H002-070)(1.5g，75％产率)。LCMS：[M+1] +255.3。 N-(2,4-Difluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H002-070), using 8.8mmol(1-methylpiperidin-4-yl ) Methylamine gave the brown oily intermediate (H002-070) (1.5 g, 75% yield). LCMS: [M+1] + 255.3.
实施例1：合成3-(色烷-6-基甲基)-1-(4-氟-苯甲基)-1-(1-甲基-哌啶-4-基)-脲(compound#45)，ER10058Example 1: Synthesis of 3-(chroman-6-ylmethyl)-1-(4-fluoro-benzyl)-1-(1-methyl-piperidin-4-yl)-urea (compound# 45), ER10058
Figure PCTCN2021072899-appb-000011
Figure PCTCN2021072899-appb-000011
0℃下，三光气(148mg，0.500mmol)的DCM(5.0mL)溶液慢慢加入到色烷-6-基-甲胺单-盐酸(99mg，0.500mmol)和三乙胺(50mg，0.500mmol)的DCM溶液(5.0mL)中。混合物在室温下搅拌1小时。加入冰水(20毫升)，用DCM(20mL×2)提取混合物。将有机相用盐水清洗，用Na 2SO 4干燥，在真空下过滤和浓缩，得油状产物(45-1)(80mg，85％的产率)。 At 0°C, a solution of triphosgene (148mg, 0.500mmol) in DCM (5.0mL) was slowly added to chroman-6-yl-methylamine mono-hydrochloric acid (99mg, 0.500mmol) and triethylamine (50mg, 0.500mmol) ) In DCM (5.0 mL). The mixture was stirred at room temperature for 1 hour. Ice water (20 mL) was added, and the mixture was extracted with DCM (20 mL×2). The organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum to obtain the oily product (45-1) (80 mg, 85% yield).
Figure PCTCN2021072899-appb-000012
Figure PCTCN2021072899-appb-000012
室温下，在1-甲基-哌啶-4-基胺(19g，88mmol)的500.0mL二氯甲烷溶液中添加4-氟苯甲醛(11g，90mmol)，然后分批慢慢加入三乙酰氧基氢硼化物钠(33g，180mmol)，及10ml醋酸。混合物在室温下搅拌过夜。加入冰水(500ml)，用10％(v/v)异丙醇/氯仿(500ml×4)提取混合物。有机相用Na 2SO 4干燥，在真空条件下过滤和浓缩，得到无色油状中间体(45-2)(12.7g，产率65％)。LCMS：[M+1] +223.4。 At room temperature, add 4-fluorobenzaldehyde (11g, 90mmol) to a 500.0mL dichloromethane solution of 1-methyl-piperidin-4-ylamine (19g, 88mmol), and then slowly add triacetoxy in batches Sodium borohydride (33g, 180mmol), and 10ml of acetic acid. The mixture was stirred overnight at room temperature. Ice water (500ml) was added, and the mixture was extracted with 10% (v/v) isopropanol/chloroform (500ml×4). The organic phase was dried with Na 2 SO 4 , filtered and concentrated under vacuum to obtain a colorless oily intermediate (45-2) (12.7 g, yield 65%). LCMS: [M+1] + 223.4.
Figure PCTCN2021072899-appb-000013
Figure PCTCN2021072899-appb-000013
0℃下把色烷-6-甲基异氰酸酯(45-1)(79mg，0.42mmol)的无水THF(5ml)溶液慢慢加到(4-氟-苯甲基)-(1-甲基-哌啶-4-基)-胺(45-2)(100mg，0.45mmol)的DCM(5.0mL)溶液中。生成的混合物在40℃加热约10分钟。在真空下去除溶剂。粗产物高效液相色谱法进行纯化。得到黄色固体compound #45 ER10058(109mg，产率62％)。LCMS：[M+1] +411.9。 Slowly add a solution of chromane-6-methyl isocyanate (45-1) (79mg, 0.42mmol) in anhydrous THF (5ml) to (4-fluoro-benzyl)-(1-methyl) at 0℃ -Piperidin-4-yl)-amine (45-2) (100 mg, 0.45 mmol) in DCM (5.0 mL). The resulting mixture was heated at 40°C for about 10 minutes. The solvent was removed under vacuum. The crude product was purified by high performance liquid chromatography. A yellow solid compound #45 ER10058 (109 mg, yield 62%) was obtained. LCMS: [M+1] + 411.9.
实施例2：合成3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H001-064)ER10191Example 2: Synthesis of 3-(chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea ( H001-064)ER10191
Figure PCTCN2021072899-appb-000014
Figure PCTCN2021072899-appb-000014
3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H001-064)ER10191合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.25mmol)得到白色固体H001-064 ER10191(12mg，产率12％)。LCMS：[M+1] +398.3。 3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea(H001-064)ER10191 The synthesis method is similar to compound#45: Chromane-6-methyl isocyanate (45-1) (0.25 mmol) is used to obtain white solid H001-064 ER10191 (12 mg, yield 12%). LCMS: [M+1] + 398.3.
实施例3：合成(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-065)ER10192Example 3: Synthesis of (S)-3-(chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea (H001-065) ER10192
Figure PCTCN2021072899-appb-000015
Figure PCTCN2021072899-appb-000015
(S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-065)ER10192(S)-3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea (H001- 065)ER10192
合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.5mmol)得到白色固体H001-065 ER10192(70mg，产率34％)。LCMS：[M+1] +412.3。 The synthesis method is similar to compound#45: Chroman-6-methyl isocyanate (45-1) (0.5 mmol) is used to obtain white solid H001-065 ER10192 (70 mg, yield 34%). LCMS: [M+1] + 412.3.
