WO2022022542A1 - 双环类衍生物调节剂、其制备方法和应用 - Google Patents

双环类衍生物调节剂、其制备方法和应用 Download PDF

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WO2022022542A1
WO2022022542A1 PCT/CN2021/108795 CN2021108795W WO2022022542A1 WO 2022022542 A1 WO2022022542 A1 WO 2022022542A1 CN 2021108795 W CN2021108795 W CN 2021108795W WO 2022022542 A1 WO2022022542 A1 WO 2022022542A1
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alkyl
cycloalkyl
alkenyl
alkynyl
hydroxyalkyl
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PCT/CN2021/108795
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French (fr)
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刘世强
王永升
袁逸达
鲍孟
黄胜爱
包如迪
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority to CN202180061354.5A priority Critical patent/CN116249691A/zh
Publication of WO2022022542A1 publication Critical patent/WO2022022542A1/zh

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a bicyclic derivative regulator and a preparation method and application thereof.
  • Depression is a common mental disorder that recurs and severely impairs patients' ability to perform daily activities.
  • the exact neurobiological processes leading to depression and the mechanisms by which antidepressant drugs produce therapeutic effects are not fully understood. Nearly 20% of people will suffer from depression at different stages in their lives, and about 350 million people are currently suffering from depression, and the number is gradually expanding.
  • Existing drugs are often unsatisfactory in the treatment of severe depression, at least 30% of depressed patients do not achieve satisfactory efficacy, and less than 50% of patients achieve remission. Therefore, antidepressant drugs have great market demand.
  • melatonin receptor agonist antidepressant which has a strong agonistic effect on melatonin MT1 and MT2 receptors and an antagonistic effect on 5-HT2C receptors.
  • Melatonin receptors have the functions of regulating circadian rhythm and sleep, and 5-HT2C receptors are involved in antidepressant functions. It has been clinically proven to have significant antidepressant effects, better tolerance and compliance, and can increase the continuity and quality of sleep in patients with major depressive disorder (MDD), with significantly less sexual dysfunction than other antidepressants.
  • MDD major depressive disorder
  • Agomelatine is a multi-targeted antidepressant with a new mechanism target. It has a good antidepressant effect, but its bioavailability is low (about 5%), and it has an obvious liver first-pass effect. After absorption, 90% is metabolized by CYP1A2 enzyme. 10% is metabolized by CYP2C9 enzyme, which can lead to individual differences in liver damage. Agomelatine has been clinically found to have adverse effects on liver enzymes, with ALT/AST elevations (more than 3 times the upper limit of normal) occurring in more than 1% of patients, and the elevations are dose-dependent, exposure in patients with mild and severe hepatic impairment Significantly increased, causing further damage to liver function.
  • the object of the present invention is to provide a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, and the structure of the compound is as follows:
  • M 1 is N or CR 1 ;
  • M 2 is N or CR 2 ;
  • M 3 is N or CR 3 ;
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
  • R is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, Cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl radicals and heteroaryl radicals, optionally further substituted;
  • R4 , R5 and R6 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy radical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
  • R 7 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy alkynyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
  • R 8 , R 8 ′, R 9 and R 9 ′ are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkane Oxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy alkenyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
  • any two of R 8 , R 8 ′, R 9 , R 9 ′ and the carbon atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl , heterocyclyl, aryl and heteroaryl, optionally further substituted.
  • R 9 and R 9 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclyl, optionally further deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 deuterated alkyl, C 1-6 hal
  • R 9 and R 9 ' together can form an oxo or thio group
  • M 1 when M 1 is CR 1 , M 2 is CR 2 , and M 3 is CR 3 , at least one of R 2 and R 3 is not hydrogen, and when M 1 is CR 1 , M 2 is CR 2 , M 3 is CR 3 , R is selected from C 1-6 alkyl, deuterated methyl, , R 3 is not hydrogen.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is further represented by the general formula (II):
  • R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 -membered aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C6-14 membered aryl and 5-14 membered heteroaryl, optionally further by deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6alkane base, C 2-6 alken
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclic group, C 6-14 aryl group or 5-14-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1- 6 -deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12-membered heteroalkyl Cyclic, C 6-14 aryl
  • R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclic group, C 6-14 aryl group or 5-14-membered heteroaryl group, said amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1- 6 -deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12-membered heteroalkyl Cyclic, C 6-14 ary
  • R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 14 -aryl or 5-14-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, hal
  • R 8 and R 8 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-14 aryl and 5-14 membere
  • R 8 and R 8 ' are linked to form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl, optionally further Deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkane group, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5 -14-membered heteroaryl substituted with one or more substituents.
  • At least one of R 2 and R 3 is not hydrogen, and when R is selected from C 1-6 alkyl, deuterated methyl, , R 3 is not hydrogen.
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that, the compound is further represented by the general formula (II-A):
  • M 1 is N or CR 1 , preferably N or CH;
  • R is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3 -12 -cycloalkyl or 3-12-membered heterocyclyl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl, optionally further deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, substituted by one or more substituents in C 1-6 hydroxy
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl and 3-12 membered Heterocyclyl, optionally further deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated Alkyl, C 1-6 haloalkyl, C 1-6
  • R 9 and R 9 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl and 3-12 membered heterocycle group, optionally further deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl , C 1-6 haloalkyl, C 1-6 al
  • R 9 and R 9 ' together can form an oxo or thio group
  • R 2 and R 3 when M 1 is CR 1 , at least one of R 2 and R 3 is not hydrogen, and when M 1 is CR 1 , R is selected from C 1-6 alkyl, deuterated methyl , , R 3 is not hydrogen.
  • the R is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkane base, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12-membered heterocyclic group, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl, optionally further deuterium, halogen, amino , hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxy
  • the R is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the C 1-6 alkyl, C 1-6 deuterated alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further deuterium, halogen, amino, hydroxyl, cyano, nitro base, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- Substituted by one or more substituents in 6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group.
  • the R is selected from deuterated methyl, ethyl, n-propyl, isopropyl, tert-butyl, tert-amyl, 3-pentyl, cyclopropyl or oxygen Hetetanyl, described ethyl, n-propyl, isopropyl, tert-butyl, tert-amyl, 3-pentyl, cyclopropyl or oxetanyl, further deuterium, halogen, Amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C Substituted by one or more substituents in 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl.
  • said R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl group, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
  • said R 1 , R 2 and R 3 are each independently selected from hydrogen, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl , C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1- 3 -hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl.
  • said R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tertiary Butyl.
  • said R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl group, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
  • said R 4 , R 5 and R 6 are each independently selected from hydrogen, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl , C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1- 3 -hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl.
  • said R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tertiary Butyl.
  • the R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
  • the R 7 is selected from C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1- 3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group.
  • said R 7 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl.
  • said R 8 and R 8 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
  • said R 8 and R 8 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2- 3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl or 5-10 membered heteroaryl.
  • said R 8 and R 8 ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl.
  • the R 8 , R 8 ' and the carbon atoms to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclic group, and the C 3- 8 -cycloalkyl and 3-8 membered heterocyclyl, optionally further hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 ring Substituted with one or more substituents in alkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl.
  • the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is further represented by the general formula (III):
  • M 3 is N or CR 3 ;
  • R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl;
  • More preferred is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl or methoxy.
  • R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1 -6 haloalkoxy or C 1-6 hydroxyalkyl; preferably hydrogen;
  • R 8 and R 8 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl or 3-12 membered Heterocyclyl;
  • R 8 and R 8 ' are linked to form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl, optionally further Deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkane group, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5 Substituted with one or more substituents in the -14-membered heteroaryl; preferably forming a C 3-12 cycloalkylcycloalkyl.
  • the compound of the general formula (III), its stereoisomer or its pharmaceutically acceptable salt when M 3 is CH, R 8 and R 8 ' are hydrogen, R 2 is not hydrogen.
  • the compound, its stereoisomer or its pharmaceutically acceptable salt is further represented by the general formula (IV-A):
  • R is selected from C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, cyano-substituted C 1-3 alkyl or C 3-6 cycloalkyl;
  • C 1-3 alkyl Preferably C 1-3 deuterated alkyl or C 3-6 cycloalkyl;
  • Still more preferable is a methyl group.
  • the compound, its stereoisomer or its pharmaceutically acceptable salt is further represented by the general formula (IV-B):
  • R2 or R3 is independently selected from deuterium, halogen, cyano or C1-3 alkyl; preferably deuterium, fluorine, chlorine, bromine or methyl;
  • n 1, 2 or 3.
  • the compound represented by the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, the specific structure of the compound is as follows:
  • the present invention further relates to the preparation method of the compound of general formula (IV-A), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • the compound of formula (V-A) is reacted with R-X in the presence of a base to obtain a compound of general formula (IV-A), preferably, the base is selected from potassium carbonate or cesium carbonate;
  • X is bromine or iodine
  • R is as defined in general formula (IV-A).
  • the present invention further relates to the preparation method of the compound of general formula (IV-B), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • the compound of general formula (VB) reacts with a base in the presence of a base
  • the reaction obtains the compound of general formula (IV-B), preferably, the base is selected from potassium carbonate or cesium carbonate;
  • X is bromine or iodine
  • R 2 , R 3 and n are as defined in general formula (IV-B).
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipient.
  • the object of the present invention is to provide a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition is used in the preparation of melatonin receptors. Use in agonist drugs.
