WO2023116915A1 - Ache/sert dual-target inhibitor, preparation method therefor and use thereof - Google Patents

Ache/sert dual-target inhibitor, preparation method therefor and use thereof Download PDF

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WO2023116915A1
WO2023116915A1 PCT/CN2022/141611 CN2022141611W WO2023116915A1 WO 2023116915 A1 WO2023116915 A1 WO 2023116915A1 CN 2022141611 W CN2022141611 W CN 2022141611W WO 2023116915 A1 WO2023116915 A1 WO 2023116915A1
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halogens
substituted
alkyl
formula
alkoxy
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PCT/CN2022/141611
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French (fr)
Chinese (zh)
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杨新春
李剑
成佳兴
赵金龙
李晓康
许祥诚
梅丹
陈亮
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珠海市藤栢医药有限公司
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    • 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
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a novel AChE/SERT dual-target inhibitor, a preparation method thereof, a pharmaceutical composition containing this type of compound, and as an acetylcholinesterase inhibitor and a serotonin transporter inhibitor , especially the preparation of medicines for preventing and/or treating Alzheimer's disease, depression, Alzheimer's disease and depression comorbidities.
  • AD Alzheimer's disease
  • dementia dementia
  • senile dementia dementia
  • dementia is a progressive and fatal neurodegenerative disease, clinically manifested as memory dysfunction, aphasia, apraxia, agnosia, visuospatial Generalized dementia manifests as impaired skills, executive dysfunction, and changes in personality and behavior, with psychiatric symptoms such as depression, irritability, and anxiety.
  • psychiatric symptoms such as depression, irritability, and anxiety.
  • 90% of AD patients will be accompanied by neuropsychiatric symptoms, among which depression is one of the most common comorbidities, accounting for about 50% of AD patients, which is 10 times the incidence rate of the general population, and is different from the general population.
  • Patients with depression, AD-depression co-morbidity are more difficult to treat and have higher mortality.
  • depression patients are often accompanied by memory and cognitive impairment. About two-thirds of depressed patients will be accompanied by cognitive impairment. 94% of depressed patients still have cognitive impairment after recovery. Depression is considered to be a prodromal symptom of AD. or risk factors. At present, there are 35 million AD patients and 264 million depression patients in the world. Therefore, the potential number of patients with AD-depression co-morbidity is huge, and the development of related therapeutic drugs has broad market prospects and important social value.
  • AD-depression co-morbidity is still unclear, and there is no targeted treatment.
  • the existing method is to use anti-AD drugs and antidepressants for combined administration.
  • the curative effect of such combination drugs is often poor, and it cannot achieve the effect of single drug in treating a single disease, and because the patients are mainly elderly, it is accompanied by a higher risk of drug-drug interactions.
  • Acetylcholinesterase inhibitors are the most important anti-AD drugs, including Tacrine developed by Warner-Lambert in the United States (later withdrawn due to liver toxicity), Japan's Eisai Pharmaceuticals (Eisai) Donepezil developed by Novartis, Rivastigmine developed by Novartis, Galanthamine developed by Johnson & Johnson, and Huperzine A developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Among them, donepezil is a reversible acetylcholinesterase inhibitor, which increases the concentration of acetylcholine in the synaptic cleft by inhibiting the hydrolysis of acetylcholine by acetylcholinesterase.
  • Antidepressant drugs are mainly selective serotonin reuptake inhibitors (SSRIs), which selectively inhibit the reuptake of serotonin (5-HT) by inhibiting the serotonin transporter (SERT). , Increase the concentration of 5-HT in the synaptic gap in the brain of depressed patients.
  • SSRIs selective serotonin reuptake inhibitors
  • SERT serotonin transporter
  • SSRIs selective serotonin reuptake inhibitors
  • 5-HT serotonin transporter
  • Vilazodone an anti-major depressive drug, has both selective 5-HT reuptake inhibitory activity and 5-HT 1A agonistic activity. Therefore, for the mature targets of AD and depression, the development of drugs that simultaneously increase the levels of acetylcholine and serotonin in the brain may be expected to treat AD-depression co-morbidity.
  • 5-HT 1A agonistic activity may aggravate memory impairment in AD patients.
  • 5-HT 1A receptors affect memory function by affecting the activity of glutamatergic, cholinergic and GABAergic neurons in the cerebral cortex and hippocampal projection areas. Studies have shown that human subjects who take the 5-HT 1A receptor agonist Ipsapirone or the 5-HT 1A receptor partial agonist Tandospirone have impaired verbal memory.
  • 5-HT 1A receptor antagonists can enhance cholinergic transmission and improve cognitive function, such as NAD-299, WAY-100635 and Lecozotan (SRA-333) SR. It has been shown to improve memory in animal models of cognitive impairment.
  • Lecozotan developed by Wyeth can significantly improve the task completion efficiency of aged rhesus monkeys and reverse the memory deficits in marmoset monkeys caused by glutamate antagonists, and entered clinical phase II in 2005 for the treatment of mild to moderate AD patients.
  • 5-HT 1A agonistic activity may play a role that is not conducive to disease treatment, and it is urgent to develop a more beneficial treatment for AD-depression co-morbidity.
  • AChE/SERT dual-target inhibitor of the disease may play a role that is not conducive to disease treatment, and it is urgent to develop a more beneficial treatment for AD-depression co-morbidity.
  • the pathological mechanism of AD-depression co-morbidity is complex, the market demand is huge, and the treatment drug is facing a gap.
  • the development of effective treatment drug has important social value and medical value.
  • the resulting drug-drug interaction reduces the difficulty of taking medicine and the physical burden of patients.
  • the object of the present invention is to provide a dual-target inhibitor of acetylcholinesterase (AChE)/serotonin transporter (SERT) with novel structure.
  • AChE acetylcholinesterase
  • SERT serotonin transporter
  • the present invention provides the compound shown in formula I, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I, its tautomer or its stereo isomer), or any of the foregoing (referring to the pharmaceutically acceptable salt of the foregoing compound as shown in formula I, its tautomer, its stereoisomer, or any of the foregoing The solvate of the salt of );
  • each are independently double bonds or single bonds
  • Each R 1 is independently CN, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or C 1 -C 6 alkoxy substituted by 3 halogens;
  • n1 0, 1, 2, 3 or 4;
  • R 2 is H, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens;
  • Each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens or substituted by 1, 2 or 3 Halogen substituted C 1 -C 6 alkoxy;
  • n2 0, 1, 2, 3 or 4;
  • R 4 is C 6 -C 10 aryl, C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, benzyl, benzyl substituted by 1, 2 or 3 halogens, cyclopentane, substituted by 1, 2 or 3 halogen substituted cyclopentane, cyclohexane, 1, 2 or 3 halogen substituted cyclohexane, "heteroatoms selected from 1, 2 or 3 of N, O and S species, 5-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", “heteroatoms substituted by 1, 2 or 3 halogens are selected from one or two of N, O and S or 3 kinds, 5-12 membered heterocycloalkyl groups with 1, 2 or 3 heteroatoms", “heteroatoms are selected from 1, 2 or 3 kinds of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heteroaryls" or "heteroatoms substituted by 1,
  • R 5 is H, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or 3 halogens Substituted C 1 -C 6 alkoxy; or, R5 is connected to the carbon marked with * to form -(CH 2 ) n2 -; n2 is 0 or 1;
  • n 1, 2, 3, 4, 5 or 6;
  • n1 0, 1, 2 or 3.
  • the compound shown in formula I, its tautomer, its stereoisomer, or any of the foregoing referring to the aforementioned compound shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or
  • Certain groups in the solvate of any of the aforementioned pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are as described in any scheme of the present invention (referred to as "in a certain scheme of the present invention") ,
  • R 1 among the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens,
  • the halogen is independently F, Cl, Br or I, such as F.
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens is trifluoromethyl.
  • the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the halogens are independently F, Cl, Br or I, such as F.
  • the halogen in R 3 , is independently F, Cl, Br or I, such as F.
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
  • Aryl is phenyl or naphthyl, eg phenyl.
  • the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens is phenyl substituted by 1, 2 or 3 Fs, for example
  • the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered Heterocycloalkyl" and the "heteroatom” substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 In 5-12 membered heterocycloalkyl", said "heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • Cycloalkyl is independently "a 5-6 membered heterocycloalkyl group with 1 or 2 heteroatoms selected from one or two of N, O and S".
  • the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered Heteroaryl" and the "heteroatoms substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, 5 with 1, 2 or 3 heteroatoms -12-membered heteroaryl", said "heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12-membered heteroaryl "independently means "a 5-6 membered heteroaryl group with 1 or 2 heteroatoms selected from one or two of N, O and S".
  • the halogen in R 5 , is independently F, Cl, Br or I, such as F.
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
  • R 1 is independently CN, halogen or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens; preferably F, CF 3 or CN, more preferably F or CN .
  • m1 is 1.
  • R 2 is H or C 1 -C 6 alkyl, preferably H or methyl, more preferably H.
  • R 3 is halogen, such as F.
  • m2 is 0 or 1.
  • R 4 is C 6 -C 10 aryl or C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, preferably phenyl, More preferably phenyl or
  • R 5 is H; or, R 5 is connected with a carbon marked with * to form -CH 2 -.
  • n1 is 0.
  • n 1, 2, 3 or 4.
  • the compound shown in formula I has a structure shown in formula I-A or I-B:
  • n, m1, m2, R 1 , R 2 , R 3 and R 4 are as described in any one of the present invention.
  • the compound shown in formula I is any one of the following compounds:
  • the present invention also provides a preparation method of the compound shown in formula I, which is the following method 1 or method 2:
  • Described method one comprises the steps:
  • X is a halogen
  • Described method two comprises the following steps:
  • n3 n-1 (ie 0, 1, 2, 3, 4 or 5);
  • n, n1, m1, m2, R 1 , R 2 , R 3 , R 4 and R 5 are as described in any one of the present invention.
  • the present invention also provides compounds as shown in formula II:
  • n1, m2, R 3 , R 4 and R 5 are as described in any one of the present invention.
  • the compound shown in formula II is any one of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing referring to the aforementioned formula I
  • the pharmaceutically acceptable salt of the shown compound, its tautomer or its stereoisomer), or any of the foregoing referring to the aforementioned compound shown in formula I, its tautomer, its Stereoisomers or pharmaceutically acceptable salts of any of the foregoing) solvates are active ingredients, and the content thereof is a safe and effective amount.
  • Safe and effective amount means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose.
  • the "one dose” is a tablet.
  • the administration method of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other therapeutic agents.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is generally 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention also provides the compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I , its tautomer or its stereoisomer), or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or a pharmaceutically acceptable salt of any of the foregoing), or the use of the pharmaceutical composition, selected from:
  • the present invention also provides a method for preventing and/or treating diseases, which comprises: administering a therapeutically effective amount of a compound represented by formula I as described in any one of the present invention, or its tautomorphism, to a subject in need isomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the solvate of the aforementioned compound shown in formula I, its tautomer, its stereoisomer or any of the aforementioned pharmaceutically acceptable salts), or the pharmaceutical composition, the Disease selected from:
  • a substituent may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond.
  • pharmaceutically acceptable means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid, arginine) and the like.
  • the compounds of the present invention When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.
  • base addition salts For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
  • solvate refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric solvent.
  • Solvent molecules in solvates can exist in an ordered or non-ordered arrangement.
  • the solvent includes but not limited to: water, methanol, ethanol and the like.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds.
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • any variable such as halogen
  • the definition at each position of the variable has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 halogens, that is to say, the group may be substituted by up to 3 halogens, the definition of halogen at this position is independent of the definition of halogen at other positions. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • alkoxy refers to the group -ORx , wherein Rx is alkyl as defined above.
  • heterocycloalkyl refers to a group having a specified number of ring atoms (eg, 5-12 members), a specified number of heteroatoms (eg, 1, 2, or 3), a specified type of heteroatom (N, O, and S 1, 2 or 3) of the cyclic group, which is a monocyclic, bridged or spiro ring, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • aryl refers to a C 6 -C 10 aryl group such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic ring groups independently selected from nitrogen, oxygen and sulfur, which are monocyclic or bicyclic, when When bicyclic, at least one ring is aromatic, such as furyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzene Azoxazolyl, benzisoxazolyl, quinolinyl, isoquinolyl, etc.
  • pharmaceutically acceptable carrier refers to the excipients and additives used in the production of medicines and the formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except the active ingredient.
  • Can refer to Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • patient refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • the acetylcholinesterase inhibitor, the serotonin transporter inhibitor or the dual inhibitor of acetylcholinesterase and serotonin transporter can be used in mammalian organisms; it can also be used in vitro, mainly as Experimental purposes, for example: providing comparison as a standard or control sample, or making a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of acetylcholinesterase and/or serotonin transporter.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: the inventors of the present invention have developed a compound as shown in formula I after extensive and in-depth research, which has both acetylcholinesterase inhibitory activity and serotonin transporter inhibitory activity, and has good in vitro And blood-brain barrier permeability in vivo, used for the treatment of Alzheimer's disease, depression, Alzheimer's disease and depression comorbidities, avoiding harmful drug interactions caused by combined drugs, reducing the difficulty of taking drugs and Physical burden.
  • Figure 1 shows the effect of compound Ib - 7 on the activity of acetylcholinesterase AChE in mouse brain.
  • Figure 2 shows the experimental results of the antidepressant effect of compound Ib - 7 on tail suspension depression model mice.
  • Figure 3 shows the results of the antidepressant effect of compound Ib - 7 on forced swimming model mice.
  • Figure 4 shows the experimental results of the antidepressant effect of compound Ib - 4 on tail suspension depression model mice.
  • Fig. 5 shows the experimental results of the drug effect of compound Ib - 7 on cognitive impairment model mice.
  • Example 1 The 4-bromoacetophenone in step a in Example 1 was replaced by 5-bromoindanone, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product Ia - 4, a yellow solid, with a yield of 52 %.
  • step a in Example 1 The 4-bromoacetophenone in step a in Example 1 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-formonitrile in step e is replaced by 3 -(3-Bromopropyl)-1H-indole-5-carbonitrile, the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 5, a yellow solid, with a yield of 50%.
  • Example 1 The 4-bromoacetophenone in step a in Example 1 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-formonitrile in step e is replaced by 3 -(2-Bromoethyl)-1H-indole-5-carbonitrile, the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 6, a yellow solid, with a yield of 52%.
  • step a The 4-bromoacetophenone in step a is replaced by 5-bromoindanone, and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidine-4 -yl)-2,3-dihydro-1H-inden-1-one.
  • step a in the above-mentioned Example 1, and it is prepared by Aldol condensation reaction of 4-bromoacetophenone and 1-benzyl-4-piperidinecarbaldehyde.
  • the trichlorosilane was formulated into a 25% (volume ratio) anhydrous dichloromethane solution, and the bottle was sealed for later use.
  • Step b tert-Butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Synthesis
  • Step d Synthesis of 3-(1-benzylpiperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one
  • Example 11 The 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e of Example 11 was replaced by 3-(3-bromopropyl)-1H-indole-5-carbonitrile, and the rest The required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product I a -8, a yellow solid, with a yield of 54%.
  • Example 11 The 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e of Example 11 was replaced by 3-(2-bromoethyl)-1H-indole-5-carbonitrile, and the rest The required raw materials, reagents and preparation method are the same as in Example 11 to obtain the product Ia - 9, a yellow solid, with a yield of 57%.
  • Example 11 The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (2-Bromoethyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 10, a yellow solid, with a yield of 57%.
  • Example 11 The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (3-Bromopropyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 11, a yellow solid, with a yield of 57%.
  • Example 11 The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (2-Bromoethyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 12, a yellow solid, with a yield of 53%.
  • Example 7 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one in Example 7 is replaced by 3-(1-benzyl Piperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one, the rest of the required raw materials, reagents and preparation methods are the same Example 7, the product Ib - 5 was obtained as a white solid with a yield of 57%.
  • Step b tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step c tert-butyl-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Synthesis of -yl)piperidine-1-carboxylate
  • Step d 2-((1-Benzyl-4-fluoropiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1- Ketone synthesis
  • Step e 3-((4-(2-((1-Benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Synthesis of -yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step n of Example 19 The benzyl bromide in Step n of Example 19 was replaced by 2-fluorobenzyl bromide, and the remaining raw materials, reagents and preparation methods were the same as in Step n of Example 19 to obtain 350 mg of (E)-5-bromo-2-((4-fluoro -1-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one, white solid, yield 52%.
  • Step b tert-butyl-(E)-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2, Synthesis of 3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step c tert-butyl-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)piperidine-1-carboxylate
  • Step d 2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H -Synthesis of inden-1-one
  • Step f 3-((4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step b tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3 , Synthesis of 6-dihydropyridine-1(2H)-carboxylate
  • Step f 3-((4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step a tert-butyl-4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
  • Step b 2-((1-(3-Fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1 -Synthesis of ketones
  • Step c 3-((4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step a tert-butyl-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
  • Step f 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step d Synthesis of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one
  • Step f 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((5-fluoro-1H-indol-3-yl)methyl)piperidine-4- Synthesis of -2,3-dihydro-1H-inden-1-one
  • Step a tert-butyl-(E)-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2,3-dihydro Synthesis of -1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step b (E)-2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl )-2,3-dihydro-1H-inden-1-one synthesis
  • Step c 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step d (E)-2-((1-Benzyl-4-fluoropiperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl) Synthesis of -2,3-dihydro-1H-inden-1-one
  • 530mg tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro-1H -Inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour.
  • Step f (E)-3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Synthesis of 1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole-5-carbonitrile
  • This effect example shows the activity inhibition experiment and activity results of the compound of the present invention on acetylcholinesterase (AChE).
  • the compound with acetylcholinesterase inhibitory activity can inhibit the hydrolysis of acetylcholine in the brain, thereby increasing the concentration of acetylcholine in the brain, promoting memory cognition, and can be used to improve symptoms and treat AD.
  • the modified Ellman method was used to measure the activity of acetylcholinesterase. Using the cerebral cortex of SD mice as the source of AChE enzyme, thioacetylcholine was added to the reaction template under the optimal enzyme reaction conditions, and the AChE enzyme activity was detected by colorimetry after adding the test substance.
  • the cerebral cortex of SD rats was used as the source of acetylcholinesterase.
  • the sampling method was that after the rats were put to death, the brain was quickly taken out and the cortex was separated on ice, and the brain homogenate was prepared with 75mM phosphate buffer (pH 7.4). Store in a centrifuge tube at -20°C for later use.
  • the solution was diluted with pre-cooled PBS to an absorbance of 0.3-0.35, and 10% volume fraction of butyrylcholinesterase inhibitor OMPA was added to the solution.
  • the experimental operation is as follows: (1) Take a 96-well plate, add 10 ⁇ L of cerebral cortex homogenate, 50 ⁇ L of phosphate buffer (0.1M), and 50 ⁇ L of chromogenic agent 5,5’-dithiobis(2 -nitrobenzoic acid) (DTNB), 109 ⁇ L of deionized water, 30 ⁇ L of the choline substrate thioacetylcholine (S-Ach) at a concentration of 2 mM, and 1 ⁇ L of the compound to be tested (concentration gradient from 1 nM to 10 mM). (2) After reacting at room temperature for 20 minutes, 50 ⁇ L of 3% SDS was added to terminate the reaction.
  • DTNB chromogenic agent 5,5’-dithiobis(2 -nitrobenzoic acid)
  • thioacetylcholine will be decomposed into Thiocholine (Thiocholine) under the action of AChE in the cortex, and then quickly react with the chromogenic agent DTNB to generate a yellow substance 5-mercapto-2-nitrobenzene with a maximum absorption wavelength of 412nm Formate.
  • DTX 880 Beckman Coulter
  • Table 1 The inhibitory activity data of compound of the present invention to acetylcholinesterase
  • This effect example shows the activity inhibition experiment and activity results of the compound of the present invention on serotonin transporter (SERT).
  • SERT serotonin transporter
  • the compound with this activity can increase the concentration of serotonin in the brain by inhibiting the reuptake of serotonin in the brain, and can be used for treating depression or improving AD.
  • human embryonic kidney cells HEK293 were used to express the human 5-HT transporter, and the commercially available kit Neurotransmitter Transporter Uptake Assay Kit (Molecular Devices, Cat. No. R8173) was used for testing.
  • the kit uses fluorescent substrates to simulate monoamine neurotransmitters such as 5-HT, and enters cells through specific transporters such as serotonin transporters, resulting in an increase in the fluorescence intensity of cells.
  • the specific experimental methods are as follows: (1) Cell plating: Thaw the cells and culture them for 3-4 days. After passage, cells were cultured for another 3 days in the cell culture incubator. Cells were collected by centrifugation at 1000 rpm for five minutes after digestion with trypsin-EDTA. Resuspend cells in 10 mL medium. Pipette cells to prevent adhesion. cell counts. Dilute the cells with medium to 1 million cells/mL, plant 20,000 cells per well, and incubate at 37°C/5% CO 2 for 16–20 hours. (2) Transport experiment: configure 20mM HEPES HBSS solution containing 0.1% BSA as diluent and working solution. Positive compounds were serially diluted 4 times to 10 concentrations, with the highest concentration being 2 ⁇ M.
  • the compounds of the present invention have potent serotonin transporter inhibitory activity, wherein the inhibitory activity of some preferred compounds is lower than 10nM (better than positive control citalopram hydrobromide), illustrating the present invention
  • the compounds can be developed into serotonin transporter inhibitors antidepressants or anti-AD drugs. Since the compound of the present invention has the inhibitory activity of acetylcholinesterase and five serotonin transporter, it is a kind of multi-target drug which is expected to treat AD-depression co-morbidity.
  • This effect example shows the agonistic activity test and activity results of the compound of the present invention on 5-HT 1A receptors.
  • the human 5-HT 1A receptor was overexpressed using HEK293 cells.
  • the culture medium is DMEM medium containing 50 mg/mL G418 and 10% FBS, cultured under the condition of 5% CO 2 /37°C. When the cells grow to 70%, digest the cells, resuspend the cells with buffer after centrifugation, and incubate in a 384-well plate for 16-20 hours.
  • Table 3 Agonistic activity data of compounds of the present invention on 5-HT 1A
  • comparative compound A comes from "Design Synthesis and Activity Research of Multi-target Anti-AD Active Compounds and Research on Synthesis Methodology of 3-aryl-3-oxindolinone", Li Xiaokang, East China University of Science and Technology, 2018.
  • the EC50 of most compounds of the present invention to the 5-HT 1A receptor is more than several hundred nanomoles, which is more than a hundred times different from the positive control, and compared with the AChE/SERT activity of the compound itself. The difference is quite large, indicating that the compound of the present invention basically eliminates the agonistic activity of 5-HT 1A and avoids memory damage that may be caused by 5-HT 1A receptor stimulation.
  • Effect Example 4 This effect example shows the inhibitory experiment and activity results of the compound of the present invention on the activity of acetylcholinesterase in mouse brain.
  • the compound with acetylcholinesterase inhibitory activity can inhibit the hydrolysis of acetylcholine in the brain, thereby increasing the concentration of acetylcholine in the brain, promoting memory cognition, and can be used to improve symptoms and treat AD.
  • the AChE inhibition experiment in the mouse brain is a fast and efficient experiment, which is used to evaluate the inhibitory activity of the test compound on the activity of AChE in the animal brain, and can also reflect the brain-penetrating ability of the compound.
  • the experimental animals were ICR mice, male, weighing about 17–21 g. Weigh a certain amount of compound and dissolve it in PEG400, vortex to dissolve it, then add HS-15 and mix evenly to form a transparent and clear solution. It was orally administered at a dose of 0.3 mg/kg-30 mg/kg, and the solvent control group was given the corresponding solvent control. After administration, the appearance and state of the mice were observed to judge whether there were peripheral cholinergic side effects such as salivation, sweating, and convulsions.
  • mice were killed by denecking at the sampling point (0.5-24 hours), and the brain was quickly taken out, and the hemibrain was diluted into a homogenate with pre-cooled phosphate buffer solution, and the butyrylcholinesterase inhibitor OMPA was added, and then Add thioacetylcholine (S-Ach) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTBN) and react at room temperature for 20 minutes. No brain homogenate was added to blank wells. After the experiment, SDS was added to each well to terminate the reaction, and an appropriate amount of enzyme was added to the blank well.
  • S-Ach thioacetylcholine
  • DTBN 5,5'-dithiobis(2-nitrobenzoic acid)
  • the inhibitory rate of the compound to AChE was calculated by detecting the absorbance of each well.
  • the calculated inhibition rate and the corresponding concentration were nonlinearly fitted to calculate the IC 50 value of the compound against AChE in the mouse brain.
  • the values in Table 4 are the activity of acetylcholinesterase in the mouse brain 1 hour and 6 hours after administration.
  • the solvent control group (control group) is the 20% PEG400 solution that does not contain compound, is set as 100%, and all the other groups are percentage values (Mean ⁇ SD) compared with the solvent control group, *P ⁇ 0.05 (with the solvent control group group), **P ⁇ 0.01 (compared with solvent control group).
  • Table 5 Effect of 1 mg/kg preferred compound Ib - 7 on the activity of acetylcholinesterase in the ICR mouse brain
  • the values in Table 5 are the activity of acetylcholinesterase in the mouse brain after administration for 0.5-24 hours.
  • the solvent control group is deionized water, which is set as 100%, and all the other groups are percentage values (Mean ⁇ SD) compared with the solvent control group, *P ⁇ 0.05 (compared with the solvent control group), **P ⁇ 0.01 (compared with the solvent control group).
  • the AChE activity in the data in Table 4 has a value higher than 100% because of the low AChE activity in the hippocampus of a mouse in the control group, which belongs to individual differences. , but it does not affect the experimental conclusion.
  • Compound Ib -7 can significantly inhibit the activity of AChE in the mouse brain endocortex and hippocampus at a dose of 5 mg/kg orally, and the inhibitory activity is dose-dependent and time-dependent .
  • the inhibitory activity is dose-dependent and time-dependent .
  • the AChE activities in the hippocampus and cortex were inhibited to 23.0% and 27.8%, respectively.
  • Ib - 7 can reduce the AChE activity in the mouse brain endocortex to 49.49% at a dose of 1 mg/kg orally, and has no peripheral cholinergic side effects.
  • the values in Table 6 are the activity of acetylcholinesterase in the mouse brain 24 hours after administration.
  • the solvent control group (control group) is the 20% PEG400 solution that does not contain compound, is set as 100%, and all the other groups are percentage values (Mean ⁇ SD) compared with the solvent control group, *P ⁇ 0.05 (with the solvent control group group), **P ⁇ 0.01 (compared with solvent control group), ***P ⁇ 0.005 (compared with solvent control group).
  • compound Ib - 4 can significantly inhibit the activity of AChE in the mouse brain endocortex and hippocampus at an oral dose of 1 mg/kg, and the inhibitory activity is dose-dependent. After oral administration of 10 mg/kg Ib -4 for 24 hours, it inhibited the AChE activity in the hippocampus and cortex of the mouse brain to 36.87% and 34.00%, respectively.
  • the tail-suspension test is a classic, fast and convenient test for evaluating the efficacy of antidepressants, and it belongs to the behavioral hopelessness model.
  • the experimental principle is to carry out short-term and inescapable acute stress on mice by tail suspension, so that the mice enter a static state of giving up resistance, so as to establish a mouse depression model.
  • Forced swimming is also a classic model of behavioral desperation. Mice try to escape but cannot escape, so they give up struggling and enter a unique state of depression and immobility. During the experiment, the immobility time of animals is recorded to reflect the state of depression.
  • Antidepressant drugs have the effect of reversing this static state and promoting related behaviors such as escaping in mice, so they can reduce the immobility time of mice, and the antidepressant effect of drugs can be effectively evaluated by measuring the immobility time of mice. effect.
  • compounds Ib -7 and Ib -4 with strong dual-target inhibitory activities of AChE and serotonin transporter were selected for experiments. The experiment adopts the tail suspension test method reported by Steru et al., or the forced swimming method, and evaluates the antidepressant efficacy of the compound by examining whether the administration of the test compound can significantly shorten the immobility time of the tail suspension mice.
  • mice with an average body weight of 20-25 g and 5-6 weeks old were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd. They were fed with free access to water and pre-acclimated to the environment for one week. Before the experiment, number the tails of the mice and group them into groups of 10, and weigh them. The experiment was divided into solvent control group, positive drug vilazodone group and test compound group. On the day of the experiment, the test drug solution was prepared. First, the test compound was dissolved in PEG400, and then 20% HS-15 physiological saline solution was added to form a clear and uniform solution. The final liquid composition is 25% PEG400+15% HS+60% saline.
  • the solvent control group was given 0.9% physiological saline, and the positive drug and test compound group were prepared with the above method and administered orally. According to the order of mouse numbering, the two mice were given medicine at an interval of 8 minutes, and then returned to the original cage, and the tail suspension test was carried out 1 hour later.
  • the tail suspension test was carried out 1 hour later.
  • the experiment video was recorded for 6 minutes. After the completion, the mice were removed, put into the original cage, and the tail suspension box was wiped with alcohol to remove the animal smell.
  • the experimental animals were placed in a glass cylinder filled with water, and the water temperature was controlled at about 25°C (up and down not exceeding 1°C), and the liquid level was adjusted according to the size of the experimental animals, generally about 18cm.
  • Experimental video 6 Minutes change the water to start the next group after completing one group each time, so as to avoid the influence of mouse smell on the experiment.
  • the experiment adopts a double-blind system, that is, the operator who administers the drug and performs the tail suspension test and the statistician of the immobility time need to be different personnel and do not know each other.
  • the statistician counts the immobility time of the mouse in the last 4 minutes of the 6-minute video recording, and can divide the mouse's motor behavior (the subjective and obvious escape behavior) into (1) the action of running forward or backward; 2) The body twists, trying to grab the suspension; (3) The body shakes, swings, and twitches. After the recording was completed, the average immobility time of mice in each group was statistically plotted.
  • the compound I b -7 with strong dual-target inhibitory activity of AChE and serotonin transporter was selected for antidepressant efficacy experiment.
  • the experiment set up solvent control group normal saline, 10mL/kg
  • vilazodone multiple administration group (15mg/kg, once a day, continuous administration for 5 days
  • vilazodone Single administration group (30mg/kg, administration once)
  • Ib -7 multi-administration group (3mg/kg, once a day, continuous administration for 5 days) carried out mouse tail suspension behavior experiment, by mice
  • the degree of reduction of immobility time reflects the antidepressant efficacy of the compound, and the experimental results are shown in FIG. 2 .
  • **P ⁇ 0.01 compared with solvent control group).
  • the preferred compound Ib - 7 can significantly reduce the immobility time of tail-suspension mice at a dose of 3 mg/kg orally for 5 consecutive days, indicating that it has antidepressant effects and is expected to be used for the treatment of depression .
  • the experiment set solvent control group normal saline
  • vilazodone multiple administration group 10mg/kg, once a day, continuous administration for 7 days
  • Ib -7 multiple administration group Drug group (0.1mg/kg, once a day, continuously administered for 7 days), I b -7 multiple administration group (0.3mg/kg, once a day, continuously administered for 7 days) and I b -7 repeatedly administered
  • the drug group 1.0 mg/kg, once a day, administered continuously for 7 days
  • the experimental results are shown in Figure 3.
  • the preferred compound Ib - 7 can significantly reduce the immobility time of forced swimming mice under the dose of 0.1-1.0mg/kg orally administered for 7 consecutive days, indicating that it has antidepressant effects and is expected to be used in Treat depression.
  • the scopolamine-induced cognitive impairment animal model is a classic pharmacological model commonly used to evaluate drug candidates against Alzheimer's disease.
  • As an M-choline receptor blocker scopolamine has similar affinity with various subtypes of M-receptors, can hinder the combination of acetylcholine and M-receptors in the brain, and mainly acts on the acquisition stage of memory, thereby affecting the transmission of information. It can lead to impairment of learning and memory functions, which can be used as one of the classic methods for modeling Alzheimer's disease. Studies have proved that a single administration of scopolamine can be used as a model of learning and memory impairment, which can cause functional changes, and the damage of this model is reversible.
  • a model was established by administering 1 mg/kg scopolamine, and 22-25 g C57 mice were used as experimental subjects to receive the test compound once to observe whether the animals could improve the memory impairment caused by scopolamine.
  • the target compound was dissolved with 20% PEG400 to prepare a clear oral reagent, the dosage was 0.1-5 mg/kg, and donepezil hydrochloride 10 mg/kg was used as a positive control group.
  • 1 mg/kg scopolamine was injected intraperitoneally 30 minutes after compound administration, and the behavior of the test mice was observed by Y maze/water maze experiment 30 minutes later.
  • compound I b -7 which has strong dual-target inhibitory activity of AChE and serotonin transporter, was selected for cognitive impairment model experiments.
  • compound Ib - 4 with strong activity was selected for pharmacokinetic properties and blood-brain distribution ratio experiments.
  • oral administration of compound I b -4 (10 mg/kg) or intravenous injection of compound I b -4 (2 mg/kg) to ICR mice plasma and brain tissue were collected at different time points, and the ICR mice were detected The concentration of the test substance in plasma and brain tissue, and calculate the relevant parameters.
  • the experimental results are shown in Table 7 and Table 8. As shown in Table 7, the oral bioavailability of compound Ib -4 was 35.83. It can be seen from Table 8 that the plasma drug concentration of compound Ib - 4 reached a peak rapidly after oral administration, and continued to decline slowly after 0.5 hours.
  • the concentration of compound Ib -4 in the brain first increased gradually, reached the peak at 16-24 hours, and then decreased slowly and was gradually excreted by metabolism.
  • the brain-to-blood ratio of Compound Ib -4 was greater than 1, indicating that Compound Ib -4 has a good ability to penetrate the blood-brain barrier.
  • the oral plasma metabolic half-life of compound Ib -4 is 23.97 hours longer, so once-a-day administration can be considered.

Abstract

Disclosed are an AChE/SERT dual-target inhibitor, a preparation method therefor and the use thereof, and specifically disclosed are a compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing, or a solvate of any one of the foregoing. The compound has both an acetylcholinesterase inhibitory activity and a serotonin transporter inhibitory activity, has a good in-vitro and in-vivo blood-brain barrier permeability, and is used for treating Alzheimer's disease, depression, and the comorbidity between Alzheimer's disease and depression, thereby avoiding harmful drug interactions caused by combined administration, and reducing the administration difficulty and physical burden of patients.

Description

AChE/SERT双靶点抑制剂及其制备方法和用途AChE/SERT dual-target inhibitor and its preparation method and use
本申请要求申请日为2021/12/24的中国专利申请202111602500.9的优先权。本申请要求申请日为2021/12/24的中国专利申请PCT/CN2021/141314的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of the Chinese patent application 202111602500.9 with the filing date of 2021/12/24. This application claims the priority of Chinese patent application PCT/CN2021/141314 with a filing date of 2021/12/24. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明涉及药物化学和药物治疗学领域，具体涉及一类新型AChE/SERT双靶点抑制剂及其制备方法、含此类化合物的药物组合物及作为乙酰胆碱酯酶抑制剂和五羟色胺转运体抑制剂，特别是制备用于预防和/或治疗阿尔茨海默病、抑郁症、阿尔茨海默病和抑郁症共患病的药物的用途。The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a novel AChE/SERT dual-target inhibitor, a preparation method thereof, a pharmaceutical composition containing this type of compound, and as an acetylcholinesterase inhibitor and a serotonin transporter inhibitor , especially the preparation of medicines for preventing and/or treating Alzheimer's disease, depression, Alzheimer's disease and depression comorbidities.
背景技术Background technique
阿尔茨海默病(Alzheimer's disease，AD)，俗称老年痴呆、痴呆症，是一种进行性发展的致死的神经退行性疾病，临床表现为记忆功能障碍、失语、失用、失认、视空间技能损害、执行功能障碍以及人格和行为改变等全面性痴呆表现，并伴有抑郁、易怒和焦虑等精神症状。据临床资料显示，90％的AD患者会伴有神经精神症状，其中抑郁是最常见的共患病之一，约占AD患者的50％，是普通人群发病率的10倍，且区别于普通抑郁症，AD-抑郁共患病的患者更难治愈，死亡率更高。与此同时，抑郁症患者也常伴随记忆认知障碍，约三分之二的抑郁患者会伴随认知损伤，94％的抑郁患者康复后认知障碍仍然存在，抑郁被认为是AD的前驱症状或风险因素。目前，全球共有3500万AD患者，2亿6400万抑郁患者，因此AD-抑郁共患病的潜在患病人数庞大，研发相关治疗药物具有广阔的市场前景和重要的社会价值。Alzheimer's disease (AD), commonly known as senile dementia, dementia, is a progressive and fatal neurodegenerative disease, clinically manifested as memory dysfunction, aphasia, apraxia, agnosia, visuospatial Generalized dementia manifests as impaired skills, executive dysfunction, and changes in personality and behavior, with psychiatric symptoms such as depression, irritability, and anxiety. According to clinical data, 90% of AD patients will be accompanied by neuropsychiatric symptoms, among which depression is one of the most common comorbidities, accounting for about 50% of AD patients, which is 10 times the incidence rate of the general population, and is different from the general population. Patients with depression, AD-depression co-morbidity are more difficult to treat and have higher mortality. At the same time, depression patients are often accompanied by memory and cognitive impairment. About two-thirds of depressed patients will be accompanied by cognitive impairment. 94% of depressed patients still have cognitive impairment after recovery. Depression is considered to be a prodromal symptom of AD. or risk factors. At present, there are 35 million AD patients and 264 million depression patients in the world. Therefore, the potential number of patients with AD-depression co-morbidity is huge, and the development of related therapeutic drugs has broad market prospects and important social value.