实施例4：合成(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-066)ER10193Example 4: Synthesis of (R)-3-(chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea (H001-066) ER10193
Figure PCTCN2021072899-appb-000016
Figure PCTCN2021072899-appb-000016
(R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-066)ER10193(R)-3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea (H001- 066)ER10193
合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.5mmol)得到白色固体H001-066 ER10193(45mg，产率22％)。LCMS：[M+1] +412.3。 The synthesis method is similar to compound#45: Chroman-6-methyl isocyanate (45-1) (0.5 mmol) is used to obtain white solid H001-066 ER10193 (45 mg, yield 22%). LCMS: [M+1] + 412.3.
实施例5：合成3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-074)ER10216Example 5: Synthesis of 3-(chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea (H002-074) ER10216
Figure PCTCN2021072899-appb-000017
Figure PCTCN2021072899-appb-000017
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-074)ER10216合成方法类似于compound#45：用色烷-6-甲基异氰酸酯(45-1)(0.15mmol)得到白色固体H002-074 ER10216(28mg，产率42％)。LCMS：[M+1] +444.3。 3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (H002-074 ) The synthesis method of ER10216 is similar to compound#45: Chromane-6-methyl isocyanate (45-1) (0.15 mmol) is used to obtain H002-074 ER10216 (28 mg, 42% yield) as a white solid. LCMS: [M+1] + 444.3.
实施例6：合成3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲(H002-075)ER10217Example 6: Synthesis of 3-(chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea (H002- 075)ER10217
Figure PCTCN2021072899-appb-000018
Figure PCTCN2021072899-appb-000018
N-(2，4-二氟苯甲基)-1-甲基哌啶-4-胺(H002-069)：合成方法类似于(45-2)。用1-甲基哌啶-4-基胺(8.8mmol)得到棕色油状中间体(H002-069)(0.8g，产率38％)。LCMS：[M+1] +241.3。 N-(2,4-Difluorobenzyl)-1-methylpiperidin-4-amine (H002-069): The synthesis method is similar to (45-2). A brown oily intermediate (H002-069) (0.8 g, yield 38%) was obtained with 1-methylpiperidin-4-ylamine (8.8 mmol). LCMS: [M+1] + 241.3.
Figure PCTCN2021072899-appb-000019
Figure PCTCN2021072899-appb-000019
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲(H002-075)ER10217合成方法类似于compound#45。用0.15mmol色烷-6-甲基异氰酸酯(45-1)得到白色固体H002-075 ER10217(32mg，50％产率)。 1H NMR(400MHz，Chloroform-d)δ11.61(s，1H)，7.11(td，J＝8.8，8.3，6.1Hz，1H)，6.86-6.75(m，3H)，6.73(d，J＝2.1Hz，1H)，6.66(d，J＝8.3Hz，1H)，4.74(s，1H)，4.34(s，2H)，4.22(s，2H)，4.20-4.09(m，2H)，3.59(d，J＝11.6Hz，2H)，2.87(s，2H)，2.78(s，3H)，2.77-2.63(m，2H)，2.13(d，J＝13.0Hz，2H)，2.03-1.85(m，4H)。LCMS：[M+1] +430.2。 Synthetic method of 3-(chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea (H002-075) ER10217 Similar to compound#45. Using 0.15 mmol of chromane-6-methyl isocyanate (45-1), H002-075 ER10217 was obtained as a white solid (32 mg, 50% yield). 1 H NMR (400MHz, Chloroform-d) δ 11.61 (s, 1H), 7.11 (td, J = 8.8, 8.3, 6.1 Hz, 1H), 6.86-6.75 (m, 3H), 6.73 (d, J = 2.1Hz, 1H), 6.66(d, J=8.3Hz, 1H), 4.74(s, 1H), 4.34(s, 2H), 4.22(s, 2H), 4.20-4.09(m, 2H), 3.59( d, J=11.6Hz, 2H), 2.87 (s, 2H), 2.78 (s, 3H), 2.77-2.63 (m, 2H), 2.13 (d, J=13.0Hz, 2H), 2.03-1.85 (m , 4H). LCMS: [M+1] + 430.2.
实施例7：合成(R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-080)ER10220Example 7: Synthesis of (R)-3-(chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl) )Methyl)urea (H002-080)ER10220
Figure PCTCN2021072899-appb-000020
Figure PCTCN2021072899-appb-000020
(S)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-078)：合成方法类似于(45-2)。用(S)-(1-甲基吡咯烷-3-基)甲胺(4mmol)得到棕色油状中间体(H002-078)(0.6g，产率63％)。LCMS：[M+1] +241.3。 (S)-N-(2,4-Difluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-078): The synthesis method is similar to (45-2). (S)-(1-methylpyrrolidin-3-yl)methylamine (4mmol) was used to obtain brown oily intermediate (H002-078) (0.6g, yield 63%). LCMS: [M+1] + 241.3.