  • the object of the present invention is also to provide a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition described above can be used in the preparation of MT1 and MT2 receptors.
  • Agonist and 5-HT 2C receptor antagonist drug use are also provided.
  • the object of the present invention is to provide a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition is used in the preparation of treatment or prevention of cardiovascular disease. , digestive system disease, central nervous system disease and/or use in the medicament of psychiatric disease.
  • the present invention also relates to a method of treating central nervous system disorders and/or psychiatric disorders.
  • the central nervous system disease and/or mental disease is selected from the group consisting of melatonin system disease, stress, anxiety, seasonal affective disorder, schizophrenia, phobia, depression, major depression sleep disorders, sleep disorders, insomnia or fatigue due to jet lag, weight disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and/or cognitive disorders, movement disorders, personality disorders, autism Spectrum Disorders, Pain, Traumatic Brain Injury, Substance Use Disorder and/or Withdrawal Syndrome, Tinnitus, Autism, Alzheimer's, Seizures, Neuralgia, or Detox Symptoms Major Depressive or Manic Illness.
  • melatonin system disease stress, anxiety, seasonal affective disorder, schizophrenia, phobia, depression, major depression sleep disorders, sleep disorders, insomnia or fatigue due to jet lag, weight disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and/or cognitive disorders, movement disorders, personality disorders, autism Spectrum Disorders, Pain, Traumatic Brain Injury, Substance Use Disorder and/or Withdrawal Syndrome, Tinnitus, Autism, Alzheimer
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms atomic alkyl group, further preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl yl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n- Heptyl, 4-heptyl, 1-propylbutyl, 2-methyl
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylbutyl pentyl, 3-methylpentyl, 4-methylpentyl, 2,3-
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH2- , “ethylene” means -( CH2 ) 2- , “propylene” Refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • a membered heterocyclic group, optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, includes a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, Dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azetyl, 1,4-diazepine Cycloheptyl, pyranyl or tetrahydrothiopyran dioxide group, etc., preferably oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl , tetrahydrothio
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group of sulfur atom; or a three-membered nitrogen-containing fused ring containing a benzene ring.
  • ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazole more preferably pyridyl, oxadiazolyl, pyrazolyl, pyrroly
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy
  • alkoxy may be is optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Sulfur group, carboxy
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • alkenyl refers to an alkenyl group, also known as an alkenyl group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms, still more preferably an alkenyl group of 2 to 4 carbon atoms , most preferably an alkenyl group of 2 to 3 carbon atoms.
  • alkenyl groups include: vinyl, propenyl.
  • the alkenyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Alkynyl refers to an alkenyl group, also known as an alkynyl group, referring to an unsaturated hydrocarbon group containing (CH ⁇ C-); preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group containing 2 to 6 carbon atoms , even more preferably alkynyl groups of 2 to 4 carbon atoms, most preferably alkynyl groups of 2 to 3 carbon atoms.
  • the alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carbonyl refers to -C(O)-.
  • Carboxyl refers to -C(O)OH.
  • THF tetrahydrofuran
  • Ethyl acetate refers to ethyl acetate.
  • MeOH refers to methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • TAA triethylamine
  • MeCN means acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et2O refers to diethyl ether.
  • DCM dichloromethane
  • DMAP refers to 4-dimethylaminopyridine.
  • DCC refers to dicyclohexylcarbodiimide.
  • DCE 1,2 dichloroethane
  • DDQ refers to 2,3-dichloro-5,6-dicyanobenzoquinone.
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • NMP refers to N-methylpyrrolidone
  • Cbz-Cl refers to benzyl chloroformate
  • Pd2(dba )3 refers to tris(dibenzylideneacetone)dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • X is A, B and C
  • the hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS Methylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the first step the preparation of 7-methoxynaphthalene-2-amine
  • the second step the preparation of 1-bromo-7-methoxynaphthalene-2-amine
  • the third step the preparation of 1-bromo-2-fluoro-7-methoxynaphthalene
  • the fourth step the preparation of 2-(2-fluoro-7-methoxynaphthalene-1-yl) acetonitrile
  • the fifth step the preparation of N-(2-(2-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide
  • the sixth step preparation of N-(2-(2-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide
  • the seventh step the preparation of N-(2-(7-cyclopropoxy-2-fluoronaphthalene-1-yl)ethyl)acetamide
  • N-(2-(2-Fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide 100 mg, 0.41 mmol was dissolved in DMF (5 mL), cyclopropyl bromide (150 mg, 1.24 mmol) was added, Cs 2 CO 3 (400 mg, 1.22 mmol), microwave reaction at 160°C for 4 hours, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to obtain N-(2-(7 -Cyclopropoxy-2-fluoronaphthalen-1-yl)ethyl)acetamide (56 mg, 48% yield).
  • the first step the preparation of 5-amino-8-bromonaphthalene-2-phenol
  • the second step the preparation of 8-bromo-5-fluoronaphthalene-2-phenol
  • 5-Amino-8-bromonaphthalen-2-ol (5 g, 21.0 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and a solution of HBF4 ( 40 mL, 48%) was added followed by NaNO2 (4.4 g ) , 63.8 mmol) in water (10 mL), stirring was continued at 0 °C for 1 hour, and NaBF 4 (11.5 g, 104.5 mmol) was added. The temperature was gradually raised to room temperature, and the precipitated solid was filtered, washed with water, and washed with ether. Vacuum dry. The obtained solid was dissolved in xylene (100 mL) and heated to reflux for 2 hours.
  • the third step the preparation of 4-bromo-1-fluoro-6-methoxynaphthalene
  • the fourth step the preparation of 2-(4-fluoro-7-methoxynaphthalene-1-yl) acetonitrile
  • the fifth step the preparation of N-(2-(4-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide
  • the first step preparation of N-(2-(4-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide
  • the second step preparation of N-(2-(7-cyclopropoxy-4-fluoronaphthalen-1-yl)ethyl)acetamide
  • N-(2-(4-Fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide 100 mg, 0.41 mmol was dissolved in DMF (5 mL), cyclopropyl bromide (150 mg, 1.24 mmol) was added, Cs 2 CO 3 (400 mg, 1.22 mmol), microwave reaction at 160°C for 4 hours, water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to obtain N-(2-(7 -Cyclopropoxy-4-fluoronaphthalen-1-yl)ethyl)acetamide (44 mg, 38% yield).
  • the first step preparation of N-(2-(4-fluoro-7-(methoxy-d3)naphthalen-1-yl)ethyl)acetamide
  • N-(2-(4-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide 80 mg, 323.54 ⁇ mol
  • KI 5.4 mg, 32.35 ⁇ mol
  • Cs2CO3 210 mg , 647.08 ⁇ mol
  • deuterated iodomethane 188 mg, 1.29 mmol
  • reaction solution was poured into water, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain N-(2-(4-fluoro-7-( Methoxy-d3)naphthalen-1-yl)ethyl)acetamide (71.4 mg, 82% yield) as a white solid.
  • the first step preparation of N-(2-(7-hydroxynaphthalen-1-yl)ethyl)acetamide
  • the substrate N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (511 mg, 2.1 mmol) was dissolved in anhydrous dichloromethane (10 mL), replaced with nitrogen three times, cooled under protection At 0°C, BBr 3 (4.2 mmol, 4.2 mL) was added dropwise. After the dropwise addition was completed, the mixture was heated to room temperature and stirred for 30 minutes. The reaction solution was slowly poured into 150 mL of saturated NaHCO 3 solution to quench the reaction.
  • the second step preparation of N-(2-(7-(oxetan-3-oxy)naphthalene-1-yl)ethyl)acetamide
  • N-(2-(7-hydroxynaphthalen-1-yl)ethyl)acetamide (61.6 mg, 0.2 mmol), KI (49.8 mg, 300 ⁇ mol) and Cs 2 CO 3 (97.8 mg, 300 ⁇ mol) were dissolved In DMF (1.5 mL) in a 5.0 mL microwave tube was added 3-bromooxetane (137 mg, 1.0 mmol). Microwave at 130°C for 1.5 hours.
  • reaction solution was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, the organic layer was dried over anhydrous Na 2 SO 4 and concentrated to obtain crude product, which was purified by flash column chromatography to obtain crude product, and then purified by preparative HPLC to obtain N- (2-(7-(oxbutane-3-oxy)naphthalen-1-yl)ethyl)acetamide (36 mg, 48% yield) as a white solid.
  • the first step preparation of N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide
  • the substrate N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide (5 g, 20.6 mmol) was dissolved in glacial acetic acid (50 mL) and heated to 85°C (oil bath temperature), Bromine (4.0 g, 25.0 mmol) in AcOH (30 mL) was added dropwise. After the dropwise addition was completed, heating and stirring were continued for 3 hours.
  • reaction solution was cooled to room temperature, poured into water (150 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain N-(2-(7-Methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide (4.5 g, 68% yield).
  • the second step preparation of N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide
  • the third step preparation of N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide
  • N-(2-(7-Methoxynaphthalen-1-yl-3-d)ethyl)acetamide 80 mg, 0.33 mmol was dissolved in dichloromethane (10 mL), cooled to 0 °C under nitrogen protection , BBr 3 (270 mg, 1.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. It was quenched by adding aqueous NaHCO 3 and extracted with dichloromethane. Washed with water and 10% aqueous sodium bicarbonate.