目前对AD-抑郁共患病的发病机制尚不明确，尚无针对性的治疗方法。现有方法为同时使用抗AD药物和抗抑郁药物进行联合给药。但值得注意的是，这样的联合用药疗效往往不佳，无法达到单药治单病的疗效，且由于患者主要为老年群体，伴随较高的药物-药物相互作用的风险。目前，临床上尚无针对性改善/治疗AD-抑郁共患病的药物。乙酰胆碱酯酶抑制剂类(acetylcholinesterase inhibitors，AChEIs)是最主要的抗AD药物，包括美国Warner-Lambert公司研发的他克林(Tacrine，后续由于肝毒性问题撤市)、日本卫材制药(Eisai)研发的多奈哌齐(Donepezil)、诺华研发的利斯的明(Rivastigmine)，强生公司研发的加兰他敏(Galanthamine)、中国科学院上海药物所研发的石杉碱甲。其中多奈哌齐是 一种可逆的乙酰胆碱酯酶抑制剂，通过抑制乙酰胆碱酯酶对乙酰胆碱的水解提高突触间隙内乙酰胆碱的浓度。同时，多奈哌齐还是选择性的乙酰胆碱酯酶抑制剂，毒副作用小，是目前治疗轻至中度阿尔茨海默病的首选药物。抗抑郁治疗药物主要为选择性五羟色胺重摄取抑制剂类(selective serotonin reuptake inhibitors，SSRIs)，通过抑制五羟色胺转运蛋白(serotonin transporter,SERT)，选择性地抑制五羟色胺(serotonin，5-HT)的重摄取，提高抑郁患者脑内神经突触间隙内5-HT的浓度。例如抗重度抑郁症药物维拉佐酮(Vilazodone)，其同时具有选择性5-HT重摄取抑制活性和5-HT 1A激动活性。因此，针对AD和抑郁症的已有成熟靶点，开发同时提高脑内乙酰胆碱和五羟色胺水平的药物可有望治疗AD-抑郁共患病。 At present, the pathogenesis of AD-depression co-morbidity is still unclear, and there is no targeted treatment. The existing method is to use anti-AD drugs and antidepressants for combined administration. However, it is worth noting that the curative effect of such combination drugs is often poor, and it cannot achieve the effect of single drug in treating a single disease, and because the patients are mainly elderly, it is accompanied by a higher risk of drug-drug interactions. Currently, there is no targeted improvement/treatment of AD-depression co-morbidity clinically. Acetylcholinesterase inhibitors (AChEIs) are the most important anti-AD drugs, including Tacrine developed by Warner-Lambert in the United States (later withdrawn due to liver toxicity), Japan's Eisai Pharmaceuticals (Eisai) Donepezil developed by Novartis, Rivastigmine developed by Novartis, Galanthamine developed by Johnson & Johnson, and Huperzine A developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Among them, donepezil is a reversible acetylcholinesterase inhibitor, which increases the concentration of acetylcholine in the synaptic cleft by inhibiting the hydrolysis of acetylcholine by acetylcholinesterase. At the same time, donepezil is also a selective acetylcholinesterase inhibitor with less toxic and side effects, and is currently the drug of choice for the treatment of mild to moderate Alzheimer's disease. Antidepressant drugs are mainly selective serotonin reuptake inhibitors (SSRIs), which selectively inhibit the reuptake of serotonin (5-HT) by inhibiting the serotonin transporter (SERT). , Increase the concentration of 5-HT in the synaptic gap in the brain of depressed patients. For example, Vilazodone, an anti-major depressive drug, has both selective 5-HT reuptake inhibitory activity and 5-HT 1A agonistic activity. Therefore, for the mature targets of AD and depression, the development of drugs that simultaneously increase the levels of acetylcholine and serotonin in the brain may be expected to treat AD-depression co-morbidity.
先前华东理工大学李晓康博士的毕业论文中曾公开过一类AChE/SERT/5-HT 1A三靶点活性小分子，用于治疗AD-抑郁共患病，但经大量文献调研发现其中的5-HT 1A激动活性可能加重AD患者的记忆障碍。5-HT 1A受体通过影响大脑皮层和海马投射区谷氨酸能、胆碱能和GABA能神经元的活性，影响记忆功能。研究显示，人类受试者服用5-HT 1A受体激动剂Ipsapirone或5-HT 1A受体部分激动剂Tandospirone后，其语言记忆能力受损。此外，许多研究表明，5-HT 1A受体拮抗剂具有增强胆碱能传递，改善认知功能的作用，如NAD-299、WAY-100635以及Lecozotan(SRA-333)SR，这些拮抗剂在认知功能障碍的动物模型中被证明可以改善记忆。如惠氏公司开发的Lecozotan可显著提高老年恒河猴的任务完成效率、逆转谷氨酸拮抗剂导致的狨猴记忆缺陷，并于2005年进入临床II期用于治疗轻至中度AD患者。因此，先前报道的AChE/SERT/5-HT 1A三靶点活性小分子中，5-HT 1A激动活性可能发挥不利于疾病治疗的作用，亟需开发一种更有利于治疗AD-抑郁共患病的AChE/SERT双靶点抑制剂。 Previously, Dr. Li Xiaokang of East China University of Science and Technology disclosed a class of AChE/SERT/5-HT 1A three-target active small molecules for the treatment of AD-depression co-morbidity, but found that 5- HT 1A agonistic activity may aggravate memory impairment in AD patients. 5-HT 1A receptors affect memory function by affecting the activity of glutamatergic, cholinergic and GABAergic neurons in the cerebral cortex and hippocampal projection areas. Studies have shown that human subjects who take the 5-HT 1A receptor agonist Ipsapirone or the 5-HT 1A receptor partial agonist Tandospirone have impaired verbal memory. In addition, many studies have shown that 5-HT 1A receptor antagonists can enhance cholinergic transmission and improve cognitive function, such as NAD-299, WAY-100635 and Lecozotan (SRA-333) SR. It has been shown to improve memory in animal models of cognitive impairment. For example, Lecozotan developed by Wyeth can significantly improve the task completion efficiency of aged rhesus monkeys and reverse the memory deficits in marmoset monkeys caused by glutamate antagonists, and entered clinical phase II in 2005 for the treatment of mild to moderate AD patients. Therefore, among the AChE/SERT/5-HT 1A triple-target active small molecules reported previously, 5-HT 1A agonistic activity may play a role that is not conducive to disease treatment, and it is urgent to develop a more beneficial treatment for AD-depression co-morbidity. AChE/SERT dual-target inhibitor of the disease.
AD-抑郁共患病病理机制复杂，市场需求庞大，治疗药物面临空白，研发有效治疗药物具有重要的社会价值和医学价值，不仅可以满足巨大的市场需求，而且可避免共患病患者联合用药后产生的药物-药物相互作用，降低患者的服药难度和身体负担。The pathological mechanism of AD-depression co-morbidity is complex, the market demand is huge, and the treatment drug is facing a gap. The development of effective treatment drug has important social value and medical value. The resulting drug-drug interaction reduces the difficulty of taking medicine and the physical burden of patients.
发明内容Contents of the invention
本发明的目的在于提供一种结构新颖的乙酰胆碱酯酶(AChE)/5-羟色胺转运体(SERT)双靶点抑制剂。The object of the present invention is to provide a dual-target inhibitor of acetylcholinesterase (AChE)/serotonin transporter (SERT) with novel structure.
本发明是通过下述技术方案来解决上述技术问题：The present invention solves the above technical problems through the following technical solutions:
本发明提供了如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者(指前述如式I所示的化合物、其互变异构体或其立体异构体)的药学上可接受的盐，或 前述任一者(指前述如式I所示的化合物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物；The present invention provides the compound shown in formula I, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I, its tautomer or its stereo isomer), or any of the foregoing (referring to the pharmaceutically acceptable salt of the foregoing compound as shown in formula I, its tautomer, its stereoisomer, or any of the foregoing The solvate of the salt of );
Figure PCTCN2022141611-appb-000001
Figure PCTCN2022141611-appb-000001
各
Figure PCTCN2022141611-appb-000002
独立地为双键或单键； each
Figure PCTCN2022141611-appb-000002
are independently double bonds or single bonds;
各R 1独立地为CN、卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或被1、2或3个卤素取代的C 1-C 6烷氧基； Each R 1 is independently CN, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or C 1 -C 6 alkoxy substituted by 3 halogens;
m1为0、1、2、3或4；m1 is 0, 1, 2, 3 or 4;
R 2为H、C 1-C 6烷基或被1、2或3个卤素取代的C 1-C 6烷基； R 2 is H, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens;
各R 3独立地为卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或被1、2或3个卤素取代的C 1-C 6烷氧基； Each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens or substituted by 1, 2 or 3 Halogen substituted C 1 -C 6 alkoxy;
m2为0、1、2、3或4；m2 is 0, 1, 2, 3 or 4;
R 4为C 6-C 10芳基、被1、2或3个卤素取代的C 6-C 10芳基、苄基、被1、2或3个卤素取代的苄基、环戊烷、被1、2或3个卤素取代的环戊烷、环己烷、被1、2或3个卤素取代的环己烷、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”、被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”或被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”； R 4 is C 6 -C 10 aryl, C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, benzyl, benzyl substituted by 1, 2 or 3 halogens, cyclopentane, substituted by 1, 2 or 3 halogen substituted cyclopentane, cyclohexane, 1, 2 or 3 halogen substituted cyclohexane, "heteroatoms selected from 1, 2 or 3 of N, O and S species, 5-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", "heteroatoms substituted by 1, 2 or 3 halogens are selected from one or two of N, O and S or 3 kinds, 5-12 membered heterocycloalkyl groups with 1, 2 or 3 heteroatoms", "heteroatoms are selected from 1, 2 or 3 kinds of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heteroaryls" or "heteroatoms substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, the number of heteroatoms 1, 2 or 3 5-12 membered heteroaryl";
R 5为H、卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或被1、2或3个卤素取代的C 1-C 6烷氧基；或者，R5与*标记的碳相连形成-(CH 2) n2-；n2为0或1； R 5 is H, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or 3 halogens Substituted C 1 -C 6 alkoxy; or, R5 is connected to the carbon marked with * to form -(CH 2 ) n2 -; n2 is 0 or 1;
n为1、2、3、4、5或6；n is 1, 2, 3, 4, 5 or 6;
n1为0、1、2或3。n1 is 0, 1, 2 or 3.
在本发明某些优选实施方案中，所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者(指前述如式I所示的化合物、其互变异构体或其立体异构体)的药学上可接受的盐，或前述任一者(指前述如式I所示的化合物、其互变异构体、其立体 异构体或前述任一者的药学上可接受的盐)的溶剂化物中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”)，In some preferred embodiments of the present invention, the compound shown in formula I, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or Certain groups in the solvate of any of the aforementioned pharmaceutically acceptable salts) are defined as follows, and the unmentioned groups are as described in any scheme of the present invention (referred to as "in a certain scheme of the present invention") ,
R 1中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F、Cl、Br或I，例如F。 In R 1 , among the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, The halogen is independently F, Cl, Br or I, such as F.
在本发明某一方案中，R 1中，所述被1、2或3个卤素取代的C 1-C 6烷基和所述C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。 In a certain aspect of the present invention, in R 1 , among the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkyl, the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
在本发明某一方案中，R 1中，所述被1、2或3个卤素取代的C 1-C 6烷基为三氟甲基。 In a certain aspect of the present invention, in R 1 , the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens is trifluoromethyl.
在本发明某一方案中，R 1中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。 In a certain aspect of the present invention, in R 1 , in the C 1 -C 6 alkoxy group and the C 1 -C 6 alkoxy group substituted by 1, 2 or 3 halogens, the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
在本发明某一方案中，R 2中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。 In a certain aspect of the present invention, in R 2 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
在本发明某一方案中，R 2中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述卤素独立地为F、Cl、Br或I，例如F。 In a certain aspect of the present invention, in R 2 , in the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the halogens are independently F, Cl, Br or I, such as F.
在本发明某一方案中，R 3中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F、Cl、Br或I，例如F。 In a certain aspect of the present invention, in R 3 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 substituted by 1, 2 or 3 halogens In -C 6 alkoxy, the halogen is independently F, Cl, Br or I, such as F.
在本发明某一方案中，R 3中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。 In a certain aspect of the present invention, in R 3 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
在本发明某一方案中，R 3中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。 In a certain scheme of the present invention, in R 3 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
在本发明某一方案中，R 4中，所述C 6-C 10芳基和所述被1、2或3个卤素取代的C 6-C 10芳基中，所述C 6-C 10芳基为苯基或萘基，例如苯基。 In a certain aspect of the present invention, in R 4 , in the C 6 -C 10 aryl group and the C 6 -C 10 aryl group substituted by 1, 2 or 3 halogens, in the C 6 -C 10 aryl group Aryl is phenyl or naphthyl, eg phenyl.
在本发明某一方案中，R 4中，所述被1、2或3个卤素取代的C 6-C 10芳基、所述被1、2或3个卤素取代的苄基、所述被1、2或3个卤素取代的环戊烷、所述被1、2或3个卤素取代的环己烷、所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”和所述被1、2或3个卤素取代 的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”中，所述卤素独立地为F、Cl、Br或I，例如F。 In a certain scheme of the present invention, in R 4 , said C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, said benzyl substituted by 1, 2 or 3 halogens, said substituted by 1, 2 or 3 halogen substituted cyclopentane, said 1, 2 or 3 halogen substituted cyclohexane, said 1, 2 or 3 halogen substituted "heteroatoms selected from N, O and 1, 2 or 3 of S, 5-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms" and the "heteroatoms substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, 5-12 membered heteroaryl with 1, 2 or 3 heteroatoms", the halogen is independently F, Cl, Br or I , such as F.
在本发明某一方案中，R 4中，所述被1、2或3个卤素取代的C 6-C 10芳基为被1、2或3个F取代的苯基，例如
Figure PCTCN2022141611-appb-000003
In a certain scheme of the present invention, in R 4 , the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens is phenyl substituted by 1, 2 or 3 Fs, for example
Figure PCTCN2022141611-appb-000003
在本发明某一方案中，R 4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”和所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”独立地为“杂原子选自N、O和S中的1种或2种，杂原子数为1或2个的5-6元杂环烷基”。 In a certain scheme of the present invention, in R 4 , the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered Heterocycloalkyl" and the "heteroatom" substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 In 5-12 membered heterocycloalkyl", said "heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3. "Cycloalkyl" is independently "a 5-6 membered heterocycloalkyl group with 1 or 2 heteroatoms selected from one or two of N, O and S".
在本发明某一方案中，R 4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”和所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”独立地为“杂原子选自N、O和S中的1种或2种，杂原子数为1或2个的5-6元杂芳基”。 In a certain scheme of the present invention, in R 4 , the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered Heteroaryl" and the "heteroatoms substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, 5 with 1, 2 or 3 heteroatoms -12-membered heteroaryl", said "heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12-membered heteroaryl "independently means "a 5-6 membered heteroaryl group with 1 or 2 heteroatoms selected from one or two of N, O and S".
在本发明某一方案中，R 5中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F、Cl、Br或I，例如F。 In a certain aspect of the present invention, in R 5 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 substituted by 1, 2 or 3 halogens In -C 6 alkoxy, the halogen is independently F, Cl, Br or I, such as F.
在本发明某一方案中，R 5中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。 In a certain aspect of the present invention, in R 5 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
在本发明某一方案中，R 5中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。 In a certain scheme of the present invention, in R 5 , in the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
在本发明某一方案中，R 1独立地为CN、卤素或被1、2或3个卤素取代的C 1-C 6烷基；优选为F、CF 3或CN，进一步优选为F或CN。 In a certain aspect of the present invention, R 1 is independently CN, halogen or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens; preferably F, CF 3 or CN, more preferably F or CN .
在本发明某一方案中，m1为1。In a certain aspect of the present invention, m1 is 1.
在本发明某一方案中，R 2为H或C 1-C 6烷基，优选H或甲基，进一步优选为H。 In a certain aspect of the present invention, R 2 is H or C 1 -C 6 alkyl, preferably H or methyl, more preferably H.
在本发明某一方案中，
Figure PCTCN2022141611-appb-000004
为
Figure PCTCN2022141611-appb-000005
Figure PCTCN2022141611-appb-000006
优选为
Figure PCTCN2022141611-appb-000007
Figure PCTCN2022141611-appb-000008
In a certain scheme of the present invention,
Figure PCTCN2022141611-appb-000004
for
Figure PCTCN2022141611-appb-000005
Figure PCTCN2022141611-appb-000006
preferably
Figure PCTCN2022141611-appb-000007
Figure PCTCN2022141611-appb-000008
在本发明某一方案中，R 3为卤素，例如F。 In a certain aspect of the present invention, R 3 is halogen, such as F.
在本发明某一方案中，m2为0或1。In a certain aspect of the present invention, m2 is 0 or 1.
在本发明某一方案中，R 4为C 6-C 10芳基或被1、2或3个卤素取代的C 6-C 10芳基，优选为苯基、
Figure PCTCN2022141611-appb-000009
进一步优选为苯基或
Figure PCTCN2022141611-appb-000010
In a certain aspect of the present invention, R 4 is C 6 -C 10 aryl or C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, preferably phenyl,
Figure PCTCN2022141611-appb-000009
More preferably phenyl or
Figure PCTCN2022141611-appb-000010
在本发明某一方案中，R 5为H；或者，R 5与*标记的碳相连形成-CH 2-。 In a certain aspect of the present invention, R 5 is H; or, R 5 is connected with a carbon marked with * to form -CH 2 -.
在本发明某一方案中，n1为0。In a certain aspect of the present invention, n1 is 0.
在本发明某一方案中，n为1、2、3或4。In a certain aspect of the present invention, n is 1, 2, 3 or 4.
在本发明某一方案中，所述如式I所示的化合物具有如式I-A或I-B所示的结构：In a certain scheme of the present invention, the compound shown in formula I has a structure shown in formula I-A or I-B:
Figure PCTCN2022141611-appb-000011
Figure PCTCN2022141611-appb-000011
Figure PCTCN2022141611-appb-000012
Figure PCTCN2022141611-appb-000012
其中，n、m1、m2、R 1、R 2、R 3和R 4的定义如本发明任一项所述。 Wherein, the definitions of n, m1, m2, R 1 , R 2 , R 3 and R 4 are as described in any one of the present invention.
在本发明某一方案中，所述如式I所示的化合物为如下任一化合物：In a certain scheme of the present invention, the compound shown in formula I is any one of the following compounds:
Figure PCTCN2022141611-appb-000013
Figure PCTCN2022141611-appb-000013
Figure PCTCN2022141611-appb-000014
Figure PCTCN2022141611-appb-000014
Figure PCTCN2022141611-appb-000015
Figure PCTCN2022141611-appb-000015
本发明还提供了一种如式I所示的化合物的制备方法，其为如下方法一或方法二：The present invention also provides a preparation method of the compound shown in formula I, which is the following method 1 or method 2:
所述方法一包括如下步骤：Described method one comprises the steps:
溶剂中，在缚酸剂的作用下，如式II所示的化合物和如式III所示的化合物进行取代反应，得如式I所示的化合物；In a solvent, under the action of an acid-binding agent, the compound shown in formula II and the compound shown in formula III undergo a substitution reaction to obtain a compound shown in formula I;
Figure PCTCN2022141611-appb-000016
Figure PCTCN2022141611-appb-000016
X为卤素；X is a halogen;
所述方法二包括如下步骤：Described method two comprises the following steps:
在氰基硼氢化钠作用下，如式II所示的化合物和如式IV所示的化合物进行还原胺化反应，得如式I所示的化合物；Under the action of sodium cyanoborohydride, the compound shown in formula II and the compound shown in formula IV undergo reductive amination reaction to obtain the compound shown in formula I;
Figure PCTCN2022141611-appb-000017
Figure PCTCN2022141611-appb-000017
n3＝n-1(即0、1、2、3、4或5)；n3=n-1 ( ie 0, 1, 2, 3, 4 or 5);
*、
Figure PCTCN2022141611-appb-000018
n、n1、m1、m2、R 1、R 2、R 3、R 4和R 5的定义如本发明任一项所述。 *,
Figure PCTCN2022141611-appb-000018
The definitions of n, n1, m1, m2, R 1 , R 2 , R 3 , R 4 and R 5 are as described in any one of the present invention.
本发明还提供了如式II所示的化合物：The present invention also provides compounds as shown in formula II:
Figure PCTCN2022141611-appb-000019
Figure PCTCN2022141611-appb-000019
其中，*、
Figure PCTCN2022141611-appb-000020
n1、m2、R 3、R 4和R 5的定义如本发明任一项所述。 in,*,
Figure PCTCN2022141611-appb-000020
The definitions of n1, m2, R 3 , R 4 and R 5 are as described in any one of the present invention.
在本发明某一方案中，所述如式II所示的化合物为如下任一化合物：In a certain scheme of the present invention, the compound shown in formula II is any one of the following compounds:
Figure PCTCN2022141611-appb-000021
Figure PCTCN2022141611-appb-000021
Figure PCTCN2022141611-appb-000022
Figure PCTCN2022141611-appb-000022
本发明还提供了一种药物组合物，其包括：The present invention also provides a pharmaceutical composition comprising:
(1)如本发明任一项所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者(指前述如式I所示的化合物、其互变异构体或其立体异构体)的药学上可接受的盐，或前述任一者(指前述如式I所示的化合物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物；和(1) The compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or the foregoing A solvate of a pharmaceutically acceptable salt of either); and
(2)药学上可接受的载体。(2) A pharmaceutically acceptable carrier.
所述药物组合物中，所述如本发明任一项所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者(指前述如式I所示的化合物、其互变异构体或其立体异构体)的药学上可接受的盐，或前述任一者(指前述如式I所示的化合物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物为活性成分，其含量为安全有效量。“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。In the pharmaceutical composition, the compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned formula I The pharmaceutically acceptable salt of the shown compound, its tautomer or its stereoisomer), or any of the foregoing (referring to the aforementioned compound shown in formula I, its tautomer, its Stereoisomers or pharmaceutically acceptable salts of any of the foregoing) solvates are active ingredients, and the content thereof is a safe and effective amount. "Safe and effective amount" means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose. Preferably, the "one dose" is a tablet.
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)等。The administration method of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and the like.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨 醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
本发明化合物可以单独给药，或者与其他治疗药物联合给药。The compounds of the present invention may be administered alone or in combination with other therapeutic agents.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1-2000mg，优选20-500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
本发明还提供了如本发明任一项所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者(指前述如式I所示的化合物、其互变异构体或其立体异构体)的药学上可接受的盐，或前述任一者(指前述如式I所示的化合物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物、或所述药物组合物的用途，选自：The present invention also provides the compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I , its tautomer or its stereoisomer), or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or a pharmaceutically acceptable salt of any of the foregoing), or the use of the pharmaceutical composition, selected from:
(i)用于制备乙酰胆碱酯酶抑制剂；(i) for the preparation of acetylcholinesterase inhibitors;
(ii)用于制备五羟色胺转运体抑制剂；(ii) for the preparation of serotonin transporter inhibitors;
(iii)用于制备乙酰胆碱酯酶和五羟色胺转运体双重抑制剂；(iii) for the preparation of dual inhibitors of acetylcholinesterase and serotonin transporter;
(iv)用于制备治疗阿尔茨海默病的药物；(iv) for the preparation of drugs for the treatment of Alzheimer's disease;
(v)用于制备治疗抑郁症的药物；(v) for the preparation of medicines for the treatment of depression;
(vi)用于制备治疗阿尔茨海默病和抑郁症的共患病的药物。(vi) For the preparation of a medicament for the treatment of comorbidities of Alzheimer's disease and depression.
本发明还提供了一种预防和/或治疗疾病的方法，其包括：向有需要的对象施用治疗有效量的如本发明任一项所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者(指前述如式I所示的化合物、其互变异构体或其立体异构体)的药学上可接受的盐，或前述任一者(指前述如式I所示的化合物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物、或所述药物组合物，所述疾病选自：The present invention also provides a method for preventing and/or treating diseases, which comprises: administering a therapeutically effective amount of a compound represented by formula I as described in any one of the present invention, or its tautomorphism, to a subject in need isomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the solvate of the aforementioned compound shown in formula I, its tautomer, its stereoisomer or any of the aforementioned pharmaceutically acceptable salts), or the pharmaceutical composition, the Disease selected from:
(i)阿尔茨海默病；(i) Alzheimer's disease;
(ii)抑郁症；(ii) depression;
(iii)阿尔茨海默病和抑郁症的共患病。(iii) Co-morbidities of Alzheimer's disease and depression.
如无特别说明，本发明所用术语具有如下含义：Unless otherwise specified, terms used in the present invention have the following meanings:
本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中所使用的
Figure PCTCN2022141611-appb-000023
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。 Those skilled in the art can understand that, according to the practice used in this field, the present invention describes the structural formula used in the group
Figure PCTCN2022141611-appb-000023
means that the corresponding group is connected with other fragments and groups in the compound through this site.
本文中，所用的取代基前面可以加单破折号“-”，表明被命名取代基与母体部分之间通过单键相连。As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond.
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。The term "pharmaceutically acceptable" means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid, arginine) and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
术语“溶剂化物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂化物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。The term "solvate" refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric solvent. Solvent molecules in solvates can exist in an ordered or non-ordered arrangement. The solvent includes but not limited to: water, methanol, ethanol and the like.
术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
当任意变量(例如卤素)在化合物的定义中多次出现时，该变量每一位置出现的定义与其余位置出现的定义无关，它们的含义互相独立、互不影响。因此，若某基团被1个、 2个或3个卤素取代，也就是说，该基团可能会被最多3个卤素取代，该位置卤素的定义与其余位置卤素的定义是互相独立的。另外，取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。When any variable (such as halogen) appears multiple times in the definition of a compound, the definition at each position of the variable has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 halogens, that is to say, the group may be substituted by up to 3 halogens, the definition of halogen at this position is independent of the definition of halogen at other positions. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
术语“烷氧基”是指基团-O-R X，其中，R X为如上文所定义的烷基。 The term "alkoxy" refers to the group -ORx , wherein Rx is alkyl as defined above.
术语“杂环烷基”是指具有指定环原子数(例如5-12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的1种、2种或3种)的环状基团，其为单环、桥环或螺环，且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基和哌啶基等。The term "heterocycloalkyl" refers to a group having a specified number of ring atoms (eg, 5-12 members), a specified number of heteroatoms (eg, 1, 2, or 3), a specified type of heteroatom (N, O, and S 1, 2 or 3) of the cyclic group, which is a monocyclic, bridged or spiro ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
术语“芳基”是指C 6-C 10芳基，例如苯基或萘基。 The term "aryl" refers to a C 6 -C 10 aryl group such as phenyl or naphthyl.
术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族环状基团，其为单环或双环，当为双环时，至少有一个环具有芳香性，例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、***基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基等。The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic ring groups independently selected from nitrogen, oxygen and sulfur, which are monocyclic or bicyclic, when When bicyclic, at least one ring is aromatic, such as furyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzene Azoxazolyl, benzisoxazolyl, quinolinyl, isoquinolyl, etc.
术语“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)。The term "pharmaceutically acceptable carrier" refers to the excipients and additives used in the production of medicines and the formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except the active ingredient. Can refer to Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009Sixth Edition).
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treatment" refers to therapeutic therapy. In relation to a specific condition, treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。The term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient. A "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实 例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。The term "patient" refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
在所述的用途中，所述乙酰胆碱酯酶抑制剂、所述五羟色胺转运体抑制剂或所述乙酰胆碱酯酶和五羟色胺转运体双重抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为乙酰胆碱酯酶和/或五羟色胺转运体的抑制效果提供快速检测。In the use, the acetylcholinesterase inhibitor, the serotonin transporter inhibitor or the dual inhibitor of acetylcholinesterase and serotonin transporter can be used in mammalian organisms; it can also be used in vitro, mainly as Experimental purposes, for example: providing comparison as a standard or control sample, or making a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of acetylcholinesterase and/or serotonin transporter.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明的发明人经过广泛而深入地研究，研发出一种如式I所示的化合物，同时具有乙酰胆碱酯酶抑制活和五羟色胺转运体抑制活性，具有良好的体外和体内血脑屏障通透性，用于治疗阿尔茨海默病、抑郁症、阿尔茨海默病和抑郁症共患病，避免联合用药产生的有害的药物相互作用、降低患者的服药难度和身体负担。The positive progress effect of the present invention is that: the inventors of the present invention have developed a compound as shown in formula I after extensive and in-depth research, which has both acetylcholinesterase inhibitory activity and serotonin transporter inhibitory activity, and has good in vitro And blood-brain barrier permeability in vivo, used for the treatment of Alzheimer's disease, depression, Alzheimer's disease and depression comorbidities, avoiding harmful drug interactions caused by combined drugs, reducing the difficulty of taking drugs and Physical burden.
附图说明Description of drawings
图1示出化合物I b-7对小鼠脑内乙酰胆碱酯酶AChE的活性影响。 Figure 1 shows the effect of compound Ib - 7 on the activity of acetylcholinesterase AChE in mouse brain.
图2示出化合物I b-7对悬尾抑郁模型小鼠的抗抑郁药效实验结果。 Figure 2 shows the experimental results of the antidepressant effect of compound Ib - 7 on tail suspension depression model mice.
图3示出化合物I b-7对强迫游泳模型小鼠的抗抑郁药效实验结果。 Figure 3 shows the results of the antidepressant effect of compound Ib - 7 on forced swimming model mice.
图4示出化合物I b-4对悬尾抑郁模型小鼠的抗抑郁药效实验结果。 Figure 4 shows the experimental results of the antidepressant effect of compound Ib - 4 on tail suspension depression model mice.
图5示出化合物I b-7对认知损伤模型小鼠的药效实验结果。 Fig. 5 shows the experimental results of the drug effect of compound Ib - 7 on cognitive impairment model mice.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.
实施例1 3-(4-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)丁基)-1H-吲哚-5-甲腈(I a–1)的制备 Example 1 3-(4-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)butyl)-1H-indole - Preparation of 5-carbonitrile (I a -1)
Figure PCTCN2022141611-appb-000024
Figure PCTCN2022141611-appb-000024
步骤a (E)-3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-2-烯-1-酮的合成Step a Synthesis of (E)-3-(1-benzylpiperidin-4-yl)-1-(4-bromophenyl)prop-2-en-1-one
Figure PCTCN2022141611-appb-000025
Figure PCTCN2022141611-appb-000025
-78℃下，在N 2保护的双口烧瓶中加入无水THF(250mL)后加入LDA(2M的THF溶液)(60mmol)，搅拌片刻，用恒压漏斗滴加4-溴苯乙酮(10g,50mmol)的无水THF溶液(100mL)，滴加完毕后搅拌0.5h，用恒压漏斗缓慢滴加1-苄基-4-哌啶甲醛(10.2g,50mmol)的无水THF溶液(100mL)，继续搅拌1～2h，恢复至室温。向反应液中加入NH 4Cl饱和溶液淬灭反应，减压蒸除THF，残留物用二氯甲烷萃取(200mL×3)，合并有机相用饱和NaCl溶液洗后，无水Na 2SO 4干燥，蒸干后的粗品经柱层析纯化，乙酸乙酯:石油醚＝1:8洗脱，得到白色固体10g，为(E)-3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-2-烯-1-酮，收率51.8％。 1H NMR(400MHz,CDCl 3)δ7.78(d,J＝9.7,2.9Hz,2H),7.60(d,J＝8.6Hz,2H),7.42–7.31(m,J＝7.1,4.6Hz,5H),7.03(dd,J＝15.5,6.7Hz,1H),6.81(dd,J＝15.5,1.1Hz,1H),3.57(s,2H),2.97(d,J＝10.1Hz,2H),2.27(s,1H),2.18–2.03(m,2H),1.86–1.75(m,2H),1.70–1.57(m,2H). At -78°C, add anhydrous THF (250mL) to a N2- protected two-necked flask, then add LDA (2M THF solution) (60mmol), stir for a while, and then add 4-bromoacetophenone ( 10g, 50mmol) of anhydrous THF solution (100mL), stirred for 0.5h after the dropwise addition, and slowly added dropwise 1-benzyl-4-piperidinecarbaldehyde (10.2g, 50mmol) of anhydrous THF solution ( 100mL), continue stirring for 1-2h, and return to room temperature. Add saturated NH 4 Cl solution to the reaction liquid to quench the reaction, evaporate THF under reduced pressure, extract the residue with dichloromethane (200 mL×3), combine the organic phases, wash with saturated NaCl solution, and dry over anhydrous Na 2 SO 4 , the crude product after evaporation to dryness was purified by column chromatography, and ethyl acetate:petroleum ether=1:8 was eluted to obtain 10 g of white solid, which was (E)-3-(1-benzylpiperidin-4-yl)- 1-(4-bromophenyl)prop-2-en-1-one, yield 51.8%. 1 H NMR (400MHz, CDCl 3 ) δ7.78(d, J=9.7, 2.9Hz, 2H), 7.60(d, J=8.6Hz, 2H), 7.42–7.31(m, J=7.1, 4.6Hz, 5H), 7.03(dd, J=15.5, 6.7Hz, 1H), 6.81(dd, J=15.5, 1.1Hz, 1H), 3.57(s, 2H), 2.97(d, J=10.1Hz, 2H), 2.27(s,1H),2.18–2.03(m,2H),1.86–1.75(m,2H),1.70–1.57(m,2H).
步骤b 叔丁基-(E)-4-(4-(3-(1-苄基哌啶-4-基)丙烯酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成Step b Tert-butyl-(E)-4-(4-(3-(1-benzylpiperidin-4-yl)acryloyl)phenyl)-3,6-dihydropyridine-1(2H)- Synthesis of Carboxylate
Figure PCTCN2022141611-appb-000026
Figure PCTCN2022141611-appb-000026
将(E)-3-(1-苄基哌啶-4-基)-1-(4-溴苯)丙-2-烯-1-酮(10g，25mmol)和N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(9.4g，30mmol)溶于无水四氢呋喃(250mL)中，加入Pd(dppf)Cl 2催化剂(1g，0.025mmol)、K 2CO 3(10g，1.5mmol)，水泵脱气2分钟，氮气保护下加热至80℃反应过夜。反应结束后趁热过滤除去无机物，减压蒸除溶剂，残留物用乙酸乙酯(80mL)打浆1小时后过滤，将滤饼用水(80mL)洗一遍，二氯甲烷(80mL)萃取有机相三遍，合并有机相用饱和NaCl溶液洗后，无水Na 2SO 4干燥，过滤掉Na 2SO 4，旋蒸除去溶剂得白色固体10g，为叔丁基-(E)-4-(4-(3-(1-苄基哌啶-4-基)丙烯酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸酯，收率79.5％。 1H NMR(400MHz,CDCl 3)δ7.78(d,J＝9.7,2.9Hz,2H),7.60(d,J＝8.6Hz,2H),7.42–7.31(m,J＝7.1,4.6Hz,5H),7.03(dd,J＝15.5,6.7Hz,1H),6.81(dd,J＝15.5,1.1Hz,1H),3.57(s,2H),2.97(d,J＝10.1Hz,2H),2.27(s,1H),2.18–2.03(m,2H),1.86–1.75(m,2H),1.70–1.57(m,2H). (E)-3-(1-benzylpiperidin-4-yl)-1-(4-bromophenyl)prop-2-en-1-one (10g, 25mmol) and N-Boc-1,2 , 5,6-tetrahydropyridine-4-boronic acid pinacol ester (9.4 g, 30 mmol) was dissolved in anhydrous THF (250 mL), and Pd(dppf)Cl 2 catalyst (1 g, 0.025 mmol), K 2 CO 3 (10g, 1.5mmol), degassed with a water pump for 2 minutes, and heated to 80°C under nitrogen protection to react overnight. After the reaction was completed, filter while hot to remove inorganic matter, evaporate the solvent under reduced pressure, and filter the residue with ethyl acetate (80 mL) for 1 hour, wash the filter cake with water (80 mL), and extract the organic phase with dichloromethane (80 mL) Three times, the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , filtered off Na 2 SO 4 , and the solvent was removed by rotary evaporation to obtain 10 g of a white solid, which was tert-butyl-(E)-4-(4 -(3-(1-benzylpiperidin-4-yl)acryloyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate, yield 79.5%. 1 H NMR (400MHz, CDCl 3 ) δ7.78(d, J=9.7, 2.9Hz, 2H), 7.60(d, J=8.6Hz, 2H), 7.42–7.31(m, J=7.1, 4.6Hz, 5H), 7.03(dd, J=15.5, 6.7Hz, 1H), 6.81(dd, J=15.5, 1.1Hz, 1H), 3.57(s, 2H), 2.97(d, J=10.1Hz, 2H), 2.27(s,1H),2.18–2.03(m,2H),1.86–1.75(m,2H),1.70–1.57(m,2H).