Figure PCTCN2021072899-appb-000021
Figure PCTCN2021072899-appb-000021
(R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-080)ER10220：合成方法类似于compound#45。用色烷-6-甲基异氰酸酯(45-1)(0.15mmol)得到白色固体H002-080 ER10220(7mg，产率11％)。LCMS：[M+1] +430.2。 (R)-3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea (H002-080) ER10220: The synthesis method is similar to compound#45. Chromane-6-methyl isocyanate (45-1) (0.15 mmol) was used to obtain H002-080 ER10220 (7 mg, yield 11%) as a white solid. LCMS: [M+1] + 430.2.
实施例8：合成(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-083)ER10223Example 8: Synthesis of (S)-3-(chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl) )Methyl)urea (H002-083)ER10223
Figure PCTCN2021072899-appb-000022
Figure PCTCN2021072899-appb-000022
(S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-083)ER10223：合成方法类似于compound#45。用色烷-6-甲基异氰酸酯(45-1)(0.15mmol)得到白色固体H002-083 ER10223(9mg，产率13％)。LCMS：[M+1] +430.2。 (S)-3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea (H002-083) ER10223: The synthesis method is similar to compound#45. Chromane-6-methyl isocyanate (45-1) (0.15 mmol) was used to obtain H002-083 ER10223 (9 mg, yield 13%) as a white solid. LCMS: [M+1] + 430.2.
生物学活性试验Biological activity test
以下生物学活性试验中，使用的ER10152是阳性对照物，结构式为：In the following biological activity test, the ER10152 used is the positive control, and the structural formula is:
Figure PCTCN2021072899-appb-000023
可商购，或按照US7601740B2中记载的方法合成制备。
Figure PCTCN2021072899-appb-000023
It is commercially available or synthetically prepared according to the method described in US7601740B2.
1、5-HT2A受体拮抗剂活性筛选试验1. 5-HT2A receptor antagonist activity screening test
为证实本发明化合物对5-HT2A受体的拮抗活性，选择IP-One实验完成检测。以下实验采用Flp-In-CHO-5HT2A稳定细胞系完成。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。细胞产生的IP1和试剂盒所提供的标记了d2的IP1竞争抗IP1抗体的抗原结合位点，当铽标记抗IP1抗体与d2标记的IP1结合后，会发生能量共振转移，从而产生信号，随细胞内IP1产生增多，游离的IP1与抗体结合增多，信号逐渐减小。In order to confirm the antagonistic activity of the compound of the present invention on 5-HT2A receptor, the IP-One experiment was selected to complete the test. The following experiments were done using Flp-In-CHO-5HT2A stable cell line. The IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2-labeled IP1. The IP1 produced by the cells and the IP1 labeled with d2 provided in the kit compete for the antigen binding site of the anti-IP1 antibody. When the terbium-labeled anti-IP1 antibody binds to the IP1 labeled with d2, energy resonance transfer occurs, thereby generating a signal. The production of intracellular IP1 increases, the binding of free IP1 to antibodies increases, and the signal gradually decreases.
材料和方法：Materials and Method:
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-In TM-CHO cell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择Zeocin TM抗性克隆产生Flp-In TM-CHO细胞系。Flp-In TM-CHO细胞系于加有10％FBS (Hyclone)+1×Penicilin-Streptomycin(15140-122，Gibco)的Ham’s F-12K完全培养基(Hyclone)中培养，之后以人HTR2A基因(Human HTR2A，GeneBank，NM_000621)稳定转染得到Flp-In-CHO-5HT2A细胞。稳定转染的细胞系培养于加有10％FBS(Hyclone)+1×Penicilin-Streptomycin+800μg/ml Hygromycin B(ant-hg-5，Invivogen)的Ham’s F-12K完全培养基(Hyclone)中。为验证化合物活性，Flp-In-CHO-5HT2A稳定细胞系在37℃，5％CO 2条件下，于384孔板中培养(7.5K)20小时。化合物用Ham’s F-12K培养基稀释成不同浓度，与新鲜培养基一同以100μl/孔更换培养过夜的培养基，细胞用化合物处理30分钟后加入5-HT在37摄氏度下培养45分钟，之后顺序加入裂解检测缓冲液、IP1-d2和IP1-Ab室温培养1小时后在Envision上读板(HTRF模块)。 According to the user manual, the Chinese hamster ovary cell transformed cell line (Flp-In TM -CHO cell line) (purchased from invitrogen, R75807) was produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp- In TM -CHO cell line. Flp-In TM -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone)+1×Penicilin-Streptomycin (15140-122, Gibco), and then with human HTR2A gene ( Human HTR2A, GeneBank, NM_000621) was stably transfected to obtain Flp-In-CHO-5HT2A cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1 x Penicilin-Streptomycin + 800 μg/ml Hygromycin B (ant-hg-5, Invivogen). To verify the activity of the compound, the Flp-In-CHO-5HT2A stable cell line was cultured in a 384-well plate (7.5K) for 20 hours at 37°C and 5% CO 2. The compounds were diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100μl/well overnight. After the cells were treated with the compound for 30 minutes, 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding lysis detection buffer, IP1-d2 and IP1-Ab, incubate for 1 hour at room temperature and read the plate on Envision (HTRF module).
根据所示结果，Flp-In-CHO-5HT2A稳定细胞系的5HT2A受体活性会被化合物所抑制，提示所述化合物具有5HT2A受体拮抗活性。According to the results shown, the 5HT2A receptor activity of the Flp-In-CHO-5HT2A stable cell line was inhibited by the compound, suggesting that the compound has 5HT2A receptor antagonistic activity.