  • the fourth step the preparation of N-(2-(7-isopropoxynaphthalene-1-yl-3-d)ethyl)acetamide
  • N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide 50 mg, 217.13 umol
  • 2 -iodopropane 110.7 mg, 651.4 umol
  • Cs 2 CO 3 141.1 mg, 434.2 umol
  • potassium iodide 18 mg, 108.56 umol
  • the first step preparation of N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide
  • the substrate N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide (14.6 g, 60.0 mmol) was dissolved in AcOH (120 mL) and heated to 85°C (oil bath temperature), Bromine (11.5 g, 72.0 mmol, 3.69 mL) in AcOH (30 mL) was added dropwise. After the dropwise addition was completed, stirring was continued for 0.5 hours.
  • the second step preparation of N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide
  • the substrate N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide (3.9 g, 12 mmol) was dissolved in THF (60 mL) and cooled to - 75°C to -70°C, n-BuLi (30.0mmol, 12.5mL) was added dropwise, then stirred at -75°C for 1.5 hours, D 2 O (1.20g, 60.00mmol) was added dropwise, the addition was completed, the temperature was raised to room temperature and stirred overnight.
  • reaction solution was slowly poured into 200 mL of water for quenching, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous Na 2 SO 4 , concentrated to obtain the crude product, and purified by column chromatography to obtain the target compound N-(2-(7-methoxyl) Naphthalen-1-yl-3-d)ethyl)acetamide (1.2 g, 41% yield) as a yellow solid.
  • the third step preparation of N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide
  • the substrate N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide (1.2 g, 4.91 mmol) was dissolved in dry dichloromethane (60 mL) under nitrogen , cooled to 0° C., BBr 3 (10 mmol, 10 mL) was added dropwise, the dropwise addition was completed, and the mixture was heated to room temperature and stirred for 30 min. The reaction was quenched by slowly pouring the reaction into 150 mL of saturated NaHCO 3 solution.
  • the fourth step preparation of N-(2-(7-(tert-butoxy)naphthalene-1-yl-3-d)ethyl)acetamide
  • the substrate N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide 134 mg, 582 umol
  • O (317.5 mg, 1.45 mmol) and Mg(ClO 4 ) 2 26 mg, 116 umol
  • the reaction solution was cooled to room temperature, and 100 mL of water was slowly added, followed by 50 mL of saturated aqueous NaHCO 3 solution.
  • the first step the preparation of 4-(3-chloro-4-methoxyphenyl)-4-carbonyl butyric acid
  • the second step the preparation of 4-(3-chloro-4-methoxyphenyl) butyric acid
  • the third step the preparation of 6-chloro-7-methoxy-3,4-dihydronaphthalene-1(2H)-one
  • MeSO 3 H (7 mL) was added dropwise to 4-(3-chloro-4-methoxyphenyl)butyric acid (7 g, 30.7 mmol) in TFA (30 mL) under nitrogen protection, heated to 120° C. and stirred for 7 hours. Cool to room temperature, pour the reaction solution into ice water, filter, wash the filter cake with water, filter with ethanol-water beating, and dry to obtain a yellow solid 6-chloro-7-methoxy-3,4-dihydronaphthalene-1(2H )-one (3.6 g, 56% yield).
  • the fourth step the preparation of 2-(6-chloro-7-methoxy-3,4-dihydronaphthalene-1-yl) acetonitrile
  • reaction solution was quenched by adding brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated and then slurried with ethanol-water at 90°C, filtered, and dried to obtain a yellow solid 2-(6-chloro- 7-Methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (3 g, 76% yield).
  • the fifth step the preparation of 2-(6-chloro-7-methoxynaphthalene-1-yl) acetonitrile
  • the sixth step preparation of N-(2-(6-chloro-7-methoxynaphthalen-1-yl)ethyl)acetamide
  • NiCl 2 was added to 2-(6-chloro-7-methoxynaphthalen-1-yl)acetonitrile (2.8 g, 12 mmol) in CH 2 Cl 2 -MeOH (100 mL-50 mL) under nitrogen protection .6H 2 O (1.8 g, 0.8 mmol), acetic anhydride (2.72 mL, 0.8 mmol), NaBH 4 (2.1 g, 54 mmol) was added in portions and stirred at 20° C. for 12 hours.
  • the seventh step the preparation of N-(2-(6-chloro-7-hydroxynaphthalene-1-yl)ethyl)acetamide
  • the eighth step preparation of N-(2-(6-chloro-7-cyclopropoxynaphthalene-1-yl)ethyl)acetamide
  • N-(2-(6-chloro-7-hydroxynaphthalen-1-yl)ethyl)acetamide 100 mg, 0.4 mmol
  • bromocyclopropane 100 mg, 0.8 mmol
  • Cs 2 CO 3 160 mg, 0.5 mmol
  • potassium iodide 30 mg, 0.2 mmol
  • the first step preparation of N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide
  • the substrate N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide (14.6 g, 60.0 mmol) was dissolved in glacial acetic acid (120 mL) and heated to 85°C (oil bath temperature) , and a solution of bromine (11.51 g, 72.0 mmol, 3.69 mL) in AcOH (30 mL) was added dropwise. After the dropwise addition was completed, heating and stirring were continued for 3 hours.
  • the substrate N-[2-(3-bromo-7-methoxy-1-naphthyl)ethyl]acetamide (1.61 g, 5.0 mmol), guanacol boronate (2.54 g, 7.9 mmol) and potassium acetate (1.47 g, 15.0 mmol) were dissolved in anhydrous dioxane (45 mL), nitrogen was replaced three times, Pd(dppf)Cl 2 (731 mg, 1.0 mmol) was added, and the reaction was heated to 90° C. for 2 hours.
  • reaction solution was concentrated to obtain crude product, which was purified by column chromatography to obtain the target compound N-(2-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxo) Boron-2-yl)naphthalen-1-yl)ethyl)acetamide (1.6 g, 87% yield) as a yellow solid.
  • the third step preparation of N-(2-(7-methoxy-3-(boronic acid)naphthalene-1-yl)ethyl)acetamide
  • the substrate N-(2-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronic acid-2-yl)naphthalen-1-yl) Ethyl)acetamide (1.4 g, 3.8 mmol) was dissolved in acetone (40 mL) and water (40 mL), ammonium acetate (1.46 g, 19.0 mmol) and NaIO4 (4.05 g, 19.0 mmol) were added. Heated to 25°C and reacted for 4 hours.
  • the fourth step preparation of N-[2-(3-fluoro-7-methoxy-1-naphthyl)ethyl]acetamide
  • the reagent NaOH (121 mg, 3.0 mmol) was dissolved in MeOH (10 mL) at room temperature, followed by the addition of the substrate N-(2-(7-methoxy-3-(boronic acid)naphthalen-1-yl)ethyl) Acetamide (722 mg, 2.5 mmol), then stirred at 25 °C for 15 min. Then, the reaction solution was cooled to 0°C, a reagent AgOTf (1.94 g, 7.5 mmol) was added, and the mixture was stirred at 0°C for 30 minutes.
  • reaction solution was solvent-concentrated with an oil pump at a low temperature of 0° C., and acetone (5 mL ⁇ 3) was used to azeotrope the residual methanol with the solvent to obtain a crude product.
  • the crude product was dissolved in acetone (10 mL), activated 3A molecular sieves (350 mg) were added, followed by F-TEDA - BF4 (935 mg, 2.6 mmol). It was then stirred at 0°C for 1 hour.
  • reaction solution was slowly added to 100 mL of water, extracted with ethyl acetate (150 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain N-[2-(3-fluoro-7 -Methoxy-1-naphthyl)ethyl]acetamide (214 mg, 33% yield).
  • the fifth step preparation of N-[2-(3-fluoro-7-hydroxy-1-naphthyl)ethyl]acetamide
  • the substrate N-[2-(3-fluoro-7-methoxy-1-naphthyl)ethyl]acetamide (241 mg, 922.3 ⁇ mol) was dissolved in dry dichloromethane (10 mL) and protected by nitrogen replacement Cooled to 0°C under lower temperature, BBr 3 (1.84 mmol, 3.0 mL) was added dropwise, the dropwise addition was completed, and stirring was continued for 30 minutes. The reaction was added dropwise to 100 mL of water to quench, then 100 mL of saturated aqueous NaHCO 3 solution was added, extracted with dichloromethane (100 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography gave the target compound N-[2-(3-fluoro-7-hydroxy-1-naphthyl)ethyl]acetamide (204 mg, 89% yield).
  • the sixth step preparation of N-(2-(7-cyclopropyl-3-fluoronaphthalene-1-yl)ethyl)acetamide
  • N-[2-(3-fluoro-7-hydroxy-1-naphthyl)ethyl]acetamide (49 mg, 0.2 mmol) and cyclopropyl bromide (121 mg, 1.0 mmol) were dissolved in NMP (1 mL) , placed in a 5.0 mL microwave tube, Cs 2 CO 3 (98 mg, 300 ⁇ mol) and KI (50 mg, 300 ⁇ mol) were added.
  • the reaction was microwaved at 180°C for 2 hours.
  • the reaction solution was concentrated, and the solvent was removed to give crude N-(2-(7-cyclopropyl-3-fluoronaphthalen-1-yl)ethyl)acetamide (10 mg, 17% yield) as a yellow liquid.