步骤c 叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-羧酸酯的合成Step c Synthesis of tert-butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidine-1-carboxylate
Figure PCTCN2022141611-appb-000027
Figure PCTCN2022141611-appb-000027
将700mg叔丁基-(E)-4-(4-(3-(1-苄基哌啶-4-基)丙烯酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸酯溶于10mL甲醇中，加入10％wt的10％Pd/C(含水55％)70mg，搅拌下置换氢气3～4次，剧烈搅拌，室温反应过夜。待反应完毕后，垫硅藻土过滤Pd/C，旋干滤液。粗产品直接投下一步，未纯化，得透明油状物330mg，为叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-羧酸酯，收率66％。700mg of tert-butyl-(E)-4-(4-(3-(1-benzylpiperidin-4-yl)acryloyl)phenyl)-3,6-dihydropyridine-1(2H)- The carboxylate was dissolved in 10 mL of methanol, 70 mg of 10% wt of 10% Pd/C (55% water) was added, the hydrogen was replaced 3 to 4 times under stirring, vigorously stirred, and reacted overnight at room temperature. After the reaction is complete, filter the Pd/C with a pad of diatomaceous earth, and spin the filtrate to dryness. The crude product was directly sent to the next step without purification, and 330 mg of transparent oily substance was obtained, which was tert-butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidine-1 -Carboxylate, yield 66%.
步骤d 3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮的合成Step d Synthesis of 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one
Figure PCTCN2022141611-appb-000028
Figure PCTCN2022141611-appb-000028
将500mg叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-羧酸酯溶于10mL二氯甲烷中，搅拌下滴加3mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入20mL饱和碳酸氢钠溶液洗涤有机相，分离有机相，将水相用二氯甲烷萃取3～4遍(20mL)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤后将滤液旋干，粗产品经柱层析纯化，洗脱剂为甲醇:二氯甲烷＝1:10，得无色油状物200mg，为3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮，收率50％。 1H NMR(400MHz,CD 3OD)δ7.97(d,J＝8.4Hz,1H),7.46(d,J＝7.6Hz,2H),7.41(d,J＝8.3Hz,1H),4.13(s,1H),3.51(d,J＝12.7Hz,1H),3.36(s,1H),3.33(s,1H),3.15(td,J＝12.8,2.8Hz,1H),3.07(t,J＝7.3Hz,1H),3.00(tt,J＝12.1,3.6Hz,1H),2.79(t,J＝11.7Hz,1H),2.08(d,J＝13.9Hz,1H),2.00–1.86(m,J＝23.4,12.8Hz,2H),1.69(dd,J＝14.1,7.1Hz,1H),1.60(s,1H),1.43(dd,J＝23.3,11.6Hz,1H). Dissolve 500mg tert-butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidine-1-carboxylate in 10mL dichloromethane, stir Add 3 mL of trifluoroacetic acid dropwise, and stir at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 20 mL of saturated sodium bicarbonate solution was added to wash the organic phase, the organic phase was separated, and the aqueous phase was extracted with dichloromethane for 3 ~4 times (20mL), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried the filtrate, the crude product was purified by column chromatography, the eluent was methanol:dichloromethane=1:10 , 200mg of colorless oil was obtained, which was 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one, yield 50% . 1 H NMR (400MHz, CD 3 OD) δ7.97(d, J=8.4Hz, 1H), 7.46(d, J=7.6Hz, 2H), 7.41(d, J=8.3Hz, 1H), 4.13( s,1H),3.51(d,J=12.7Hz,1H),3.36(s,1H),3.33(s,1H),3.15(td,J=12.8,2.8Hz,1H),3.07(t,J ＝7.3Hz, 1H), 3.00(tt, J＝12.1, 3.6Hz, 1H), 2.79(t, J＝11.7Hz, 1H), 2.08(d, J＝13.9Hz, 1H), 2.00–1.86(m ,J=23.4,12.8Hz,2H),1.69(dd,J=14.1,7.1Hz,1H),1.60(s,1H),1.43(dd,J=23.3,11.6Hz,1H).
步骤e 3-(4-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)丁基)-1H-吲哚-5-甲腈(I a–1)的合成 Step e 3-(4-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)butyl)-1H-indole- Synthesis of 5-carbonitrile (I a -1)
Figure PCTCN2022141611-appb-000029
Figure PCTCN2022141611-appb-000029
将3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮(100mg，0.248mmol)和3-(4-氯丁基)-1H-吲哚-5-甲腈(69mg，0.298mmol)置于烧瓶中，乙腈(10mL)作溶剂，三乙胺(103μL，0.745mmol)作缚酸剂，碘化钾做催化剂，80℃回流反应过夜。待反应完成后蒸干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得I a–1 77mg，黄色固体，为3-(4-(4- (4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)丁基)-1H-吲哚-5-甲腈，收率53％。 1H NMR(600MHz,CD 3OD)δ8.02–7.99(s,1H),7.94(s,1H),7.93(s,1H),7.49–7.46(m,1H),7.40–7.33(m,8H),7.26(s,1H),3.79(s,2H),3.38–3.33(m,2H),3.09(d,J＝11.9Hz,2H),3.03(t,J＝7.5Hz,2H),2.89–2.78(m,5H),2.64(t,J＝11.7Hz,2H),2.36(t,J＝11.5Hz,2H),1.97(m,2H),1.90(m,2H),1.86–1.71(m,7H),1.65(q,J＝7.2Hz,2H),1.46(m,1H),1.39–1.34(m,1H).HRMS(ESI)m/z calcd for C 39H 47N 4O[M+H] +587.3750,found 587.3752. 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one (100mg, 0.248mmol) and 3-(4-chloro Butyl)-1H-indole-5-carbonitrile (69 mg, 0.298 mmol) was placed in a flask, acetonitrile (10 mL) was used as a solvent, triethylamine (103 μL, 0.745 mmol) was used as an acid-binding agent, potassium iodide was used as a catalyst, and 80 °C reflux reaction overnight. After the reaction was completed, the solvent was evaporated to dryness, and the crude product was purified by column chromatography (methanol:dichloromethane=1:20) to obtain 77 mg of Ia-1, a yellow solid, which was 3-(4-(4-(4-( 3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)butyl)-1H-indole-5-carbonitrile, yield 53%. 1 H NMR (600MHz, CD 3 OD) δ8.02–7.99(s,1H),7.94(s,1H),7.93(s,1H),7.49–7.46(m,1H),7.40–7.33(m, 8H),7.26(s,1H),3.79(s,2H),3.38–3.33(m,2H),3.09(d,J=11.9Hz,2H),3.03(t,J=7.5Hz,2H), 2.89–2.78(m,5H),2.64(t,J=11.7Hz,2H),2.36(t,J=11.5Hz,2H),1.97(m,2H),1.90(m,2H),1.86–1.71 (m,7H),1.65(q,J=7.2Hz,2H),1.46(m,1H),1.39–1.34(m,1H).HRMS(ESI)m/z calcd for C 39 H 47 N 4 O [M+H] + 587.3750, found 587.3752.
实施例2 3-(3-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)丙基)-1H-吲哚-5-甲腈(I a–2)的制备 Example 2 3-(3-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)propyl)-1H-indole - Preparation of 5-carbonitrile (I a -2)
Figure PCTCN2022141611-appb-000030
Figure PCTCN2022141611-appb-000030
将实施例1中步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(3-溴丙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例1，得产物I a–2，黄色固体，收率55％。 1H NMR(600MHz,CD 3OD)δ8.05(d,J＝0.8Hz,1H),7.95(s,1H),7.93(s,1H),7.48(d,J＝8.4Hz,1H),7.43–7.36(m,8H),7.30(s,1H),3.89(s,2H),3.41(d,J＝11.6Hz,2H),3.18(d,J＝15.1Hz,2H),3.04(t,J＝7.4Hz,2H),2.93–2.86(m,J＝13.7,6.4Hz,4H),2.86–2.80(m,1H),2.69(t,J＝11.3Hz,2H),2.49(s,2H),2.13–2.06(m,2H),1.99(d,J＝13.0Hz,2H),1.95–1.84(m,J＝27.2,18.8,8.9Hz,4H),1.66(dd,J＝14.5,7.2Hz,2H),1.51(s,1H),1.44–1.34(m,J＝24.2,7.9Hz,2H).HRMS(ESI)m/z calcd for C 38H 45N 4O[M+H] +573.3593,found 573.3592. 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e in Example 1 is replaced by 3-(3-bromopropyl)-1H-indole-5-carbonitrile, The rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 2, a yellow solid, with a yield of 55%. 1 H NMR (600MHz, CD 3 OD) δ8.05(d, J=0.8Hz, 1H), 7.95(s, 1H), 7.93(s, 1H), 7.48(d, J=8.4Hz, 1H), 7.43–7.36(m,8H),7.30(s,1H),3.89(s,2H),3.41(d,J=11.6Hz,2H),3.18(d,J=15.1Hz,2H),3.04(t ,J=7.4Hz,2H),2.93–2.86(m,J=13.7,6.4Hz,4H),2.86–2.80(m,1H),2.69(t,J=11.3Hz,2H),2.49(s, 2H),2.13–2.06(m,2H),1.99(d,J＝13.0Hz,2H),1.95–1.84(m,J＝27.2,18.8,8.9Hz,4H),1.66(dd,J＝14.5, 7.2Hz,2H),1.51(s,1H),1.44–1.34(m,J＝24.2,7.9Hz,2H).HRMS(ESI)m/z calcd for C 38 H 45 N 4 O[M+H] + 573.3593,found 573.3592.
实施例3 3-(2-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)乙基)-1H-吲哚-5-甲腈(I a–3)的制备 Example 3 3-(2-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)ethyl)-1H-indole - Preparation of 5-carbonitrile (I a -3)
Figure PCTCN2022141611-appb-000031
Figure PCTCN2022141611-appb-000031
将实施例1中步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(2-溴乙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例1，得产物I a–3，黄色固体，收率58％。 1H NMR(400MHz,DMSO-d 6)δ11.56(s,1H),8.22(s,1H),7.96(d,J＝8.0Hz,2H),7.56(d,J＝8.4Hz,1H),7.53–7.46(m,2H),7.45–7.34(m,7H),4.05(s,2H),3.64(s,2H),3.23–3.10(m,4H),3.08–2.83(m,6H),2.11–1.70(m,8H),1.57(q,J＝7.2,6.7Hz,2H),1.45(s,1H),1.36–1.21(m,3H).HRMS(ESI)m/z calcd for C 37H 43N 4O[M+H] +559.3437,found 559.3436. 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e in Example 1 is replaced by 3-(2-bromoethyl)-1H-indole-5-carbonitrile, The rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product I a -3, a yellow solid, with a yield of 58%. 1 H NMR (400MHz,DMSO-d 6 )δ11.56(s,1H),8.22(s,1H),7.96(d,J=8.0Hz,2H),7.56(d,J=8.4Hz,1H) ,7.53–7.46(m,2H),7.45–7.34(m,7H),4.05(s,2H),3.64(s,2H),3.23–3.10(m,4H),3.08–2.83(m,6H) ,2.11–1.70(m,8H),1.57(q,J＝7.2,6.7Hz,2H),1.45(s,1H),1.36–1.21(m,3H).HRMS(ESI)m/z calcd for C 37 H 43 N 4 O [M+H] + 559.3437, found 559.3436.
实施例4 3-(4-(4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基) 丁基)-1H吲哚-5-甲腈(I a–4)的制备 Example 4 3-(4-(4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl )Piperidin-1-yl)butyl)-1H indole-5-carbonitrile (Ia - 4) preparation
Figure PCTCN2022141611-appb-000032
Figure PCTCN2022141611-appb-000032
将实施例1中步骤a中的4-溴苯乙酮替换为5-溴茚酮，其余所需原料、试剂及制备方法同实施例1，得产物I a–4，黄色固体，收率52％。 1H NMR(400MHz,CD 3OD)δ8.02(d,J＝0.8Hz,1H),7.68–7.63(m,1H),7.52–7.43(m,J＝9.6,6.3,3.4Hz,7H),7.38(dd,J＝8.5,1.5Hz,1H),7.33(d,J＝8.1Hz,1H),7.28(s,J＝7.1Hz,1H),4.14(s,2H),3.57(d,J＝12.2Hz,2H),3.44–3.34(m,3H),3.16–3.06(m,2H),3.06–2.94(m,J＝12.2Hz,3H),2.92–2.75(m,6H),2.13–1.91(m,6H),1.89–1.78(m,6H),1.56–1.36(m,3H).HRMS(ESI)m/z calcd for C 40H 47N 4O[M+H] +599.3750,found 599.3751. The 4-bromoacetophenone in step a in Example 1 was replaced by 5-bromoindanone, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product Ia - 4, a yellow solid, with a yield of 52 %. 1 H NMR (400MHz, CD 3 OD) δ8.02 (d, J = 0.8Hz, 1H), 7.68–7.63 (m, 1H), 7.52–7.43 (m, J = 9.6, 6.3, 3.4Hz, 7H) ,7.38(dd,J=8.5,1.5Hz,1H),7.33(d,J=8.1Hz,1H),7.28(s,J=7.1Hz,1H),4.14(s,2H),3.57(d, J＝12.2Hz, 2H), 3.44–3.34(m, 3H), 3.16–3.06(m, 2H), 3.06–2.94(m, J＝12.2Hz, 3H), 2.92–2.75(m, 6H), 2.13 –1.91(m,6H),1.89–1.78(m,6H),1.56–1.36(m,3H).HRMS(ESI)m/z calcd for C 40 H 47 N 4 O[M+H] + 599.3750, found 599.3751.
实施例5 3-(3-(4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)丙基)-1H-吲哚-5-甲腈(I a–5)的制备 Example 5 3-(3-(4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl )Piperidin-1-yl)propyl)-1H-indole-5-carbonitrile ( Ia- 5)
Figure PCTCN2022141611-appb-000033
Figure PCTCN2022141611-appb-000033
将实施例1中步骤a中的4-溴苯乙酮替换为5-溴茚酮，将步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(3-溴丙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例1，得产物I a–5，黄色固体，收率50％。 1H NMR(400MHz,CD 3OD)δ8.05(d,J＝2.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.52–7.47(m,1H),7.46–7.37(m,7H),7.32(d,J＝7.7Hz,2H),3.97(s,2H),3.45(d,J＝12.2Hz,2H),3.42–3.36(m,1H),3.35(s,1H),3.23(s,1H),2.99–2.85(m,5H),2.85–2.69(m,4H),2.61(t,J＝11.6Hz,2H),2.17–2.06(m,2H),2.06–1.91(m,5H),1.90–1.72(m,3H),1.51–1.35(m,3H).HRMS(ESI)m/z calcd for C 39H 45N 4O[M+H] +585.3593,found 585.3594. The 4-bromoacetophenone in step a in Example 1 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-formonitrile in step e is replaced by 3 -(3-Bromopropyl)-1H-indole-5-carbonitrile, the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 5, a yellow solid, with a yield of 50%. 1 H NMR (400MHz, CD 3 OD) δ8.05 (d, J = 2.0Hz, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.52–7.47 (m, 1H), 7.46–7.37 (m ,7H),7.32(d,J=7.7Hz,2H),3.97(s,2H),3.45(d,J=12.2Hz,2H),3.42–3.36(m,1H),3.35(s,1H) ,3.23(s,1H),2.99–2.85(m,5H),2.85–2.69(m,4H),2.61(t,J＝11.6Hz,2H),2.17–2.06(m,2H),2.06–1.91 (m,5H),1.90–1.72(m,3H),1.51–1.35(m,3H).HRMS(ESI)m/z calcd for C 39 H 45 N 4 O[M+H] + 585.3593,found 585.3594 .
实施例6 3-(2-(4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)乙基)-1H-吲哚-5-甲腈(I a–6)的制备 Example 6 3-(2-(4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl )Piperidin-1-yl)ethyl)-1H-indole-5-carbonitrile (Ia - 6)
Figure PCTCN2022141611-appb-000034
Figure PCTCN2022141611-appb-000034
将实施例1中步骤a中的4-溴苯乙酮替换为5-溴茚酮，将步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(2-溴乙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同 实施例1，得产物I a–6，黄色固体，收率52％。 1H NMR(400MHz,CD 3OD)δ8.13(s,1H),7.69(d,J＝7.9Hz,1H),7.57–7.47(m,7H),7.45(dd,J＝8.5,1.4Hz,1H),7.42(d,J＝2.6Hz,1H),7.38(d,J＝8.0Hz,1H),4.18(s,2H),3.66(s,2H),3.53–3.39(m,3H),3.26(s,4H),3.07–2.76(m,7H),2.19–1.78(m,9H),1.55–1.44(m,J＝9.1Hz,2H).HRMS(ESI)m/z calcd for C 38H 43N 4O[M+H] +571.3437,found 571.3438. The 4-bromoacetophenone in step a in Example 1 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-formonitrile in step e is replaced by 3 -(2-Bromoethyl)-1H-indole-5-carbonitrile, the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 6, a yellow solid, with a yield of 52%. 1 H NMR (400MHz, CD 3 OD) δ8.13(s, 1H), 7.69(d, J=7.9Hz, 1H), 7.57–7.47(m, 7H), 7.45(dd, J=8.5, 1.4Hz ,1H),7.42(d,J=2.6Hz,1H),7.38(d,J=8.0Hz,1H),4.18(s,2H),3.66(s,2H),3.53–3.39(m,3H) ,3.26(s,4H),3.07–2.76(m,7H),2.19–1.78(m,9H),1.55–1.44(m,J＝9.1Hz,2H).HRMS(ESI)m/z calcd for C 38 H 43 N 4 O [M+H] + 571.3437, found 571.3438.
实施例7 3-((4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–1)的制备 Example 7 3-((4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)methyl)-1H-indole-5 - Preparation of formonitrile (I b -1)
Figure PCTCN2022141611-appb-000035
Figure PCTCN2022141611-appb-000035
中间体3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮(4-1)的制备方法同实施例1步骤a-d。The preparation method of intermediate 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one (4-1) is the same as in Example 1 Steps a-d.
将5-氰基吲哚-3-甲醛(51mg，0.298mmol)和3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮(100mg，0.248mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(31mg，0.497mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得81mg I b–1，白色固体，为3-((4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈。 1H NMR(400MHz,CD 3OD)δ8.21(s,1H),7.94(s,1H),7.92(s,1H),7.59(s,1H),7.56(d,J＝8.6Hz,1H),7.50–7.33(m,9H),4.17(s,2H),3.89(s,2H),3.16(s,2H),3.04(t,J＝7.4Hz,2H),2.73(d,J＝39.5Hz,3H),2.50(s,2H),1.95(s,2H),1.86(d,J＝13.3Hz,4H),1.73–1.61(m,2H),1.49(s,1H),1.43–1.30(m,3H).HRMS(ESI)m/z calcd for C 36H 41N 4O[M+H] +545.3280,found 545.3281. Mix 5-cyanindole-3-carbaldehyde (51mg, 0.298mmol) and 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propane -1-ketone (100mg, 0.248mmol) was placed in a flask, anhydrous methanol: anhydrous dichloromethane = 1:1 (v:v) was added to dissolve, then sodium cyanoborohydride (31mg, 0.497mmol) was added, React overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol: dichloromethane = 1:20), 81 mg I b -1 was obtained as a white solid, which was 3-((4-(4-(3-(1-benzylpiperidin-4-yl)propane acyl)phenyl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile. 1 H NMR (400MHz, CD 3 OD) δ8.21(s, 1H), 7.94(s, 1H), 7.92(s, 1H), 7.59(s, 1H), 7.56(d, J=8.6Hz, 1H ),7.50–7.33(m,9H),4.17(s,2H),3.89(s,2H),3.16(s,2H),3.04(t,J＝7.4Hz,2H),2.73(d,J＝ 39.5Hz, 3H), 2.50(s, 2H), 1.95(s, 2H), 1.86(d, J=13.3Hz, 4H), 1.73–1.61(m, 2H), 1.49(s, 1H), 1.43– 1.30(m,3H).HRMS(ESI)m/z calcd for C 36 H 41 N 4 O[M+H] + 545.3280,found 545.3281.
实施例8 3-((4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–2)的制备 Example 8 3-((4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piper Preparation of pyridin-1-yl)methyl)-1H-indole-5-carbonitrile (I b -2)
Figure PCTCN2022141611-appb-000036
Figure PCTCN2022141611-appb-000036
将步骤a中的4-溴苯乙酮替换为5-溴茚酮，经步骤a-d可得2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮。The 4-bromoacetophenone in step a is replaced by 5-bromoindanone, and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidine-4 -yl)-2,3-dihydro-1H-inden-1-one.
将3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮替换为2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，其余所需原料、试剂及制备方法同实施例7，得产物I b–2，白色固体，收率60％。 1H NMR(400MHz,CD 3OD)δ8.06(d,J＝0.8Hz,1H),7.50(d,J＝7.9Hz,1H),7.42(d,J＝8.5Hz,1H),7.36(s,1H),7.34–7.29(m,2H),7.24(d,J＝4.4Hz,4H),7.22–7.17(m,J＝6.3Hz,2H),3.77(s,2H),3.50(s,2H),3.07(d,J＝10.8Hz,2H),2.87(t,2H),2.72–2.52(m,4H),2.20(t,2H),2.03(t,2H),1.83–1.67(m,7H),1.63(d,J＝13.6Hz,1H),1.48(s,1H).HRMS(ESI)m/z calcd for C 37H 41N 4O[M+H] +557.3280,found 557.3279. Replace 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one with 2-((1-benzylpiperidin- 4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, the rest of the required raw materials, reagents and preparation methods are the same as in Example 7 to obtain the product I b -2, white solid, yield 60%. 1 H NMR (400MHz, CD 3 OD) δ8.06(d, J=0.8Hz, 1H), 7.50(d, J=7.9Hz, 1H), 7.42(d, J=8.5Hz, 1H), 7.36( s,1H),7.34–7.29(m,2H),7.24(d,J＝4.4Hz,4H),7.22–7.17(m,J＝6.3Hz,2H),3.77(s,2H),3.50(s ,2H),3.07(d,J＝10.8Hz,2H),2.87(t,2H),2.72–2.52(m,4H),2.20(t,2H),2.03(t,2H),1.83–1.67( m,7H),1.63(d,J＝13.6Hz,1H),1.48(s,1H).HRMS(ESI)m/z calcd for C 37 H 41 N 4 O[M+H] + 557.3280,found 557.3279 .
实施例9 3-((4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)哌啶-1-基)甲基)-1-甲基-1H-吲哚-5-甲腈(I b–3)的制备 Example 9 3-((4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H - Preparation of indole-5-carbonitrile (I b -3)
Figure PCTCN2022141611-appb-000037
Figure PCTCN2022141611-appb-000037
将步骤e中的5-氰基-吲哚-3-甲醛替换为3-甲酰基-1-甲基-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例7，得产物I b–3，透明油状物，收率59％。 1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.88(d,J＝8.0Hz,2H),7.44(d,J＝8.6Hz,1H),7.40–7.27(m,7H),7.25–7.19(m,1H),7.15(s,1H),3.80(s,3H),3.73(s,2H),3.50(s,2H),3.08(d,J＝10.4Hz,2H),3.00–2.81(m,4H),2.63–2.47(m,1H),2.20–2.07(m,2H),2.02–1.90(m,2H),1.88–1.76(m,4H),1.74–1.66(m,3H),1.39–1.30(m,4H).HRMS(ESI)m/z calcd for C 37H 43N 4O[M+H] +559.3437,found 559.3438. Replace the 5-cyano-indole-3-carbaldehyde in step e with 3-formyl-1-methyl-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in the examples 7. The product I b -3 was obtained as a transparent oily product with a yield of 59%. 1 H NMR (400MHz, CDCl 3 ) δ8.13(s, 1H), 7.88(d, J=8.0Hz, 2H), 7.44(d, J=8.6Hz, 1H), 7.40–7.27(m, 7H) ,7.25–7.19(m,1H),7.15(s,1H),3.80(s,3H),3.73(s,2H),3.50(s,2H),3.08(d,J=10.4Hz,2H), 3.00–2.81(m,4H),2.63–2.47(m,1H),2.20–2.07(m,2H),2.02–1.90(m,2H),1.88–1.76(m,4H),1.74–1.66(m ,3H),1.39–1.30(m,4H).HRMS(ESI)m/z calcd for C 37 H 43 N 4 O[M+H] + 559.3437,found 559.3438.
实施例10 3-((4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1-甲基-1H-吲哚-5-甲腈(I b–4)的制备 Example 10 3-((4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piper Preparation of pyridin-1-yl)methyl)-1-methyl-1H-indole-5-carbonitrile (I b -4)
Figure PCTCN2022141611-appb-000038
Figure PCTCN2022141611-appb-000038
将3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮替换为2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，将5-氰基-吲哚-3-甲醛替换为3-甲酰基-1-甲基- 1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例7，得产物I b–4，透明油状物，收率63％。 1H NMR(400MHz,CDCl 3)δ8.15(d,J＝1.6Hz,1H),7.66(d,J＝7.9Hz,1H),7.49–7.43(m,1H),7.39–7.28(m,7H),7.24–7.16(m,2H),3.81(s,3H),3.75(s,2H),3.56(s,2H),3.28(s,1H),3.10(d,J＝11.1Hz,2H),2.98–2.90(m,2H),2.78–2.64(m,2H),2.63–2.52(m,1H),2.19–2.10(m,2H),2.08–1.98(m,2H),1.91–1.79(m,5H),1.76–1.66(m,2H),1.58–1.48(m,1H),1.42–1.32(m,3H).HRMS(ESI)m/z calcd for C 38H 43N 4O[M+H] +571.3437,found 571.3438. Replace 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one with 2-((1-benzylpiperidin- 4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, replacing 5-cyano-indole-3-carbaldehyde with 3- Formyl-1-methyl-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 7 to obtain the product Ib -4, a transparent oil, with a yield of 63%. 1 H NMR (400MHz, CDCl 3 ) δ8.15(d, J=1.6Hz, 1H), 7.66(d, J=7.9Hz, 1H), 7.49–7.43(m, 1H), 7.39–7.28(m, 7H), 7.24–7.16(m, 2H), 3.81(s, 3H), 3.75(s, 2H), 3.56(s, 2H), 3.28(s, 1H), 3.10(d, J=11.1Hz, 2H ),2.98–2.90(m,2H),2.78–2.64(m,2H),2.63–2.52(m,1H),2.19–2.10(m,2H),2.08–1.98(m,2H),1.91–1.79 (m,5H),1.76–1.66(m,2H),1.58–1.48(m,1H),1.42–1.32(m,3H).HRMS(ESI)m/z calcd for C 38 H 43 N 4 O[ M+H] + 571.3437, found 571.3438.
实施例11 3-(4-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-基)丁基)-1H-吲哚-5-甲腈(I a–7)的制备 Example 11 3-(4-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridin-1(2H)-yl )Butyl)-1H-indole-5-formonitrile (Ia - 7) preparation
Figure PCTCN2022141611-appb-000039
Figure PCTCN2022141611-appb-000039
步骤a (E)-3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-2-烯-1-酮的合成Step a Synthesis of (E)-3-(1-benzylpiperidin-4-yl)-1-(4-bromophenyl)prop-2-en-1-one
Figure PCTCN2022141611-appb-000040
Figure PCTCN2022141611-appb-000040
具体操作同上述实施例1中步骤a，由4-溴苯乙酮和1-苄基-4-哌啶甲醛经Aldol缩合反应制备而得。The specific operation is the same as step a in the above-mentioned Example 1, and it is prepared by Aldol condensation reaction of 4-bromoacetophenone and 1-benzyl-4-piperidinecarbaldehyde.
3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-1-酮的合成Synthesis of 3-(1-benzylpiperidin-4-yl)-1-(4-bromophenyl)propan-1-one
Figure PCTCN2022141611-appb-000041
Figure PCTCN2022141611-appb-000041
冰浴下，将三氯硅烷配成25％(体积比)的无水二氯甲烷溶液，封住瓶口备用。Under an ice bath, the trichlorosilane was formulated into a 25% (volume ratio) anhydrous dichloromethane solution, and the bottle was sealed for later use.
冰浴下将(E)-3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-2-烯-1-酮(800mg，2.08mmol)溶于无水二氯甲烷(16mL)中，搅拌下依次加入HMPA(73μL，0.416mmol)和三氯硅烷的无水二氯甲烷溶液(420μL，4.16mmol)，冰浴搅拌1小时后室温搅拌至TLC显示原料反应完全。将反应液转移至大烧杯中，缓慢加入100mL碳酸氢钠饱和溶液和100mL乙酸乙酯搅拌1h，硅藻土过滤出去白色不溶物，得到滤液分液后，用乙酸乙酯(30mL)萃取水相三次，合并有机相，饱和NaCl溶液洗涤，无水Na 2SO 4干燥后，旋蒸除去溶剂，得到的粗品经柱层析纯化(乙酸乙酯:石油醚＝1:6)，得3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-1-酮，白色固体，收率69％。 1H NMR(400MHz,CDCl 3)δ7.81(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),7.44–7.30(m,J＝14.5,7.7Hz,5H),3.68(s,2H),3.16–2.88(m,J＝23.9,16.5Hz,4H),2.09(d,J＝29.7Hz,2H),1.87–1.66(m,J＝13.9,6.7Hz,5H),1.38(d,J＝36.9Hz,2H). Dissolve (E)-3-(1-benzylpiperidin-4-yl)-1-(4-bromophenyl)prop-2-en-1-one (800mg, 2.08mmol) in Add HMPA (73 μL, 0.416 mmol) and anhydrous dichloromethane solution (420 μL, 4.16 mmol) of trichlorosilane sequentially under stirring in water dichloromethane (16 mL), stir in an ice bath for 1 hour, then stir at room temperature until TLC shows the raw material The response is complete. Transfer the reaction solution to a large beaker, slowly add 100 mL of saturated sodium bicarbonate solution and 100 mL of ethyl acetate and stir for 1 h, filter out the white insoluble matter through diatomaceous earth, obtain the filtrate for liquid separation, and extract the aqueous phase with ethyl acetate (30 mL) Three times, the organic phases were combined, washed with saturated NaCl solution, and dried over anhydrous Na 2 SO 4 . 1-benzylpiperidin-4-yl)-1-(4-bromophenyl)propan-1-one, white solid, yield 69%. 1 H NMR (400MHz, CDCl 3 ) δ7.81 (d, J=8.6Hz, 2H), 7.60 (d, J=8.6Hz, 2H), 7.44–7.30 (m, J=14.5, 7.7Hz, 5H) ,3.68(s,2H),3.16–2.88(m,J＝23.9,16.5Hz,4H),2.09(d,J＝29.7Hz,2H),1.87–1.66(m,J＝13.9,6.7Hz,5H ), 1.38(d, J=36.9Hz, 2H).
步骤b：叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成Step b: tert-Butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Synthesis
Figure PCTCN2022141611-appb-000042
Figure PCTCN2022141611-appb-000042
将实施例1步骤b中的(E)-3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-2-烯-1-酮替换为3-(1-苄基哌啶-4-基)-1-(4-溴苯基)丙-1-酮，其余所需原料、试剂及制备方法同实施例1，得叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸酯，白色固体，收率54％。 1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.43–7.29(m,5H),6.28–6.07(m,1H),4.11(s,2H),3.94–3.57(m,4H),3.29–2.92(m,J＝44.0Hz,4H),2.54(s,2H),2.12(s,2H),1.92–1.59(m,7H),1.50(s,9H). (E)-3-(1-benzylpiperidin-4-yl)-1-(4-bromophenyl)prop-2-en-1-one in step b of Example 1 is replaced by 3-( 1-benzylpiperidin-4-yl)-1-(4-bromophenyl)propan-1-one, all the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain tert-butyl-4-(4 -(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate, white solid, yield 54%. 1 H NMR (400MHz, CDCl 3 ) δ7.91(d, J=8.4Hz, 2H), 7.45(d, J=8.4Hz, 2H), 7.43–7.29(m,5H), 6.28–6.07(m, 1H), 4.11(s, 2H), 3.94–3.57(m, 4H), 3.29–2.92(m, J＝44.0Hz, 4H), 2.54(s, 2H), 2.12(s, 2H), 1.92–1.59 (m,7H),1.50(s,9H).
步骤d：3-(1-苄基哌啶-4-基)-1-(4-(1,2,3,6-四氢吡啶-4-基)苯基)丙-1-酮的合成Step d: Synthesis of 3-(1-benzylpiperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one
Figure PCTCN2022141611-appb-000043
Figure PCTCN2022141611-appb-000043
将实施例1步骤d中的叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基苯基)哌啶-1-羧酸酯替换为叔丁基-4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-羧酸酯，其余所需原料、试剂及制备方法同实施例1，得3-(1-苄基哌啶-4-基)-1-(4-(1,2,3,6-四氢吡啶-4-基)苯基)丙-1-酮，透明油状物，收率73％。 1H NMR(400MHz,CD 3OD)δ7.98(d,J＝8.2Hz,2H),7.60(d,J＝8.4Hz,2H),7.46–7.34(m,5H),6.32(s,1H),3.88(s,2H),3.83(d,J＝3.0Hz,2H),3.43(t,J＝6.1Hz,2H),3.17(d,J＝12.2Hz,2H),3.06(t,J＝7.4Hz,2H),2.79(d,J＝1.9Hz,2H),2.48(t,J＝11.7Hz,2H),1.87(d,J＝13.6Hz,2H),1.68(dd,J＝14.3,7.1Hz,2H),1.52(t,J＝16.4Hz,1H),1.45–1.31(m,2H). Replace tert-butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionylphenyl)piperidine-1-carboxylate in step d of Example 1 with tert-butyl -4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate, other required raw materials, The reagent and preparation method are the same as in Example 1 to obtain 3-(1-benzylpiperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) Propan-1-one, transparent oil, yield 73% .1 H NMR (400MHz, CD 3 OD) δ7.98(d, J=8.2Hz, 2H), 7.60(d, J=8.4Hz, 2H) ,7.46–7.34(m,5H),6.32(s,1H),3.88(s,2H),3.83(d,J＝3.0Hz,2H),3.43(t,J＝6.1Hz,2H),3.17( d, J=12.2Hz, 2H), 3.06(t, J=7.4Hz, 2H), 2.79(d, J=1.9Hz, 2H), 2.48(t, J=11.7Hz, 2H), 1.87(d, J＝13.6Hz, 2H), 1.68(dd, J＝14.3, 7.1Hz, 2H), 1.52(t, J＝16.4Hz, 1H), 1.45–1.31(m, 2H).