IDID 5HT2A EC50(nM)5HT2A EC50(nM)
ER10152ER10152 4545
ER10058ER10058 1515
ER10216ER10216 88
ER10217ER10217 7.57.5
ER10220ER10220 2626
ER10223ER10223 2020
2、5-HT2B/2C VGV受体拮抗剂活性筛选试验 2. 5-HT2B/2C VGV receptor antagonist activity screening test
为证实本发明化合物对5-HT2B/2C VGV受体的拮抗活性，选择IP-One实验完成检测。以下实验采用Flp-In-CHO-5HT2B/2C VGV稳定细胞系完成。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。细胞产生的IP1和试剂盒所提供的标记了d2的IP1竞争抗IP1抗体的抗原结合位点，当铽标记抗IP1抗体与d2标记的IP1结合后，会发生能量共振转移，从而产生信号，随细胞内IP1产生增多，游离的IP1与抗体结合增多，信号逐渐减小。 In order to confirm the antagonistic activity of the compound of the present invention on the 5-HT2B/2C VGV receptor, the IP-One experiment was selected to complete the test. The following experiments were performed using Flp-In-CHO-5HT2B/2C VGV stable cell line. The IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2 labeled IP1. The IP1 produced by the cells and the IP1 labeled with d2 provided in the kit compete for the antigen binding site of the anti-IP1 antibody. When the terbium-labeled anti-IP1 antibody binds to the IP1 labeled with d2, energy resonance transfer occurs, thereby generating a signal. The production of intracellular IP1 increases, the binding of free IP1 to antibodies increases, and the signal gradually decreases.
材料和方法：Materials and Method:
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-In TM-CHOcell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择Zeocin TM抗性克隆产生Flp-In TM-CHO细胞系。Flp-In TM-CHO细胞系于加有10％FBS (Gibco)+1×Penicilin-Streptomycin(15140122，Gibco)的Ham’s F-12K完全培养基(Hyclone)中培养，之后以人HTR2B/2C VGV基因 (Human HTR2B，GeneBank， NM 000867；Human HTR2C(5-HT2C VGV)，GeneBank，NM 000868) 稳定转染得到Flp-In-CHO-5HT2B/2C VGV细胞。稳定转染的细胞系培养于加有10％FBS(Gibco)+1×Penicilin-Streptomycin+800μg/ml Hygromycin B(ant-hg-5，Invivogen)的Ham’s F-12K完全培养基(Hyclone)中。为验证化合物活性，Flp-In-CHO-5HT2B/2C VGV稳定细胞系在37摄氏度，5％CO 2条件下，于384孔板中培养(5K，7.5K)20小时。化合物用Ham’s F-12K培养基稀释成不同浓度，与新鲜培养基一同以100μl/孔更换培养过夜的培养基，细胞用化合物处理30分钟后加入5-HT在37摄氏度下培养45分钟，之后顺序加入裂解检测缓冲液、IP1-d2和IP1-Ab室温培养1小时后在Envision上读板(HTRF模块)，计算化合物对细胞5-HT2B/2C VGV受体的抑制率。 According to the user manual, the Chinese Hamster Ovary Cell Transformed Cell Line (Flp-In TM -CHOcell line) (purchased from invitrogen, R75807) was produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp-In TM- CHO cell line. Flp-In TM -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco)+1×Penicilin-Streptomycin (15140122, Gibco), and then human HTR2B/2C VGV gene (Human HTR2B, GeneBank, NM 000867; Human HTR2C (5-HT2C VGV ), GeneBank, NM 000868) were stably transfected to obtain Flp-In-CHO-5HT2B/2C VGV cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco) + 1 x Penicilin-Streptomycin + 800 μg/ml Hygromycin B (ant-hg-5, Invivogen). To verify the activity of the compound, the Flp-In-CHO-5HT2B/2C VGV stable cell line was cultured in a 384-well plate (5K, 7.5K) for 20 hours at 37 degrees Celsius and 5% CO 2. The compound was diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100μl/well for overnight culture. The cells were treated with compound for 30 minutes and 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding the lysis detection buffer, IP1-d2 and IP1-Ab, incubating for 1 hour at room temperature, the plate was read on Envision (HTRF module), and the inhibition rate of the compound on the 5-HT2B/2C VGV receptor of the cells was calculated.
将每个化合物对5-HT2B或5-HT2C的EC50值除以其对5-HT2A的EC50值，计算出每个化合物对5-HT2B或5-HT2C的选择性相对于5-HT2A的选择性的倍数：Divide the EC50 value of each compound for 5-HT2B or 5-HT2C by its EC50 value for 5-HT2A to calculate the selectivity of each compound to 5-HT2B or 5-HT2C relative to the selectivity of 5-HT2A Multiples of:
IDID 对2B选择性(倍数)Selectivity to 2B (multiple) 对2C选择性(倍数)Selectivity to 2C (multiple)
ER10152ER10152 86×86× 4×4×
ER10058ER10058 199×199× 19×19×
ER10217ER10217 1000×1000× 28×28×
3、hERG膜蛋白特异性结合实验3. hERG membrane protein specific binding experiment
为检验本发明化合物对心脏的毒性，选择hERG膜蛋白特异性结合实验完成检测。该实验采用稳定表达hERG(human Ether-a-go-go Related Gene)编码钾通道的HEK293细胞系完成实验。在心肌中，hERG编码的钾通道介导一种延迟整流钾电流(IKr)，Ikr抑制是药物导致QT间期延长最重要的机制。hERG因其特殊的分子结构，其功能缺失或药物抑制都会影响心脏动作电位复极过程并会引起QT间期延长，同时可能诱发尖端扭转性室性心动过速，导致心律失常。In order to test the toxicity of the compound of the present invention to the heart, the hERG membrane protein specific binding experiment was selected to complete the detection. The experiment used the HEK293 cell line stably expressing hERG (human Ether-a-go-go Related Gene) encoding potassium channel to complete the experiment. In the myocardium, the potassium channel encoded by hERG mediates a delayed rectifier potassium current (IKr), and Ikr inhibition is the most important mechanism for the prolongation of the QT interval caused by drugs. Because of its special molecular structure, hERG's lack of function or drug inhibition will affect the repolarization process of cardiac action potentials and cause the QT interval to prolong. At the same time, it may induce torsade de pointes ventricular tachycardia and lead to arrhythmia.