  • the first step the preparation of N-(2-(7-cyclopropyl-3-chloronaphthalene-1-yl)ethyl)acetamide
  • the first step preparation of N-(2-(7-hydroxy-3-bromonaphthalen-1-yl)ethyl)acetamide
  • N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide 3.3 g, 10.24 mmol
  • dichloromethane 30 mL
  • BBr 3 1M, 20.48 mL
  • the mixture was stirred at 30° C. for 1 hour, and the reaction was completed.
  • the mixture was poured into saturated aqueous NaHCO3 and extracted with dichloromethane-methanol (10/1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-(2-(7-hydroxy-3-bromonaphthalen-1-yl)ethyl)acetamide (3 g, 95% yield).
  • the second step preparation of N-(2-(7-cyclopropyl-3-bromonaphthalen-1-yl)ethyl)acetamide
  • the first step preparation of N-(2-(3-bromo-6-chloro-7-cyclopropoxynaphthalen-1-yl)ethyl)acetamide
  • N-(2-(6-chloro-7-cyclopropoxynaphthalen-1-yl)ethyl)acetamide (0.2 g, 658.37 ⁇ mol) in AcOH (5 mL) was added dropwise at 60 °C under N2 Bromine (126 mg, 790 ⁇ mol, 40.47 ⁇ L) in AcOH (1 mL) was stirred at 60° C. for 2 hours. It was cooled to 0°C, saturated brine was added, and the mixture was extracted with ethyl acetate.
  • the second step preparation of N-(2-(3,6-dichloro-7-cyclopropoxynaphthalen-1-yl)ethyl)acetamide
  • the first step preparation of 1-(7-methoxynaphthalen-1-yl)propan-2-amine
  • the substrate N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide (3.94 g, 0.02 mol) was dissolved in anhydrous THF (15 mL), and MeMgI was added dropwise under the protection of nitrogen replacement. (30.0 mmol, 10.0 mL, 3M in THF), added dropwise, and stirred at room temperature for 3 hours.
  • the reaction solution was cooled to 0°C, MeOH (40 mL) was slowly added dropwise, and after the addition was completed, NaBH 4 (2.26 g, 60.00 mmol) was added. Stir at room temperature for 24 hours.
  • reaction solution was slowly poured into 200 mL of water for quenching, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, the organic layer was dried over anhydrous Na 2 SO 4 and concentrated to obtain the crude product, 1-(7-methoxynaphthalene) -1-yl)propan-2-amine (368 mg, 8% yield) as a yellow liquid.
  • the second step preparation of N-(1-(7-methoxynaphthalen-1-yl)propan-2-yl)acetamide
  • the substrate 1-(7-methoxynaphthalen-1-yl)propan-2-amine (368 mg, 1.7 mmol) was dissolved in dichloromethane (30 mL), TEA (519 mg, 5.12 mmol, 0.72 mL) was added, It was stirred at room temperature for 10 minutes, cooled to 0°C, and acetic anhydride (262 mg, 2.56 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was poured into 100 mL of water to quench, extracted with dichloromethane, the organic layers were combined, dried over anhydrous Na 2 SO 4 , and concentrated to obtain the crude product. Purification by column chromatography gave the target compound N-(1-(7-methoxynaphthalen-1-yl)propan-2-yl)acetamide (300 mg, 82% yield) as a white solid.
  • the third step preparation of N-(1-(3-bromo-7-methoxynaphthalen-1-yl)propan-2-yl)acetamide
  • the substrate N-(1-(7-methoxynaphthalen-1-yl)propan-2-yl)acetamide (230 mg, 0.89 mmol) was dissolved in AcOH (5 mL) and heated to 85°C (oil bath temperature ), a solution of bromine (144 mg, 0.9 mmol) in AcOH (1 mL) was added dropwise. After the dropwise addition was completed, heating and stirring were continued for 0.5 hours.
  • reaction solution was concentrated to dryness to obtain crude product, which was purified by column chromatography to obtain the target compound N-(1-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolane-2-yl)naphthalen-1-yl)propan-2-yl)acetamide (276 mg, 90% yield) as a yellow solid.
  • the fifth step the preparation of (4-(2-acetamidopropyl)-6-methoxynaphthalene-2-yl)boronic acid
  • the substrate N-(1-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalene-1- yl)propan-2-yl)acetamide (276 mg, 0.72 mmol) was dissolved in acetone (10 mL) and water (10 mL), NH4OAc (280 mg, 3.6 mmol) and NaIO4 (770 mg, 3.6 mmol) were added. It was heated to 25°C (external temperature) and reacted for 1.5 hours. The reaction solution was concentrated to dryness to obtain a crude product, which was added with water and extracted with ethyl acetate.
  • the sixth step preparation of N-(1-(3-fluoro-7-methoxynaphthalen-1-yl)propan-2-yl)acetamide
  • the reagent NaOH (21 mg, 525 ⁇ mol) was dissolved in MeOH (1 mL) at room temperature, followed by the addition of the substrate (4-(2-acetamidopropyl)-6-methoxynaphthalen-2-yl)boronic acid (130 mg, 432 ⁇ mol), then stirred at 25° C. (external temperature, oil bath temperature) for 15 minutes.
  • the reaction solution was cooled to 0°C, reagent AgOTf (334 mg, 1.3 mmol) was added, and the mixture was stirred at 0°C for 30 minutes.
  • reaction solution was slowly added to 10 mL of water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated to obtain the crude product, which was purified by column chromatography to obtain the target compound N-(1-(3-fluoro-7- Methoxynaphthalen-1-yl)propan-2-yl)acetamide (86 mg, 60% yield), white solid.
  • the seventh step preparation of N-(1-(3-fluoro-7-hydroxynaphthalene-1-yl)propan-2-yl)acetamide
  • the substrate N-(1-(3-fluoro-7-hydroxynaphthalen-1-yl)propan-2-yl)acetamide (86 mg, 310.8 ⁇ mol) was dissolved in dichloromethane (15 mL), cooled under nitrogen At 0°C, BBr 3 (3 mL, 1M in CH 2 Cl 2 ) was added dropwise, the dropwise addition was completed, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by slowly pouring the reaction into 100 mL of saturated NaHCO 3 solution.
  • the eighth step preparation of N-(1-(7-cyclopropoxy-3-fluoronaphthalene-1-yl)propan-2-yl)acetamide
  • N-(1-(3-fluoro-7-hydroxynaphthalen-1-yl)propan-2-yl)acetamide 39 mg, 0.15 mmol
  • bromocyclopropane 91 mg, 0.75 mmol
  • Cs 2 CO 3 73 mg, 225 ⁇ mol
  • KI 37 mg, 225 ⁇ mol
  • reaction solution was concentrated, and the solvent was removed to obtain a crude product, which was purified by preparative HPLC (alkali method) to obtain the target compound N-(1-(7-cyclopropoxy-3-fluoronaphthalen-1-yl)propan-2-yl)acetamide (9.5 mg, 21% yield), white solid.
  • the first step preparation of 1-((7-cyclopropoxy-3-fluoronaphthalen-1-yl)methyl)cyclopropane-1-amine
  • the second step preparation of N-(1-((7-cyclopropoxy-3-fluoronaphthalen-1-yl)methyl)cyclopropyl)acetamide
  • the first step the preparation of N-(2-(7-cyclopropyl-3-methylnaphthalene-1-yl)ethyl)acetamide
  • Substrate N-(2-(7-cyclopropyl-3-bromonaphthalen-1-yl)ethyl)acetamide (104 mg, 0.3 mmol), Cs2CO3 ( 293 mg, 900 ⁇ mol) and trimethyl borate ( 75 mg, 720 ⁇ mol, 83.87 ⁇ L) was dissolved in anhydrous dioxane (5 mL) and water (1 mL), nitrogen was replaced three times, Pd(dppf)Cl 2 (44 mg, 60 ⁇ mol) was added, and the reaction was heated to 110° C. for 4 hours.
  • reaction solution was concentrated to obtain a crude product, water was added, extracted with ethyl acetate (80 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, purified by column chromatography to obtain a crude product, and then purified by preparative HPLC to obtain a white Solid product N-(2-(7-cyclopropyl-3-methylnaphthalen-1-yl)ethyl)acetamide (24 mg, 27% yield).
  • the first step the preparation of 1,1-dideutero-2-(7-methoxy-1-naphthalene)ethylamine
  • the second step preparation of N-[1,1-dideutero-2-(7-methoxy-1-naphthalene)ethyl]acetamide
  • the third step preparation of N-[1,1-duteutero-2-(7-hydroxy-1-naphthyl)ethyl]acetamide
  • the fourth step the preparation of N-(2-(7-cyclopropoxynaphthalene-1-yl)ethyl-1,1-dideuterium)acetamide
  • N-[1,1-dideutero-2-(7-hydroxy-1-naphthyl)ethyl]acetamide (1.5 g, 6.5 mmol), KI (108 mg, 648 ⁇ mol) and Cs 2 CO 3 (4.2 g, 13 mmol) in DMF (8 mL) solution was added bromocyclopropane (2.35 g, 19.5 mmol), and the mixture was stirred at 170°C with microwave for 2 hours. Cool to room temperature, add brine, and extract with dichloromethane.