步骤e：3-(4-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-基)丁基)-1H-吲哚-5-甲腈(I a–7)的合成 Step e: 3-(4-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridin-1(2H)-yl )Butyl)-1H-indole-5-carbonitrile (Ia - 7) synthesis
Figure PCTCN2022141611-appb-000044
Figure PCTCN2022141611-appb-000044
将实施例1步骤e中的3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙基-1-酮替换为3-(1-苄基哌啶-4-基)-1-(4-(1,2,3,6-四氢吡啶-4-基)苯基)丙-1-酮，其余所需原料、试剂及制备方法同实施例1，得I a–7，为3-(4-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-基)丁基)-1H-吲哚-5-甲腈，黄色固体，收率56％。 1H NMR(600MHz,CD 3OD)δ 7.99(d,J＝0.8Hz,1H),7.94(d,J＝8.5Hz,2H),7.55(d,J＝8.5Hz,2H),7.46(d,J＝8.4Hz,1H),7.38–7.35(m,J＝5.4,2.9Hz,5H),7.34–7.30(m,1H),7.23(s,1H),6.30–6.27(m,1H),3.71(s,2H),3.27(s,2H),3.04(t,J＝7.5Hz,4H),2.86–2.81(m,J＝7.1Hz,4H),2.67–2.59(m,4H),2.26(s,2H),1.84–1.75(m,J＝14.7,9.4Hz,4H),1.73–1.63(m,4H),1.42(s,1H),1.37–1.32(m,2H).HRMS(ESI)m/z calcd for C 39H 45N 4O[M+H] +585.3593,found 585.3592. 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propyl-1-ketone in step e of Example 1 is replaced by 3-( 1-benzylpiperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one, other required raw materials, reagents and The preparation method is the same as in Example 1 to obtain Ia - 7, which is 3-(4-(4-(4-(3-(1-benzylpiperidin-4-yl) propionyl) phenyl)-3,6 -Dihydropyridin-1(2H)-yl)butyl)-1H-indole-5-carbonitrile, yellow solid, yield 56%. 1 H NMR (600MHz, CD 3 OD) δ 7.99(d, J=0.8Hz, 1H), 7.94(d, J=8.5Hz, 2H), 7.55(d, J=8.5Hz, 2H), 7.46(d ,J=8.4Hz,1H),7.38–7.35(m,J=5.4,2.9Hz,5H),7.34–7.30(m,1H),7.23(s,1H),6.30–6.27(m,1H), 3.71(s,2H),3.27(s,2H),3.04(t,J=7.5Hz,4H),2.86–2.81(m,J=7.1Hz,4H),2.67–2.59(m,4H),2.26 (s,2H),1.84–1.75(m,J＝14.7,9.4Hz,4H),1.73–1.63(m,4H),1.42(s,1H),1.37–1.32(m,2H).HRMS(ESI )m/z calcd for C 39 H 45 N 4 O[M+H] + 585.3593,found 585.3592.
实施例12 3-(3-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-基)丙基)-1H-吲哚-5-甲腈(I a–8)的制备 Example 12 3-(3-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridin-1(2H)-yl ) Propyl)-1H-indole-5-formonitrile (Ia - 8) preparation
Figure PCTCN2022141611-appb-000045
Figure PCTCN2022141611-appb-000045
将实施例11步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(3-溴丙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例11，得产物I a–8，黄色固体，收率54％。 1H NMR(400MHz,CD 3OD)δ8.01(d,J＝1.6Hz,1H),7.96–7.89(m,2H),7.56–7.51(m,2H),7.46(d,J＝8.4Hz,1H),7.36(dd,J＝8.5,1.6Hz,1H),7.31(d,J＝4.3Hz,4H),7.29–7.24(m,2H),6.31–6.26(m,1H),3.51(d,J＝2.1Hz,2H),3.20(q,J＝3.0Hz,2H),3.06–2.97(m,1H),2.90(dd,J＝12.1,3.4Hz,2H),2.82(t,J＝7.4Hz,2H),2.75(t,J＝5.7Hz,2H),2.64–2.53(m,4H),2.06–1.93(m,5H),1.79–1.68(m,3H),1.62(q,J＝7.0Hz,3H),1.38–1.33(m,1H).HRMS(ESI)m/z calcd for C 38H 43N 4O[M+H] +571.3437,found 571.3436. The 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e of Example 11 was replaced by 3-(3-bromopropyl)-1H-indole-5-carbonitrile, and the rest The required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product I a -8, a yellow solid, with a yield of 54%. 1 H NMR (400MHz, CD 3 OD) δ8.01 (d, J = 1.6Hz, 1H), 7.96–7.89 (m, 2H), 7.56–7.51 (m, 2H), 7.46 (d, J = 8.4Hz ,1H),7.36(dd,J=8.5,1.6Hz,1H),7.31(d,J=4.3Hz,4H),7.29–7.24(m,2H),6.31–6.26(m,1H),3.51( d,J=2.1Hz,2H),3.20(q,J=3.0Hz,2H),3.06–2.97(m,1H),2.90(dd,J=12.1,3.4Hz,2H),2.82(t,J ＝7.4Hz, 2H), 2.75(t, J＝5.7Hz, 2H), 2.64–2.53(m, 4H), 2.06–1.93(m, 5H), 1.79–1.68(m, 3H), 1.62(q, J=7.0Hz,3H),1.38–1.33(m,1H).HRMS(ESI)m/z calcd for C 38 H 43 N 4 O[M+H] + 571.3437,found 571.3436.
实施例13 3-(2-(4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-基)乙基)-1H-吲哚-5-甲腈(I a–9)的制备 Example 13 3-(2-(4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridin-1(2H)-yl ) ethyl)-1H-indole-5-formonitrile (Ia - 9) preparation
Figure PCTCN2022141611-appb-000046
Figure PCTCN2022141611-appb-000046
将实施例11步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(2-溴乙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例11，得产物I a–9，黄色固体，收率57％。 1H NMR(400MHz,CD 3OD)δ8.09(d,J＝1.5Hz,1H),8.03–7.96(m,2H),7.62(d,J＝8.5Hz,2H),7.51(dd,J＝8.4,0.7Hz,1H),7.48–7.39(m,6H),7.34(s,1H),6.41–6.35(m,1H),3.99(s,2H),3.49(d,J＝3.5Hz,2H),3.37(s,2H),3.25(d,J＝13.5Hz,2H),3.11(dt,J＝14.7,7.3Hz,4H),3.03(t,J＝5.8Hz,2H),3.00–2.91(m,2H),2.74(s,2H),2.62(s,2H),1.93(d,J＝13.7Hz,2H),1.71(q,J＝7.2Hz,2H),1.64–1.52(m,1H).HRMS(ESI)m/z calcd for C 37H 41N 4O[M+H] +557.3280,found 557.3281. The 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e of Example 11 was replaced by 3-(2-bromoethyl)-1H-indole-5-carbonitrile, and the rest The required raw materials, reagents and preparation method are the same as in Example 11 to obtain the product Ia - 9, a yellow solid, with a yield of 57%. 1 H NMR (400MHz, CD 3 OD) δ8.09 (d, J = 1.5Hz, 1H), 8.03–7.96 (m, 2H), 7.62 (d, J = 8.5Hz, 2H), 7.51 (dd, J =8.4,0.7Hz,1H),7.48–7.39(m,6H),7.34(s,1H),6.41–6.35(m,1H),3.99(s,2H),3.49(d,J=3.5Hz, 2H), 3.37(s, 2H), 3.25(d, J=13.5Hz, 2H), 3.11(dt, J=14.7, 7.3Hz, 4H), 3.03(t, J=5.8Hz, 2H), 3.00– 2.91(m, 2H), 2.74(s, 2H), 2.62(s, 2H), 1.93(d, J＝13.7Hz, 2H), 1.71(q, J＝7.2Hz, 2H), 1.64–1.52(m ,1H).HRMS(ESI)m/z calcd for C 37 H 41 N 4 O[M+H] + 557.3280,found 557.3281.
实施例14 3-(4-(4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-基)丁基)-1H-吲哚-5-甲腈(I a–10)的制备 Example 14 3-(4-(4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl )-3,6-dihydropyridin-1(2H)-yl)butyl)-1H-indole-5-carbonitrile (Ia - 10)
Figure PCTCN2022141611-appb-000047
Figure PCTCN2022141611-appb-000047
将实施例11步骤a中的4-溴苯乙酮替换为5-溴茚酮，将步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(2-溴乙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例11，得产物I a–10，黄色固体，收率57％。 1H NMR(400MHz,CD 3OD)δ8.01(s,1H),7.66(d,J＝8.2Hz,1H),7.62(s,1H),7.52(d,J＝8.5Hz,1H),7.50–7.43(m,J＝7.6Hz,6H),7.36(d,J＝8.5Hz,1H),7.27(s,1H),6.31(s,1H),4.21(s,2H),3.70(s,2H),3.50–3.35(m,J＝16.7,7.2Hz,3H),3.10–3.00(m,2H),2.99–2.76(m,J＝39.3,18.6Hz,8H),2.01(dd,J＝34.7,14.4Hz,2H),1.84(d,J＝19.6Hz,6H),1.59–1.38(m,3H),1.37–1.20(m,2H).HRMS(ESI)m/z calcd for C 40H 45N 4O[M+H] +597.3593,found 597.3592. The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (2-Bromoethyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 10, a yellow solid, with a yield of 57%. 1 H NMR (400MHz, CD 3 OD) δ8.01(s, 1H), 7.66(d, J=8.2Hz, 1H), 7.62(s, 1H), 7.52(d, J=8.5Hz, 1H), 7.50–7.43(m, J＝7.6Hz, 6H), 7.36(d, J＝8.5Hz, 1H), 7.27(s, 1H), 6.31(s, 1H), 4.21(s, 2H), 3.70(s ,2H),3.50–3.35(m,J＝16.7,7.2Hz,3H),3.10–3.00(m,2H),2.99–2.76(m,J＝39.3,18.6Hz,8H),2.01(dd,J =34.7,14.4Hz,2H),1.84(d,J=19.6Hz,6H),1.59–1.38(m,3H),1.37–1.20(m,2H).HRMS(ESI)m/z calcd for C 40 H 45 N 4 O[M+H] + 597.3593, found 597.3592.
实施例15 3-(3-(4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢吡啶-1H-茚-5-基)-3,6-二氢-1(2H)-基)丙基)-1H-吲哚-5-甲腈(I a–11)的制备 Example 15 3-(3-(4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydropyridine-1H-indene-5- Preparation of -3,6-dihydro-1(2H)-yl)propyl)-1H-indole-5-carbonitrile ( Ia- 11)
Figure PCTCN2022141611-appb-000048
Figure PCTCN2022141611-appb-000048
将实施例11步骤a中的4-溴苯乙酮替换为5-溴茚酮，将步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(3-溴丙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例11，得产物I a–11，黄色固体，收率57％。 1H NMR(400MHz,CD 3OD)δ8.03(d,J＝1.5Hz,1H),7.63(d,J＝8.1Hz,1H),7.57(s,1H),7.52–7.45(m,2H),7.43–7.35(m,6H),7.27(s,1H),6.35–6.29(m,1H),3.89(s,2H),3.40–3.36(m,1H),3.23–3.12(m,3H),2.95–2.76(m,6H),2.74–2.64(m,4H),2.57–2.46(m,2H),2.03(p,J＝7.6Hz,2H),1.93(d,J＝13.8Hz,1H),1.89–1.77(m,2H),1.73(d,J＝4.0Hz,1H),1.48–1.32(m,4H).HRMS(ESI)m/z calcd for C 39H 43N 4O[M+H] +583.3437,found 583.3436. The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (3-Bromopropyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 11, a yellow solid, with a yield of 57%. 1 H NMR (400MHz, CD 3 OD) δ8.03 (d, J = 1.5Hz, 1H), 7.63 (d, J = 8.1Hz, 1H), 7.57 (s, 1H), 7.52–7.45 (m, 2H ),7.43–7.35(m,6H),7.27(s,1H),6.35–6.29(m,1H),3.89(s,2H),3.40–3.36(m,1H),3.23–3.12(m,3H ),2.95–2.76(m,6H),2.74–2.64(m,4H),2.57–2.46(m,2H),2.03(p,J＝7.6Hz,2H),1.93(d,J＝13.8Hz, 1H),1.89–1.77(m,2H),1.73(d,J＝4.0Hz,1H),1.48–1.32(m,4H).HRMS(ESI)m/z calcd for C 39 H 43 N 4 O[ M+H] + 583.3437, found 583.3436.
实施例16 3-(2-(4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-基)乙基)-1H-吲哚-5-甲腈(I a–12)的制备 Example 16 3-(2-(4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl )-3,6-dihydropyridin-1(2H)-yl)ethyl)-1H-indole-5-carbonitrile (Ia - 12)
Figure PCTCN2022141611-appb-000049
Figure PCTCN2022141611-appb-000049
将实施例11步骤a中的4-溴苯乙酮替换为5-溴茚酮，将步骤e中的3-(4-氯丁基)-1H-吲哚-5-甲腈替换为3-(2-溴乙基)-1H-吲哚-5-甲腈，其余所需原料、试剂及制备方法同实施例11，得产物I a–12，黄色固体，收率53％。 1H NMR(600MHz,CD 3OD)δ8.10(d,J＝0.6Hz,1H),7.67(d,J＝8.1Hz,1H),7.63(s,1H),7.55(d,J＝8.1Hz,1H),7.53–7.49(m,3H),7.49–7.46(m,3H),7.40(dd,J＝8.5,1.4Hz,1H),7.38(s,1H),6.37(s,1H),4.23(s,2H),3.73(s,2H),3.47–3.38(m,J＝17.1,8.1Hz,3H),3.29–3.25(m,2H),3.20(s,3H),2.96(t,J＝12.0Hz,2H),2.88–2.81(m,3H),2.11–1.79(m,5H),1.58–1.40(m,4H).HRMS(ESI)m/z calcd for C 38H 41N 4O[M+H] +569.3280,found 569.3282. The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (2-Bromoethyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 12, a yellow solid, with a yield of 53%. 1 H NMR (600MHz, CD 3 OD) δ8.10(d, J=0.6Hz, 1H), 7.67(d, J=8.1Hz, 1H), 7.63(s, 1H), 7.55(d, J=8.1 Hz,1H),7.53–7.49(m,3H),7.49–7.46(m,3H),7.40(dd,J＝8.5,1.4Hz,1H),7.38(s,1H),6.37(s,1H) ,4.23(s,2H),3.73(s,2H),3.47–3.38(m,J＝17.1,8.1Hz,3H),3.29–3.25(m,2H),3.20(s,3H),2.96(t ,J＝12.0Hz,2H),2.88–2.81(m,3H),2.11–1.79(m,5H),1.58–1.40(m,4H).HRMS(ESI)m/z calcd for C 38 H 41 N 4 O[M+H] + 569.3280, found 569.3282.
实施例17 3-((4-(4-(3-(1-苄基哌啶-4-基)丙酰基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1H-吲哚-5-甲腈(I b–5)的制备 Example 17 3-((4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl base)-1H-indole-5-carbonitrile (I b -5)
Figure PCTCN2022141611-appb-000050
Figure PCTCN2022141611-appb-000050
将实施例7中的3-(1-苄基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮替换为3-(1-苄基哌啶-4-基)-1-(4-(1,2,3,6-四氢吡啶-4-基)苯基)丙-1-酮，其余所需原料、试剂及制备方法同实施例7，得产物I b–5，白色固体，收率57％。 1H NMR(400MHz,CD 3OD)δ8.17(d,J＝1.6Hz,1H),7.93(d,2H),7.57–7.50(m,3H),7.48(s,1H),7.43–7.39(m,1H),7.39–7.30(m,5H),6.34–6.25(m,1H),3.95(s,2H),3.75(s,2H),3.12–2.98(m,4H),2.88(t,2H),2.63(s,2H),2.31(t,J＝11.8Hz,2H),1.91(s,1H),1.85–1.77(m,2H),1.70–1.61(m,2H),1.45(s,1H),1.38–1.30(m,3H).HRMS(ESI)m/z calcd for C 36H 39N 4O[M+H] +543.3124,found 543.3123. 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one in Example 7 is replaced by 3-(1-benzyl Piperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one, the rest of the required raw materials, reagents and preparation methods are the same Example 7, the product Ib - 5 was obtained as a white solid with a yield of 57%. 1 H NMR (400MHz, CD 3 OD) δ8.17 (d, J = 1.6Hz, 1H), 7.93 (d, 2H), 7.57–7.50 (m, 3H), 7.48 (s, 1H), 7.43–7.39 (m,1H),7.39–7.30(m,5H),6.34–6.25(m,1H),3.95(s,2H),3.75(s,2H),3.12–2.98(m,4H),2.88(t ,2H),2.63(s,2H),2.31(t,J＝11.8Hz,2H),1.91(s,1H),1.85–1.77(m,2H),1.70–1.61(m,2H),1.45( s,1H),1.38–1.30(m,3H).HRMS(ESI)m/z calcd for C 36 H 39 N 4 O[M+H] + 543.3124,found 543.3123.
实施例18 3-((4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1H吲哚-5-甲腈(I b–6)的制备 Example 18 3-((4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)- Preparation of 3,6-dihydropyridin-1(2H)-yl)methyl)-1Hindole-5-carbonitrile (I b- 6)
Figure PCTCN2022141611-appb-000051
Figure PCTCN2022141611-appb-000051
将3-(1-苯基哌啶-4-基)-1-(4-(哌啶-4-基)苯基)丙-1-酮替换为2-((1-苯基哌啶-4-基)甲基)-5-(1,2,3,6-四氢哌啶-4-基)-2,3-二氢-1H-吲哚-1-酮，其余所需原料、试剂及制备方法同实施例7，得产物I b–6，黄色固体，收率52％。 1H NMR(400MHz,CD 3OD)δ8.24(s,1H),7.64(d,J＝9.5Hz,2H),7.60(s,1H),7.58(d,J＝8.6Hz,1H),7.49(q,J＝8.1Hz,7H),6.32(s,1H),4.35(s,2H),4.23(s,2H),3.68(s,2H),3.41(dd,J＝16.9,7.4Hz,3H),3.28(d,J＝5.6Hz,2H),2.95(t,J＝11.5Hz,2H),2.87–2.74(m,4H),2.07(d,J＝14.1Hz,1H),1.97(d,J＝14.1Hz,1H),1.93–1.79(m,2H),1.57–1.38(m,3H).HRMS(ESI)m/z calcd for C 37H 39N 4O[M+H] +555.3124,found 555.3123. Replace 3-(1-phenylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one with 2-((1-phenylpiperidin- 4-yl)methyl)-5-(1,2,3,6-tetrahydropiperidin-4-yl)-2,3-dihydro-1H-indol-1-one, other required raw materials, The reagents and preparation method were the same as in Example 7, and the product Ib - 6 was obtained as a yellow solid with a yield of 52%. 1 H NMR (400MHz, CD 3 OD) δ8.24(s, 1H), 7.64(d, J=9.5Hz, 2H), 7.60(s, 1H), 7.58(d, J=8.6Hz, 1H), 7.49(q,J=8.1Hz,7H),6.32(s,1H),4.35(s,2H),4.23(s,2H),3.68(s,2H),3.41(dd,J=16.9,7.4Hz ,3H),3.28(d,J=5.6Hz,2H),2.95(t,J=11.5Hz,2H),2.87–2.74(m,4H),2.07(d,J=14.1Hz,1H),1.97 (d,J＝14.1Hz,1H),1.93–1.79(m,2H),1.57–1.38(m,3H).HRMS(ESI)m/z calcd for C 37 H 39 N 4 O[M+H] + 555.3124,found 555.3123.
实施例19 3-((4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–7)的制备 Example 19 3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Preparation of -yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile (I b -7)
Figure PCTCN2022141611-appb-000052
Figure PCTCN2022141611-appb-000052
步骤i 6-叔丁氧羰基-1-氧杂-6-氮杂螺[2.5]辛烷的合成Step i Synthesis of 6-tert-butoxycarbonyl-1-oxa-6-azaspiro[2.5]octane
Figure PCTCN2022141611-appb-000053
Figure PCTCN2022141611-appb-000053
冰浴搅拌下，将60％钠氢2.4g缓慢加入40mL无水DMSO中，加料完毕后升至65℃搅拌1小时，使钠氢充分溶解。反应液恢复至室温后，缓慢加入13.3g三甲基碘化亚砜，室温搅拌0.5小时，生成反应活性高的亚砜硫鎓盐。随后将5.0g N-叔丁氧羰基-4-哌啶酮溶于50mL无水DMSO，搅拌下缓慢滴加至反应液中，室温反应1小时，亚砜硫鎓盐与羰基反应后生成环丙烷化合物。待反应完毕后，向反应液中加入100mL水和100mL乙酸乙酯，将反应产物萃取至乙酸乙酯中，分离得有机相，将水相用乙酸乙酯萃取三遍(100mL×3)，合并有机相，用水洗三遍(200mL×3)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，旋干后产物不经纯化可直接投下一步，得中间体6-叔丁氧羰基-1-氧杂-6-氮杂螺[2.5]辛烷，棕色油状物5.35g，收率99％。 1H NMR(400MHz,CDCl 3)δ3.73(d,J＝13.1Hz,2H),3.43(ddd,J＝13.3,9.5,3.7Hz,2H),2.69(s,2H),1.80(ddd,J＝13.8,9.4,4.5Hz,2H),1.48(s,9H),1.43(s,2H). Under stirring in an ice bath, slowly add 2.4 g of 60% sodium hydrogen into 40 mL of anhydrous DMSO. After the addition, raise the temperature to 65° C. and stir for 1 hour to fully dissolve the sodium hydrogen. After the reaction solution returned to room temperature, 13.3 g of trimethylsulfoxide iodide was slowly added and stirred at room temperature for 0.5 hour to generate a highly reactive sulfoxide sulfonium salt. Subsequently, 5.0 g of N-tert-butoxycarbonyl-4-piperidone was dissolved in 50 mL of anhydrous DMSO, and slowly added dropwise to the reaction solution under stirring, and reacted at room temperature for 1 hour, and the sulfoxide sulfonium salt reacted with the carbonyl group to generate cyclopropane compound. After the reaction is complete, add 100 mL of water and 100 mL of ethyl acetate to the reaction solution, extract the reaction product into ethyl acetate, separate the organic phase, extract the aqueous phase three times with ethyl acetate (100 mL×3), and combine Wash the organic phase three times with water (200mL×3), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. -1-Oxa-6-azaspiro[2.5]octane, 5.35 g of brown oil, yield 99%. 1 H NMR (400MHz, CDCl 3 ) δ 3.73 (d, J = 13.1 Hz, 2H), 3.43 (ddd, J = 13.3, 9.5, 3.7 Hz, 2H), 2.69 (s, 2H), 1.80 (ddd, J＝13.8,9.4,4.5Hz,2H),1.48(s,9H),1.43(s,2H).
步骤j 1-叔丁氧羰基-4-氟-4-(羟甲基)哌啶的合成Synthesis of step j 1-tert-butoxycarbonyl-4-fluoro-4-(hydroxymethyl)piperidine
Figure PCTCN2022141611-appb-000054
Figure PCTCN2022141611-appb-000054
将1.0g棕色油状物中间体6-叔丁氧羰基-1-氧杂-6-氮杂螺[2.5]辛烷置于50mL塑料管内，置于冰盐浴维持的-10℃环境下，加入20mL二氯甲烷溶解，搅拌下滴加0.6mL70％氢氟酸吡啶溶液(olah’s reagent)，-10℃反应1小时。待反应完毕后，将反应液移至塑料烧杯中，搅拌下加入碳酸钾颗粒中和反应液至中性，二氯甲烷萃取三遍(100mL×3)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，旋干后产物经柱层析纯化，洗脱剂为乙酸乙酯:石油醚＝1:3，得中间体1-叔丁氧羰基-4-氟-4-(羟甲基)哌啶，透明油状物550mg，收率50％。 1H NMR(400MHz,DMSO-d 6)δ5.76(s,1H),4.98(t,J＝6.0Hz,1H),3.76(d,J＝13.4Hz,2H),3.41(dd,J＝20.1,6.0Hz,2H),2.98(s,2H),1.70(dd,J＝13.9,10.4Hz,2H),1.54(dtd,J＝35.8,13.8,13.0,5.1Hz,2H),1.40(s,9H). Put 1.0g of the brown oily intermediate 6-tert-butoxycarbonyl-1-oxa-6-azaspiro[2.5]octane in a 50mL plastic tube at -10°C maintained in an ice-salt bath, add 20 mL of dichloromethane was dissolved, and 0.6 mL of 70% pyridinium hydrofluoric acid solution (olah's reagent) was added dropwise with stirring, and reacted at -10°C for 1 hour. After the reaction is complete, move the reaction solution to a plastic beaker, add potassium carbonate particles to neutralize the reaction solution with stirring, extract three times with dichloromethane (100mL×3), combine the organic phases, and wash with saturated brine. Dry over anhydrous sodium sulfate, spin dry the product and purify by column chromatography, the eluent is ethyl acetate:petroleum ether=1:3, to obtain the intermediate 1-tert-butoxycarbonyl-4-fluoro-4-(hydroxymethyl Base) piperidine, transparent oil 550mg, yield 50%. 1 H NMR (400MHz, DMSO-d 6 )δ5.76(s, 1H), 4.98(t, J=6.0Hz, 1H), 3.76(d, J=13.4Hz, 2H), 3.41(dd, J= 20.1,6.0Hz,2H),2.98(s,2H),1.70(dd,J＝13.9,10.4Hz,2H),1.54(dtd,J＝35.8,13.8,13.0,5.1Hz,2H),1.40(s ,9H).
步骤k 1-叔丁氧羰基-4-氟-4-哌啶甲醛的合成Step k Synthesis of 1-tert-butoxycarbonyl-4-fluoro-4-piperidinecarbaldehyde
Figure PCTCN2022141611-appb-000055
Figure PCTCN2022141611-appb-000055
将1.5g中间体1-叔丁氧羰基-4-氟-4-(羟甲基)哌啶溶于15mL无水二氯甲烷中，将4.1g戴斯马丁试剂溶于30mL无水二氯甲烷中，0℃冰浴下，一边搅拌一边将戴斯马丁溶液缓慢滴加至(4-氟-1-叔丁氧羰基取代哌啶-4-基)甲醇的溶液中，滴加完毕后，室温反应1～2小时。原料反应完毕后，向反应中加入40mL饱和碳酸氢钠溶液和40mL 10％硫代硫酸钠溶液搅拌半小时，加入二氯甲烷萃取三遍(50mL×3)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，旋干后产物经柱层析纯化，洗脱剂为乙酸乙酯:石油醚＝1:2.5，得中间体1-叔丁氧羰基-4-氟-4-哌啶甲醛，透明油状物750mg，收率48％。 1H NMR(400MHz,CDCl 3)δ9.74(d,J＝4.9Hz,1H),4.03(d,J＝13.3Hz,2H),3.20–3.05(m,2H),1.89–1.69(m,4H),1.47(s,9H). Dissolve 1.5 g of the intermediate 1-tert-butoxycarbonyl-4-fluoro-4-(hydroxymethyl)piperidine in 15 mL of anhydrous dichloromethane, and dissolve 4.1 g of Dess Martin’s reagent in 30 mL of anhydrous dichloromethane , under ice bath at 0°C, slowly add the Dess Martin solution dropwise to the solution of (4-fluoro-1-tert-butoxycarbonyl substituted piperidin-4-yl)methanol while stirring. React for 1 to 2 hours. After the raw materials have been reacted, add 40 mL of saturated sodium bicarbonate solution and 40 mL of 10% sodium thiosulfate solution to the reaction, stir for half an hour, add dichloromethane for extraction three times (50 mL×3), combine the organic phases, and wash with saturated brine , dried over anhydrous sodium sulfate, and the product was purified by column chromatography after spin-drying, and the eluent was ethyl acetate:petroleum ether=1:2.5 to obtain the intermediate 1-tert-butoxycarbonyl-4-fluoro-4-piperidine Formaldehyde, transparent oil 750mg, yield 48%. 1 H NMR (400MHz, CDCl 3 ) δ9.74(d, J=4.9Hz, 1H), 4.03(d, J=13.3Hz, 2H), 3.20–3.05(m, 2H), 1.89–1.69(m, 4H), 1.47(s, 9H).
步骤l 叔丁基-(E)-4-((5-溴-1-氧代-1,3-二氢-2H-茚-2-亚基)甲基)-4-氟哌啶-1-羧酸酯的合成Step l tert-butyl-(E)-4-((5-bromo-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methyl)-4-fluoropiperidine-1 -Synthesis of Carboxylate
Figure PCTCN2022141611-appb-000056
Figure PCTCN2022141611-appb-000056
将550mg粘稠的糖状中间体1-叔丁氧羰基-4-氟-4-哌啶甲醛称量于100mL圆底烧瓶中，加入30mL四氢呋喃溶解，搅拌下加入500mg 5-溴茚酮、660mg氢氧化钠，剧烈搅拌8～10分钟，待反应液由黄色变为黑色的瞬间，将反应液转移至烧杯中，加入40mL 水稀释反应液，再滴加1N的盐酸水溶液中和反应液至中性，溶液由黑色变为红色。用乙酸乙酯(50mL)萃取反应液三次，合并有机相，用饱和食盐水洗涤，无水Na 2SO 4干燥，抽滤，旋蒸除去溶剂，剩余有机物经柱层析纯化，乙酸乙酯:石油醚＝1:11洗脱，得目标化合物叔丁基-(E)-4-((5-溴-1-氧代-1,3-二氢-2H-茚-2-亚基)甲基)-4-氟哌啶-1-羧酸酯共668mg，白色固体，收率76％。 1H NMR(400MHz,CDCl 3)δ7.72(d,J＝8.2Hz,1H),7.68(s,1H),7.55(dd,J＝8.2,1.7Hz,1H),6.69(dt,J＝26.6,2.2Hz,1H),4.01(d,J＝13.6Hz,2H),3.90(s,2H),3.16(t,J＝12.7Hz,2H),1.98–1.85(m,3H),1.83–1.73(m,1H),1.48(s,9H). Weigh 550mg of viscous sugar-like intermediate 1-tert-butoxycarbonyl-4-fluoro-4-piperidinecarbaldehyde into a 100mL round bottom flask, add 30mL tetrahydrofuran to dissolve, add 500mg 5-bromoindanone, 660mg Sodium hydroxide, stir vigorously for 8 to 10 minutes. When the reaction solution turns from yellow to black, transfer the reaction solution to a beaker, add 40 mL of water to dilute the reaction solution, and then add dropwise 1N hydrochloric acid aqueous solution to neutralize the reaction solution. The solution turns from black to red. The reaction solution was extracted three times with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered with suction, and the solvent was removed by rotary evaporation, and the remaining organic matter was purified by column chromatography, ethyl acetate: Petroleum ether = 1:11 elution to obtain the target compound tert-butyl-(E)-4-((5-bromo-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methanol Base)-4-fluoropiperidine-1-carboxylate total 668mg, white solid, yield 76%. 1 H NMR (400MHz, CDCl 3 ) δ7.72(d, J=8.2Hz, 1H), 7.68(s, 1H), 7.55(dd, J=8.2, 1.7Hz, 1H), 6.69(dt, J= 26.6,2.2Hz,1H),4.01(d,J=13.6Hz,2H),3.90(s,2H),3.16(t,J=12.7Hz,2H),1.98–1.85(m,3H),1.83– 1.73(m,1H),1.48(s,9H).
步骤m：(E)-5-溴-2-((4-氟哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮的合成Step m: Synthesis of (E)-5-bromo-2-((4-fluoropiperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one
Figure PCTCN2022141611-appb-000057
Figure PCTCN2022141611-appb-000057
将叔丁基-(E)-4-((5-溴-1-氧代-1,3-二氢-2H-茚-2-亚基)甲基)-4-氟哌啶-1-羧酸酯(500mg，1.18mmol)溶于10mL二氯甲烷中，搅拌下滴加3mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入20mL饱和碳酸氢钠溶液洗涤有机相，析出大量白色固体，得380mg，为(E)-5-溴-2-((4-氟哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮，收率99％。 1H NMR(400MHz,DMSO-d 6)δ8.81(s,1H),8.64(s,1H),7.93(s,1H),7.74–7.65(m,2H),6.73(d,J＝25.5,2.3Hz,1H),3.93(s,2H),3.32(s,2H),3.11(s,2H),2.24–2.07(m,3H). tert-Butyl-(E)-4-((5-bromo-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methyl)-4-fluoropiperidine-1- Carboxylate (500 mg, 1.18 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, and then 20 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and a large amount of white solid was precipitated to obtain 380 mg, which was (E)- 5-Bromo-2-((4-fluoropiperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one, yield 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.81(s, 1H), 8.64(s, 1H), 7.93(s, 1H), 7.74–7.65(m, 2H), 6.73(d, J=25.5 ,2.3Hz,1H),3.93(s,2H),3.32(s,2H),3.11(s,2H),2.24–2.07(m,3H).
步骤n：(E)-2-((1-苄基-4-氟哌啶-4-基)亚甲基)-5-溴-2,3-二氢-1H-茚-1-酮的合成Step n: (E)-2-((1-Benzyl-4-fluoropiperidin-4-yl)methylene)-5-bromo-2,3-dihydro-1H-inden-1-one synthesis
Figure PCTCN2022141611-appb-000058
Figure PCTCN2022141611-appb-000058
将2.0g(E)-5-溴-2-((4-氟哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮溶于20mL DMF中，搅拌下滴加806μL苄溴，加入1.28g碳酸钾固体，室温反应1小时。反应完毕后向反应体系中加入80mL乙酸乙酯和80mL水萃取，有机相水洗三遍(100mL×3)，合并有机相，用饱和食盐水洗涤，无水Na 2SO 4干燥，抽滤，旋蒸除去溶剂，所得产物不经纯化直接投下一步。得到2.0g(E)-2-((1-苄基-4-氟哌啶-4-基)亚甲基)-5-溴-2,3-二氢-1H-茚-1-酮，白色固体，收率75％。 1H NMR(400MHz,CDCl 3)δ7.72(d,J＝8.1Hz,1H),7.67(s,1H),7.54(d,J＝8.2,1.7Hz,1H),7.42–7.28(m,5H),6.75(dt,J＝26.4,2.2Hz,1H),3.89(s,2H),3.61(s,2H),2.80(s,2H),2.45(s,2H),2.16–1.87(m,4H). Dissolve 2.0 g of (E)-5-bromo-2-((4-fluoropiperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one in 20 mL of DMF, 806 μL of benzyl bromide was added dropwise with stirring, and 1.28 g of solid potassium carbonate was added, and reacted at room temperature for 1 hour. After the reaction was completed, 80 mL of ethyl acetate and 80 mL of water were added to the reaction system for extraction, the organic phase was washed three times with water (100 mL×3), the combined organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 , suction filtered, and spin The solvent was evaporated, and the obtained product was directly used in the next step without purification. 2.0 g of (E)-2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-5-bromo-2,3-dihydro-1H-inden-1-one were obtained, White solid, yield 75%. 1 H NMR (400MHz, CDCl 3 ) δ7.72(d, J=8.1Hz, 1H), 7.67(s, 1H), 7.54(d, J=8.2, 1.7Hz, 1H), 7.42–7.28(m, 5H), 6.75(dt, J＝26.4, 2.2Hz, 1H), 3.89(s, 2H), 3.61(s, 2H), 2.80(s, 2H), 2.45(s, 2H), 2.16–1.87(m ,4H).
步骤b：叔丁基-(E)-4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成Step b: tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
Figure PCTCN2022141611-appb-000059
Figure PCTCN2022141611-appb-000059
将(E)-2-((1-苄基-4-氟哌啶-4-基)亚甲基)-5-溴-2,3-二氢-1H-茚-1-酮(500mg，1.2mmol)和N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(448mg，1.5mmol)溶于无水1，4-二氧六环(15mL)中，加入Pd(PPh 3) 4(70mg，0.060mmol)和K 2CO 3(500mg，3.6mmol)，水泵脱气2分钟，氮气保护下100℃反应过夜。旋干反应液，反应体系中加入100mL乙酸乙酯和100mL水萃取，有机相经饱和食盐水洗涤，无水Na 2SO 4干燥，抽滤，旋蒸除去溶剂，加入20mL乙酸乙酯打浆，过滤得300mg叔丁基-(E)-4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯，白色固体，收率48％。 1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.1Hz,1H),7.46(d,J＝1.5Hz,1H),7.42(dd,J＝8.1,1.6Hz,1H),7.38–7.27(m,5H),6.71(d,J＝26.5Hz,1H),3.89(s,2H),3.66(t,J＝5.6Hz,2H),3.56(s,2H),2.75(d,J＝11.8,3.9Hz,2H),2.56(s,2H),2.40(t,J＝11.8,11.2,3.7Hz,2H),2.03–1.89(m,4H),1.50(s,9H). (E)-2-((1-Benzyl-4-fluoropiperidin-4-yl)methylene)-5-bromo-2,3-dihydro-1H-inden-1-one (500mg, 1.2mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (448mg, 1.5mmol) were dissolved in anhydrous 1,4-dioxane (15mL), Pd(PPh 3 ) 4 (70mg, 0.060mmol) and K 2 CO 3 (500mg, 3.6mmol) were added, degassed by water pump for 2 minutes, and reacted overnight at 100°C under nitrogen protection. Spin to dry the reaction solution, add 100mL ethyl acetate and 100mL water to the reaction system for extraction, wash the organic phase with saturated brine, dry over anhydrous Na2SO4 , filter with suction, remove the solvent by rotary evaporation, add 20mL ethyl acetate for beating, and filter 300 mg tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro-1H -Inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate, white solid, yield 48%. 1 H NMR (400MHz, CDCl3) δ7.81 (d, J = 8.1Hz, 1H), 7.46 (d, J = 1.5Hz, 1H), 7.42 (dd, J = 8.1, 1.6Hz, 1H), 7.38– 7.27(m,5H),6.71(d,J=26.5Hz,1H),3.89(s,2H),3.66(t,J=5.6Hz,2H),3.56(s,2H),2.75(d,J =11.8,3.9Hz,2H),2.56(s,2H),2.40(t,J=11.8,11.2,3.7Hz,2H),2.03–1.89(m,4H),1.50(s,9H).