该实验将hERG膜蛋白、检测化合物与固定浓度的放射性配体混合，使检测化合物和放射性配体竞争性地与hERG膜蛋白结合，孵育一定时间达到平衡后，用真空过滤掉没有与膜蛋白结合的放射性配体，烘干过滤板后加入闪烁液，并在Microbeta上检测同位素信号(CPM)。信号越高代表检测化合物与hERG膜蛋白结合能力越弱。In this experiment, hERG membrane protein, detection compound and a fixed concentration of radioligand are mixed, so that the detection compound and radioligand can competitively bind to hERG membrane protein. After incubating for a certain period of time to reach equilibrium, vacuum filtration is used to remove no binding to membrane protein. After drying the filter plate, add scintillation fluid, and detect the isotope signal (CPM) on Microbeta. The higher the signal, the weaker the binding ability of the detection compound to hERG membrane protein.
材料和方法：Materials and Method:
将化合物、稀释好的hERG膜蛋白以及稀释好的H3-多菲利特配体(NET1144100UC，PerkinElmer)先后加入到96孔板(3631，Coming)内，封板膜封板后，室温摇动孵育1小时，使用PerkinElmer细胞收集器将孵育后的hERG膜蛋白转移至GF/B板(600517，PerkinElmer)上，使用冲洗缓冲液(20mmol/L HEPES(PH 7.4)(Sigma-H3375)；10mmol/L氯化钾(Sigma-P9333)；1mmol/L氯化镁(Sigma-449172)，4℃保存)清洗5次(4℃，每次0.4mL)。随后将GF/B板于50℃烘箱内烘烤30min，使GF/B板充分干燥后，底部封板膜(6005199，PerkinElmer)封闭GF/B板底部，向板子每孔加入50μL闪烁液20(6013621，PerkinElmer)后用顶部封板膜(6005250，PerkinElmer)封板，Microbeta上读板检测放射性信号。Add the compound, the diluted hERG membrane protein and the diluted H3-Dofetilide ligand (NET1144100UC, PerkinElmer) to a 96-well plate (3631, Coming) one after another. After the plate is sealed with a sealing membrane, incubate at room temperature with shaking1 After hours, use the PerkinElmer cell harvester to transfer the incubated hERG membrane protein to the GF/B plate (600517, PerkinElmer), and use the washing buffer (20mmol/L HEPES (PH 7.4) (Sigma-H3375)); 10mmol/L chlorine Potassium chloride (Sigma-P9333); 1mmol/L magnesium chloride (Sigma-449172), stored at 4°C) and washed 5 times (4°C, 0.4 mL each time). Then bake the GF/B plate in an oven at 50°C for 30 minutes to fully dry the GF/B plate, seal the bottom of the GF/B plate with a bottom sealing film (6005199, PerkinElmer), and add 50 μL of scintillation fluid 20 ( 6013621, PerkinElmer) and then use the top sealing film (6005250, PerkinElmer) to seal the plate, and read the plate on Microbeta to detect the radioactive signal.
测试化合物以及它们的结合率值Test compounds and their binding rate values
IDID hERG结合率(％，化合物为10μM时)hERG binding rate (%, when the compound is 10μM)
ER10152ER10152 9191
ER10058ER10058 6666
ER10217ER10217 5353
4、人肝微粒体代谢稳定性实验4. Metabolic stability test of human liver microsomes
肝脏是内源性基质及外源性药物代谢的主要器官。有几种体外工具可以帮助研究人员研究候选药物的代谢，包括分离的新鲜或冷冻保存的肝细胞、肝脏切片以及肝微粒和S9组分等亚细胞成分。这些亚细胞成分是通过一系列的均质化和超速离心的方式从肝脏中制备出来。The liver is the main organ for the metabolism of endogenous matrix and exogenous drugs. There are several in vitro tools that can help researchers study the metabolism of candidate drugs, including isolated fresh or cryopreserved liver cells, liver slices, and subcellular components such as liver microparticles and S9 components. These subcellular components are prepared from the liver through a series of homogenization and ultracentrifugation methods.