  • the fifth step preparation of N-[2-[3-bromo-7-(cyclopropoxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide
  • the first step preparation of N-[2-[3-chloro-7-(cyclopropoxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide
  • N-[2-[3-bromo-7-(cyclopropoxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide (20 mg, 57 ⁇ mol) in DMF (2 mL) was added under nitrogen protection. ), CuCl (113 mg, 1.14 mmol) was added, and the mixture was stirred under microwave at 140°C for 3 hours. Saturated brine was added to the reaction solution, followed by extraction with dichloromethane.
  • the first step preparation of N-(2-(3-bromo-7-hydroxynaphthalen-1-yl)ethyl)acetamide
  • the substrate N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide (1.29 g, 4.0 mmol) was dissolved in dichloromethane (40 mL), under nitrogen protection, After cooling to 0°C, BBr 3 (40 mL, 1M dichloromethane solution) was added dropwise, the dropwise addition was completed, and the mixture was heated to room temperature and stirred for 30 minutes. The reaction was quenched by slowly pouring into 200 mL of saturated NaHCO 3 solution.
  • the second step preparation of N-(2-(3-bromo-7-cyclopropoxynaphthalen-1-yl)ethyl)acetamide
  • the third step N-(2-(7-cyclopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalene- Preparation of 1-yl)ethyl)acetamide
  • the substrate N-(2-(3-bromo-7-cyclopropoxynaphthalen-1-yl)ethyl)acetamide (700 mg, 2.01 mmol), 4,4,5,5-tetramethyl-2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.02 g, 4.02 mmol) and KOAc (591 mg, 6.03 mmol) was dissolved in anhydrous dioxane (10 mL), Pd(dppf)Cl 2 (294 mg, 402 ⁇ mol) was added under nitrogen protection, and the reaction was heated at 100° C. (external temperature) for 10 hours.
  • reaction solution should be concentrated to dryness to obtain crude product, which was purified by column chromatography to obtain the target compound N-(2-(7-cyclopropoxy-3-(4,4,5,5-tetramethyl-1,3,2). - Dioxaborolane-2-yl)naphthalen-1-yl)ethyl)acetamide (760 mg, 79% yield) as a yellow solid.
  • the fourth step the preparation of (4-(2-acetamidoethyl)-6-cyclopropoxynaphthalene-2-yl)boronic acid
  • the substrate N-(2-(7-cyclopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1 -yl)ethyl)acetamide (760 mg, 1.92 mmol) was dissolved in acetone (15 mL) and H2O (15 mL), NH4OAc (741 mg, 9.61 mmol) and NaIO4 (2.06 g, 9.61 mmol) were added. It was heated to 25°C (external temperature) and reacted for 1.5 hours.
  • the reaction solution was concentrated to dryness to obtain the crude product, which was added with water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous Na 2 SO 4 , concentrated to obtain the crude product, and purified by column chromatography to obtain the target compound (4-(2-acetamidoethyl) )-6-cyclopropoxynaphthalen-2-yl)boronic acid (245 mg, 33% yield) as a yellow solid.
  • the fifth step the preparation of N-(2-(7-cyclopropoxy-3-hydroxynaphthalene-1-yl)ethyl)acetamide
  • the sixth step the preparation of N-(2-(7-cyclopropoxy-3-methoxynaphthalen-1-yl)ethyl)acetamide
  • reaction solution was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, the organic layer was dried over anhydrous Na 2 SO 4 and concentrated to obtain a crude product, which was then purified by preparative HPLC (acid method, followed by alkali method) to obtain N- (2-(7-Cyclopropoxy-3-methoxynaphthalen-1-yl)ethyl)acetamide (25 mg, 41.70% yield) as a white solid.
  • the first step the preparation of 2-(6-methoxy-4-quinolinyl)-N,N-dimethyl-vinylamine
  • the second step the preparation of 2-(6-methoxy-4-quinolinyl) acetonitrile
  • the third step preparation of N-[2-(6-methoxy-4-quinolinyl)ethyl]acetamide
  • the fifth step the preparation of N-(2-(6-cyclopropoxyquinolin-4-yl)ethyl)acetamide
  • N-(2-(6-hydroxyquinolin-4-yl)ethyl)acetamide 100 mg, 0.43 mmol
  • bromocyclopropane 100 mg, 0.8 mmol
  • N-methylpyrrolidone 3 mL
  • carbonic acid Cesium 160 mg, 0.5 mmol
  • potassium iodide 30 mg, 0.2 mmol
  • microwave stirring 170° C. for 2 hours.
  • the reaction solution was added to water (40 mL), extracted with dichloromethane, separated by high performance liquid chromatography after concentration, and lyophilized to obtain N-(2-(6-cyclopropoxyquinolin-4-yl)ethyl)acetamide (10 mg, 8% yield).
  • the first step 4-(2-acetamidoethyl)-6-cyclopropoxyquinoline 1-oxidation preparation
  • the second step preparation of N-(2-(2-chloro-6-cyclopropoxyquinolin-4-yl)ethyl)acetamide
  • the first step the preparation of 7-methoxy-1-methylisoquinoline
  • the second step preparation of (Z)-2-(7-methoxyisoquinolin-1-yl)-N,N-dimethylethene-1-amine
  • the third step the preparation of 2-(7-methoxyisoquinolin-1-yl)acetonitrile
  • reaction solution was adjusted to pH ⁇ 9 with solid sodium carbonate, water (60 mL) was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated, and purified by column chromatography to obtain 2 -(7-Methoxyisoquinolin-1-yl)acetonitrile (1.7 g, 83% yield for two steps).
  • the fourth step the preparation of N-(2-(7-methoxyisoquinolin-1-yl)ethyl)acetamide
  • the first step 1-(2-acetamidoethyl)-7-methoxyisoquinoline 2-oxidation preparation
  • the second step preparation of N-(2-(3-chloro-7-methoxyisoquinolin-1-yl)ethyl)acetamide
  • the first step preparation of N-[2-[3-bromo-7-(cyanomethoxy)-1-naphthyl]ethyl]acetamide
  • N-[2-(3-Bromo-7-hydroxy-1-naphthyl)ethyl]acetamide 50 mg, 162.25 ⁇ mol
  • bromoacetonitrile 58 mg, 486 ⁇ mol
  • potassium carbonate 67 mg, 486 ⁇ mol
  • the first step preparation of N-(2-(3-chloro-7-hydroxynaphthalen-1-yl)ethyl)acetamide
  • N-[2-(3-Bromo-7-hydroxy-1-naphthyl)ethyl]acetamide 130 mg, 422 ⁇ mol
  • cuprous chloride 418 mg, 4.22 mmol
  • N,N-dimethylformamide 3 mL
  • To the reaction solution was added water (30 mL) and ethyl acetate (20 mL), filtered, and extracted with ethyl acetate (20 mL ⁇ 2).
  • the second step preparation of N-(2-(3-chloro-7-(cyanomethoxy)naphthalen-1-yl)ethyl)acetamide
  • N-[2-(3-Chloro-7-hydroxy-1-naphthyl)ethyl]acetamide 70 mg, 265 ⁇ mol
  • bromoacetonitrile 95 mg, 796 ⁇ mol
  • potassium carbonate 110 mg, 796 ⁇ mol
  • the first step preparation of N-(2-(7-hydroxy-3-methyl-naphthalen-1-yl)ethyl)acetamide
  • N-[2-(3-Bromo-7-hydroxy-1-naphthyl)ethyl]acetamide (100 mg, 324 ⁇ mol), trimethylcyclotriboroxane (122 mg, 973 ⁇ mol), Cs 2 CO 3 (211 mg) , 649 ⁇ mol), Pd(dppf)Cl 2 -DCM (27 mg, 32 ⁇ mol) in dioxane (3 mL) and water (0.3 mL) under nitrogen, stirred at 100° C. with microwave for 1 hour. LC-MS showed the reaction was complete. The reaction solution was directly used in the next reaction.
  • the second step preparation of N-(2-(7-(cyanomethoxy)-3-methyl-1-naphthyl)ethyl)acetamide
  • the first step the preparation of ethyl 2-cyano-2-(7-methoxyl-1-naphthyl) acetate
  • the second step the preparation of 3-amino-2-(7-methoxy-1-naphthyl) propan-1-ol
  • the third step 3-acetamido-2-(7-methoxynaphthalen-1-yl)propyl acetate
  • the fourth step the preparation of [3-acetamido-2-(3-bromo-7-methoxy-1-naphthyl)propyl] acetate
  • the fifth step the preparation of N-(2-(3-bromo-7-hydroxynaphthalene-1-yl)-3-hydroxypropyl)acetamide
  • N-(2-(3-Bromo-7-hydroxynaphthalen-1-yl)-3-hydroxypropyl)acetamide (20 mg, 59 ⁇ mol), bromocyclopropane (31.8 mg, 263.0 ⁇ mol), KI (1.1 mg) , 6.57 ⁇ mol), Cs 2 CO 3 (42.7 mg, 131.5 ⁇ mol) was added to DMF (2 mL), mixed well, reacted at 170 ° C for 4 hours, concentrated under reduced pressure, and the crude product was separated and purified by Pre-HPLC to obtain the target compound N-[2-[3-Bromo-7-(cyclopropoxy)-1-naphthyl]-3-hydroxy-propyl]acetamide (4 mg, 16% yield).