步骤c：叔丁基-4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step c: tert-butyl-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Synthesis of -yl)piperidine-1-carboxylate
Figure PCTCN2022141611-appb-000060
Figure PCTCN2022141611-appb-000060
将1.0g叔丁基-(E)-4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯溶于10mL甲醇和10mL二氯甲烷的混合溶剂中，加入100mg 10％Pd/C(含水55％)，搅拌下置换氢气3～4次，室温反应过夜。反应完毕后垫硅藻土过滤掉Pd/C，用30mL甲醇、二氯甲烷混合溶液洗涤滤饼，旋干滤液。粗产品柱层析纯化，洗脱剂为乙酸乙酯:二氯甲烷＝1:1。得262mg叔丁基-4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，白色固体，收率26％。 1H NMR(400MHz,CDCl 3)δ7.72(d,J＝8.0Hz,1H),7.44–7.30(m,5H),7.29(s,1H),7.24(d,J＝8.0Hz,1H),4.29(s,2H),3.62(s,2H),3.43(dd,J＝17.3,7.9Hz,1H),2.95(dd,J＝17.4,4.5Hz,1H),2.89–2.70(m,6H),2.44(dd,J＝28.5,14.7Hz,2H),2.04–1.96(m,1H),1.94–1.80(m,4H),1.77–1.62(m,5H),1.51(s,9H) 1.0g tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- 1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in a mixed solvent of 10mL methanol and 10mL dichloromethane, and 100mg 10% Pd/C (water 55% ), replaced hydrogen 3 to 4 times under stirring, and reacted overnight at room temperature. After the reaction was completed, the Pd/C was filtered out with a pad of diatomaceous earth, the filter cake was washed with 30 mL of a mixed solution of methanol and dichloromethane, and the filtrate was spin-dried. The crude product was purified by column chromatography, and the eluent was ethyl acetate:dichloromethane=1:1. 262 mg of tert-butyl-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5- Base) piperidine-1-carboxylate, white solid, yield 26%. 1 H NMR (400MHz, CDCl 3 ) δ7.72(d, J=8.0Hz, 1H), 7.44–7.30(m, 5H), 7.29(s, 1H), 7.24(d, J=8.0Hz, 1H) ,4.29(s,2H),3.62(s,2H),3.43(dd,J＝17.3,7.9Hz,1H),2.95(dd,J＝17.4,4.5Hz,1H),2.89–2.70(m,6H ),2.44(dd,J＝28.5,14.7Hz,2H),2.04–1.96(m,1H),1.94–1.80(m,4H),1.77–1.62(m,5H),1.51(s,9H)
步骤d：2-((1-苄基-4-氟哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step d: 2-((1-Benzyl-4-fluoropiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1- Ketone synthesis
Figure PCTCN2022141611-appb-000061
Figure PCTCN2022141611-appb-000061
将500mg叔丁基-4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶于10mL二氯甲烷中，搅拌下滴加3mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入20mL饱和碳酸氢钠溶液洗涤有机相，分离有机相，将水相用二氯甲烷萃取3～4遍(20mL)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤后将滤液旋干，未经纯化可直接投下一步，得200mg目标中间体2-((1-苄基-4-氟哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率95％。500mg tert-butyl-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5- Base) piperidine-1-carboxylate was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 20 mL of saturated sodium bicarbonate solution was added to wash the organic phase, the organic phase was separated, and the aqueous phase was extracted with dichloromethane for 3 ~ 4 times (20mL), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried the filtrate, and directly used in the next step without purification to obtain 200 mg of the target intermediate 2-((1-benzyl -4-fluoropiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, white solid, yield 95%.
步骤e：3-((4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈的合成Step e: 3-((4-(2-((1-Benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Synthesis of -yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000062
Figure PCTCN2022141611-appb-000062
将5-氰基-吲哚-3-甲醛(53mg，0.314mmol)和2-((1-苄基-4-氟哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(120mg，0.285mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(36mg，0.571mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到80mg 3-((4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率49％。 1H NMR(600MHz,CDCl 3)δ8.83(s,1H),8.10(s,1H),7.59(d,J＝7.9Hz,1H),7.34(s,2H),7.26–7.22(m,5H),7.21–7.17(m,2H),7.15(d,J＝8.1Hz,1H),3.67(s,2H),3.46(s,2H),3.32(dd,J＝17.4,7.9Hz,1H),3.01(dd,J＝11.3,3.5Hz,2H),2.85(dd,J＝17.4,4.4Hz,1H),2.76–2.70(m,1H),2.69–2.60(m,2H),2.54–2.47(m,1H),2.36–2.24(m,3H),2.08–2.01(m,2H),1.91–1.83(m,1H),1.80–1.71(m,5H),1.70–1.63(m,1H),1.60–1.52(m,1H).HRMS(ESI)m/z calcd for C 36H 40N 4O[M+H] +575.3186,found 575.3188. Mix 5-cyano-indole-3-carbaldehyde (53 mg, 0.314 mmol) and 2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-5-(piperidine-4- Base)-2,3-dihydro-1H-inden-1-one (120mg, 0.285mmol) was placed in a flask, added anhydrous methanol:anhydrous dichloromethane=1:1 (v:v) to dissolve, and then Sodium cyanoborohydride (36mg, 0.571mmol) was added and reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 80 mg of 3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo -2,3-Dihydro-1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile, white solid, yield 49%. 1 H NMR (600MHz, CDCl 3 ) δ8.83(s, 1H), 8.10(s, 1H), 7.59(d, J=7.9Hz, 1H), 7.34(s, 2H), 7.26–7.22(m, 5H),7.21–7.17(m,2H),7.15(d,J=8.1Hz,1H),3.67(s,2H),3.46(s,2H),3.32(dd,J=17.4,7.9Hz,1H ),3.01(dd,J＝11.3,3.5Hz,2H),2.85(dd,J＝17.4,4.4Hz,1H),2.76–2.70(m,1H),2.69–2.60(m,2H),2.54– 2.47(m,1H),2.36–2.24(m,3H),2.08–2.01(m,2H),1.91–1.83(m,1H),1.80–1.71(m,5H),1.70–1.63(m,1H ),1.60–1.52(m,1H).HRMS(ESI)m/z calcd for C 36 H 40 N 4 O[M+H] + 575.3186,found 575.3188.
实施例20 3-((4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–8)的制备 Example 20 3-((4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Preparation of 1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile (I b -8)
Figure PCTCN2022141611-appb-000063
Figure PCTCN2022141611-appb-000063
(E)-5-溴-2-((4-氟哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮的合成方法同实施例19。The synthesis method of (E)-5-bromo-2-((4-fluoropiperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one is the same as in Example 19.
步骤a：(E)-5-溴-2-((4-氟-1-1-(2-氟代苄基)哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮的合成Step a: (E)-5-Bromo-2-((4-fluoro-1-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-2,3-dihydro- Synthesis of 1H-inden-1-one
Figure PCTCN2022141611-appb-000064
Figure PCTCN2022141611-appb-000064
将实施例19步骤n的苄溴替换为2-氟苄溴，其余所需原料、试剂及制备方法同实施例19步骤n，得350mg(E)-5-溴-2-((4-氟-1-1-(2-氟代苄基)哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮，白色固体，收率52％。 1H NMR(400MHz,DMSO-d 6)δ7.91(s,1H),7.71–7.63(m,2H),7.44(t,J＝7.7Hz,1H),7.33(q,J＝7.0Hz,1H),7.18(q,J＝8.6,7.9Hz,2H),6.70(d,1H),3.90(s,2H),3.58(s,2H),2.76–2.66(m,2H),2.37–2.25(m,2H),2.08–1.95(m,2H),1.95–1.83(m,4H). The benzyl bromide in Step n of Example 19 was replaced by 2-fluorobenzyl bromide, and the remaining raw materials, reagents and preparation methods were the same as in Step n of Example 19 to obtain 350 mg of (E)-5-bromo-2-((4-fluoro -1-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one, white solid, yield 52%. 1 H NMR (400MHz, DMSO-d 6 )δ7.91(s,1H),7.71–7.63(m,2H),7.44(t,J=7.7Hz,1H),7.33(q,J=7.0Hz, 1H), 7.18(q, J=8.6, 7.9Hz, 2H), 6.70(d, 1H), 3.90(s, 2H), 3.58(s, 2H), 2.76–2.66(m, 2H), 2.37–2.25 (m,2H),2.08–1.95(m,2H),1.95–1.83(m,4H).
步骤b：叔丁基-(E)-4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成Step b: tert-butyl-(E)-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2, Synthesis of 3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
Figure PCTCN2022141611-appb-000065
Figure PCTCN2022141611-appb-000065
将(E)-2-((1-苯基-4-氟苄基-4-基)亚甲基)-5-溴-2,3-二氢-1H-茚-1-酮替换为(E)-5-溴-2-((4-氟-1-1-(2-氟代苄基)哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮，其余所需原料、试剂及制备方法同实施例19步骤b，得叔丁基-(E)-4-(2-((4-氟-1-(2-氟苯基)哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯，白色固体，收率43％。 1H NMR(400MHz,CDCl 3)δ7.81(d,J＝8.1Hz,1H),7.46(s,1H),7.42(d,J＝8.2Hz,1H),7.15(t,J＝7.5Hz,1H),7.06(t,J＝9.2Hz,1H),6.70(d,J＝26.4Hz,1H),6.20(s,1H),4.12(d,J＝3.9Hz,2H),3.89(d,J＝2.9Hz,2H),3.66(t,J＝5.7Hz,4H),2.81(s,2H),2.62–2.37(m,4H),2.13–1.85(m,4H),1.50(s,9H). Replace (E)-2-((1-phenyl-4-fluorobenzyl-4-yl)methylene)-5-bromo-2,3-dihydro-1H-inden-1-one with ( E)-5-bromo-2-((4-fluoro-1-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-2,3-dihydro-1H-indene- 1-ketone, the rest of the required raw materials, reagents and preparation methods are the same as step b in Example 19 to obtain tert-butyl-(E)-4-(2-((4-fluoro-1-(2-fluorophenyl)piperene) Pyridine-4-yl)methylene)-1-oxo-2,3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate, white Solid, yield 43%. 1 H NMR (400MHz, CDCl 3 ) δ7.81(d, J=8.1Hz, 1H), 7.46(s, 1H), 7.42(d, J=8.2Hz, 1H), 7.15(t, J=7.5Hz ,1H),7.06(t,J=9.2Hz,1H),6.70(d,J=26.4Hz,1H),6.20(s,1H),4.12(d,J=3.9Hz,2H),3.89(d ,J=2.9Hz,2H),3.66(t,J=5.7Hz,4H),2.81(s,2H),2.62–2.37(m,4H),2.13–1.85(m,4H),1.50(s, 9H).
步骤c：叔丁基-4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step c: tert-butyl-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)piperidine-1-carboxylate
Figure PCTCN2022141611-appb-000066
Figure PCTCN2022141611-appb-000066
将1.0g叔丁基-(E)-4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯溶于10mL甲醇和10mL二氯甲烷的混合溶剂中，加入100mg 10％Pd/C(含水55％)，搅拌下置换氢气3～4次，室温反应过夜。反应完毕后垫硅藻土过滤掉Pd/C，用30mL甲醇、二氯甲烷混合溶液洗涤滤饼，旋干滤液。粗产品柱层析纯化，洗脱剂为乙酸乙酯:二氯甲烷＝1:1。得230mg中间体叔丁基-4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，白色固体，收率23％。 1H NMR(400MHz,Acetone-d 6)δ7.59(t,J＝8.1Hz,1H),7.52–7.46(m,1H),7.43(d,J＝6.1Hz,1H),7.35–7.25(m,2H),7.20–7.13(m,1H),7.13–7.04(m,1H),4.22(d,J＝13.2Hz,2H),3.57(d,J＝22.9Hz,2H),3.50–3.31(m,1H),2.98–2.83(m,4H),2.78–2.66(m,2H),2.44–2.34(m,1H),2.01–1.91(m,1H),1.89–1.75(m,4H),1.74–1.53(m,4H),1.46(s,9H),1.38–1.23(m,3H). 1.0g tert-butyl-(E)-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2, 3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in a mixed solvent of 10mL methanol and 10mL dichloromethane, and 100mg 10%Pd/ C (water content 55%), replaced hydrogen 3 to 4 times under stirring, and reacted overnight at room temperature. After the reaction was completed, the Pd/C was filtered out with a pad of diatomaceous earth, the filter cake was washed with 30 mL of a mixed solution of methanol and dichloromethane, and the filtrate was spin-dried. The crude product was purified by column chromatography, and the eluent was ethyl acetate:dichloromethane=1:1. 230 mg intermediate tert-butyl-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro -1H-inden-5-yl)piperidine-1-carboxylate, white solid, yield 23%. 1 H NMR (400MHz, Acetone-d 6 ) δ7.59(t, J=8.1Hz, 1H), 7.52–7.46(m, 1H), 7.43(d, J=6.1Hz, 1H), 7.35–7.25( m,2H),7.20–7.13(m,1H),7.13–7.04(m,1H),4.22(d,J＝13.2Hz,2H),3.57(d,J＝22.9Hz,2H),3.50–3.31 (m,1H),2.98–2.83(m,4H),2.78–2.66(m,2H),2.44–2.34(m,1H),2.01–1.91(m,1H),1.89–1.75(m,4H) ,1.74–1.53(m,4H),1.46(s,9H),1.38–1.23(m,3H).
步骤d：2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step d: 2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H -Synthesis of inden-1-one
Figure PCTCN2022141611-appb-000067
Figure PCTCN2022141611-appb-000067
将叔丁基-4-(2-((1-苄基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯替换为叔丁基-4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，其余所需原料、试剂及制备方法同实施例19步骤d，得200mg目标中间体2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率95％。 1H NMR(600MHz,CD 3OD)δ7.64(d,J＝7.9Hz,1H),7.45–7.40(m,1H),7.34–7.29(m,1H),7.16(td,J＝7.5,1.2Hz,1H),7.09(t,J＝9.7,8.2,1.1Hz,1H),3.64(s,1H),3.43(d,J＝17.4Hz,1H),3.35–3.32(m,1H),2.97–2.86(m,2H),2.81–2.73(m,1H),2.42(t,J＝13.7,11.4,2.9Hz,1H),2.30(dd,J＝27.2,14.7Hz,1H),2.01–1.92(m,2H),1.90–1.71(m,3H),1.65(t,J＝17.3,14.7Hz,1H). tert-Butyl-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl )piperidine-1-carboxylate was replaced by tert-butyl-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo -2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate, the rest of the required raw materials, reagents and preparation methods are the same as step d in Example 19 to obtain 200 mg of the target intermediate 2-(( 4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, White solid, yield 95%. 1 H NMR (600MHz, CD 3 OD) δ7.64(d, J=7.9Hz, 1H), 7.45–7.40(m, 1H), 7.34–7.29(m, 1H), 7.16(td, J=7.5, 1.2Hz, 1H), 7.09(t, J=9.7, 8.2, 1.1Hz, 1H), 3.64(s, 1H), 3.43(d, J=17.4Hz, 1H), 3.35–3.32(m, 1H), 2.97–2.86(m,2H),2.81–2.73(m,1H),2.42(t,J=13.7,11.4,2.9Hz,1H),2.30(dd,J=27.2,14.7Hz,1H),2.01– 1.92(m,2H),1.90–1.71(m,3H),1.65(t,J=17.3,14.7Hz,1H).
步骤f：3-((4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈的合成Step f: 3-((4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000068
Figure PCTCN2022141611-appb-000068
将2-((1-苄基-4-氟哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮替换为2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，其余所需原料、试剂及制备方法同实施例19步骤f，得3-((4-(2-((4-氟-1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率58％。 1H NMR(600MHz,CD 3OD)δ8.05(s,1H),7.51(d,J＝8.0Hz,1H),7.41(d,J＝8.5Hz,1H),7.35–7.28(m,4H),7.23–7.17(m,2H),7.06(td,J＝7.4,1.2Hz,1H),7.01–6.96(m,1H),3.73(s,2H),3.53(s,2H),3.36–3.28(m,1H),3.04(d,J＝11.3Hz,2H),2.81(dd,J＝17.3,4.7Hz,1H),2.73(s,1H),2.70–2.63(m,2H),2.59–2.52(m,1H),2.35–2.28(m,2H),2.24–2.13(m,3H),1.90–1.83(m,1H),1.78–1.60(m,7H),1.59–1.49(m,1H).HRMS(ESI)m/z calcd for C 37H 39N 4O[M+H] +593.3092,found 593.3092. Replace 2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one with For 2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene -1-ketone, all the other required raw materials, reagents and preparation methods are the same as in Example 19 step f, to obtain 3-((4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidine-4 -yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile, white solid , yield 58%. 1 H NMR (600MHz, CD 3 OD) δ8.05(s, 1H), 7.51(d, J=8.0Hz, 1H), 7.41(d, J=8.5Hz, 1H), 7.35–7.28(m, 4H ),7.23–7.17(m,2H),7.06(td,J＝7.4,1.2Hz,1H),7.01–6.96(m,1H),3.73(s,2H),3.53(s,2H),3.36– 3.28(m,1H),3.04(d,J=11.3Hz,2H),2.81(dd,J=17.3,4.7Hz,1H),2.73(s,1H),2.70–2.63(m,2H),2.59 –2.52(m,1H),2.35–2.28(m,2H),2.24–2.13(m,3H),1.90–1.83(m,1H),1.78–1.60(m,7H),1.59–1.49(m, 1H).HRMS(ESI)m/z calcd for C 37 H 39 N 4 O[M+H] + 593.3092,found 593.3092.
实施例21 3-((4-(2-((1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–9)的制备 Example 21 3-((4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Preparation of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile (I b -9)
Figure PCTCN2022141611-appb-000069
Figure PCTCN2022141611-appb-000069
方案4：Option 4:
Figure PCTCN2022141611-appb-000070
Figure PCTCN2022141611-appb-000070
步骤a 叔丁基-(E)-4-((5-溴-1-氧代-1,3-二氢-2H-茚-2-亚基)甲基)哌啶-1-羧酸酯的合 成Step a Tert-butyl-(E)-4-((5-bromo-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methyl)piperidine-1-carboxylate Synthesis
Figure PCTCN2022141611-appb-000071
Figure PCTCN2022141611-appb-000071
-78℃下，在N 2保护的双口烧瓶中加入无水THF(250mL)后加入LDA(2M的THF溶液)(60mmol)，搅拌片刻，用恒压漏斗滴加5-溴茚酮(10g,50mmol)的无水THF溶液(100mL)，滴加完毕后搅拌0.5h，用恒压漏斗缓慢滴加N-叔丁氧羰基-4-哌啶甲醛(10.2g,50mmol)的无水THF溶液(100mL)，继续搅拌1～2h，恢复至室温。向反应液中加入NH 4Cl饱和溶液淬灭反应，减压蒸除THF，残留物用二氯甲烷萃取(200mL×3)，合并有机相用饱和NaCl溶液洗后，无水Na 2SO 4干燥，蒸干后的粗品经柱层析纯化，乙酸乙酯:石油醚＝1:11洗脱，得到白色固体11.6g，为叔丁基-(E)-4-((5-溴-1-氧代-1,3-二氢-2H-茚-2-亚基)甲基)哌啶-1-羧酸酯，收率55％。 1H NMR(400MHz,Acetone-d 6)δ7.84(s,1H),7.71–7.62(m,2H),6.62(dt,J＝9.7,2.2Hz,1H),4.12(d,J＝13.5Hz,2H),3.87–3.82(m,2H),2.96–2.93(m,4H),2.73–2.60(m,1H),1.78–1.69(m,2H),1.45(s,9H). At -78°C, add anhydrous THF (250mL) to a N2 - protected two-necked flask, then add LDA (2M solution in THF) (60mmol), stir for a while, then add 5-bromoindanone (10g , 50mmol) in anhydrous THF solution (100mL), after the dropwise addition, stir for 0.5h, and slowly add N-tert-butoxycarbonyl-4-piperidinecarbaldehyde (10.2g, 50mmol) in anhydrous THF solution dropwise with a constant pressure funnel (100 mL), continue stirring for 1-2 h, and return to room temperature. Add saturated NH 4 Cl solution to the reaction liquid to quench the reaction, evaporate THF under reduced pressure, extract the residue with dichloromethane (200 mL×3), combine the organic phases, wash with saturated NaCl solution, and dry over anhydrous Na 2 SO 4 , The crude product after evaporating to dryness was purified by column chromatography, and ethyl acetate:petroleum ether=1:11 was eluted to obtain 11.6g of white solid, which was tert-butyl-(E)-4-((5-bromo-1- Oxo-1,3-dihydro-2H-inden-2-ylidene)methyl)piperidine-1-carboxylate, yield 55%. 1 H NMR (400MHz, Acetone-d 6 ) δ7.84(s, 1H), 7.71–7.62(m, 2H), 6.62(dt, J=9.7, 2.2Hz, 1H), 4.12(d, J=13.5 Hz,2H),3.87–3.82(m,2H),2.96–2.93(m,4H),2.73–2.60(m,1H),1.78–1.69(m,2H),1.45(s,9H).
步骤m：(E)-5-溴-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-1-酮的合成Step m: Synthesis of (E)-5-bromo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-1-one
Figure PCTCN2022141611-appb-000072
Figure PCTCN2022141611-appb-000072
将叔丁基-(E)-4-((5-溴-1-氧代-1,3-二氢-2H-茚-2-亚基)甲基)哌啶-1-羧酸酯(1g，2.46mmol)溶于250mL二氯甲烷中，搅拌下滴加80mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入100mL二氯甲烷复溶，再加入50mL饱和碳酸氢钠溶液洗涤有机相，析出大量白色固体，得675mg(E)-5-溴-2-((4-氟哌啶-4-基)亚甲基)-2,3-二氢-1H-茚-1-酮，收率90％。未纯化可直接投下一步。Tert-butyl-(E)-4-((5-bromo-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methyl)piperidine-1-carboxylate ( 1g, 2.46mmol) was dissolved in 250mL of dichloromethane, 80mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 100 mL of dichloromethane was added to the crude product to redissolve, and then 50 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and a large amount of white solid was precipitated to obtain 675 mg of (E)-5- Bromo-2-((4-fluoropiperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one, yield 90%. Unpurified can be directly submitted to the next step.
步骤b：叔丁基-(E)-4-(1-氧代-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成Step b: tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3 , Synthesis of 6-dihydropyridine-1(2H)-carboxylate
Figure PCTCN2022141611-appb-000073
Figure PCTCN2022141611-appb-000073
将(E)-5-溴-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-1-酮(900mg，2.94mmol)和N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(1.1g，3.53mmol)溶于无水四氢呋喃(30mL)中，加入Pd(dppf)Cl 2(108mg，0.147mmol)和K 2CO 3(1.22g，8.82mmol)，水泵脱气2分钟，氮气保护下100℃反应过夜。旋干反应液，反应体系中加入100mL乙酸乙酯和100mL水萃 取，有机相经饱和食盐水洗涤，无水Na 2SO 4干燥，抽滤，旋蒸除去溶剂，加入20mL乙酸乙酯打浆，过滤得451mg叔丁基-(E)-4-(1-氧代-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯，褐色固体，收率38％。 1H NMR(400MHz,CD 3OD)δ7.78(d,J＝8.1Hz,1H),7.66(s,1H),7.57(d,J＝8.1Hz,1H),6.65(d,J＝9.8Hz,1H),6.35(s,1H),4.14(s,2H),3.80(s,2H),3.69(s,2H),3.63(q,J＝7.0Hz,1H),3.28(d,J＝12.6Hz,2H),2.97–2.88(m,2H),2.62(s,2H),1.89(d,J＝13.6Hz,2H),1.69–1.56(m,2H),1.52(s,9H). (E)-5-bromo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-1-one (900mg, 2.94mmol) and N-Boc-1, 2,5,6-Tetrahydropyridine-4-boronic acid pinacol ester (1.1 g, 3.53 mmol) was dissolved in anhydrous THF (30 mL), Pd(dppf)Cl 2 (108 mg, 0.147 mmol) and K 2 were added CO 3 (1.22g, 8.82mmol), degassed by water pump for 2 minutes, reacted overnight at 100°C under nitrogen protection. Spin to dry the reaction solution, add 100mL ethyl acetate and 100mL water to the reaction system for extraction, wash the organic phase with saturated brine, dry over anhydrous Na2SO4 , filter with suction, remove the solvent by rotary evaporation, add 20mL ethyl acetate for beating, and filter Obtained 451 mg tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3, 6-Dihydropyridine-1(2H)-carboxylate, brown solid, yield 38%. 1 H NMR (400MHz, CD 3 OD) δ7.78(d, J=8.1Hz, 1H), 7.66(s, 1H), 7.57(d, J=8.1Hz, 1H), 6.65(d, J=9.8 Hz,1H),6.35(s,1H),4.14(s,2H),3.80(s,2H),3.69(s,2H),3.63(q,J＝7.0Hz,1H),3.28(d,J ＝12.6Hz, 2H), 2.97–2.88(m, 2H), 2.62(s, 2H), 1.89(d, J＝13.6Hz, 2H), 1.69–1.56(m, 2H), 1.52(s, 9H) .
步骤c：叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step c: tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylic acid Synthesis of esters
Figure PCTCN2022141611-appb-000074
Figure PCTCN2022141611-appb-000074
将1.0g叔丁基-(E)-4-(1-氧代-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯溶于10mL甲醇和10mL二氯甲烷的混合溶剂中，加入100mg 10％Pd/C，搅拌下置换氢气3～4次，室温反应过夜。反应完毕后垫硅藻土过滤掉Pd/C，用30mL甲醇、二氯甲烷混合溶液洗涤滤饼，旋干滤液。粗产品柱层析纯化，洗脱剂为乙酸乙酯:二氯甲烷＝1:1。得285mg叔丁基-4-(2-((1-苯基-4-氟哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，白色固体，收率45％。 1H NMR(400MHz,CD3OD)δ7.63(d,J＝8.0Hz,1H),7.42(s,1H),7.32(d,J＝8.0Hz,1H),4.22(d,2H),3.46–3.34(m,3H),3.01(td,J＝12.9,3.1Hz,2H),2.92–2.73(m,4H),2.12–2.03(m,1H),1.98(s,2H),1.84(d,J＝11.8,3.6Hz,2H),1.63(qd,J＝12.7,4.3Hz,2H),1.48(s,9H),1.46–1.41(m,2H). 1.0g tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3 , 6-dihydropyridine-1(2H)-carboxylate was dissolved in a mixed solvent of 10mL methanol and 10mL dichloromethane, added 100mg 10% Pd/C, replaced hydrogen 3-4 times under stirring, and reacted overnight at room temperature. After the reaction was completed, the Pd/C was filtered out with a pad of diatomaceous earth, the filter cake was washed with 30 mL of a mixed solution of methanol and dichloromethane, and the filtrate was spin-dried. The crude product was purified by column chromatography, and the eluent was ethyl acetate:dichloromethane=1:1. 285 mg of tert-butyl-4-(2-((1-phenyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5- Base) piperidine-1-carboxylate, white solid, yield 45%. 1 H NMR (400MHz, CD3OD) δ7.63(d, J=8.0Hz, 1H), 7.42(s, 1H), 7.32(d, J=8.0Hz, 1H), 4.22(d, 2H), 3.46– 3.34(m,3H),3.01(td,J＝12.9,3.1Hz,2H),2.92–2.73(m,4H),2.12–2.03(m,1H),1.98(s,2H),1.84(d, J＝11.8, 3.6Hz, 2H), 1.63(qd, J＝12.7, 4.3Hz, 2H), 1.48(s, 9H), 1.46–1.41(m, 2H).
步骤n：叔丁基-4-(2-((1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step n: tert-butyl-4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
Figure PCTCN2022141611-appb-000075
Figure PCTCN2022141611-appb-000075
将361mg叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶解于10mL乙腈和5mL DMF中，搅拌下滴加160μL 2-氟苄溴，加入363mg碳酸钾固体，室温反应1小时。过滤除去盐，加入1N HCl溶液中和至中性，加入乙酸乙酯萃取三遍(30mL×3)，合并有机相，水洗一遍(30mL)，饱和氯化钠洗涤有机相，无水硫酸钠干燥，过滤得滤液，旋干后粗产品经柱层析纯化，洗脱剂为甲醇:二氯甲烷＝1:60，得174mg中间体叔丁基-4-(2-((1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，无色油状液体，收率38％。 1H NMR(400MHz,Acetone-d 6)δ7.58(d,J＝7.9Hz, 1H),7.50(s,1H),7.43(s,1H),7.36–7.27(m,2H),7.17(t,J＝7.4Hz,1H),7.09(t,J＝9.3Hz,1H),4.22(d,J＝13.2Hz,2H),3.58(s,2H),3.37(dd,J＝17.0,7.8Hz,1H),3.00–2.67(m,9H),1.82(dq,J＝12.8,4.6Hz,4H),1.71(d,J＝12.5Hz,1H),1.62(qd,J＝12.6,4.3Hz,3H),1.46(s,9H),1.39–1.25(m,3H). 361 mg tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate Dissolve in 10 mL of acetonitrile and 5 mL of DMF, add 160 μL of 2-fluorobenzyl bromide dropwise with stirring, add 363 mg of solid potassium carbonate, and react at room temperature for 1 hour. Filter to remove salt, add 1N HCl solution to neutralize to neutral, add ethyl acetate to extract three times (30mL×3), combine the organic phase, wash once with water (30mL), wash the organic phase with saturated sodium chloride, and dry over anhydrous sodium sulfate , filtered to get the filtrate, and the crude product was purified by column chromatography after being spin-dried, and the eluent was methanol:dichloromethane=1:60 to obtain 174mg intermediate tert-butyl-4-(2-((1-(2- Fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate, colorless oily liquid, rate of 38%. 1 H NMR (400MHz, Acetone-d 6 ) δ7.58(d, J=7.9Hz, 1H), 7.50(s, 1H), 7.43(s, 1H), 7.36–7.27(m, 2H), 7.17( t,J=7.4Hz,1H),7.09(t,J=9.3Hz,1H),4.22(d,J=13.2Hz,2H),3.58(s,2H),3.37(dd,J=17.0,7.8 Hz, 1H), 3.00–2.67(m, 9H), 1.82(dq, J=12.8, 4.6Hz, 4H), 1.71(d, J=12.5Hz, 1H), 1.62(qd, J=12.6, 4.3Hz ,3H),1.46(s,9H),1.39–1.25(m,3H).
步骤d：2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step d: 2-((1-(2-Fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1 -Synthesis of ketones
Figure PCTCN2022141611-appb-000076
Figure PCTCN2022141611-appb-000076
将453mg叔丁基-4-(2-((1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶于25mL二氯甲烷中，搅拌下滴加8mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入5mL饱和碳酸氢钠溶液洗涤有机相，二氯甲烷萃取水相三遍(20mL×3)，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液，旋干后得329mg 2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，未经纯化直接可投下一步。白色固体，收率90％。453mg of tert-butyl-4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 -yl) piperidine-1-carboxylate was dissolved in 25 mL of dichloromethane, 8 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 5 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and the aqueous phase was extracted three times with dichloromethane (20 mL×3) , the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and spin-dried to obtain 329mg 2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)- 5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, without purification, it can be directly used for the next step. White solid, yield 90%.
步骤f：3-((4-(2-((1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈的合成Step f: 3-((4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000077
Figure PCTCN2022141611-appb-000077
将5-氰基-吲哚-3-甲醛(49mg，0.285mmol)和2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(100mg，0.174mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(30mg，0.476mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到80mg 3-((4-(2-((1-(2-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率60％。 1H NMR(600MHz,CD 3OD)δ8.27–8.25(m,1H),7.63–7.60(m,2H),7.58(dd,J＝8.5,0.8Hz,1H),7.49(dd,J＝8.5,1.6Hz,1H),7.46–7.41(m,2H),7.37–7.31(m,2H),7.19(td,J＝7.6,1.2Hz,1H),7.14–7.09(m,1H),3.68(s,2H),3.40–3.34(m,2H),3.31–3.29(m,1H),3.00(t,J＝13.8Hz,2H),2.87–2.80(m,2H),2.79–2.65(m,4H),2.29(td,J＝11.5,2.6Hz,1H),2.24–2.14(m,2H),2.08–1.99(m,2H),1.88– 1.79(m,3H),1.74(d,J＝13.2Hz,1H),1.66(qd,J＝12.3,4.0Hz,1H),1.57(s,1H),1.43–1.34(m,3H).HRMS(ESI)m/z calcd for C 37H 40N 4O[M-H] +573.3030,found 573.3031. Mix 5-cyano-indole-3-carbaldehyde (49mg, 0.285mmol) and 2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidine-4 -yl)-2,3-dihydro-1H-inden-1-one (100mg, 0.174mmol) was placed in a flask, and anhydrous methanol:anhydrous dichloromethane=1:1 (v:v) was added to dissolve, Add sodium cyanoborohydride (30mg, 0.476mmol) and react overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 80 mg of 3-((4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo Dihydro-2,3-dihydro-1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile, white solid, yield 60%. 1 H NMR (600MHz, CD 3 OD) δ8.27–8.25 (m, 1H), 7.63–7.60 (m, 2H), 7.58 (dd, J=8.5, 0.8Hz, 1H), 7.49 (dd, J= 8.5,1.6Hz,1H),7.46–7.41(m,2H),7.37–7.31(m,2H),7.19(td,J＝7.6,1.2Hz,1H),7.14–7.09(m,1H),3.68 (s,2H),3.40–3.34(m,2H),3.31–3.29(m,1H),3.00(t,J＝13.8Hz,2H),2.87–2.80(m,2H),2.79–2.65(m ,4H),2.29(td,J＝11.5,2.6Hz,1H),2.24–2.14(m,2H),2.08–1.99(m,2H),1.88–1.79(m,3H),1.74(d,J =13.2Hz,1H),1.66(qd,J=12.3,4.0Hz,1H),1.57(s,1H),1.43–1.34(m,3H).HRMS(ESI)m/z calcd for C 37 H 40 N 4 O[MH] + 573.3030, found 573.3031.
实施例22 3-((4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–10)的制备 Example 22 3-((4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Preparation of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile (I b -10)
Figure PCTCN2022141611-appb-000078
Figure PCTCN2022141611-appb-000078
叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成方法同实施例21。Synthesis of tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate The method is the same as in Example 21.
步骤a：叔丁基-4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step a: tert-butyl-4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
Figure PCTCN2022141611-appb-000079
Figure PCTCN2022141611-appb-000079
将500mg叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶解于10mL乙腈和5mL DMF中，搅拌下滴加220μL 3-氟苄溴，加入502mg碳酸钾固体，室温反应1小时。过滤除去盐，加入1N HCl溶液中和至中性，加入乙酸乙酯萃取三遍(30mL×3)，合并有机相，水洗一遍(30mL)，饱和氯化钠洗涤有机相，无水硫酸钠干燥，过滤得滤液，旋干后粗产品经柱层析纯化，洗脱剂为甲醇:二氯甲烷＝1:60，得254mg中间体叔丁基-4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，白色固体，收率40％。 1H NMR(400MHz,CDCl 3)δ7.67(d,J＝7.9Hz,1H),7.35–7.28(m,1H),7.27(d,J＝2.9Hz,1H),7.21(d,J＝7.9Hz,2H),7.15(d,J＝9.8Hz,1H),6.99(td,J＝8.5,2.6Hz,1H),4.27(s,2H),3.67(s,2H),3.31(dd,J＝16.9,7.6Hz,1H),3.03(d,J＝10.8Hz,2H),2.73(m,5H),2.19(s,2H),1.96–1.88(m,1H),1.86–1.74(m,4H),1.54(s,5H),1.49(s,9H),1.43–1.36(m,1H). 500mg tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate Dissolve in 10 mL of acetonitrile and 5 mL of DMF, add 220 μL of 3-fluorobenzyl bromide dropwise with stirring, add 502 mg of solid potassium carbonate, and react at room temperature for 1 hour. Filter to remove salt, add 1N HCl solution to neutralize to neutral, add ethyl acetate to extract three times (30mL×3), combine the organic phase, wash once with water (30mL), wash the organic phase with saturated sodium chloride, and dry over anhydrous sodium sulfate , filtered to get the filtrate, the crude product was purified by column chromatography after being spin-dried, and the eluent was methanol:dichloromethane=1:60 to obtain 254mg intermediate tert-butyl-4-(2-((1-(3- Fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate, white solid, yield 40 %. 1 H NMR (400MHz, CDCl 3 ) δ7.67(d, J=7.9Hz, 1H), 7.35–7.28(m, 1H), 7.27(d, J=2.9Hz, 1H), 7.21(d, J= 7.9Hz, 2H), 7.15(d, J=9.8Hz, 1H), 6.99(td, J=8.5, 2.6Hz, 1H), 4.27(s, 2H), 3.67(s, 2H), 3.31(dd, J＝16.9, 7.6Hz, 1H), 3.03(d, J＝10.8Hz, 2H), 2.73(m, 5H), 2.19(s, 2H), 1.96–1.88(m, 1H), 1.86–1.74(m ,4H), 1.54(s,5H), 1.49(s,9H), 1.43–1.36(m,1H).