10,000g肝脏匀浆的初始低速离心法产生的S9组分是此离心方法得到的上清液中的组分。S9组分包含所有I相和II相酶，S9组分进一步离心100,000g得到内质网衍生微粒。微粒体富含细胞色素P450(CYP)和黄素单加氧酶(FMO)。此外，一些II相酶(如某些苷葡糖苷酸转移酶UGT亚型和环氧水解酶EH)也在微粒体中存在。微粒体可用于研究UGT的活性，然而，微粒体膜限制UGT基质和/或辅助因子的进入。通过添加MgCl 2以及成孔抗生素(如丙甲菌素)可以达到最佳UGT活性。这些组件使得微粒体网络中的葡萄糖醛酸产物和辅助因子UDPGA能够有效转运。个体或组合的供者肝微粒体可用于进行代谢相关研究。组合的供者可以代表人群平均水平或特定研究因素，如年龄，BMI或特定CYP亚型的限制能 力。本研究的目的是评定化合物在人肝微粒体中的代谢稳定性。 The S9 fraction produced by the initial low-speed centrifugation of 10,000g liver homogenate is the fraction in the supernatant obtained by this centrifugation method. The S9 component contains all phase I and phase II enzymes, and the S9 component is further centrifuged at 100,000 g to obtain endoplasmic reticulum-derived microparticles. Microsomes are rich in cytochrome P450 (CYP) and flavin monooxygenase (FMO). In addition, some phase II enzymes (such as certain glycoside glucuronyltransferase UGT subtypes and cyclohydrolase EH) are also present in the microsomes. Microsomes can be used to study the activity of UGT, however, the microsomal membrane restricts the entry of UGT matrix and/or cofactors. The best UGT activity can be achieved by adding MgCl 2 and pore-forming antibiotics (such as propylmethacin). These components allow the glucuronic acid product and the cofactor UDPGA in the microsomal network to be efficiently transported. Individual or combined donor liver microsomes can be used for metabolism-related research. The combined donors can represent population averages or specific research factors such as age, BMI, or the limiting capacity of specific CYP subtypes. The purpose of this study is to evaluate the metabolic stability of the compound in human liver microsomes.
材料和方法Materials and Method
该测试体系用到的人肝微粒体购买自Corning(Cat No.452117)，使用前储存于低于-60℃的冰箱内。辅酶为NADPH(Chem-impex international，Cat.No.00616)和UDPGA(Sigma，Cat.No.U6751)辅因子。将称量好的NADPH粉末和UDPGA粉末溶解在MgCl 2溶液中配置25mM UGPDA和10mM NADPH的工作液。准备八块96孔板(T0，T5，T10，T20，T30，T60，NFC60，BLANK)，使用Apricot自动液体工作站(PP-550DS，USA)，每孔加入10μL化合物工作液(T0，T5，T10，T20，T30，T60，NFC60)，T0板加入冷乙腈终止液，随后向八块板中加入80μL/孔人肝微粒体，37度预孵育10分钟。NCF60板加入10μL/孔100mM磷酸钾缓冲液放入37度水浴锅中孵育计时1小时。其他板在孵育结束后加入10μL/孔NADPH+UDPGA辅因子组合，按照每板设定做不同时间孵育。孵育结束后加入300μL/孔冷乙腈终止反应，封板震荡10分钟后4000rpm，4度离心20分钟。取100μL/孔离心上清液加入到已添加300μL/孔HPLC水的新板中，混匀递交LC-MS/MS生物分析。 The human liver microsomes used in this test system were purchased from Corning (Cat No. 452117) and stored in a refrigerator below -60°C before use. Coenzymes are NADPH (Chem-impex international, Cat. No. 00616) and UDPGA (Sigma, Cat. No. U6751) cofactors. Dissolve the weighed NADPH powder and UDPGA powder in the MgCl 2 solution to prepare a working solution of 25 mM UGPDA and 10 mM NADPH. Prepare eight 96-well plates (T0, T5, T10, T20, T30, T60, NFC60, BLANK), use Apricot automatic liquid workstation (PP-550DS, USA), add 10 μL of compound working solution (T0, T5, T10) to each well , T20, T30, T60, NFC60), T0 plate was added with cold acetonitrile stop solution, and then 80μL/well human liver microsomes were added to eight plates, and pre-incubated at 37°C for 10 minutes. Add 10 μL/well of 100 mM potassium phosphate buffer to the NCF60 plate and place it in a 37-degree water bath and incubate for 1 hour. Add 10μL/well of NADPH+UDPGA cofactor combination to other plates after the incubation, and incubate at different times according to the setting of each plate. After the incubation, 300 μL/well of cold acetonitrile was added to terminate the reaction, the plate was sealed and shaken for 10 minutes, and then centrifuged at 4000 rpm at 4 degrees for 20 minutes. Take 100μL/well of centrifugal supernatant and add it to a new plate to which 300μL/well of HPLC water has been added, mix well and submit to LC-MS/MS bioanalysis.
计算化合物与内标峰面积比值转化成剩余百分比求得供试品和对照化合物体外消除速率常数ke：％剩余量＝任意时间点对照品与内标的峰面积比值/0分钟时对照品与内标的峰面积比值×100％。Calculate the peak area ratio of the compound to the internal standard and convert it into the remaining percentage to obtain the in vitro elimination rate constant ke of the test product and the reference compound:% remaining = the peak area ratio of the reference product and the internal standard at any time point/the ratio of the reference product and the internal standard at 0 minutes Peak area ratio×100%.