  • Test Example 1 Determination of the effect of the compounds of the present invention on calcium flux in cells stably expressing MT1/MT2 receptors
  • DMEM high glucose
  • Cell seeding medium DMEM+10%FBS+1X PS;
  • Assay Buffer 2 1X HBSS+20mM HEPES+0.075% Pluronic F-127; 1X Matrigel: 5X Matrigel diluted with DMEM;
  • HEK293-MT1/HEK293-MT2 cell line was cultured in complete medium at 37°C 5% CO 2 to 70%-90% confluency.
  • the compounds of the examples shown in the present invention showed good agonistic activity in the experiment of stably expressing MT1 and MT2 receptor cells on calcium flux.
  • Test Example 2 Determination of the effect of the compounds of the present invention on calcium flux in cells stably expressing 5-HT 2C receptors
  • the compounds were tested for antagonism of HEK293-5HT 2C cell activity.
  • DMEM high glucose
  • Cell seeding medium DMEM+10%FBS+1X PS;
  • Assay Buffer 2 1X HBSS+20mM HEPES+0.075% Pluronic F-127; 1X Matrigel: 5X Matrigel diluted with DMEM;
  • HEK293-5HT 2C cell line was cultured in complete medium at 37°C, 5% CO 2 to 70%-90% confluency.
  • the compounds of the examples shown in the present invention showed a certain antagonistic effect in the experiment of stably expressing 5HT 2C receptor cells on calcium flux.
  • SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in rats (plasma) administered intravenously and orally.
  • Intravenous drug preparation (5%DMSO+10%Solutol HS15+85%PBS preparation method)
  • CMC-Na sodium carboxymethylcellulose
  • 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-2K test tube, and centrifuged at 6000 rpm at 4°C for 6 min to separate plasma. Store at -80°C; eat 4 hours after administration.
  • 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-2K test tube, centrifuged at 6000 rpm at 4°C for 6 min to separate plasma, and stored at -80°C; Food was taken 4 hours after administration.

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Abstract

一种通式(I)所示的双环类化合物或其立体异构体、其制备方法及含有该化合物的药物组合物，及其在制备治疗心血管疾病、消化系统疾病、中枢神经系统疾病和/或精神疾病药物中的用途。

Description

双环类衍生物调节剂、其制备方法和应用 技术领域
本发明属于生物医药领域，具体涉及一种双环类衍生物调节剂及其制备方法和应用。
背景技术
抑郁症是一种常见的精神障碍，反复发作并严重损害患者的日常生活能力。尽管进行了大量的研究，导致抑郁的确切神经生物学过程和抗抑郁药物产生治疗效果的机制仍未完全清楚。将近20％的人会在人生中不同阶段患上抑郁症，目前约有3.5亿人患有抑郁症，数量还在逐步扩大。现有药物对于重度抑郁症治疗效果往往不理想，至少30％的抑郁患者没有达到满意疗效，只有不到50％的患者达到缓解。因此，抗抑郁症药物具有极大市场需求。
临床发现抑郁症常与生物节律有关，通过调节昼夜节律可能具有抗抑郁作用。Servier公司开发的Agomelatine是唯一已被批准褪黑素受体激动剂类抗抑郁药，对褪黑素MT1和MT2受体具有强激动作用，同时对5-HT2C受体具有拮抗作用。褪黑素受体具有调节昼夜节律，调节睡眠功能，5-HT2C受体参与抗抑郁功能。临床上已证明其具有明显的抗抑郁效果，较好的耐受性和依从性，能增加重度抑郁症患者(MDD)睡眠连续性和质量，且性功能障碍明显小于其他抗抑郁药。
Agomelatine为一个全新机制靶点的多靶点抗抑郁药，具有良好抗抑郁效果，但是其生物利用度低(5％左右)，有明显的肝脏首过效应，吸收后90％经CYP1A2酶代谢，10％经CYP2C9酶代谢，会导致个体差异性的肝损伤。临床上发现Agomelatine对肝酶有不良影响，超过1％的患者会出现ALT/AST升高(超过正常上限3倍)，且升高具有剂量依赖性，轻度和重度肝功能损伤患者的暴露量明显升高，对肝功能造成进一步损伤的作用。
国际申请WO2019011279A1报道了具有MT1、MT2激动剂和5-HT2C拮抗剂的化合物临床前生物活性数据，显示提高了绝对生物利用度，但还未有相应的药物上市。因此，亟待开发具有肝脏首过效应低，绝对生物利用度高，且具有MT1和MT2受体激动活性以及5-HT2C拮抗作用的新抗抑郁药物，以满足巨大的市场需求。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述化合物的结构如下：
Figure PCTCN2021108795-appb-000001
其中：
M 1为N或CR 1；
M 2为N或CR 2；
M 3为N或CR 3；
R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；
R选自氢、氘、卤素、氨基、硝基、羟基、氰基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选可以进一步被取代；
R 4、R 5和R 6各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；
R 7选自氢、氘、卤素、氨基、硝基、羟基、氰基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选可以进一步被取代；
R 8、R 8’、R 9和R 9’各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；
或者，R 8、R 8’、R 9、R 9’中任意两个以及它们所连接的碳原子形成一个环烷 基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代。
在本发明进一步优选的实施方式中，所述的
Figure PCTCN2021108795-appb-000002
选自
Figure PCTCN2021108795-appb-000003
Figure PCTCN2021108795-appb-000004
在本发明进一步优选的实施方式中，R 9和R 9’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
或者，R 9和R 9’一起可形成氧代基或硫代基；
或者，R 9和R 9’以及它们所在的碳原子一起形成C 3-12环烷基或3-12元杂环基，所述的C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
在本发明优选的实施方式中，当M 1为CR 1、M 2为CR 2、M 3为CR 3时，R 2和R 3至少一个不为氢，并且当M 1为CR 1、M 2为CR 2、M 3为CR 3、R选自C 1-6烷基、氘代甲基、
Figure PCTCN2021108795-appb-000005
时，R 3不为氢。
在本发明进一步优选的实施方式中，通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述化合物进一步如通式(II)所示：
Figure PCTCN2021108795-appb-000006
其中：
R选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
R 4、R 5和R 6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
R 7选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷 基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
或者，R 8和R 8’链接形成一个C 3-12环烷基或3-12元杂环基，所述的C 3-12环烷基或3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代。
在本发明优选的实施方式中，R 2和R 3至少一个不为氢，并且当R选自C 1-6烷基、氘代甲基、
Figure PCTCN2021108795-appb-000007
时，R 3不为氢。
在本发明进一步优选的实施方式中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(II-A)所示：
Figure PCTCN2021108795-appb-000008
其中：
M 1为N或CR 1，优选N或CH；
R选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选 地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
R 9和R 9’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
或者，R 9和R 9’一起可形成氧代基或硫代基；
或者，R 9和R 9’以及它们所在的碳原子一起形成C 3-12环烷基或3-12元杂环基，所述的C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
在本发明优选的实施方式中，当M 1为CR 1时，R 2和R 3至少一个不为氢，并且当M 1为CR 1，R选自C 1-6烷基、氘代甲基、
Figure PCTCN2021108795-appb-000009
时，R 3不为氢。
在本发明优选的实施方式中，所述的R选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
在本发明进一步优选的实施方式中，所述的R选自C 1-6烷基、C 1-6氘代烷基、 C 3-8环烷基或3-8元杂环基，所述的C 1-6烷基、C 1-6氘代烷基、C 3-8环烷基或3-8元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-8环烷基或3-8元杂环基中的一个或多个取代基所取代。
在本发明进一步优选的实施方式中，所述的R选自氘代甲基、乙基、正丙基、异丙基、叔丁基、叔戊基、3-戊基、环丙基或氧杂环丁烷基，所述的乙基、正丙基、异丙基、叔丁基、叔戊基、3-戊基、环丙基或氧杂环丁烷基，进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基中的一个或多个取代基所取代。
在本发明优选的实施方式中，所述的R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基。
在本发明进一步优选的实施方式中，所述的R 1、R 2和R 3各自独立地选自氢、氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基。
在本发明进一步优选的实施方式中，所述的R 1、R 2和R 3各自独立地选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基或叔丁基。
在本发明优选的实施方式中，所述的R 4、R 5和R 6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基。
在本发明进一步优选的实施方式中，所述的R 4、R 5和R 6各自独立地选自氢、氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基。
在本发明进一步优选的实施方式中，所述的R 4、R 5和R 6各自独立地选自氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基或叔丁基。
在本发明优选的实施方式中，所述的R 7选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基。
在本发明进一步优选的实施方式中，所述的R 7选自C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基。
在本发明进一步优选的实施方式中，所述的R 7选自甲基、乙基、丙基、异丙基、叔丁基、环丙基或三氟甲基。
在本发明优选的实施方式中，所述的R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基。