步骤b：2-((1-(3-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step b: 2-((1-(3-Fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1 -Synthesis of ketones
Figure PCTCN2022141611-appb-000080
Figure PCTCN2022141611-appb-000080
将615mg叔丁基-4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌 啶-1-羧酸酯溶于25mL二氯甲烷中，搅拌下滴加8mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入5mL饱和碳酸氢钠溶液洗涤有机相，二氯甲烷萃取水相三遍(20mL×3)，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液，旋干后得392mg 2-((1-(3-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，未经纯化直接可投下一步。白色固体，收率78％。 1H NMR(400MHz,CD 3OD)δ7.65(d,J＝7.9Hz,1H),7.46(s,1H),7.42–7.31(m,2H),7.24–7.14(m,2H),7.07(td,J＝8.5,2.6Hz,1H),3.76(s,2H),3.51(d,J＝13.4,2.8Hz,2H),3.38(dd,J＝17.2,7.5Hz,1H),3.15(td,J＝13.0,3.1Hz,2H),3.10–2.99(m,3H),2.86–2.72(m,2H),2.33(t,J＝11.9Hz,2H),2.09(d,J＝14.7,4.0Hz,2H),2.03–1.75(m,5H),1.66(s,1H),1.49–1.30(m,3H). 615mg of tert-butyl-4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 -yl) piperidine-1-carboxylate was dissolved in 25 mL of dichloromethane, 8 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 5 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and the aqueous phase was extracted three times with dichloromethane (20 mL×3) , the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and spin-dried to obtain 392 mg of 2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)- 5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, without purification, it can be directly used for the next step. White solid, yield 78%. 1 H NMR (400MHz, CD 3 OD) δ7.65 (d, J=7.9Hz, 1H), 7.46 (s, 1H), 7.42–7.31 (m, 2H), 7.24–7.14 (m, 2H), 7.07 (td,J=8.5,2.6Hz,1H),3.76(s,2H),3.51(d,J=13.4,2.8Hz,2H),3.38(dd,J=17.2,7.5Hz,1H),3.15( td,J=13.0,3.1Hz,2H),3.10–2.99(m,3H),2.86–2.72(m,2H),2.33(t,J=11.9Hz,2H),2.09(d,J=14.7, 4.0Hz, 2H), 2.03–1.75(m, 5H), 1.66(s, 1H), 1.49–1.30(m, 3H).
步骤c：3-((4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈的合成Step c: 3-((4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000081
Figure PCTCN2022141611-appb-000081
将5-氰基-吲哚-3-甲醛(49mg，0.285mmol)和2-((1-(3-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(100mg，0.238mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(30mg，0.476mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到73mg 3-((4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率55％。 1H NMR(600MHz,CDCl 3)δ8.81(s,1H),8.19(s,1H),7.66(d,J＝8.0Hz,1H),7.43(s,2H),7.33–7.28(m,2H),7.28–7.21(m,2H),7.11–7.03(m,2H),6.93(td,J＝8.5,2.7Hz,1H),3.77(s,2H),3.50(s,2H),3.30(dd,J＝17.1,7.8Hz,1H),3.11(dt,J＝11.7,3.5Hz,2H),2.89(t,J＝11.3Hz,2H),2.76(dd,J＝17.1,3.9Hz,1H),2.73–2.67(m,1H),2.64–2.55(m,1H),2.20–2.12(m,2H),2.04–1.96(m,2H),1.94–1.88(m,1H),1.87–1.81(m,4H),1.73(d,J＝12.6,3.1Hz,1H),1.67(d,J＝12.8,3.1Hz,1H),1.58–1.48(m,1H),1.42–1.30(m,2H).HRMS(ESI)m/z calcd for C 37H 40FN 4O[M+H] +575.3186,found 575.3187. Mix 5-cyano-indole-3-carbaldehyde (49mg, 0.285mmol) and 2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4 -yl)-2,3-dihydro-1H-inden-1-one (100mg, 0.238mmol) was placed in a flask, and anhydrous methanol:anhydrous dichloromethane=1:1 (v:v) was added to dissolve, Add sodium cyanoborohydride (30mg, 0.476mmol) and react overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 73 mg of 3-((4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo Dihydro-2,3-dihydro-1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile, white solid, yield 55%. 1 H NMR (600MHz, CDCl 3 ) δ8.81(s, 1H), 8.19(s, 1H), 7.66(d, J=8.0Hz, 1H), 7.43(s, 2H), 7.33–7.28(m, 2H),7.28–7.21(m,2H),7.11–7.03(m,2H),6.93(td,J＝8.5,2.7Hz,1H),3.77(s,2H),3.50(s,2H),3.30 (dd, J=17.1,7.8Hz,1H),3.11(dt,J=11.7,3.5Hz,2H),2.89(t,J=11.3Hz,2H),2.76(dd,J=17.1,3.9Hz, 1H),2.73–2.67(m,1H),2.64–2.55(m,1H),2.20–2.12(m,2H),2.04–1.96(m,2H),1.94–1.88(m,1H),1.87– 1.81(m,4H),1.73(d,J=12.6,3.1Hz,1H),1.67(d,J=12.8,3.1Hz,1H),1.58–1.48(m,1H),1.42–1.30(m, 2H).HRMS(ESI)m/z calcd for C 37 H 40 FN 4 O[M+H] + 575.3186,found 575.3187.
实施例23 3-((4-(2-((1-(3-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈(I b–11)的制备 Example 23 3-((4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Preparation of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile (I b -11)
Figure PCTCN2022141611-appb-000082
Figure PCTCN2022141611-appb-000082
叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成方法同实施例21。Synthesis of tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate The method is the same as in Example 21.
步骤a：叔丁基-4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step a: tert-butyl-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
Figure PCTCN2022141611-appb-000083
Figure PCTCN2022141611-appb-000083
将500mg叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶解于10mL乙腈和5mL DMF中，搅拌下滴加227μL4-氟苄溴，加入502mg碳酸钾固体，室温反应1小时。过滤除去盐，加入1N HCl溶液中和至中性，加入乙酸乙酯萃取三遍(30mL×3)，合并有机相，水洗一遍(30mL)，饱和氯化钠洗涤有机相，无水硫酸钠干燥，过滤得滤液，旋干后粗产品经柱层析纯化，洗脱剂为甲醇:二氯甲烷＝1:60，得200mg中间体叔丁基-4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，无色油状液体，收率32％。 1H NMR(400MHz,CDCl 3)δ7.67(d,J＝7.9Hz,1H),7.40(s,2H),7.24–7.18(m,2H),7.04(t,J＝8.4Hz,2H),4.27(s,2H),3.69(s,2H),3.31(dd,J＝17.0,7.7Hz,1H),3.04(s,2H),2.88–2.62(m,5H),2.35–2.05(m,2H),1.94–1.73(m,6H),1.70–1.60(m,5H),1.49(s,9H). 500mg tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate Dissolve in 10 mL of acetonitrile and 5 mL of DMF, add 227 μL of 4-fluorobenzyl bromide dropwise with stirring, add 502 mg of solid potassium carbonate, and react at room temperature for 1 hour. Filter to remove salt, add 1N HCl solution to neutralize to neutral, add ethyl acetate to extract three times (30mL×3), combine the organic phase, wash once with water (30mL), wash the organic phase with saturated sodium chloride, and dry over anhydrous sodium sulfate , filtered to get the filtrate, and the crude product was purified by column chromatography after being spin-dried, and the eluent was methanol:dichloromethane=1:60 to obtain 200mg intermediate tert-butyl-4-(2-((1-(4- Fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate, colorless oily liquid, rate of 32%. 1 H NMR (400MHz, CDCl 3 ) δ7.67(d, J=7.9Hz, 1H), 7.40(s, 2H), 7.24–7.18(m, 2H), 7.04(t, J=8.4Hz, 2H) ,4.27(s,2H),3.69(s,2H),3.31(dd,J＝17.0,7.7Hz,1H),3.04(s,2H),2.88–2.62(m,5H),2.35–2.05(m ,2H),1.94–1.73(m,6H),1.70–1.60(m,5H),1.49(s,9H).
步骤d：2-((1-(4-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step d: 2-((1-(4-Fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1 -Synthesis of ketones
Figure PCTCN2022141611-appb-000084
Figure PCTCN2022141611-appb-000084
将619mg叔丁基-4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶于25mL二氯甲烷中，搅拌下滴加8mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入5mL饱和碳酸氢钠溶液洗涤有机相，二氯甲烷萃取水相三遍(20mL×3)，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液，旋干后得400mg 2-((1-(4-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，未经纯化直接可投下一步。白色固体，收率80％。619mg of tert-butyl-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 -yl) piperidine-1-carboxylate was dissolved in 25 mL of dichloromethane, 8 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 5 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and the aqueous phase was extracted three times with dichloromethane (20 mL×3) , the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and spin-dried to obtain 400 mg of 2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)- 5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, without purification, it can be directly used for the next step. White solid, yield 80%.
步骤f：3-((4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈的合成Step f: 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000085
Figure PCTCN2022141611-appb-000085
将5-氰基-吲哚-3-甲醛(49mg，0.285mmol)和2-((1-(4-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(100mg，0.238mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(30mg，0.476mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到80mg 3-((4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率67％。 1H NMR(400MHz,CD 3OD)δ8.17(s,1H),7.61(d,1H),7.53(d,J＝8.4Hz,1H),7.46(s,1H),7.42(d,J＝8.7,1.7Hz,2H),7.39–7.33(m,2H),7.30(d,J＝8.0Hz,1H),7.07(td,J＝8.7,1.4Hz,2H),3.85(d,J＝3.1Hz,2H),3.53(s,2H),3.39–3.34(m,1H),3.16(d,J＝11.2Hz,2H),2.92(t,J＝11.5Hz,2H),2.78(dd,J＝17.3,2.2Hz,1H),2.66(s,1H),2.33–2.20(m,2H),2.06(t,J＝12.0Hz,2H),1.93–1.76(m,6H),1.72(d,J＝13.3Hz,1H),1.56(s,1H),1.42–1.22(m,4H).HRMS(ESI)m/z calcd for C 37H 40FN 4O[M+H] +575.3186,found 575.3185. Mix 5-cyano-indole-3-carbaldehyde (49mg, 0.285mmol) and 2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4 -yl)-2,3-dihydro-1H-inden-1-one (100mg, 0.238mmol) was placed in a flask, and anhydrous methanol:anhydrous dichloromethane=1:1 (v:v) was added to dissolve, Add sodium cyanoborohydride (30mg, 0.476mmol) and react overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 80 mg of 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo Dihydro-2,3-dihydro-1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile, white solid, yield 67%. 1 H NMR (400MHz, CD 3 OD) δ8.17(s, 1H), 7.61(d, 1H), 7.53(d, J=8.4Hz, 1H), 7.46(s, 1H), 7.42(d, J =8.7,1.7Hz,2H),7.39–7.33(m,2H),7.30(d,J=8.0Hz,1H),7.07(td,J=8.7,1.4Hz,2H),3.85(d,J= 3.1Hz, 2H), 3.53(s, 2H), 3.39–3.34(m, 1H), 3.16(d, J=11.2Hz, 2H), 2.92(t, J=11.5Hz, 2H), 2.78(dd, J＝17.3, 2.2Hz, 1H), 2.66(s, 1H), 2.33–2.20(m, 2H), 2.06(t, J＝12.0Hz, 2H), 1.93–1.76(m, 6H), 1.72(d ,J＝13.3Hz,1H),1.56(s,1H),1.42–1.22(m,4H).HRMS(ESI)m/z calcd for C 37 H 40 FN 4 O[M+H] + 575.3186,found 575.3185.
实施例24 2-((1-苄基哌啶-4-基)甲基)-5-(1-((5-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮(I b–12)的制备 Example 24 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((5-fluoro-1H-indol-3-yl)methyl)piperidine-4- The preparation of -2,3-dihydro-1H-inden-1-one (I b -12)
Figure PCTCN2022141611-appb-000086
Figure PCTCN2022141611-appb-000086
叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯合成方法同实施例21。Synthesis method of tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate Same as Example 21.
步骤a：叔丁基-4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯的合成Step a: tert-Butyl-4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piper Synthesis of Pyridine-1-Carboxylate
Figure PCTCN2022141611-appb-000087
Figure PCTCN2022141611-appb-000087
将540mg叔丁基-4-(1-氧代-2-(哌啶-4-基甲基)-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯 溶解于10mL乙腈和5mL DMF中，搅拌下滴加171μL苄溴，加入542mg碳酸钾固体，室温反应1小时。过滤除去盐，加入1N HCl溶液中和至中性，加入乙酸乙酯萃取三遍(30mL×3)，合并有机相，水洗一遍(30mL)，饱和氯化钠洗涤有机相，无水硫酸钠干燥，过滤得滤液，旋干后粗产品不需要纯化，可直接投下一步，得658mg中间体叔丁基-4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯，无色油状液体，收率32％。 1H NMR(400MHz,CDCl 3)δ7.68(d,J＝7.9Hz,1H),7.41–7.27(m,5H),7.21(d,J＝8.0Hz,1H),4.27(s,1H),3.57(s,1H),3.30(dd,J＝16.9,7.6Hz,1H),2.94(s,1H),2.85–2.66(m,2H),2.05(s,1H),1.96–1.87(m,1H),1.83(d,J＝12.6Hz,2H),1.78–1.57(m,2H),1.49(s,4H),1.43–1.30(m,1H). 540mg tert-butyl-4-(1-oxo-2-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate Dissolve in 10 mL of acetonitrile and 5 mL of DMF, add 171 μL of benzyl bromide dropwise with stirring, add 542 mg of solid potassium carbonate, and react at room temperature for 1 hour. Filter to remove salt, add 1N HCl solution to neutralize to neutral, add ethyl acetate to extract three times (30mL×3), combine the organic phase, wash once with water (30mL), wash the organic phase with saturated sodium chloride, and dry over anhydrous sodium sulfate , filtered to get the filtrate, the crude product does not need to be purified after being spin-dried, and can be directly cast into the next step to obtain 658 mg of intermediate tert-butyl-4-(2-((1-benzylpiperidin-4-yl)methyl)-1 -Oxo-2,3-dihydro-1H-inden-5-yl)piperidine-1-carboxylate, colorless oily liquid, yield 32%. 1 H NMR (400MHz, CDCl 3 ) δ7.68(d, J=7.9Hz, 1H), 7.41–7.27(m, 5H), 7.21(d, J=8.0Hz, 1H), 4.27(s, 1H) ,3.57(s,1H),3.30(dd,J＝16.9,7.6Hz,1H),2.94(s,1H),2.85–2.66(m,2H),2.05(s,1H),1.96–1.87(m ,1H),1.83(d,J＝12.6Hz,2H),1.78–1.57(m,2H),1.49(s,4H),1.43–1.30(m,1H).
步骤d：2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step d: Synthesis of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one
Figure PCTCN2022141611-appb-000088
Figure PCTCN2022141611-appb-000088
将392mg叔丁基-4-(2-((1-苄基哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-羧酸酯溶于25mL二氯甲烷中，搅拌下滴加8mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入5mL饱和碳酸氢钠溶液洗涤有机相，二氯甲烷萃取水相三遍(20mL×3)，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液，旋干后得204mg 2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮，未经纯化直接可投下一步。白色固体，收率65％。 1H NMR(400MHz,CD 3OD)δ7.64(d,J＝7.9Hz,1H),7.45(s,1H),7.42–7.29(m,J＝15.2,6.8Hz,6H),3.73(s,2H),3.57–3.45(m,2H),3.42–3.26(m,3H),3.23–2.96(m,5H),2.79(d,J＝17.2Hz,2H),2.31(t,J＝11.6Hz,2H),2.07(d,J＝13.9Hz,2H),2.01–1.73(m,5H),1.65(s,1H),1.43–1.31(m,3H). 392mg tert-butyl-4-(2-((1-benzylpiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)piperidine -1-Carboxylate was dissolved in 25 mL of dichloromethane, 8 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 5 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and the aqueous phase was extracted three times with dichloromethane (20 mL×3) , the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and spin-dried to obtain 204 mg of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidine -4-yl)-2,3-dihydro-1H-inden-1-one, without purification, it can be sent to the next step directly. White solid, yield 65%. 1 H NMR (400MHz, CD 3 OD) δ7.64(d, J=7.9Hz, 1H), 7.45(s, 1H), 7.42–7.29(m, J=15.2, 6.8Hz, 6H), 3.73(s ,2H),3.57–3.45(m,2H),3.42–3.26(m,3H),3.23–2.96(m,5H),2.79(d,J＝17.2Hz,2H),2.31(t,J＝11.6 Hz,2H),2.07(d,J＝13.9Hz,2H),2.01–1.73(m,5H),1.65(s,1H),1.43–1.31(m,3H).
步骤f：2-((1-苄基哌啶-4-基)甲基)-5-(1-((5-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step f: 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((5-fluoro-1H-indol-3-yl)methyl)piperidine-4- Synthesis of -2,3-dihydro-1H-inden-1-one
Figure PCTCN2022141611-appb-000089
Figure PCTCN2022141611-appb-000089
将5-氟-吲哚-3-甲醛(99mg，0.608mmol)和2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(204mg，0.507mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(64mg，1.01mmol)，30℃反应过夜。加水淬灭反应， 分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到89mg 2-((1-苄基哌啶-4-基)甲基)-5-(1-((5-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率33％。 1H NMR(600MHz,CD 3OD)δ7.59(d,J＝8.0Hz,1H),7.39(s,1H),7.37(s,1H),7.36–7.30(m,6H),7.30–7.25(m,2H),6.90(td,J＝9.1,2.5Hz,1H),3.92(s,2H),3.58(s,2H),3.34(d,J＝7.9Hz,1H),3.24(d,J＝11.6Hz,2H),2.99–2.92(m,2H),2.79–2.67(m,3H),2.43(t,J＝11.9Hz,2H),2.11(t,J＝12.2,3.4Hz,2H),1.93–1.77(m,7H),1.71(d,J＝13.3,3.1Hz,1H),1.62–1.53(m,2H),1.35(d,J＝4.9Hz,1H).HRMS(ESI)m/z calcd for C 36H 41FN 3O[M+H] +550.3234,found 550.3231. Mix 5-fluoro-indole-3-carbaldehyde (99mg, 0.608mmol) and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2, 3-Dihydro-1H-inden-1-one (204mg, 0.507mmol) was placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane = 1:1 (v:v), then adding cyanoborohydrogenation Sodium (64mg, 1.01mmol), react overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 89 mg of 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((5-fluoro-1H-indole) was obtained -3-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, white solid, yield 33%. 1 H NMR (600MHz, CD 3 OD) δ7.59 (d, J = 8.0Hz, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.36–7.30 (m, 6H), 7.30–7.25 (m,2H),6.90(td,J=9.1,2.5Hz,1H),3.92(s,2H),3.58(s,2H),3.34(d,J=7.9Hz,1H),3.24(d, J＝11.6Hz, 2H), 2.99–2.92(m, 2H), 2.79–2.67(m, 3H), 2.43(t, J＝11.9Hz, 2H), 2.11(t, J＝12.2, 3.4Hz, 2H ),1.93–1.77(m,7H),1.71(d,J＝13.3,3.1Hz,1H),1.62–1.53(m,2H),1.35(d,J＝4.9Hz,1H).HRMS(ESI) m/z calcd for C 36 H 41 FN 3 O[M+H] + 550.3234, found 550.3231.
实施例25 2-((1-苄基哌啶-4-基)甲基)-5-(1-((4-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮(I b–13)的制备 Example 25 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((4-fluoro-1H-indol-3-yl)methyl)piperidine-4- The preparation of -2,3-dihydro-1H-inden-1-one (I b -13)
Figure PCTCN2022141611-appb-000090
Figure PCTCN2022141611-appb-000090
2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成方法同实施例24。The synthetic method of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one is the same as the embodiment twenty four.
步骤f：将4-氟-吲哚-3-甲醛(92mg，0.563mmol)和2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(189mg，0.469mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(59mg，0.940mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到97mg 2-((1-苄基哌啶-4-基)甲基)-5-(1-((4-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率38％。 1H NMR(400MHz,CD 3OD)δ7.58(d,J＝8.0Hz,1H),7.38(s,1H),7.34–7.30(m,4H),7.29–7.22(m,3H),7.17(d,J＝8.1Hz,1H),7.03(td,J＝8.0,5.0Hz,1H),6.69(dd,J＝11.6,7.7Hz,1H),3.93(s,2H),3.52(s,2H),3.24–3.14(m,2H),2.91(t,J＝11.4Hz,2H),2.80–2.68(m,2H),2.67–2.56(m,1H),2.37–2.25(m,2H),2.08–1.99(m,2H),1.89–1.75(m,6H),1.69(dt,J＝13.0,3.1Hz,1H),1.59–1.47(m,1H),1.39–1.29(m,4H).HRMS(ESI)m/z calcd for C 36H 41FN 3O[M+H] +550.3234,found 550.3231. Step f: Mix 4-fluoro-indole-3-carbaldehyde (92 mg, 0.563 mmol) and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl) -2,3-Dihydro-1H-inden-1-one (189mg, 0.469mmol) was placed in a flask, dissolved by adding anhydrous methanol:anhydrous dichloromethane=1:1 (v:v), and then adding cyanide Sodium borohydride (59mg, 0.940mmol) was reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 97 mg of 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((4-fluoro-1H-indole) was obtained -3-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, white solid, yield 38%. 1 H NMR (400MHz, CD 3 OD) δ7.58 (d, J = 8.0Hz, 1H), 7.38 (s, 1H), 7.34–7.30 (m, 4H), 7.29–7.22 (m, 3H), 7.17 (d,J=8.1Hz,1H),7.03(td,J=8.0,5.0Hz,1H),6.69(dd,J=11.6,7.7Hz,1H),3.93(s,2H),3.52(s, 2H),3.24–3.14(m,2H),2.91(t,J＝11.4Hz,2H),2.80–2.68(m,2H),2.67–2.56(m,1H),2.37–2.25(m,2H) ,2.08–1.99(m,2H),1.89–1.75(m,6H),1.69(dt,J＝13.0,3.1Hz,1H),1.59–1.47(m,1H),1.39–1.29(m,4H) .HRMS(ESI)m/z calcd for C 36 H 41 FN 3 O[M+H] + 550.3234,found 550.3231.
实施例26 2-((1-苄基哌啶-4-基)甲基)-5-(1-((6-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮(I b–14)的制备 Example 26 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((6-fluoro-1H-indol-3-yl)methyl)piperidine-4- base)-2,3-dihydro-1H-inden-1-one (I b -14) preparation
Figure PCTCN2022141611-appb-000091
Figure PCTCN2022141611-appb-000091
2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成方法同实施例24。The synthetic method of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one is the same as the embodiment twenty four.
步骤f：将6-氟-吲哚-3-甲醛(85mg，0.519mmol)和2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(174mg，0.432mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(54mg，0.864mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到84mg 2-((1-苄基哌啶-4-基)甲基)-5-(1-((6-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率36％。 1H NMR(600MHz,CD 3OD)δ7.63(dd,J＝8.7,5.2Hz,1H),7.59(d,J＝8.0Hz,1H),7.38(s,1H),7.35–7.31(m,4H),7.30–7.21(m,3H),7.08(dd,J＝9.8,2.3Hz,1H),6.85(ddd,J＝9.7,8.7,2.3Hz,1H),3.92(s,2H),3.58(s,2H),3.23(d,J＝11.6Hz,2H),3.01–2.91(m,2H),2.79–2.72(m,1H),2.71–2.63(m,1H),2.45–2.38(m,2H),2.11(tt,J＝12.0,2.9Hz,2H),1.92–1.76(m,6H),1.70(dt,J＝13.2,3.1Hz,1H),1.60–1.51(m,1H),1.37–1.28(m,5H).HRMS(ESI)m/z calcd for C 36H 41FN 3O[M+H] +550.3234,found550.3233. Step f: Mix 6-fluoro-indole-3-carbaldehyde (85 mg, 0.519 mmol) and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl) -2,3-Dihydro-1H-inden-1-one (174mg, 0.432mmol) was placed in a flask, dissolved by adding anhydrous methanol:anhydrous dichloromethane=1:1 (v:v), and then adding cyanide Sodium borohydride (54mg, 0.864mmol) was reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 84 mg of 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((6-fluoro-1H-indole) was obtained -3-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, white solid, yield 36%. 1 H NMR (600MHz, CD 3 OD) δ7.63 (dd, J = 8.7, 5.2Hz, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.38 (s, 1H), 7.35–7.31 (m ,4H),7.30–7.21(m,3H),7.08(dd,J＝9.8,2.3Hz,1H),6.85(ddd,J＝9.7,8.7,2.3Hz,1H),3.92(s,2H), 3.58(s,2H),3.23(d,J＝11.6Hz,2H),3.01–2.91(m,2H),2.79–2.72(m,1H),2.71–2.63(m,1H),2.45–2.38( m,2H), 2.11(tt,J=12.0,2.9Hz,2H),1.92–1.76(m,6H),1.70(dt,J=13.2,3.1Hz,1H),1.60–1.51(m,1H) ,1.37–1.28(m,5H).HRMS(ESI)m/z calcd for C 36 H 41 FN 3 O[M+H] + 550.3234,found 550.3233.
实施例27 2-((1-苄基哌啶-4-基)甲基)-5-(1-((5-(三氟甲基)-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮(I b–15)的制备 Example 27 2-((1-Benzylpiperidin-4-yl)methyl)-5-(1-((5-(trifluoromethyl)-1H-indol-3-yl)methyl) Preparation of piperidin-4-yl)-2,3-dihydro-1H-inden-1-one (I b -15)
Figure PCTCN2022141611-appb-000092
Figure PCTCN2022141611-appb-000092
2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成方法同实施例24。The synthetic method of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one is the same as the embodiment twenty four.
步骤f：将5-三氟甲基-吲哚-3-甲醛(107mg，0.501mmol)和2-((1-苄基哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(168mg，0.417mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(52mg，0.835mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到90mg 2-((1-苄基哌啶-4-基)甲基)-5-(1-((5-(三氟甲基)-1H-吲哚-3-基)甲 基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率37％。 1H NMR(600MHz,CD 3OD)δ8.03(s,1H),7.59(d,J＝8.0Hz,1H),7.51(d,J＝8.5Hz,1H),7.42(s,1H),7.40–7.36(m,2H),7.34–7.30(m,4H),7.29–7.24(m,2H),3.86(s,2H),3.55(s,2H),3.17(d,J＝12.2Hz,2H),2.93(dd,J＝15.1,11.4Hz,2H),2.80–2.62(m,3H),2.28(td,J＝11.7,3.1Hz,2H),2.07(tt,J＝12.2,3.2Hz,2H),1.90–1.77(m,6H),1.70(dt,J＝13.3,3.1Hz,1H),1.61–1.50(m,1H),1.37–1.29(m,4H).HRMS(ESI)m/z calcd for C 37H 41F 3N 3O[M+H] +600.3202,found 600.3203. Step f: Combine 5-trifluoromethyl-indole-3-carbaldehyde (107 mg, 0.501 mmol) and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4 -yl)-2,3-dihydro-1H-inden-1-one (168mg, 0.417mmol) was placed in a flask, and anhydrous methanol:anhydrous dichloromethane=1:1 (v:v) was added to dissolve, Add sodium cyanoborohydride (52mg, 0.835mmol) and react overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 90 mg of 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((5-(trifluoromethyl) -1H-indol-3-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, white solid, yield 37%. 1 H NMR (600MHz, CD 3 OD) δ8.03(s, 1H), 7.59(d, J=8.0Hz, 1H), 7.51(d, J=8.5Hz, 1H), 7.42(s, 1H), 7.40–7.36(m,2H),7.34–7.30(m,4H),7.29–7.24(m,2H),3.86(s,2H),3.55(s,2H),3.17(d,J＝12.2Hz, 2H), 2.93(dd, J＝15.1, 11.4Hz, 2H), 2.80–2.62(m, 3H), 2.28(td, J＝11.7, 3.1Hz, 2H), 2.07(tt, J＝12.2, 3.2Hz ,2H),1.90–1.77(m,6H),1.70(dt,J＝13.3,3.1Hz,1H),1.61–1.50(m,1H),1.37–1.29(m,4H).HRMS(ESI)m /z calcd for C 37 H 41 F 3 N 3 O[M+H] + 600.3202, found 600.3203.
实施例28 5-(1-((5-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2-((1-(2-氟苄基)哌啶-4-基)甲基)-2,3-二氢-1H-茚-1-酮(I b–16)的制备 Example 28 5-(1-((5-fluoro-1H-indol-3-yl)methyl)piperidin-4-yl)-2-((1-(2-fluorobenzyl)piperidine- Preparation of 4-yl)methyl)-2,3-dihydro-1H-inden-1-one (I b -16)
Figure PCTCN2022141611-appb-000093
Figure PCTCN2022141611-appb-000093
2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成方法同实施例21。2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one The synthesis method is the same as in Example 21.
步骤f：将5-氟-吲哚-3-甲醛(62mg，0.382mmol)和2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(134mg，0.319mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(40mg，0.637mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到70mg 5-(1-((5-氟-1H-吲哚-3-基)甲基)哌啶-4-基)-2-((1-(2-氟苄基)哌啶-4-基)甲基)-2,3-二氢-1H-茚-1-酮，白色固体，收率40％。 1H NMR(600MHz,CD 3OD)δ7.59(d,J＝8.0Hz,1H),7.43–7.37(m,2H),7.36–7.24(m,5H),7.15(td,J＝7.5,1.2Hz,1H),7.07(ddd,J＝9.6,8.3,1.2Hz,1H),6.88(td,J＝9.1,2.5Hz,1H),3.83(s,2H),3.61(s,2H),3.21–3.15(m,2H),3.00–2.90(m,2H),2.78–2.62(m,3H),2.36–2.29(m,2H),2.10(tt,J＝11.9,3.4Hz,2H),1.90–1.76(m,6H),1.69(dt,J＝13.1,3.1Hz,1H),1.52(s,1H),1.37–1.28(m,4H).HRMS(ESI)m/z calcd for C 36H 40F 2N 3O[M+H] +568.3139,found 568.3138. Step f: Combine 5-fluoro-indole-3-carbaldehyde (62mg, 0.382mmol) and 2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidine -4-yl)-2,3-dihydro-1H-inden-1-one (134mg, 0.319mmol) was placed in a flask, and anhydrous methanol:anhydrous dichloromethane=1:1(v:v) was added Dissolved, then added sodium cyanoborohydride (40 mg, 0.637 mmol), and reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 70 mg of 5-(1-((5-fluoro-1H-indol-3-yl)methyl)piperidin-4-yl)-2-( (1-(2-fluorobenzyl)piperidin-4-yl)methyl)-2,3-dihydro-1H-inden-1-one, white solid, yield 40%. 1 H NMR (600MHz, CD 3 OD) δ7.59 (d, J = 8.0Hz, 1H), 7.43–7.37 (m, 2H), 7.36–7.24 (m, 5H), 7.15 (td, J = 7.5, 1.2Hz, 1H), 7.07(ddd, J＝9.6, 8.3, 1.2Hz, 1H), 6.88(td, J＝9.1, 2.5Hz, 1H), 3.83(s, 2H), 3.61(s, 2H), 3.21–3.15(m,2H),3.00–2.90(m,2H),2.78–2.62(m,3H),2.36–2.29(m,2H),2.10(tt,J＝11.9,3.4Hz,2H), 1.90–1.76(m,6H),1.69(dt,J＝13.1,3.1Hz,1H),1.52(s,1H),1.37–1.28(m,4H).HRMS(ESI)m/z calcd for C 36 H 40 F 2 N 3 O[M+H] + 568.3139,found 568.3138.
实施例29 2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(1-((5-(三氟甲基)-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮(I b–17)的制备 Example 29 2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(1-((5-(trifluoromethyl)-1H-indole-3- Preparation of (yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-inden-1-one (I b -17)
Figure PCTCN2022141611-appb-000094
Figure PCTCN2022141611-appb-000094
2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮的合成方法同实 施例21。2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one The synthesis method is the same as in Example 21.
步骤f：将5-三氟甲基-吲哚-3-甲醛(91mg，0.428mmol)和2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(哌啶-4-基)-2,3-二氢-1H-茚-1-酮(150mg，0.357mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(45mg，0.713mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到74mg 2-((1-(2-氟苄基)哌啶-4-基)甲基)-5-(1-((5-(三氟甲基)-1H-吲哚-3-基)甲基)哌啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率34％。 1H NMR(600MHz,CD 3OD)δ8.06(s,1H),7.61(d,J＝8.0Hz,1H),7.54(d,J＝8.5Hz,1H),7.47–7.39(m,4H),7.36–7.28(m,2H),7.17(td,J＝7.5,1.2Hz,1H),7.10(ddd,J＝9.7,8.3,1.2Hz,1H),3.92(s,2H),3.64(s,2H),3.25–3.19(m,2H),2.96(dt,J＝12.7,8.4Hz,2H),2.81–2.66(m,3H),2.40–2.31(m,2H),2.13(tt,J＝11.9,3.3Hz,2H),1.92–1.78(m,6H),1.73(d,J＝3.2Hz,1H),1.58–1.50(m,1H),1.39–1.31(m,4H).HRMS(ESI)m/z calcd for C 37H 40F 4N 3O[M+H] +618.3108,found 618.3107. Step f: Combine 5-trifluoromethyl-indole-3-carbaldehyde (91 mg, 0.428 mmol) and 2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5- (Piperidin-4-yl)-2,3-dihydro-1H-inden-1-one (150mg, 0.357mmol) was placed in a flask, and anhydrous methanol was added: anhydrous dichloromethane=1:1 (v :v) dissolved, then added sodium cyanoborohydride (45mg, 0.713mmol), and reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20) to obtain 74mg 2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(1-((5-( Trifluoromethyl)-1H-indol-3-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-inden-1-one, white solid, yield 34%. 1 H NMR (600MHz, CD 3 OD) δ8.06(s, 1H), 7.61(d, J=8.0Hz, 1H), 7.54(d, J=8.5Hz, 1H), 7.47–7.39(m, 4H ),7.36–7.28(m,2H),7.17(td,J=7.5,1.2Hz,1H),7.10(ddd,J=9.7,8.3,1.2Hz,1H),3.92(s,2H),3.64( s,2H),3.25–3.19(m,2H),2.96(dt,J＝12.7,8.4Hz,2H),2.81–2.66(m,3H),2.40–2.31(m,2H),2.13(tt, J=11.9,3.3Hz,2H),1.92–1.78(m,6H),1.73(d,J=3.2Hz,1H),1.58–1.50(m,1H),1.39–1.31(m,4H).HRMS (ESI)m/z calcd for C 37 H 40 F 4 N 3 O[M+H] + 618.3108,found 618.3107.
实施例30 (E)-3-((4-(2-((1-(4-氟苄基)哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1H-吲哚-5-甲腈(I b–18)的制备 Example 30 (E)-3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2,3-dihydro Preparation of -1H-inden-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole-5-carbonitrile (I b -18)
Figure PCTCN2022141611-appb-000095
Figure PCTCN2022141611-appb-000095
叔丁基-(E)-4-(1-氧代-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成方法同实施例24。tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3,6- The synthesis method of dihydropyridine-1(2H)-carboxylate is the same as in Example 24.