CL int(mic)＝0.693/T 1/2/微粒体蛋白含量(孵育时微粒体蛋白浓度mg/mL) CL int(mic) = 0.693/T 1/2 /microsomal protein content (microsomal protein concentration mg/mL during incubation)
CL int(liver)＝CL int(mic)×肝脏中微粒体蛋白量(mg/g)×肝重体重比 CL int(liver) = CL int(mic) × the amount of microsomal protein in the liver (mg/g) × liver weight-to-weight ratio
根据充分搅拌模型(well stir model)，肝固有清除率和肝清除率可以通过下式换算：According to the well stir model, the intrinsic liver clearance rate and liver clearance rate can be converted by the following formula:
CL(Liver)＝(CL int(liver)×Qh)/(CL int(liver)+Qh) CL(Liver)=(CL int(liver) ×Qh)/(CL int(liver) +Qh)
化合物的肝微粒体清除率：Compound clearance rate of liver microsomes:
IDID HLM(mL/min/Kg)HLM(mL/min/Kg)
ER10152ER10152 23.623.6
ER10058ER10058 21.621.6
ER10216ER10216 22twenty two
ER10217ER10217 1313
ER10220ER10220 22twenty two

Claims (10)

  1. 一种具有式I结构的化合物，或其药学可接受的盐，溶剂化物，或立体异构体：A compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
    Figure PCTCN2021072899-appb-100001
    Figure PCTCN2021072899-appb-100001
    其中，in,
    n、m分别选自0-4的整数，n and m are selected from integers from 0 to 4 respectively,
    X为杂原子或碳原子，所述杂原子选自O，N，S原子，优选为N原子；X is a heteroatom or a carbon atom, and the heteroatom is selected from O, N, and S atoms, preferably a N atom;
    环X即X原子所在环，通过环碳原子或者环N原子与化合物主体结构连接，Ring X is the ring where the X atom is located, and is connected to the main structure of the compound through a ring carbon atom or a ring N atom,
    环B基团选自含4-8元环烷基、4-8元杂环烷基、5-8元芳环基或5-8元杂芳环基，该环与苯环稠合；优选环B为4-8元环烷基或4-8元杂环烷基；The ring B group is selected from the group containing 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aromatic ring group or 5-8 membered heteroaromatic ring group, and the ring is fused with a benzene ring; preferably Ring B is 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl;
    R 1为1或多个取代基，位于所在环系的任意取代位置，R 1彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 1 is one or more substituents, located at any substitution position of the ring system where R 1 is located, and R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
    R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
    R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  2. 如权利要求1所述的化合物，其特征在于，所述式I结构化合物，The compound of claim 1, wherein the compound of formula I is
    其中，n为1，2或3；m为0，1或2；Wherein, n is 1, 2 or 3; m is 0, 1 or 2;
    X为杂原子，选自O，N，S原子，优选为N原子；X is a heteroatom, selected from O, N, and S atoms, preferably N atom;
    环B与苯环形成的环系选自以下结构基团：The ring system formed by ring B and benzene ring is selected from the following structural groups:
    Figure PCTCN2021072899-appb-100002
    Figure PCTCN2021072899-appb-100002
    其中，Y选自O，N，S原子；优选为O原子。Among them, Y is selected from O, N, S atoms; preferably O atom.
  3. 一种具有式IA结构的化合物，或其药物可接受的盐，溶剂化物，或立体异构体：A compound having the structure of Formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
    Figure PCTCN2021072899-appb-100003
    Figure PCTCN2021072899-appb-100003
    其中，in,
    n为1，2或3；m为0，1或2，n is 1, 2 or 3; m is 0, 1 or 2,
    X为杂原子，选自O，N，S原子，优选为N原子；X is a heteroatom, selected from O, N, and S atoms, preferably N atom;
    Y选自O，N，S原子，优选为O原子；Y is selected from O, N, S atoms, preferably O atom;
    R 1为1或多个取代基，位于所在环系的任意取代位置，R 1彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 1 is one or more substituents, located at any substitution position of the ring system where R 1 is located, and R 1 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
    R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
    R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  4. 如权利要求1-3任一项所述的化合物，或其药物可接受的盐，溶剂化物，或立体异构体，其特征在于，环X通过环碳原子与化合物主体结构连接；The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the ring X is connected to the main structure of the compound through a ring carbon atom;
    优选R 3在X位置取代。 Preferably R 3 is substituted at the X position.
  5. 如权利要求1-4任一项所述的化合物，或其药物可接受的盐，溶剂化物，或立体异构体，其特征在于，环X为吖丁啶基，吡咯烷基，或哌啶基；Y为O原子。The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring X is azetidinyl, pyrrolidinyl, or piperidinyl; Y is an O atom.
  6. 如权利要求1-5任一项所述的化合物，或其药物可接受的盐，溶剂化物，或立体异构体，其选自如下结构的具体化合物，或其药学可接受的盐，溶剂化物，或立体异构体：The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is selected from a specific compound having the following structure, or a pharmaceutically acceptable salt, or solvate thereof , Or stereoisomer:
    3-(色烷-6-基甲基)-1-(4-氟-苯甲基)-1-(1-甲基哌啶-4-基)-脲，3-(Chroman-6-ylmethyl)-1-(4-fluoro-benzyl)-1-(1-methylpiperidin-4-yl)-urea,
    3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea,
    (S)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    (R)-3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲，3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea,
    (R)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea ,
    (S)-3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，或，(S)-3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea ,or,
    3-(色烷-6-基甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲。3-(Chroman-6-ylmethyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea.