在本发明进一步优选的实施方式中，所述的R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基。
在本发明进一步优选的实施方式中，所述的R 8和R 8’各自独立地选自氢、氘、氟、氯、溴、甲基或乙基。
或者，在本发明优选的实施方式中，所述的R 8、R 8’和它们所连接的碳原子形成C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选地进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基中的一个或多个取代基所取代。
在本发明进一步优选的实施方式中，通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述化合物进一步如通式(III)所示：
Figure PCTCN2021108795-appb-000010
其中：
M 3为N或CR 3；
R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；
优选氢、氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基；
更优选氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、叔丁基或甲氧基。
R 3选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6 卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6羟烷基；优选氢；
R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；
优选氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基；
更优选氢、氘、氟、氯、溴、甲基或乙基；
或者，R 8和R 8’链接形成一个C 3-12环烷基或3-12元杂环基，所述的C 3-12环烷基或3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；优选形成C 3-12环烷基环烷基。
在本发明进一步优选的实施方式中，所述通式(III)的化合物、其立体异构体或其药学上可接受盐，当M 3为CH，R 8和R 8’为氢时，R 2不为氢。
在本发明进一步优选的实施方式中，所述化合物、其立体异构体或其药学上可接受盐进一步如通式(IV-A)所示：
Figure PCTCN2021108795-appb-000011
R选自C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、氰基取代的C 1-3烷基或C 3-6环烷基；
优选C 1-3烷基、C 1-3氘代烷基或C 3-6环烷基；
更优选甲基、乙基、氘代甲基、氘代乙基或环丙基；
进一步优选甲基、氘代甲基或环丙基；
更进一步优选甲基。
在本发明进一步优选的实施方式中，所述化合物、其立体异构体或其药学上可接受盐进一步如通式(IV-B)所示：
Figure PCTCN2021108795-appb-000012
R 2或R 3独立地选自氘、卤素、氰基或C 1-3烷基；优选氘、氟、氯、溴或甲基；
n为1、2或3。
在本发明优选的实施方式中，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，所述化合物的具体结构如下：
Figure PCTCN2021108795-appb-000013
Figure PCTCN2021108795-appb-000014
Figure PCTCN2021108795-appb-000015
本发明进一步涉及通式(IV-A)化合物、其立体异构体或其药学上可接受的盐的的制备方法，包括如下步骤：
Figure PCTCN2021108795-appb-000016
式(V-A)化合物在碱存在下与R-X反应得到通式(IV-A)化合物，优选地，碱选自碳酸钾或碳酸铯；
其中：
X为溴或碘；
所述R如通式(IV-A)所定义。
本发明进一步涉及通式(IV-B)化合物、其立体异构体或其药学上可接受的盐的的制备方法，包括如下步骤：
Figure PCTCN2021108795-appb-000017
通式(V-B)化合物在碱存在下与
Figure PCTCN2021108795-appb-000018
反应得到通式(IV-B)化合物，优选地，碱选自碳酸钾或碳酸铯；
其中：
X为溴或碘；
R 2、R 3和n如通式(IV-B)所定义。
本发明进一步涉及一种药物组合物，其包括治疗有效剂量的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
另一方面，本发明的目的还在于提供包含通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，以上所述的药物组合物在制备褪黑素受体激动剂药 物中的用途。
另一方面，本发明的目的还在于提供包含通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，以上所述的药物组合物在制备MT1和MT2受体激动剂以及5-HT 2C受体拮抗剂药物中的用途。
进一步的，本发明的目的还在于提供包含通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，以上所述的药物组合物在制备治疗或预防心血管疾病、消化系统疾病、中枢神经系统疾病和/或精神疾病药物中的用途。
本发明还涉及一种治疗中枢神经系统疾病和/或精神疾病的方法。
在一个更优选的实施方案中，所述中枢神经系统疾病和/或精神疾病选自褪黑素系统疾病、紧张、焦虑症、季节性情感障碍、精神分裂症、恐惧症、抑郁症、重度抑郁症、睡眠障碍、睡眠失调、飞行时差引起的失眠或疲劳、体重失调、心境障碍、精神分裂症谱系障碍、痉挛性障碍、记忆障碍和/或认知障碍、运动障碍、人格障碍、自闭症谱系障碍、疼痛、外伤性脑损伤、物质滥用障碍和/或戒断综合征、耳鸣、自闭症、阿尔兹海默症、癫痫发作、神经痛或戒毒症状重度抑郁症或狂躁症疾病。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至8个碳原子的烷基，进一步优选1至6个碳原子的烷基，最优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、4-庚基、1-丙基丁基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、3-戊基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正庚基、4-庚基、1-丙基丁基、1-乙基-2-甲基丙 基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子；进一步优选包含1-3氮原子的3-8元杂环基，任选地，被1-2个氧原子、硫原子、氧代基取代，包括含氮单环杂环基、含氮螺杂环基或含氮稠杂环基。
单环杂环基的非限制性实例包括氧杂环丁基、硫杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吖庚基、1,4-二氮杂环庚基、吡喃基或四氢噻喃二氧化物基等，优选氧杂环丁基、硫杂环丁基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、四氢噻喃二氧化物基、吡咯烷基、吗啉基、哌啶基、六氢吡嗪基、六氢嘧啶基、吖庚基、1,4-二氮杂环庚基和哌嗪基；多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上 的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并5-10元杂芳基、苯并3-8元环烷基和苯并3-8元杂烷基，优选苯并5-6元杂芳基、苯并3-6元环烷基和苯并3-6元杂烷基，其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。
其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021108795-appb-000019
Figure PCTCN2021108795-appb-000020
等。
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至12元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选吡啶基、噁二唑基、三唑基、噻吩基、咪唑基、吡唑基、噁唑基、噻唑基、嘧啶基或噻唑基；更有选吡啶基、噁二唑基、吡唑基、吡咯基、噻唑基和噁唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021108795-appb-000021
Figure PCTCN2021108795-appb-000022
等。
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基，烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
“烯基”指链烯基，又称烯烃基，优选含有2至8个碳原子的烯基，更优选2至6个碳原子的烯基，更进一步优选2至4个碳原子的烯基，最优选2至3个碳原子的烯基。烯基的非限制性实施例包括：乙烯基、丙烯基。其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“炔基”指链烯基，又称炔烃基，指含有(CH≡C-)的不饱和烃基；优选含有2至8个碳原子的炔基，更优选2至6个碳原子的炔基，更进一步优选2至4个碳原子的炔基，最更优选2至3个碳原子的炔基。其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“羟基”指-OH基团。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“羰基”指-C(O)-。
“羧基”指-C(O)OH。
“THF”指四氢呋喃。
“乙酸乙酯”指乙酸乙酯。
“MeOH”指甲醇。
“DMF”指N,N-二甲基甲酰胺。
“DIPEA”指二异丙基乙胺。
“TFA”指三氟乙酸。
“TEA”指三乙胺。
“MeCN”指乙晴。
“DMA”指N,N-二甲基乙酰胺。
“Et 2O”指乙醚。
“DCM”指二氯甲烷。
“DMAP”指4-二甲氨基吡啶。
“DCC”指二环己基碳二亚胺。
“DCE”指1,2二氯乙烷。
“DDQ”指2,3-二氯-5,6-二氰基苯醌。
“DIPEA”指N,N-二异丙基乙胺。
“NBS”指N-溴代琥珀酰亚胺。
“NIS”指N-碘代丁二酰亚胺。
“NMP”指N-甲基吡咯烷酮。
“Cbz-Cl”指氯甲酸苄酯。
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。
“Dppf”指1,1’-双二苯基膦二茂铁。
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
“KHMDS”指六甲基二硅基胺基钾。
“LiHMDS”指双三甲基硅基胺基锂。
“MeLi”指甲基锂。
“n-BuLi”指正丁基锂。
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C 18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。
实施例1
N-(2-(7-环丙氧基-2-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000023
第一步：7-甲氧基萘-2-胺的制备
Figure PCTCN2021108795-appb-000024
将7-甲氧基萘-2-酚(10g，57.5mmol)溶于氨水(150mL)中，加入亚硫酸氢钠(29.9g，287.5mmol)，在焖罐中加热到150℃搅拌48小时，冷却至室温，过滤出固体，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到7-甲氧基萘-2-胺(5.7g，产率57％)。
MS m/z(ESI):174.0[M+H] +.
第二步：1-溴-7-甲氧基萘-2-胺的制备
Figure PCTCN2021108795-appb-000025
将7-甲氧基萘-2-胺(5.5g，31.6mmol)溶于DMF(100mL)，加入NBS(6.2g，34.8mmol)，110℃反应4小时，冷却至室温，加入水和乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到1-溴-7-甲氧基萘-2-胺(6.8g，产率86％)。
MS m/z(ESI):252.1[M+H] +,254.1[M+H+2] +.
第三步：1-溴-2-氟-7-甲氧基萘的制备
Figure PCTCN2021108795-appb-000026
将1-溴-7-甲氧基萘-2-胺(6.5g，25.9mmol)溶于四氢呋喃(100mL)中，冷却至0℃，加入HBF 4(50mL，48％)溶液，然后加入NaNO 2(5.4g，78.3mmol)的水溶液(10mL)，继续在0℃搅拌1小时，加入NaBF 4(14.2g，129.1mmol)。逐渐升至室温，过滤析出的固体，水洗，乙醚洗涤。真空干燥。所得固体溶于二甲苯(100mL)，加热回流2小时。加水洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到1-溴-2-氟-7-甲氧基萘(2.8g，产率43％)。
第四步：2-(2-氟-7-甲氧基萘-1-基)乙酰腈的制备
Figure PCTCN2021108795-appb-000027
将1-溴-2-氟-7-甲氧基萘(2.6g，10.2mmol)溶于无水THF(50mL)，加入镁粉(1.2g，50.0mmol)和单质碘(2粒)，氮气置换三次，升温至50℃，搅拌0.5小时。冰水浴下，滴加入溴乙腈(1.6g，13.3mmol)的THF(20mL)溶液，逐渐升至室温，搅拌1小时，加水淬灭，乙酸乙酯萃取，有机相用水洗涤，无水硫酸钠干燥，过滤，柱层析纯化得到2-(2-氟-7-甲氧基萘-1-基)乙酰腈(1.5g，产率68％)。
MS m/z(ESI):216.1[M+H] +.