步骤a：叔丁基-(E)-4-(2-((1-(4-氟苄基)哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成Step a: tert-butyl-(E)-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2,3-dihydro Synthesis of -1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
Figure PCTCN2022141611-appb-000096
Figure PCTCN2022141611-appb-000096
将1.3g叔丁基-(E)-4-(1-氧代-2-(哌啶-4-基亚甲基)-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯溶解于20mL乙腈和5mL DMF中，搅拌下滴加516μL 4-氟苄溴，再加入1.3g碳酸钾，室温搅拌1小时。反应完毕后，旋干乙腈，剩余反应液加入50mL乙酸乙酯和50mL水萃取，分离得有机相用水洗涤三遍(50mL×3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干溶剂。粗产品用柱层析纯化，洗脱剂为甲醇:二氯甲烷＝1:60。 得白色固体750mg，收率47％。 1H NMR(400MHz,CDCl 3)δ7.84(d,J＝8.0Hz,1H),7.50–7.40(m,2H),7.35–7.29(m,1H),7.20–7.07(m,2H),6.98(t,J＝8.0Hz,1H),6.76(d,J＝9.6Hz,1H),6.21(s,1H),4.14(s,2H),3.74–3.65(m,4H),3.56(s,2H),2.95(s,2H),2.58(s,2H),2.39(s,1H),2.24–2.02(m,2H),1.73(s,2H),1.52(s,9H). 1.3 g of tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3 , 6-dihydropyridine-1(2H)-carboxylate was dissolved in 20 mL of acetonitrile and 5 mL of DMF, and 516 μL of 4-fluorobenzyl bromide was added dropwise with stirring, followed by 1.3 g of potassium carbonate, and stirred at room temperature for 1 hour. After the reaction is complete, spin dry the acetonitrile, add 50mL ethyl acetate and 50mL water to the remaining reaction liquid for extraction, separate the organic phase and wash it with water three times (50mL×3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and spin Dry solvent. The crude product was purified by column chromatography, and the eluent was methanol:dichloromethane=1:60. 750 mg of white solid was obtained with a yield of 47%. 1 H NMR (400MHz, CDCl 3 ) δ7.84(d, J=8.0Hz, 1H), 7.50–7.40(m, 2H), 7.35–7.29(m, 1H), 7.20–7.07(m, 2H), 6.98(t, J=8.0Hz, 1H), 6.76(d, J=9.6Hz, 1H), 6.21(s, 1H), 4.14(s, 2H), 3.74–3.65(m, 4H), 3.56(s ,2H),2.95(s,2H),2.58(s,2H),2.39(s,1H),2.24–2.02(m,2H),1.73(s,2H),1.52(s,9H).
步骤b：(E)-2-((1-(4-氟苄基)哌啶-4-基)亚甲基)-5-(1,2,3,6-四氢吡啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step b: (E)-2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl )-2,3-dihydro-1H-inden-1-one synthesis
Figure PCTCN2022141611-appb-000097
Figure PCTCN2022141611-appb-000097
将439mg叔丁基-(E)-4-(2-((1-(4-氟苄基)哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯溶于25mL二氯甲烷中，搅拌下滴加8mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入5mL饱和碳酸氢钠溶液洗涤有机相，二氯甲烷萃取水相三遍(20mL×3)，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤得滤液，旋干后得246mg(E)-2-((1-(4-氟苄基)哌啶-4-基)亚甲基)-5-(1,2,3,6-四氢吡啶-4-基)-2,3-二氢-1H-茚-1-酮，未经纯化直接可投下一步。白色固体，收率70％。439 mg tert-butyl-(E)-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2,3-dihydro- 1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in 25 mL of dichloromethane, 8 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 5 mL of saturated sodium bicarbonate solution was added to wash the organic phase, and the aqueous phase was extracted three times with dichloromethane (20 mL×3) , the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and spin-dried to obtain 246 mg of (E)-2-((1-(4-fluorobenzyl)piperidin-4-yl) Methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-one, without purification, it can be directly sent to the next step. White solid, yield 70%.
步骤c：3-((4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈的合成Step c: 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000098
Figure PCTCN2022141611-appb-000098
将5-氰基吲哚-3-甲醛(99mg，0.608mmol)和(E)-2-((1-(4-氟苄基)哌啶-4-基)亚甲基)-5-(1,2,3,6-四氢吡啶-4-基)-2,3-二氢-1H-茚-1-酮(204mg，0.507mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(64mg，1.01mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到89mg 3-((4-(2-((1-(4-氟苄基)哌啶-4-基)甲基)-1-氧代-2,3-二氢-1H-茚-5-基)哌啶-1-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率33％。 1H NMR(400MHz,CD 3OD)δ8.20(s,1H),7.73(d,J＝8.2Hz,1H),7.63(s,1H),7.54(d,J＝8.8Hz,2H),7.49(s,1H),7.43(d,J＝8.6,1.5Hz,1H),7.38(dd,J＝8.3,5.4Hz,2H),7.08(t,J＝8.6Hz,2H),6.66(d,J＝9.6Hz,1H),6.37(s,1H),3.94(s,2H),3.74(s,2H),3.57(s,2H),3.36(s,2H),2.96(d,J ＝11.6Hz,2H),2.87(t,J＝5.8Hz,2H),2.67(s,2H),2.56–2.42(m,1H),2.18(t,J＝11.5Hz,2H),1.78(d,J＝13.1Hz,2H),1.69–1.55(m,2H).HRMS(ESI)m/z calcd for C 37H 36FN 4O[M+H] +571.2873,found 571.2874. 5-cyanindole-3-carbaldehyde (99 mg, 0.608 mmol) and (E)-2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-5-( 1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-one (204mg, 0.507mmol) was placed in a flask, anhydrous methanol was added: anhydrous di Chloromethane=1:1 (v:v) was dissolved, then sodium cyanoborohydride (64mg, 1.01mmol) was added, and reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 89 mg of 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo Dihydro-2,3-dihydro-1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile, white solid, yield 33%. 1 H NMR (400MHz, CD 3 OD) δ8.20(s, 1H), 7.73(d, J=8.2Hz, 1H), 7.63(s, 1H), 7.54(d, J=8.8Hz, 2H), 7.49(s,1H),7.43(d,J=8.6,1.5Hz,1H),7.38(dd,J=8.3,5.4Hz,2H),7.08(t,J=8.6Hz,2H),6.66(d ,J=9.6Hz,1H),6.37(s,1H),3.94(s,2H),3.74(s,2H),3.57(s,2H),3.36(s,2H),2.96(d,J= 11.6Hz, 2H), 2.87(t, J=5.8Hz, 2H), 2.67(s, 2H), 2.56–2.42(m, 1H), 2.18(t, J=11.5Hz, 2H), 1.78(d, J＝13.1Hz,2H),1.69–1.55(m,2H).HRMS(ESI)m/z calcd for C 37 H 36 FN 4 O[M+H] + 571.2873,found 571.2874.
实施例31 (E)-3-((4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1H-吲哚-5-甲腈(I b–19)的制备 Example 31 (E)-3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Preparation of 1H-inden-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole-5-carbonitrile (I b -19)
Figure PCTCN2022141611-appb-000099
Figure PCTCN2022141611-appb-000099
叔丁基-(E)-4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的合成方法同实施例19。tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro-1H-indene The synthesis method of -5-yl)-3,6-dihydropyridine-1(2H)-carboxylate is the same as in Example 19.
步骤d：(E)-2-((1-苄基-4-氟哌啶-4-基)亚甲基)-5-(1,2,3,6-四氢吡啶-4-基)-2,3-二氢-1H-茚-1-酮的合成Step d: (E)-2-((1-Benzyl-4-fluoropiperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl) Synthesis of -2,3-dihydro-1H-inden-1-one
Figure PCTCN2022141611-appb-000100
Figure PCTCN2022141611-appb-000100
将530mg叔丁基-(E)-4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-茚-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯溶于10mL二氯甲烷中，搅拌下滴加3mL三氟乙酸，室温搅拌1个小时。反应完毕后旋干反应溶液及部分三氟乙酸，向粗产品中加入10mL二氯甲烷复溶，再加入20mL饱和碳酸氢钠溶液洗涤有机相，分离有机相，将水相用二氯甲烷萃取3～4遍(20mL)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤后将滤液旋干，未经纯化可直接投下一步，得440mg目标中间体(E)-2-((1-苄基-4-氟哌啶-4-基)亚甲基)-5-(1,2,3,6-四氢吡啶-4-基)-2,3-二氢-1H-茚-1-酮，白色固体，收率98％。530mg tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro-1H -Inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution and part of trifluoroacetic acid were spin-dried, and 10 mL of dichloromethane was added to the crude product to redissolve, then 20 mL of saturated sodium bicarbonate solution was added to wash the organic phase, the organic phase was separated, and the aqueous phase was extracted with dichloromethane for 3 ~ 4 times (20mL), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried the filtrate, and directly used in the next step without purification to obtain 440 mg of the target intermediate (E)-2-(( 1-Benzyl-4-fluoropiperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-indene -1-one, white solid, yield 98%.
步骤f：(E)-3-((4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-吲哚-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1H-吲哚-5-甲腈的合成Step f: (E)-3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Synthesis of 1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole-5-carbonitrile
Figure PCTCN2022141611-appb-000101
Figure PCTCN2022141611-appb-000101
将5-氰基-吲哚-3-甲醛(64mg，0.374mmol)和(E)-2-((1-苄基-4-氟哌啶-4-基)亚甲基)-5-(1,2,3,6-四氢吡啶-4-基)-2,3-二氢-1H-茚-1-酮(130mg，0.312mmol)置于烧瓶中，加入无水甲醇:无水二氯甲烷＝1:1(v:v)溶解，再加入氰基硼氢化钠(39mg，0.624mmol)，30℃反应过夜。加水淬灭反应，分离有机相，再用二氯甲烷萃取水相三次，合并有机相，水洗三 遍，有机相用饱和溶液洗涤一遍，无水硫酸钠干燥后旋干溶剂，粗产品经柱层析纯化后(甲醇:二氯甲烷＝1:20)得到78mg(E)-3-((4-(2-((1-苄基-4-氟哌啶-4-基)亚甲基)-1-氧代-2,3-二氢-1H-吲哚-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1H-吲哚-5-甲腈，白色固体，收率44％。 1H NMR(400MHz,CD 3OD)δ8.21(s,1H),7.76(d,J＝8.1Hz,1H),7.65(d,J＝4.8Hz,1H),7.58–7.53(m,2H),7.52(s,1H),7.44(dd,J＝8.5,1.5Hz,1H),7.39–7.33(m,5H),6.72(d,J＝25.7Hz,1H),6.39(s,1H),4.01(s,2H),3.93(s,2H),3.62(s,2H),2.94(s,2H),2.82(d,J＝11.6Hz,3H),2.70(s,2H),2.47(s,2H),2.15–1.94(m,5H).HRMS(ESI)m/z calcd for C 37H 36FN 4O[M+H] +571.2873,found 571.2874. 5-Cyano-indole-3-carbaldehyde (64 mg, 0.374 mmol) and (E)-2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-5-( 1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-one (130mg, 0.312mmol) was placed in a flask, anhydrous methanol was added: anhydrous di Chloromethane=1:1 (v:v) was dissolved, then sodium cyanoborohydride (39mg, 0.624mmol) was added, and reacted overnight at 30°C. Add water to quench the reaction, separate the organic phase, then extract the aqueous phase three times with dichloromethane, combine the organic phases, wash three times with water, wash the organic phase once with a saturated solution, dry the solvent after drying with anhydrous sodium sulfate, and pass the crude product through the column layer After analysis and purification (methanol:dichloromethane=1:20), 78 mg of (E)-3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene) was obtained -1-oxo-2,3-dihydro-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-indol-5-yl Nitrile, white solid, yield 44%. 1 H NMR (400MHz, CD 3 OD) δ8.21(s, 1H), 7.76(d, J=8.1Hz, 1H), 7.65(d, J=4.8Hz, 1H), 7.58–7.53(m, 2H ),7.52(s,1H),7.44(dd,J=8.5,1.5Hz,1H),7.39–7.33(m,5H),6.72(d,J=25.7Hz,1H),6.39(s,1H) ,4.01(s,2H),3.93(s,2H),3.62(s,2H),2.94(s,2H),2.82(d,J=11.6Hz,3H),2.70(s,2H),2.47( s,2H),2.15–1.94(m,5H).HRMS(ESI)m/z calcd for C 37 H 36 FN 4 O[M+H] + 571.2873,found 571.2874.
效果实施例1Effect Example 1
本效果实施例示出本发明的化合物对乙酰胆碱酯酶(AChE)的活性抑制实验及活性结果。具有乙酰胆碱酯酶抑制活性的化合物可以抑制脑内乙酰胆碱被水解，从而提高脑内乙酰胆碱的浓度，促进记忆认知，可用于症状改善治疗AD。本部分采用改良版Ellman法测定乙酰胆碱酯酶活性。以SD小鼠的大脑皮层作为AChE酶源，在最适酶反应条件下将硫代乙酰胆碱加入反应模板上，加入待测物后通过比色法检测AChE酶活性。本实验采用SD大鼠的大脑皮层作为乙酰胆碱酯酶的来源，取样方法为将大鼠处死后，迅速取出大脑并在冰上分离皮层，用75mM的磷酸缓冲液(pH 7.4)制备脑匀浆液，置于离心管-20℃保存备用。实验前为使酶源处于最佳酶活力状态，用预冷的PBS稀释溶液至吸光度为0.3～0.35，加入溶液10％体积分数的丁酰胆碱酯酶抑制剂OMPA。实验操作如下：(1)取96孔板，每孔加入10μL脑皮层匀浆、50μL磷酸缓冲液(0.1M)、50μL浓度为0.2％的显色剂5,5’-二硫代双(2-硝基苯甲酸)(DTNB)、109μL去离子水、30μL浓度为2mM的胆碱底物硫代乙酰胆碱(S-Ach)以及1μL待测试化合物(1nM到10mM的浓度梯度)。(2)室温反应20分钟后，加入50μL浓度为3％的SDS终止反应。此时硫代乙酰胆碱在皮层中的AChE作用下会分解为硫代胆碱(Thiocholine)，随后会迅速与显色剂DTNB反应生成最大吸收波长为412nm的黄色物质5-巯基-2-硝基苯甲酸盐。(3)使用多功能酶标仪(DTX 880，Beckman Coulter)在450nm波长下读取吸光值，以不加抑制剂的孔的读数作为100％，通过比较加入待测物后每孔吸光度的下降程度，计算化合物对AChE的抑制率。将所计算得到的抑制率和对应浓度进行非线性拟合，采用Graphpad软件计算化合物的半数抑制浓度(IC 50值)。实验以不加抑制剂的酶活力作为100％，以上市的抗阿尔茨海默病(AD)药物中AChE抑制剂多奈哌齐作为阳性对照，活性结果用半数抑制浓度(IC 50值)表示，活性结果见表1。 This effect example shows the activity inhibition experiment and activity results of the compound of the present invention on acetylcholinesterase (AChE). The compound with acetylcholinesterase inhibitory activity can inhibit the hydrolysis of acetylcholine in the brain, thereby increasing the concentration of acetylcholine in the brain, promoting memory cognition, and can be used to improve symptoms and treat AD. In this part, the modified Ellman method was used to measure the activity of acetylcholinesterase. Using the cerebral cortex of SD mice as the source of AChE enzyme, thioacetylcholine was added to the reaction template under the optimal enzyme reaction conditions, and the AChE enzyme activity was detected by colorimetry after adding the test substance. In this experiment, the cerebral cortex of SD rats was used as the source of acetylcholinesterase. The sampling method was that after the rats were put to death, the brain was quickly taken out and the cortex was separated on ice, and the brain homogenate was prepared with 75mM phosphate buffer (pH 7.4). Store in a centrifuge tube at -20°C for later use. Before the experiment, in order to keep the enzyme source at the best enzyme activity state, the solution was diluted with pre-cooled PBS to an absorbance of 0.3-0.35, and 10% volume fraction of butyrylcholinesterase inhibitor OMPA was added to the solution. The experimental operation is as follows: (1) Take a 96-well plate, add 10 μL of cerebral cortex homogenate, 50 μL of phosphate buffer (0.1M), and 50 μL of chromogenic agent 5,5’-dithiobis(2 -nitrobenzoic acid) (DTNB), 109 μL of deionized water, 30 μL of the choline substrate thioacetylcholine (S-Ach) at a concentration of 2 mM, and 1 μL of the compound to be tested (concentration gradient from 1 nM to 10 mM). (2) After reacting at room temperature for 20 minutes, 50 μL of 3% SDS was added to terminate the reaction. At this time, thioacetylcholine will be decomposed into Thiocholine (Thiocholine) under the action of AChE in the cortex, and then quickly react with the chromogenic agent DTNB to generate a yellow substance 5-mercapto-2-nitrobenzene with a maximum absorption wavelength of 412nm Formate. (3) Use a multifunctional microplate reader (DTX 880, Beckman Coulter) to read the absorbance at a wavelength of 450nm, take the reading of the well without inhibitor as 100%, and compare the decrease in the absorbance of each well after adding the test substance The degree of inhibition of the compound on AChE was calculated. The calculated inhibition rate and the corresponding concentration were nonlinearly fitted, and the half inhibitory concentration (IC 50 value) of the compound was calculated using Graphpad software. In the experiment, the enzyme activity without inhibitors was taken as 100%, and the AChE inhibitor donepezil in the anti-Alzheimer's disease (AD) drug listed above was used as a positive control. See Table 1.
表1：本发明的化合物对乙酰胆碱酯酶的抑制活性数据Table 1: The inhibitory activity data of compound of the present invention to acetylcholinesterase
Figure PCTCN2022141611-appb-000102
Figure PCTCN2022141611-appb-000102
由表1可以看出，本发明的化合物具有强效的乙酰胆碱酯酶抑制活性，其中部分优选化合物的抑制活性甚至超过上市抗AD药物多奈哌齐，说明本发明所述的化合物具备治疗AD的潜力。It can be seen from Table 1 that the compounds of the present invention have potent acetylcholinesterase inhibitory activity, and the inhibitory activity of some preferred compounds even exceeds that of the marketed anti-AD drug donepezil, indicating that the compounds of the present invention have the potential to treat AD.
效果实施例2Effect Example 2
本效果实施例示出本发明的化合物对五羟色胺转运体(SERT)的活性抑制实验及活性结果。具备该活性的化合物可以通过抑制脑内五羟色胺的重摄取，提高脑内五羟色胺的浓度，可用于治疗抑郁症或改善AD。本实验采用人胚胎肾细胞HEK293表达人源5-HT转运体，使用市售试剂盒Neurotransmitter Transporter Uptake Assay Kit(Molecular Devices公司，货号R8173)进行测试。该试剂盒使用荧光底物，模拟5-HT等单胺类神经递质，并通过五羟色胺转运体等特定的转运体进入细胞，导致细胞的荧光强度增加。具体实验方法如下：(1)细胞铺板：解冻细胞培养3–4天。传代后在细胞培养箱中再培养3天。使用胰酶-EDTA消化细胞后离心1000rpm五分钟，收集细胞。重新悬浮细胞于10mL培养基。吹打细胞防止粘连。细胞计数。将细胞用培养基稀释至1百万个/mL，每孔种20,000个细胞，37℃/5％CO 2条件下孵育16–20小时。(2)转运实验：配置20mM HEPES的HBSS溶液,含有0.1％BSA作为稀释液和工作液。阳性化合物4倍梯度稀释10个浓度，最高浓度2μM。待测化合物采用3倍梯度稀释10个浓度。弃去孔中的培养基，加入25μL的化合物溶液。300rpm离心15s，之后在37℃孵育30分钟，随后每孔加入25μL染 液，37℃孵育30分钟，采用Flexstation读取读数，在Ex/Em＝440nm/520nm条件下检测，计算化合物对5-HT重摄取的抑制活性。实验采用维拉佐酮和氢溴酸西酞普兰(Citalopram hydrobromide)作为阳性对照。活性结果用IC 50±SD(nM)形式表示，实验结果见表2。 This effect example shows the activity inhibition experiment and activity results of the compound of the present invention on serotonin transporter (SERT). The compound with this activity can increase the concentration of serotonin in the brain by inhibiting the reuptake of serotonin in the brain, and can be used for treating depression or improving AD. In this experiment, human embryonic kidney cells HEK293 were used to express the human 5-HT transporter, and the commercially available kit Neurotransmitter Transporter Uptake Assay Kit (Molecular Devices, Cat. No. R8173) was used for testing. The kit uses fluorescent substrates to simulate monoamine neurotransmitters such as 5-HT, and enters cells through specific transporters such as serotonin transporters, resulting in an increase in the fluorescence intensity of cells. The specific experimental methods are as follows: (1) Cell plating: Thaw the cells and culture them for 3-4 days. After passage, cells were cultured for another 3 days in the cell culture incubator. Cells were collected by centrifugation at 1000 rpm for five minutes after digestion with trypsin-EDTA. Resuspend cells in 10 mL medium. Pipette cells to prevent adhesion. cell counts. Dilute the cells with medium to 1 million cells/mL, plant 20,000 cells per well, and incubate at 37°C/5% CO 2 for 16–20 hours. (2) Transport experiment: configure 20mM HEPES HBSS solution containing 0.1% BSA as diluent and working solution. Positive compounds were serially diluted 4 times to 10 concentrations, with the highest concentration being 2 μM. The compounds to be tested were diluted to 10 concentrations using a 3-fold gradient. Discard the medium in the wells and add 25 µL of the compound solution. Centrifuge at 300rpm for 15s, then incubate at 37°C for 30 minutes, then add 25 μL of dye solution to each well, incubate at 37°C for 30 minutes, use Flexstation to read the readings, detect under the condition of Ex/Em=440nm/520nm, and calculate the effect of the compound on 5-HT Inhibitory activity of reuptake. Vilazodone and citalopram hydrobromide (Citalopram hydrobromide) were used as positive controls in the experiment. The activity results are expressed in the form of IC 50 ±SD (nM), and the experimental results are shown in Table 2.
表2：本发明的化合物对五羟色胺转运体的抑制活性数据Table 2: Inhibitory activity data of compounds of the present invention on serotonin transporter
Figure PCTCN2022141611-appb-000103
Figure PCTCN2022141611-appb-000103
由表2可以看出，本发明的化合物大多数均具有强效的五羟色胺转运体抑制活性，其中部分优选化合物的抑制活性低于10nM(优于阳性对照氢溴酸西酞普兰)，说明本发明的化合物可以发展为五羟色胺转运体抑制剂类抗抑郁药物或抗AD药物。由于本发明的化合物同时具有乙酰胆碱酯酶和五羟色胺转运体的抑制活性，因而是一类有望治疗AD-抑郁共患病的多靶点药物。As can be seen from Table 2, most of the compounds of the present invention have potent serotonin transporter inhibitory activity, wherein the inhibitory activity of some preferred compounds is lower than 10nM (better than positive control citalopram hydrobromide), illustrating the present invention The compounds can be developed into serotonin transporter inhibitors antidepressants or anti-AD drugs. Since the compound of the present invention has the inhibitory activity of acetylcholinesterase and five serotonin transporter, it is a kind of multi-target drug which is expected to treat AD-depression co-morbidity.
效果实施例3Effect Example 3
本效果实施例示出本发明的化合物对5-HT 1A受体的激动活性实验及活性结果。使用HEK293细胞过表达产生人源5-HT 1A受体。培养基为含有50mg/mL的G418和10％FBS的DMEM培养基，5％CO 2/37℃条件培养。当细胞长到70％时，消化细胞，离心后用缓冲液重悬细胞后种于384孔板中孵育16-20小时。弃去孔中培养基，加入待测化合物和阳性药的稀释液，室温孵育60分钟，加入5μL 4×Eu-cAMP tracer solution和5μL 4×ULight-anti-cAMP solution，后继续室温孵育60分钟，之后在Ex/Em＝615nm/665nm条件下检测。以空白为最小信号，以阳性药8-OH-DAPT信号为最大信号，计算化合物对5-HT 1A受体激动的EC 50。活性结果用EC 50±SD(nM)形式表示，结果见表3。 This effect example shows the agonistic activity test and activity results of the compound of the present invention on 5-HT 1A receptors. The human 5-HT 1A receptor was overexpressed using HEK293 cells. The culture medium is DMEM medium containing 50 mg/mL G418 and 10% FBS, cultured under the condition of 5% CO 2 /37°C. When the cells grow to 70%, digest the cells, resuspend the cells with buffer after centrifugation, and incubate in a 384-well plate for 16-20 hours. Discard the medium in the well, add the dilution of the compound to be tested and the positive drug, incubate at room temperature for 60 minutes, add 5 μL 4×Eu-cAMP tracer solution and 5 μL 4×ULight-anti-cAMP solution, and continue to incubate at room temperature for 60 minutes, Then detect under the condition of Ex/Em=615nm/665nm. Taking the blank as the minimum signal and the positive drug 8-OH-DAPT signal as the maximum signal, the EC 50 of the compound on 5-HT 1A receptor agonism was calculated. The activity results are expressed in the form of EC 50 ±SD (nM), and the results are shown in Table 3.
表3：本发明的化合物对5-HT 1A的激动活性数据 Table 3: Agonistic activity data of compounds of the present invention on 5-HT 1A
Figure PCTCN2022141611-appb-000104
Figure PCTCN2022141611-appb-000104
其中，对比化合物A来自“多靶点抗AD活性化合物设计合成与活性研究和3-芳基-3-羟基吲哚酮合成方法学研究”，李晓康，华东理工大学，2018年。Among them, comparative compound A comes from "Design Synthesis and Activity Research of Multi-target Anti-AD Active Compounds and Research on Synthesis Methodology of 3-aryl-3-oxindolinone", Li Xiaokang, East China University of Science and Technology, 2018.
由表3可以看出，本发明的大多数化合物对5-HT 1A受体的EC 50在几百纳摩尔以上，与阳性对照相比相差百倍以上，与化合物本身的AChE/SERT活性相比也相差很多，说明本发明的化合物基本去除了5-HT 1A的激动活性，避免了5-HT 1A受体激动后可能引发的记忆损伤。 As can be seen from Table 3, the EC50 of most compounds of the present invention to the 5-HT 1A receptor is more than several hundred nanomoles, which is more than a hundred times different from the positive control, and compared with the AChE/SERT activity of the compound itself. The difference is quite large, indicating that the compound of the present invention basically eliminates the agonistic activity of 5-HT 1A and avoids memory damage that may be caused by 5-HT 1A receptor stimulation.
效果实施例4本效果实施例示出本发明的化合物对小鼠脑内乙酰胆碱酯酶活性的抑制实验及活性结果。具有乙酰胆碱酯酶抑制活性的化合物可以抑制脑内乙酰胆碱被水解，从而提高脑内乙酰胆碱的浓度，促进记忆认知，可用于症状改善治疗AD。Effect Example 4 This effect example shows the inhibitory experiment and activity results of the compound of the present invention on the activity of acetylcholinesterase in mouse brain. The compound with acetylcholinesterase inhibitory activity can inhibit the hydrolysis of acetylcholine in the brain, thereby increasing the concentration of acetylcholine in the brain, promoting memory cognition, and can be used to improve symptoms and treat AD.
小鼠脑内AChE抑制实验是一种快速高效的实验，用以评价受试化合物对动物脑内AChE活力的抑制活性，同时还可以反映化合物的透脑能力。The AChE inhibition experiment in the mouse brain is a fast and efficient experiment, which is used to evaluate the inhibitory activity of the test compound on the activity of AChE in the animal brain, and can also reflect the brain-penetrating ability of the compound.
实验动物采用ICR小鼠，雄性，体重约17–21g。称取一定量的化合物溶于PEG400 中，涡旋震荡使其溶解，再加入HS-15混合均匀，配置成透明澄清的溶液。按0.3mg/kg～30mg/kg剂量口服给药，溶剂对照组给予相应溶剂对照。给药后观察小鼠的外观和状态，判断是否有流涎、流汗、抽搐等外周胆碱能副作用。给药后在取样点(0.5-24小时)脱颈处死小鼠，迅速取出大脑，将半脑用预冷的磷酸盐缓冲液稀释成匀浆，加入丁酰胆碱酯酶抑制剂OMPA，再加入硫代乙酰胆碱(S-Ach)、5,5'-二硫代双(2-硝基苯甲酸)(DTBN)，室温反应20分钟。空白孔中不加入大脑匀浆。实验结束后各孔加入SDS终止反应，空白孔补加适量酶。使用多功能酶标仪(DTX 880，Beckman Coulter)在450nm波长下读取吸光值，以空白孔的读数作为100％，通过检测每孔的吸光度值，计算化合物对AChE的抑制率。将所计算得到的抑制率和对应浓度进行非线性拟合，计算化合物对小鼠脑内AChE的IC 50值。 The experimental animals were ICR mice, male, weighing about 17–21 g. Weigh a certain amount of compound and dissolve it in PEG400, vortex to dissolve it, then add HS-15 and mix evenly to form a transparent and clear solution. It was orally administered at a dose of 0.3 mg/kg-30 mg/kg, and the solvent control group was given the corresponding solvent control. After administration, the appearance and state of the mice were observed to judge whether there were peripheral cholinergic side effects such as salivation, sweating, and convulsions. After the administration, the mice were killed by denecking at the sampling point (0.5-24 hours), and the brain was quickly taken out, and the hemibrain was diluted into a homogenate with pre-cooled phosphate buffer solution, and the butyrylcholinesterase inhibitor OMPA was added, and then Add thioacetylcholine (S-Ach) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTBN) and react at room temperature for 20 minutes. No brain homogenate was added to blank wells. After the experiment, SDS was added to each well to terminate the reaction, and an appropriate amount of enzyme was added to the blank well. Using a multi-functional microplate reader (DTX 880, Beckman Coulter) to read the absorbance at a wavelength of 450nm, taking the reading of the blank well as 100%, the inhibitory rate of the compound to AChE was calculated by detecting the absorbance of each well. The calculated inhibition rate and the corresponding concentration were nonlinearly fitted to calculate the IC 50 value of the compound against AChE in the mouse brain.
本实验选择AChE和五羟色胺转运体双靶点抑制活性均较强的化合物I b-7进行实验，实验结果见表4-5和图1。 In this experiment, the compound Ib - 7 with strong dual-target inhibitory activity of AChE and serotonin transporter was selected for the experiment. The experimental results are shown in Table 4-5 and Figure 1.
表4：化合物I b-7对ICR小鼠脑内乙酰胆碱酯酶活性的影响 Table 4: Effect of compound Ib - 7 on the activity of acetylcholinesterase in the brain of ICR mice
Figure PCTCN2022141611-appb-000105
Figure PCTCN2022141611-appb-000105
表4中数值为给药1小时和6小时后小鼠脑内乙酰胆碱酯酶的活性。溶剂对照组(对照组)为不含化合物的20％PEG400溶液，设为100％，其余各组为与溶剂对照组相比的百分值(Mean±SD)，*P<0.05(与溶剂对照组相比)，**P<0.01(与溶剂对照组相比)。The values in Table 4 are the activity of acetylcholinesterase in the mouse brain 1 hour and 6 hours after administration. The solvent control group (control group) is the 20% PEG400 solution that does not contain compound, is set as 100%, and all the other groups are percentage values (Mean ± SD) compared with the solvent control group, *P<0.05 (with the solvent control group group), **P<0.01 (compared with solvent control group).
表5：1mg/kg优选化合物I b-7对ICR小鼠脑内乙酰胆碱酯酶活性的影响 Table 5: Effect of 1 mg/kg preferred compound Ib - 7 on the activity of acetylcholinesterase in the ICR mouse brain
Figure PCTCN2022141611-appb-000106
Figure PCTCN2022141611-appb-000106
表5中数值为给药0.5-24小时后小鼠脑内乙酰胆碱酯酶的活性。溶剂对照组为去离子水，设为100％，其余各组为与溶剂对照组相比的百分值(Mean±SD)，*P<0.05(与溶剂对照组相比)，**P<0.01(与溶剂对照组相比)。表4数据中AChE活力有高于100％的数值是由于对照组中有一只小鼠海马AChE活力偏低，属个体差异，因此校准后I b-7给药组海马AChE活力有高于100％的数值，但不影响实验结论。 The values in Table 5 are the activity of acetylcholinesterase in the mouse brain after administration for 0.5-24 hours. The solvent control group is deionized water, which is set as 100%, and all the other groups are percentage values (Mean ± SD) compared with the solvent control group, *P<0.05 (compared with the solvent control group), **P< 0.01 (compared with the solvent control group). The AChE activity in the data in Table 4 has a value higher than 100% because of the low AChE activity in the hippocampus of a mouse in the control group, which belongs to individual differences. , but it does not affect the experimental conclusion.
由表4和图1可以看出，化合物I b-7在口服5mg/kg的剂量下就可以显著抑制小鼠脑内皮层和海马处AChE的活性，并且抑制活性具有剂量依赖性和时间依赖性。口服5mg/kg剂量的I b-7干预6小时后，其抑制作用相比于1小时的抑制活性显著提高，并且与口服30mg/kg剂量下1小时后的抑制活性相当，将小鼠脑内海马和皮层处的AChE活性分别抑制到了23.0％和27.8％。 As can be seen from Table 4 and Figure 1, Compound Ib -7 can significantly inhibit the activity of AChE in the mouse brain endocortex and hippocampus at a dose of 5 mg/kg orally, and the inhibitory activity is dose-dependent and time-dependent . After oral administration of 5mg/kg dose of Ib - 7 for 6 hours, its inhibitory effect was significantly improved compared with the inhibitory activity of 1 hour, and it was equivalent to the inhibitory activity of 1 hour after oral administration of 30mg/kg dose. The AChE activities in the hippocampus and cortex were inhibited to 23.0% and 27.8%, respectively.
由表5可以看出，I b-7在口服1mg/kg的剂量下就可将小鼠脑内皮层处的AChE活性降低至49.49％，且无外周胆碱能副作用。 It can be seen from Table 5 that Ib - 7 can reduce the AChE activity in the mouse brain endocortex to 49.49% at a dose of 1 mg/kg orally, and has no peripheral cholinergic side effects.
以上结果证明化合物I b-7口服给药后对小鼠脑内的AChE具有较强的抑制活性，具有较好的阿尔茨海默病治疗潜力。 The above results prove that compound Ib - 7 has strong inhibitory activity on AChE in mouse brain after oral administration, and has good therapeutic potential for Alzheimer's disease.
本实验选择另一AChE和五羟色胺转运体双靶点抑制活性均较强的化合物I b-4进行实验，实验结果见表6。 In this experiment, another compound Ib -4 with strong dual-target inhibitory activity of AChE and serotonin transporter was selected for the experiment, and the experimental results are shown in Table 6.
表6：化合物I b-4对ICR小鼠脑内乙酰胆碱酯酶活性的影响 Table 6: Effect of compound Ib -4 on the activity of acetylcholinesterase in the brain of ICR mice
Figure PCTCN2022141611-appb-000107
Figure PCTCN2022141611-appb-000107
表6中数值为给药24小时后小鼠脑内乙酰胆碱酯酶的活性。溶剂对照组(对照组)为不含化合物的20％PEG400溶液，设为100％，其余各组为与溶剂对照组相比的百分值(Mean±SD)，*P<0.05(与溶剂对照组相比)，**P<0.01(与溶剂对照组相比)，***P<0.005(与溶剂对照组相比)。The values in Table 6 are the activity of acetylcholinesterase in the mouse brain 24 hours after administration. The solvent control group (control group) is the 20% PEG400 solution that does not contain compound, is set as 100%, and all the other groups are percentage values (Mean ± SD) compared with the solvent control group, *P<0.05 (with the solvent control group group), **P<0.01 (compared with solvent control group), ***P<0.005 (compared with solvent control group).
由表6可以看出，化合物I b-4在口服1mg/kg的剂量下就可以显著抑制小鼠脑内皮 层和海马处AChE的活性，并且抑制活性具有剂量依赖性依赖性。口服10mg/kg剂量的I b-4干预24小时后，其将小鼠脑内海马和皮层处的AChE活性分别抑制到了36.87％和34.00％。 It can be seen from Table 6 that compound Ib - 4 can significantly inhibit the activity of AChE in the mouse brain endocortex and hippocampus at an oral dose of 1 mg/kg, and the inhibitory activity is dose-dependent. After oral administration of 10 mg/kg Ib -4 for 24 hours, it inhibited the AChE activity in the hippocampus and cortex of the mouse brain to 36.87% and 34.00%, respectively.
以上结果证明化合物I b-4口服给药后对小鼠脑内的AChE同样具有较强的抑制活性，具有较好的阿尔茨海默病治疗潜力。 The above results prove that compound Ib -4 also has strong inhibitory activity on AChE in mouse brain after oral administration, and has good therapeutic potential for Alzheimer's disease.
效果实施例5Effect Example 5
本发明的化合物对悬尾抑郁模型和强迫游泳模型小鼠的行为学实验的影响。Effects of the compound of the present invention on behavioral experiments of tail suspension depression model and forced swimming model mice.