  7. 如权利要求1-6任一项所述化合物或其药物可接受的盐，溶剂化物，或立体异构体的制备方法，其特征在于：The method for preparing the compound or its pharmaceutically acceptable salt, solvate, or stereoisomer according to any one of claims 1 to 6, characterized in that:
    步骤1、式A结构的异氰酸化合物与式B氨基化合物按如下反应式反应，合成得到式I化合物，Step 1. The isocyanate compound of formula A and the amino compound of formula B are reacted according to the following reaction formula to synthesize the compound of formula I.
    Figure PCTCN2021072899-appb-100004
    Figure PCTCN2021072899-appb-100004
    步骤2、如果需要，再根据目标产物的需要，对式I化合物进行官能团修饰，转化为具有式I结构的目标产物，或者转化为所述化合物的药学可接受的盐，或前体化合物。Step 2. If necessary, according to the needs of the target product, functional group modification is performed on the compound of formula I to convert it into a target product with the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
  8. 一种药物组合物，其特征在于包含权利要求1-6任一化合物或其药学上可接受的盐，溶剂化物，或立体异构体。A pharmaceutical composition characterized by comprising any compound of claims 1-6 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
    优选，所述药物组合物进一步包含药学上可接受的载体。Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
    优选，所述药物组合物进一步包含第二种治疗剂，所述第二种治疗剂是其他的治疗5HT2A受体活性介导的相关疾病的药物。Preferably, the pharmaceutical composition further comprises a second therapeutic agent, and the second therapeutic agent is another drug for treating related diseases mediated by 5HT2A receptor activity.
    优选，所述第二种治疗剂选自：苯二氮
    Figure PCTCN2021072899-appb-100005
    类、巴比妥类、水合氯醛、丁螺环酮、吩噻嗪类、硫杂蒽类、丁酰苯类、氯氮平、利哌利酮、三环类抗抑郁药、杂环类抗抑郁药、选择性5-HT重摄取抑制剂、单胺氧化酶抑制剂、氯胺酮、米氮平、左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺和利血平。     Preferably, the second therapeutic agent is selected from: benzodiazepine
    Figure PCTCN2021072899-appb-100005
    Class, barbiturates, chloral hydrate, buspirone, phenothiazines, thioxanthenes, butyrylbenzenes, clozapine, risperidone, tricyclic antidepressants, heterocyclics Antidepressants, selective 5-HT reuptake inhibitors, monoamine oxidase inhibitors, ketamine, mirtazapine, levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and reserpine.
  9. 权利要求1-6任一化合物或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗5HT2A受体活性介导的相关疾病的药物中的应用。Use of a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer of any one of claims 1 to 6 in the preparation of a medicine for treating related diseases mediated by 5HT2A receptor activity.
    优选，所述5HT2A受体活性介导的相关疾病是中枢神经系统疾病。Preferably, the related disease mediated by the 5HT2A receptor activity is a central nervous system disease.
    优选，所述中枢神经系统疾病是精神疾病、中枢神经系统退行性疾病、中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状。Preferably, the central nervous system disease is a mental disease, a central nervous system degenerative disease, a mental disorder symptom associated with or concurrent with a central nervous system degenerative disease, and a negative symptom of a mental disease.
    优选，所述精神疾病是抑郁症、焦虑症、躁狂症、精神分裂症、情感性分裂症、双相精神障碍、失眠、自闭症。Preferably, the mental illness is depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism.
    优选，所述中枢神经系统退行性疾病是阿尔兹海默症、帕金森病、亨廷顿病、路易小体痴呆症。Preferably, the degenerative disease of the central nervous system is Alzheimer's disease, Parkinson's disease, Huntington's disease, and Lewy body dementia.
    优选，所述中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状是情感障碍、语言功能减退、幻觉、兴趣缺失。Preferably, the mental disorder symptoms related to or concurrent with degenerative diseases of the central nervous system, and the negative symptoms of mental diseases are affective disorder, decreased language function, hallucinations, and loss of interest.
  10. 治疗5HT2A受体活性介导的相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的权利要求1-6任一化合物，或其药学上可接受的盐，溶剂化物，或立体异构体。A method for treating related diseases mediated by 5HT2A receptor activity, which is characterized by administering a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or stereo isomer.
    优选，所述方法进一步包括，对有需要的患者给予其他的治疗5HT2A受体活性介导的相关疾病的药物；优选，所述其他的治疗剂选自：苯二氮
    Figure PCTCN2021072899-appb-100006
    类、巴比妥类、水合氯醛、丁螺环酮、吩噻嗪类、硫杂蒽类、丁酰苯类、氯氮平、利哌利酮、三环类抗抑郁药、杂环类抗抑郁药、选择性5-HT重摄取抑制剂、单胺氧化酶抑制剂、氯胺酮、米氮平、左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺和利血平。     Preferably, the method further includes administering to the patient in need other drugs for treating related diseases mediated by 5HT2A receptor activity; preferably, the other therapeutic agent is selected from: benzodiazepines
    Figure PCTCN2021072899-appb-100006
    Class, barbiturates, chloral hydrate, buspirone, phenothiazines, thioxanthenes, butyrylbenzenes, clozapine, risperidone, tricyclic antidepressants, heterocyclics Antidepressants, selective 5-HT reuptake inhibitors, monoamine oxidase inhibitors, ketamine, mirtazapine, levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and reserpine.
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