悬尾实验是一种经典、快速且方便的抗抑郁药效评价实验，属于行为绝望模型。实验原理为通过尾悬挂方式来对小鼠进行短期的、不可逃避的急性应激，从而使小鼠进入一种放弃抵抗的静止状态，以此建立小鼠抑郁模型。强迫游泳同样是一种经典的行为绝望模型，利用小鼠企图逃脱但又无法逃脱，从而放弃挣扎，进入特有的抑郁不动状态，实验过程中记录动物不动时间来反映抑郁状态。而抗抑郁药物则具有逆转这种静止状态以及促进小鼠逃跑等相关行为发生的作用，因此能够减少小鼠的不动时间，通过测定小鼠的不动时间则可有效评价药物的抗抑郁药效。本实施例选择AChE和五羟色胺转运体双靶点抑制活性均较强的化合物I b-7和I b-4进行实验。实验采用Steru等人报道的悬尾实验方法，或者强迫游泳方法，通过考察给予受试化合物能否明显缩短悬尾小鼠的不动时间，评价化合物的抗抑郁药效。 The tail-suspension test is a classic, fast and convenient test for evaluating the efficacy of antidepressants, and it belongs to the behavioral hopelessness model. The experimental principle is to carry out short-term and inescapable acute stress on mice by tail suspension, so that the mice enter a static state of giving up resistance, so as to establish a mouse depression model. Forced swimming is also a classic model of behavioral desperation. Mice try to escape but cannot escape, so they give up struggling and enter a unique state of depression and immobility. During the experiment, the immobility time of animals is recorded to reflect the state of depression. Antidepressant drugs have the effect of reversing this static state and promoting related behaviors such as escaping in mice, so they can reduce the immobility time of mice, and the antidepressant effect of drugs can be effectively evaluated by measuring the immobility time of mice. effect. In this example, compounds Ib -7 and Ib -4 with strong dual-target inhibitory activities of AChE and serotonin transporter were selected for experiments. The experiment adopts the tail suspension test method reported by Steru et al., or the forced swimming method, and evaluates the antidepressant efficacy of the compound by examining whether the administration of the test compound can significantly shorten the immobility time of the tail suspension mice.
实验动物采用C57小鼠，平均体重20～25g，5～6周龄，购买自上海杰思捷实验动物有限公司。自由进水饮食饲养，预适应环境一周。实验前为小鼠尾巴编号并分组，10只为一组，并称量体重。实验分为溶剂对照组、阳性药维拉佐酮组、受试化合物组。实验当天配置受试药液，先将受试化合物溶解于PEG400中，再加入20％HS-15的生理盐水溶液配置成澄清、均匀的溶液。最终药液组成为25％PEG400+15％HS+60％saline。溶剂对照组给与0.9％生理盐水，阳性药和受试化合物组按上述方法配置药液并口服给与。按照小鼠编号顺序每间隔8分钟对两只小鼠进行给药，完成后归入原笼位，1小时后进行悬尾实验。悬尾时，将距离小鼠尾巴顶端2cm处用医用胶带固定至悬尾箱顶部，要求小鼠离最近的物体距离≥15cm。，实验录像6分钟，完成后取下小鼠，归入原笼位，用酒精擦拭悬尾箱去除动物气味。在强迫游泳实验中，将实验动物置于注水的玻璃圆柱体，水温控制在25℃左右(上下不超过1℃)，并根据实验动物的大小调整液面高低，一般为18cm左右，实验录像6分钟，每次完成一组后换水开始下一组，避免小鼠气味对实验造成影响。实验采用双盲制，即给药并进行悬尾实验的操作人员与不动时间的统计人员需为不 同人员且互不知情。统计人员对6分钟录像的后4分钟内小鼠的不动时间进行统计，可将小鼠的运动行为(主观明显逃跑的行为)主要分为(1)向前或者向后跑的动作；(2)机体扭转，企图抓住悬吊处；(3)身体摇晃、摆动、抽动。记录完成后对每组小鼠的平均不动时间统计作图。As experimental animals, C57 mice with an average body weight of 20-25 g and 5-6 weeks old were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd. They were fed with free access to water and pre-acclimated to the environment for one week. Before the experiment, number the tails of the mice and group them into groups of 10, and weigh them. The experiment was divided into solvent control group, positive drug vilazodone group and test compound group. On the day of the experiment, the test drug solution was prepared. First, the test compound was dissolved in PEG400, and then 20% HS-15 physiological saline solution was added to form a clear and uniform solution. The final liquid composition is 25% PEG400+15% HS+60% saline. The solvent control group was given 0.9% physiological saline, and the positive drug and test compound group were prepared with the above method and administered orally. According to the order of mouse numbering, the two mice were given medicine at an interval of 8 minutes, and then returned to the original cage, and the tail suspension test was carried out 1 hour later. When suspending the tail, fix the place 2cm from the top of the tail of the mouse to the top of the tail-suspension box with medical tape, and the distance between the mouse and the nearest object is required to be ≥15cm. , The experiment video was recorded for 6 minutes. After the completion, the mice were removed, put into the original cage, and the tail suspension box was wiped with alcohol to remove the animal smell. In the forced swimming test, the experimental animals were placed in a glass cylinder filled with water, and the water temperature was controlled at about 25°C (up and down not exceeding 1°C), and the liquid level was adjusted according to the size of the experimental animals, generally about 18cm. Experimental video 6 Minutes, change the water to start the next group after completing one group each time, so as to avoid the influence of mouse smell on the experiment. The experiment adopts a double-blind system, that is, the operator who administers the drug and performs the tail suspension test and the statistician of the immobility time need to be different personnel and do not know each other. The statistician counts the immobility time of the mouse in the last 4 minutes of the 6-minute video recording, and can divide the mouse's motor behavior (the subjective and obvious escape behavior) into (1) the action of running forward or backward; 2) The body twists, trying to grab the suspension; (3) The body shakes, swings, and twitches. After the recording was completed, the average immobility time of mice in each group was statistically plotted.
本实验选择AChE和五羟色胺转运体双靶点抑制活性均较强的化合物I b-7进行抗抑郁药效实验。在一组悬尾实验中，实验设置溶剂对照组(生理盐水，10mL/kg)、维拉佐酮多次给药组(15mg/kg，每天一次，连续给药5天)、维拉佐酮单次给药组(30mg/kg，给药一次)、I b-7多次给药组(3mg/kg，每天一次，连续给药5天)进行小鼠悬尾行为学实验，通过小鼠不动时间的降低程度反应化合物的抗抑郁药效，实验结果见图2。*P<0.05(与溶剂对照组相比)，**P<0.01(与溶剂对照组相比)。 In this experiment, the compound I b -7 with strong dual-target inhibitory activity of AChE and serotonin transporter was selected for antidepressant efficacy experiment. In a group of tail suspension experiments, the experiment set up solvent control group (normal saline, 10mL/kg), vilazodone multiple administration group (15mg/kg, once a day, continuous administration for 5 days), vilazodone Single administration group (30mg/kg, administration once), Ib -7 multi-administration group (3mg/kg, once a day, continuous administration for 5 days) carried out mouse tail suspension behavior experiment, by mice The degree of reduction of immobility time reflects the antidepressant efficacy of the compound, and the experimental results are shown in FIG. 2 . *P<0.05 (compared with solvent control group), **P<0.01 (compared with solvent control group).
由图2可以看出，优选化合物I b-7在连续5天口服3mg/kg的剂量下可以显著降低悬尾小鼠的不动时间，表明其具有抗抑郁药效，有望用于治疗抑郁症。 As can be seen from Figure 2, the preferred compound Ib - 7 can significantly reduce the immobility time of tail-suspension mice at a dose of 3 mg/kg orally for 5 consecutive days, indicating that it has antidepressant effects and is expected to be used for the treatment of depression .
在另一组强迫游泳实验中，实验设置溶剂对照组(生理盐水)、维拉佐酮多次给药组(10mg/kg，每天一次，连续给药7天)、I b-7多次给药组(0.1mg/kg，每天一次，连续给药7天)、I b-7多次给药组(0.3mg/kg，每天一次，连续给药7天)和I b-7多次给药组(1.0mg/kg，每天一次，连续给药7天)进行小鼠强迫游泳实验，通过小鼠不动时间的降低程度反应化合物的抗抑郁药效，实验结果见图3。*P<0.05(与溶剂对照组相比)，**P<0.01(与溶剂对照组相比)。由图3可以看出，优选化合物I b-7在连续7天口服0.1-1.0mg/kg的剂量下可以显著降低强迫游泳小鼠的不动时间，表明其具有抗抑郁药效，有望用于治疗抑郁症。 In another group of forced swimming experiments, the experiment set solvent control group (normal saline), vilazodone multiple administration group (10mg/kg, once a day, continuous administration for 7 days), Ib -7 multiple administration group Drug group (0.1mg/kg, once a day, continuously administered for 7 days), I b -7 multiple administration group (0.3mg/kg, once a day, continuously administered for 7 days) and I b -7 repeatedly administered The drug group (1.0 mg/kg, once a day, administered continuously for 7 days) was subjected to a forced swimming test on mice, and the antidepressant efficacy of the compound was reflected by the reduction of the immobility time of the mice. The experimental results are shown in Figure 3. *P<0.05 (compared with solvent control group), **P<0.01 (compared with solvent control group). As can be seen from Figure 3, the preferred compound Ib - 7 can significantly reduce the immobility time of forced swimming mice under the dose of 0.1-1.0mg/kg orally administered for 7 consecutive days, indicating that it has antidepressant effects and is expected to be used in Treat depression.
此外，本实验还选择另外一个具有较强活性的化合物I b-4进行抗抑郁药效实验。在一组悬尾实验中，实验设置溶剂对照组(生理盐水)、维拉佐酮单次给药组(30mg/kg，给药一次)、I b-4单次给药组(0.1mg/kg，给药一次)、I b-4单次给药组(0.3mg/kg，给药一次)、I b-4单次给药组(1.0mg/kg，给药一次)和I b-4单次给药组(3.0mg/kg，给药一次)进行小鼠悬尾行为学实验，通过小鼠不动时间的降低程度反应化合物的抗抑郁药效，实验结果见图4。*P<0.05(与溶剂对照组相比)，**P<0.01(与溶剂对照组相比)。由图4可以看出，优选化合物I b-4在一次性口服3mg/kg的剂量下可以显著降低悬尾小鼠的不动时间，表明其具有抗抑郁药效，有望用于治疗抑郁症。 In addition, another compound Ib -4 with stronger activity was selected for antidepressant efficacy experiment in this experiment. In a group of tail suspension experiments, the experiment set solvent control group (normal saline), vilazodone single administration group (30mg/kg, administration once), Ib -4 single administration group (0.1mg/kg kg, administered once), I b -4 single administration group (0.3mg/kg, administered once), I b -4 single administration group (1.0mg/kg, administered once) and I b - 4 A single administration group (3.0mg/kg, administered once) was subjected to a mouse tail suspension behavioral experiment, and the antidepressant efficacy of the compound was reflected by the degree of reduction of the immobility time of the mice. The experimental results are shown in Figure 4. *P<0.05 (compared with solvent control group), **P<0.01 (compared with solvent control group). As can be seen from Figure 4, the preferred compound Ib -4 can significantly reduce the immobility time of tail-suspension mice at a one-time oral dose of 3 mg/kg, indicating that it has antidepressant effects and is expected to be used for the treatment of depression.
效果实施例6Effect Example 6
本发明的化合物对东莨菪碱诱导的认知损伤C57小鼠的行为学的影响。Effects of Compounds of the Invention on the Behavior of Scopolamine-Induced Cognitively Impaired C57 Mice.
东莨菪碱诱导的认知损伤动物模型是评价抗阿尔茨海默病候选药物常用的经典药理 模型。东莨菪碱作为M胆碱受体阻断药，与多种亚型M受体有相似的亲和力，能阻碍乙酰胆碱与脑内M受体的结合，主要作用于记忆的获取阶段，从而影响信息的传递，导致学习记忆功能受损，可作为老年性痴呆症造模经典方法之一。研究证明，东莨菪碱单次给药可作为学习记忆损伤模型，可造成功能性改变，此模型损伤可逆。The scopolamine-induced cognitive impairment animal model is a classic pharmacological model commonly used to evaluate drug candidates against Alzheimer's disease. As an M-choline receptor blocker, scopolamine has similar affinity with various subtypes of M-receptors, can hinder the combination of acetylcholine and M-receptors in the brain, and mainly acts on the acquisition stage of memory, thereby affecting the transmission of information. It can lead to impairment of learning and memory functions, which can be used as one of the classic methods for modeling Alzheimer's disease. Studies have proved that a single administration of scopolamine can be used as a model of learning and memory impairment, which can cause functional changes, and the damage of this model is reversible.
本实施例采用给予1mg/kg东莨菪碱的方法造模，采用22～25g的C57小鼠作为实验对象，一次性接受受试化合物，观察动物是否能改善东莨菪碱所致记忆损伤。目标化合物用20％PEG400助溶配制成澄清口服试剂，给药剂量为0.1～5mg/kg，盐酸多奈哌齐10mg/kg作为阳性对照组。在化合物给药30min后腹腔注射1mg/kg东莨菪碱，30min后进行通过Y迷宫/水迷宫实验观察试验小鼠的行为学。In this example, a model was established by administering 1 mg/kg scopolamine, and 22-25 g C57 mice were used as experimental subjects to receive the test compound once to observe whether the animals could improve the memory impairment caused by scopolamine. The target compound was dissolved with 20% PEG400 to prepare a clear oral reagent, the dosage was 0.1-5 mg/kg, and donepezil hydrochloride 10 mg/kg was used as a positive control group. 1 mg/kg scopolamine was injected intraperitoneally 30 minutes after compound administration, and the behavior of the test mice was observed by Y maze/water maze experiment 30 minutes later.
本实验选择AChE和五羟色胺转运体双靶点抑制活性均较强的化合物I b-7进行认知损伤模型实验。实验设置溶剂对照组(生理盐水)、造模组(1mg/kg东莨菪碱)、I b-7多次给药组(0.1mg/kg，每天一次，连续给药7天)、I b-7多次给药组(0.3mg/kg，每天一次，连续给药7天)、I b-7多次给药组(1.0mg/kg，每天一次，连续给药7天)、多奈哌齐多次给药组(10mg/kg，每天一次，连续给药7天)，通过Y迷宫对实验小鼠的记忆和认知能力进行评估，考察受试化合物是否能够改善记忆认知损伤，实验结果见图5。 ##P<0.01(与溶剂对照组相比)，*P<0.05(与造模组相比)，**P<0.01(与造模组相比)。由图5可以看出，优选化合物I b-7在一次性口服0.3mg/kg和1.0mg/kg的剂量下可以显著改善小鼠的记忆认知功能，表明其有望用于治疗阿尔茨海默病。实验结果表明本发明化合物能够改善东莨菪碱诱导的认知损伤。 In this experiment, compound I b -7, which has strong dual-target inhibitory activity of AChE and serotonin transporter, was selected for cognitive impairment model experiments. Experimental settings solvent control group (normal saline), modeling group (1mg/kg scopolamine), Ib - 7 multiple administration group (0.1mg/kg, once a day, continuous administration for 7 days), Ib -7 multiple administration group Times administration group (0.3mg/kg, once a day, continuous administration for 7 days), Ib -7 multiple administration group (1.0mg/kg, once a day, continuous administration for 7 days), donepezil multiple administrations group (10mg/kg, once a day, administered continuously for 7 days), the memory and cognitive ability of experimental mice were evaluated by Y maze, and whether the test compound could improve memory cognitive impairment was investigated. The experimental results are shown in Figure 5. ## P<0.01 (compared with the solvent control group), *P<0.05 (compared with the modeling group), **P<0.01 (compared with the modeling group). As can be seen from Figure 5, the preferred compound Ib - 7 can significantly improve the memory and cognitive function of mice at the dose of one-time oral administration of 0.3mg/kg and 1.0mg/kg, indicating that it is expected to be used for the treatment of Alzheimer's sick. The experimental results show that the compound of the present invention can improve the cognitive impairment induced by scopolamine.
效果实施例7Effect Example 7
本发明的化合物的药代动力学性质和血脑分布比。任何药物发挥治疗作用都必须到达病灶部分，对于中枢***药物而言，用于良好的血脑屏障通透性和良好脑血分布比至关重要。Pharmacokinetic properties and blood-brain distribution ratios of compounds of the invention. Any drug must reach the lesion to play a therapeutic role. For the central system drug, it is very important to have a good blood-brain barrier permeability and a good brain-blood distribution ratio.
本实验选择具有较强活性的化合物I b-4进行药代动力学性质和血脑分布比实验。实验采用ICR小鼠灌胃口服给予化合物I b-4(10mg/kg)或者静脉注射给予化合物I b-4(2mg/kg)后，于不同时间点采集血浆和脑组织，并检测ICR小鼠血浆和脑组织中受试物的浓度，并计算相关参数。实验结果见表7和表8。如表7所示，化合物I b-4的口服生物利用度为35.83。由表8可知，化合物I b-4的口服给药后血浆药物浓度迅速达到峰值，并在0.5小时后持续缓慢下降。而化合物I b-4在脑中的浓度先是逐步上升，在16-24小时达到峰值，之后缓慢下降逐渐被代谢排出。在给药后8-48小时内，化合物I b-4的脑血比均大于1，表明化合物化合物I b-4具有良好的透血脑屏障能力。此外，化合物I b-4的口服血浆代谢半衰期较长为23.97小时，可考虑一天一次用药。 In this experiment, compound Ib - 4 with strong activity was selected for pharmacokinetic properties and blood-brain distribution ratio experiments. In the experiment, after oral administration of compound I b -4 (10 mg/kg) or intravenous injection of compound I b -4 (2 mg/kg) to ICR mice, plasma and brain tissue were collected at different time points, and the ICR mice were detected The concentration of the test substance in plasma and brain tissue, and calculate the relevant parameters. The experimental results are shown in Table 7 and Table 8. As shown in Table 7, the oral bioavailability of compound Ib -4 was 35.83. It can be seen from Table 8 that the plasma drug concentration of compound Ib - 4 reached a peak rapidly after oral administration, and continued to decline slowly after 0.5 hours. However, the concentration of compound Ib -4 in the brain first increased gradually, reached the peak at 16-24 hours, and then decreased slowly and was gradually excreted by metabolism. Within 8-48 hours after administration, the brain-to-blood ratio of Compound Ib -4 was greater than 1, indicating that Compound Ib -4 has a good ability to penetrate the blood-brain barrier. In addition, the oral plasma metabolic half-life of compound Ib -4 is 23.97 hours longer, so once-a-day administration can be considered.
表7.化合物I b-4的药代动力学参数 Table 7. Pharmacokinetic parameters of compound Ib - 4
Figure PCTCN2022141611-appb-000108
Figure PCTCN2022141611-appb-000108
Figure PCTCN2022141611-appb-000109
Figure PCTCN2022141611-appb-000109
表8.化合物I b-4的脑血浓度分布比 Table 8. Cerebral blood concentration distribution ratio of compound Ib - 4
Figure PCTCN2022141611-appb-000110
Figure PCTCN2022141611-appb-000110

Claims (15)

  1. 如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物；A compound represented by formula I, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing;
    Figure PCTCN2022141611-appb-100001
    Figure PCTCN2022141611-appb-100001
    各
    Figure PCTCN2022141611-appb-100002
    独立地为双键或单键；     each
    Figure PCTCN2022141611-appb-100002
    are independently double bonds or single bonds;
    各R 1独立地为CN、卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或被1、2或3个卤素取代的C 1-C 6烷氧基； Each R 1 is independently CN, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or C 1 -C 6 alkoxy substituted by 3 halogens;
    m1为0、1、2、3或4；m1 is 0, 1, 2, 3 or 4;
    R 2为H、C 1-C 6烷基或被1、2或3个卤素取代的C 1-C 6烷基； R 2 is H, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens;
    各R 3独立地为卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或被1、2或3个卤素取代的C 1-C 6烷氧基； Each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens or substituted by 1, 2 or 3 Halogen substituted C 1 -C 6 alkoxy;
    m2为0、1、2、3或4；m2 is 0, 1, 2, 3 or 4;
    R 4为C 6-C 10芳基、被1、2或3个卤素取代的C 6-C 10芳基、苄基、被1、2或3个卤素取代的苄基、环戊烷、被1、2或3个卤素取代的环戊烷、环己烷、被1、2或3个卤素取代的环己烷、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”、被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”、“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”或被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”； R 4 is C 6 -C 10 aryl, C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, benzyl, benzyl substituted by 1, 2 or 3 halogens, cyclopentane, substituted by 1, 2 or 3 halogen substituted cyclopentane, cyclohexane, 1, 2 or 3 halogen substituted cyclohexane, "heteroatoms selected from 1, 2 or 3 of N, O and S species, 5-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", "heteroatoms substituted by 1, 2 or 3 halogens are selected from one or two of N, O and S or 3 kinds, 5-12 membered heterocycloalkyl groups with 1, 2 or 3 heteroatoms", "heteroatoms are selected from 1, 2 or 3 kinds of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heteroaryls" or "heteroatoms substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, the number of heteroatoms 1, 2 or 3 5-12 membered heteroaryl";
    R 5为H、卤素、被1、2或3个卤素取代的C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或被1、2或3个卤素取代的C 1-C 6烷氧基；或者，R 5与*标记的碳相连形成-(CH 2) n2-；n2为0或1； R 5 is H, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or 3 halogens Substituted C 1 -C 6 alkoxy; or, R 5 is connected to the carbon marked with * to form -(CH 2 ) n2 -; n2 is 0 or 1;
    n为1、2、3、4、5或6；n is 1, 2, 3, 4, 5 or 6;
    n1为0、1、2或3。n1 is 0, 1, 2 or 3.
  2. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前 述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的化合物满足下述条件中的一种或多种：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I satisfies one or more of the following conditions:
    (1)R 1中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F、Cl、Br或I； (1) In R 1 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens In the group, the halogen is independently F, Cl, Br or I;
    (2)R 1中，所述被1、2或3个卤素取代的C 1-C 6烷基和所述C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； (2) In R 1 , among the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkyl, the C 1 -C 6 alkyl is independently Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (3)R 1中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； (3) In R 1 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkoxy independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    (4)R 2中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； (4) In R 2 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkyl is independently Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (5)R 2中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述卤素独立地为F、Cl、Br或I； (5) In R 2 , in the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the halogens are independently F, Cl, Br or I;
    (6)R 3中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F、Cl、Br或I； (6) In R 3 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens In the group, the halogen is independently F, Cl, Br or I;
    (7)R 3中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； (7) In R 3 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkyl is independently Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (8)R 3中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； (8) In R 3 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkoxy independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    (9)R 4中，所述C 6-C 10芳基和所述被1、2或3个卤素取代的C 6-C 10芳基中，所述C 6-C 10芳基为苯基或萘基； (9) In R 4 , among the C 6 -C 10 aryl and the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, the C 6 -C 10 aryl is phenyl or naphthyl;
    (10)R 4中，所述被1、2或3个卤素取代的C 6-C 10芳基、所述被1、2或3个卤素取代的苄基、所述被1、2或3个卤素取代的环戊烷、所述被1、2或3个卤素取代的环己烷、所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”和所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”中，所述卤素独立地为F、Cl、Br或I； (10) In R 4 , the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, the benzyl substituted by 1, 2 or 3 halogens, or the benzyl substituted by 1, 2 or 3 A halogen-substituted cyclopentane, said cyclohexane substituted by 1, 2 or 3 halogens, said "heteroatom" substituted by 1, 2 or 3 halogens is selected from one of N, O and S , 2 or 3 kinds, a 5-12 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms" and the "heteroatoms selected from N, O and S" substituted by 1, 2 or 3 halogens 1, 2 or 3 of the 5-12 membered heteroaryls with 1, 2 or 3 heteroatoms", the halogens are independently F, Cl, Br or I;
    (11)R 4中，所述被1、2或3个卤素取代的C 6-C 10芳基为被1、2或3个F取代的苯基； (11) In R 4 , the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens is phenyl substituted by 1, 2 or 3 Fs;
    (12)R 4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、 2或3个的5-12元杂环烷基”和所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”独立地为“杂原子选自N、O和S中的1种或2种，杂原子数为1或2个的5-6元杂环烷基”； (12) In R 4 , the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heterocycloalkyl" And the "heteroatom" substituted by 1, 2 or 3 halogens is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heteroatoms In "cycloalkyl", the "heteroatoms are selected from one, two or three of N, O and S, and 5-12 membered heterocycloalkyls with 1, 2 or 3 heteroatoms" are independently means "the heteroatom is selected from one or two of N, O and S, and the number of heteroatoms is 1 or 2 5-6 membered heterocycloalkyl";
    (13)R 4中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”和所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”独立地为“杂原子选自N、O和S中的1种或2种，杂原子数为1或2个的5-6元杂芳基”； (13) In R 4 , the "heteroatom is selected from 1, 2 or 3 of N, O and S, and a 5-12 membered heteroaryl group with 1, 2 or 3 heteroatoms" and The "heteroatoms" substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, and 5-12 membered heteroaryls with 1, 2 or 3 heteroatoms In the "group", the "heteroatoms are selected from one, two or three of N, O and S, and a 5-12 membered heteroaryl group with 1, 2 or 3 heteroatoms" is independently " The heteroatoms are selected from one or two of N, O and S, and the number of heteroatoms is 1 or 2. 5-6 membered heteroaryl";
    (14)R 5中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F、Cl、Br或I； (14) In R 5 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens In the group, the halogen is independently F, Cl, Br or I;
    (15)R 5中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； (15) In R 5 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkyl is independently Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (16)R 5中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。 (16) In R 5 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkoxy independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  3. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的化合物满足下述条件中的一种或多种：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I satisfies one or more of the following conditions:
    (1)R 1中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F； (1) In R 1 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens In the group, the halogen is independently F;
    (2)R 1中，所述被1、2或3个卤素取代的C 1-C 6烷基和所述C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基； (2) In R 1 , among the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkyl, the C 1 -C 6 alkyl is independently methyl;
    (3)R 1中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基； (3) In R 1 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkoxy is independently methoxy;
    (4)R 2中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基； (4) In R 2 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkyl is independently methyl;
    (5)R 2中，所述被1、2或3个卤素取代的C 1-C 6烷基中，所述卤素独立地为F； (5) In R 2 , in the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the halogens are independently F;
    (6)R 3中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F； (6) In R 3 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens In the group, the halogen is independently F;
    (7)R 3中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述 C 1-C 6烷基独立地为甲基； (7) In R 3 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkyl is independently methyl;
    (8)R 3中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基； (8) In R 3 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkoxy is independently methoxy;
    (9)R 4中，所述C 6-C 10芳基和所述被1、2或3个卤素取代的C 6-C 10芳基中，所述C 6-C 10芳基为苯基； (9) In R 4 , among the C 6 -C 10 aryl and the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, the C 6 -C 10 aryl is phenyl ;
    (10)R 4中，所述被1、2或3个卤素取代的C 6-C 10芳基、所述被1、2或3个卤素取代的苄基、所述被1、2或3个卤素取代的环戊烷、所述被1、2或3个卤素取代的环己烷、所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂环烷基”和所述被1、2或3个卤素取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子数为1、2或3个的5-12元杂芳基”中，所述卤素独立地为F； (10) In R 4 , the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, the benzyl substituted by 1, 2 or 3 halogens, or the benzyl substituted by 1, 2 or 3 A halogen-substituted cyclopentane, said cyclohexane substituted by 1, 2 or 3 halogens, said "heteroatom" substituted by 1, 2 or 3 halogens is selected from one of N, O and S , 2 or 3 kinds, a 5-12 membered heterocycloalkyl group with 1, 2 or 3 heteroatoms" and the "heteroatoms selected from N, O and S" substituted by 1, 2 or 3 halogens 1, 2 or 3 of the 5-12 membered heteroaryl groups with 1, 2 or 3 heteroatoms", the halogens are independently F;
    (11)R 5中，所述卤素、所述被1、2或3个卤素取代的C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述卤素独立地为F； (11) In R 5 , the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens In the group, the halogen is independently F;
    (12)R 5中，所述C 1-C 6烷基和所述被1、2或3个卤素取代的C 1-C 6烷基中，所述C 1-C 6烷基独立地为甲基； (12) In R 5 , among the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkyl is independently methyl;
    (13)R 5中，所述C 1-C 6烷氧基和所述被1、2或3个卤素取代的C 1-C 6烷氧基中，所述C 1-C 6烷氧基独立地为甲氧基。 (13) In R 5 , among the C 1 -C 6 alkoxy and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens, the C 1 -C 6 alkoxy are independently methoxy.
  4. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的化合物满足下述条件中的一种或多种：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I satisfies one or more of the following conditions:
    (1)R 1中，所述被1、2或3个卤素取代的C 1-C 6烷基为三氟甲基； (1) In R 1 , the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens is trifluoromethyl;
    (2)R 4中，所述被1、2或3个卤素取代的C 6-C 10芳基为
    Figure PCTCN2022141611-appb-100003
    Figure PCTCN2022141611-appb-100004
    (2) In R 4 , the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens is
    Figure PCTCN2022141611-appb-100003
    Figure PCTCN2022141611-appb-100004
  5. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的化合物满足下述条件中的一种或多种：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I satisfies one or more of the following conditions:
    (1)R 1独立地为CN、卤素或被1、2或3个卤素取代的C 1-C 6烷基； (1) R 1 is independently CN, halogen or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens;
    (2)m1为1；(2) m1 is 1;
    (3)R 2为H或C 1-C 6烷基； (3) R 2 is H or C 1 -C 6 alkyl;
    (4)R 3为卤素； (4) R 3 is halogen;
    (5)m2为0或1；(5) m2 is 0 or 1;
    (6)R 4为C 6-C 10芳基或被1、2或3个卤素取代的C 6-C 10芳基； (6) R 4 is a C 6 -C 10 aryl group or a C 6 -C 10 aryl group substituted by 1, 2 or 3 halogens;
    (7)R 5为H；或者，R 5与*标记的碳相连形成-CH 2-； (7) R 5 is H; or, R 5 is connected with the carbon marked with * to form -CH 2 -;
    (8)n1为0；(8) n1 is 0;
    (9)n为1、2、3或4。(9) n is 1, 2, 3 or 4.
  6. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的化合物满足下述条件中的一种或多种：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I satisfies one or more of the following conditions:
    (1)R 1独立地为F、CF 3或CN； (1) R 1 is independently F, CF 3 or CN;
    (2)R 2为H或甲基； (2) R 2 is H or methyl;
    (3)R 3为F； (3) R3 is F;
    (4)R 4为苯基、
    Figure PCTCN2022141611-appb-100005
    (4) R 4 is phenyl,
    Figure PCTCN2022141611-appb-100005
  7. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述的如式I所示的化合物满足下述条件中的一种或多种：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I satisfies one or more of the following conditions:
    (1)R 1独立地为F或CN； (1) R 1 is independently F or CN;
    (2)R 2为H； (2) R2 is H;
    (3)R 4为苯基或
    Figure PCTCN2022141611-appb-100006
    (3) R 4 is phenyl or
    Figure PCTCN2022141611-appb-100006
  8. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，
    Figure PCTCN2022141611-appb-100007
    为
    Figure PCTCN2022141611-appb-100008
    Figure PCTCN2022141611-appb-100009
    优选为
    Figure PCTCN2022141611-appb-100010
    Figure PCTCN2022141611-appb-100011
    The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that,
    Figure PCTCN2022141611-appb-100007
    for
    Figure PCTCN2022141611-appb-100008
    Figure PCTCN2022141611-appb-100009
    preferably
    Figure PCTCN2022141611-appb-100010
    Figure PCTCN2022141611-appb-100011
  9. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述如式I所示的化合物具有如式I-A或I-B所示的结构：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that the compound shown in formula I has a structure shown in formula I-A or I-B:
    Figure PCTCN2022141611-appb-100012
    Figure PCTCN2022141611-appb-100012
    其中，n、m1、m2、R 1、R 2、R 3和R 4的定义如权利要求1-8至少一项所述。 Wherein, n, m1, m2, R 1 , R 2 , R 3 and R 4 are as defined in at least one of claims 1-8.
  10. 如权利要求1所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物，其特征在于，所述如式I所示的化合物为如下任一化合物：The compound shown in formula I as claimed in claim 1, its tautomer, its stereoisomer, or the pharmaceutically acceptable salt of any of the foregoing, or the solvate of any of the foregoing, It is characterized in that, the compound shown in formula I is any one of the following compounds:
    Figure PCTCN2022141611-appb-100013
    Figure PCTCN2022141611-appb-100013
    Figure PCTCN2022141611-appb-100014
    Figure PCTCN2022141611-appb-100014
    Figure PCTCN2022141611-appb-100015
    Figure PCTCN2022141611-appb-100015
    Figure PCTCN2022141611-appb-100016
    Figure PCTCN2022141611-appb-100016
  11. 如式I所示的化合物的制备方法，其为如下方法一或方法二：The preparation method of the compound shown in formula I, which is the following method one or method two:
    所述方法一包括如下步骤：Described method one comprises the steps:
    溶剂中，在缚酸剂的作用下，如式II所示的化合物和如式III所示的化合物进行取代反应，得如式I所示的化合物；In a solvent, under the action of an acid-binding agent, the compound shown in formula II and the compound shown in formula III undergo a substitution reaction to obtain a compound shown in formula I;
    Figure PCTCN2022141611-appb-100017
    Figure PCTCN2022141611-appb-100017
    X为卤素；X is a halogen;
    所述方法二包括如下步骤：Described method two comprises the following steps:
    在氰基硼氢化钠作用下，如式II所示的化合物和如式IV所示的化合物进行还原胺化反应，得如式I所示的化合物；Under the action of sodium cyanoborohydride, the compound shown in formula II and the compound shown in formula IV undergo reductive amination reaction to obtain the compound shown in formula I;
    Figure PCTCN2022141611-appb-100018
    Figure PCTCN2022141611-appb-100018
    n3＝n-1；n3=n-1;
    *、
    Figure PCTCN2022141611-appb-100019
    n、n1、m1、m2、R 1、R 2、R 3、R 4和R 5的定义如权利要求1-10至少一项所述。     *,
    Figure PCTCN2022141611-appb-100019
    The definitions of n, n1, m1, m2, R 1 , R 2 , R 3 , R 4 and R 5 are as described in at least one of claims 1-10.
  12. 一种药物组合物，其包括：A pharmaceutical composition comprising:
    (1)如权利要求1-10至少一项所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物；和(1) The compound shown in formula I as described in at least one of claims 1-10, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing; and
    (2)药学上可接受的载体。(2) A pharmaceutically acceptable carrier.
  13. 如权利要求1-10至少一项所述的如式I所示的化合物、其互变异构体、其立体异构体，或前述任一者的药学上可接受的盐，或前述任一者的溶剂化物、或如权利要求12所述药物组合物的用途，选自：The compound shown in formula I according to at least one of claims 1-10, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing The solvate of or the purposes of pharmaceutical composition as claimed in claim 12, is selected from:
    (i)用于制备乙酰胆碱酯酶抑制剂；(i) for the preparation of acetylcholinesterase inhibitors;
    (ii)用于制备五羟色胺转运体抑制剂；(ii) for the preparation of serotonin transporter inhibitors;
    (iii)用于制备乙酰胆碱酯酶和五羟色胺转运体双重抑制剂；(iii) for the preparation of dual inhibitors of acetylcholinesterase and serotonin transporter;
    (iv)用于制备治疗阿尔茨海默病的药物；(iv) for the preparation of drugs for the treatment of Alzheimer's disease;
    (v)用于制备治疗抑郁症的药物；(v) for the preparation of medicines for the treatment of depression;
    (vi)用于制备治疗阿尔茨海默病和抑郁症的共患病的药物。(vi) For the preparation of a medicament for the treatment of comorbidities of Alzheimer's disease and depression.
  14. 如式II所示的化合物：Compound shown in formula II:
    Figure PCTCN2022141611-appb-100020
    Figure PCTCN2022141611-appb-100020
    其中，*、
    Figure PCTCN2022141611-appb-100021
    n1、m2、R 3、R 4和R 5的定义如权利要求1-10至少一项所述。     in,*,
    Figure PCTCN2022141611-appb-100021
    The definitions of n1, m2, R 3 , R 4 and R 5 are as described in at least one of claims 1-10.
  15. 如权利要求14所述的如式II所示的化合物，其特征在于，所述如式II所示的化合物为如下任一化合物：The compound shown in formula II as claimed in claim 14, wherein the compound shown in formula II is any one of the following compounds:
    Figure PCTCN2022141611-appb-100022
    Figure PCTCN2022141611-appb-100022
    Figure PCTCN2022141611-appb-100023
    Figure PCTCN2022141611-appb-100023
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