第五步：N-(2-(2-氟-7-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000028
将2-(2-氟-7-甲氧基萘-1-基)乙酰腈(1.4g，6.5mmol)和乙酸酐(1.4g，13.7mmol)溶于二氯甲烷/甲醇(30mL/15mL)溶液中，0℃加入NiCl 2·6H 2O(920mg，3.9mmol)，搅拌，分批加入硼氢化钠(1.1g，28.9mmol)，室温搅拌3小时。加6N HCl，加水，过滤，水相用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。柱层析纯化得到N-(2-(2-氟-7-甲氧基萘-1-基)乙基)乙酰胺(1.3g，产率76％)。
MS m/z(ESI):262.1[M+H] +.
第六步：N-(2-(2-氟-7-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000029
将N-(2-(2-氟-7-甲氧基萘-1-基)乙基)乙酰胺(1.2g，4.6mmol)溶于二氯甲烷(20mL)，氮气保护下，冷却至0℃，滴加BBr 3(2.3g，9.2mmol)，室温搅拌3小时。加NaHCO 3水溶液洗涤，用二氯甲烷/甲醇(10:1)萃取。用水和10％碳酸氢钠水溶液洗涤有机层。无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到N-(2-(2-氟-7-羟基萘-1-基)乙基)乙酰胺(930mg，产率82％)。
MS m/z(ESI):248.1[M+H] +.
第七步：N-(2-(7-环丙氧基-2-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000030
N-(2-(2-氟-7-羟基萘-1-基)乙基)乙酰胺(100mg，0.41mmol)溶于DMF(5mL)中，加入环丙基溴(150mg，1.24mmol)，Cs 2CO 3(400mg，1.22mmol)，160℃微波反应4小时，加入水，乙酸乙酯萃取，有机相用无水硫酸纳干燥，过滤，浓缩，制备HPLC纯化得到N-(2-(7-环丙氧基-2-氟萘-1-基)乙基)乙酰胺(56mg，产率48％)。
MS m/z(ESI):288.1[M+H] +.
实施例2A
N-(2-(4-氟-7-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000031
第一步：5-氨基-8-溴萘-2-酚的制备
Figure PCTCN2021108795-appb-000032
将5-氨基萘-2-酚(10g，62.9mmol)溶于DMF(100mL)，加入NBS(12.3g，69.2mmol)，110℃反应3小时，冷却至室温，加入水和乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到5-氨基-8-溴萘-2-酚(10.8g，产率72％)。
MS m/z(ESI):238.1[M+H] +,240.1[M+H+2] +.
第二步：8-溴-5-氟萘-2-酚的制备
Figure PCTCN2021108795-appb-000033
将5-氨基-8-溴萘-2-酚(5g，21.0mmol)溶于四氢呋喃(100mL)中，冷却至0℃，加入HBF 4(40mL，48％)溶液，然后加入NaNO 2(4.4g，63.8mmol)的水溶液(10mL)，继续在0℃搅拌1小时，加入NaBF 4(11.5g，104.5mmol)。逐渐升至室温，过滤析出的固体，水洗，乙醚洗涤。真空干燥。所得固体溶于二甲苯(100mL)，加热回流2小时。加水洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到8-溴-5-氟萘-2-酚(3.5g,产率69％)。
MS m/z(ESI):240.1[M+H] +,243.1[M+H+2] +.
第三步：4-溴-1-氟-6-甲氧基萘的制备
Figure PCTCN2021108795-appb-000034
将8-溴-5-氟萘-2-酚(3H)-酮(3.4g，14.2mmol)添加到DMF(30mL)中，加入K 2CO 3(5.8g，42.0mmol)，室温下滴加碘甲烷(2.4g，16.9mmol)，继续搅拌2小时。加水和乙酸乙酯萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到4-溴-1-氟-6-甲氧基萘(3.4g，产率94％)。
1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝9.0Hz,1H),7.93-7.90(m,2H),7.15(d,J＝9.0Hz,1H),6.92(dd,J＝12,7.8Hz,1H),4.01(s,3H).
第四步：2-(4-氟-7-甲氧基萘-1-基)乙酰腈的制备
Figure PCTCN2021108795-appb-000035
将4-溴-1-氟-6-甲氧基萘(3.3g，13.0mmol)溶于无水THF(50mL)，加入镁粉(1.6g，66.7mmol)和单质碘(2粒)，氮气置换三次，升温至50℃，搅拌0.5小时。冰水浴下，滴加入溴乙腈(2.0g，16.8mmol)的THF(20mL)溶液，逐渐升至室温，搅拌1小时，加水淬灭，乙酸乙酯萃取，有机相用水洗涤，无水硫酸钠干燥，过滤，柱层析纯化得到2-(4-氟-7-甲氧基萘-1-基)乙酰腈(1.8g，产率64％)。
1H NMR(400MHz,Chloroform-d)δ8.02(d,J＝9.0Hz,1H),7.63(s,1H),7.08(d,J＝9.0Hz,1H),6.92(m,2H),5.05(s,2H),3.99(s,3H).
第五步：N-(2-(4-氟-7-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000036
将2-(4-氟-7-甲氧基萘-1-基)乙酰腈(1.7g，7.9mmol)和乙酸酐(2.0g，19.8mmol)溶于二氯甲烷/甲醇(30mL/15mL)溶液中，0℃加入NiCl 2·6H 2O(1.1g，4.7mmol)，搅拌，分批加入硼氢化钠(1.3g，34.2mmol)，室温搅拌5小时。加6N HCl，加水，过滤，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩。柱层析纯化得到N-(2-(4-氟-7-甲氧基萘-1-基)乙基)乙酰胺(1.5g，产率73％)。
MS m/z(ESI):262.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.02(d,J＝8.0Hz,1H),7.47(s,1H),7.21-7.15(m,2H),6.93-6.88(m,1H),5.73(s,1H),3.99(s,3H),3.58-3.53(m,2H),3.20-3.16(t,J＝8.0Hz,2H),1.95(s,3H).
实施例2
N-(2-(7-环丙氧基-4-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000037
第一步：N-(2-(4-氟-7-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000038
将N-(2-(4-氟-7-甲氧基萘-1-基)乙基)乙酰胺(1.4g，5.4mmol)溶于二氯甲烷(20mL)，氮气保护下，冷却至0℃，滴加BBr 3(2.7g，10.8mmol)，室温搅拌3小时。加NaHCO 3水溶液洗涤，用二氯甲烷/甲醇(10/1)萃取。用水和10％碳酸氢钠水溶液洗涤有机层。无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到N-(2-(4-氟-7-羟基萘-1-基)乙基)乙酰胺(980mg，产率75％)。
MS m/z(ESI):248.1[M+H] +.
第二步：N-(2-(7-环丙氧基-4-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000039
N-(2-(4-氟-7-羟基萘-1-基)乙基)乙酰胺(100mg，0.41mmol)溶于DMF(5mL)中，加入环丙基溴(150mg，1.24mmol)，Cs 2CO 3(400mg，1.22mmol)，160℃微波反应4小时，加入水，乙酸乙酯萃取，有机相用无水硫酸纳干燥，过滤，浓缩，制备HPLC纯化得到N-(2-(7-环丙氧基-4-氟萘-1-基)乙基)乙酰胺(44mg，产率38％)。
MS m/z(ESI):288.1[M+H] +.
实施例2B
N-(2-(4-氟-7-(甲氧基-d3)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000040
第一步：N-(2-(4-氟-7-(甲氧基-d3)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000041
N 2下往N-(2-(4-氟-7-羟基萘-1-基)乙基)乙酰胺(80mg，323.54μmol),KI(5.4mg，32.35μmol)和Cs 2CO 3(210mg，647.08μmol)的DMF(2mL)溶液中，加入氘代碘甲烷(188mg，1.29mmol)，50℃下，搅拌4小时。把反应液倒入水中，用乙酸乙酯萃取，乙酸乙酯层用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩，制备HPLC纯化得到N-(2-(4-氟-7-(甲氧基-d3)萘-1-基)乙基)乙酰胺(71.4mg，产率82％)白色固体。
MS m/z(ESI):265.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝9.0Hz,1H),7.68(t,J＝2.2Hz,1H),7.26–7.14(m,2H),6.92(dd,J＝10.3,7.8Hz,1H),5.54(s,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),1.95(s,3H).
实施例5
N-(2-(7-(噁丁环-3-氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000042
第一步：N-(2-(7-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000043
将底物N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺(511mg，2.1mmol)溶于无水二氯甲烷(10mL)，氮气置换三次，保护下，冷却到0℃，滴加BBr 3(4.2mmol，4.2mL)，滴加完毕，升到室温搅拌30分钟，将反应液缓慢倒入150mL饱和NaHCO 3溶液中，淬灭反应。二氯甲烷萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，快速柱层析纯化得到白色固体产品N-(2-(7-羟基萘-1-基)乙基)乙酰胺(300mg，产率62％),为白色固体。
MS m/z(ESI):230.1[M+H] +.
1H NMR(400MHz,DMSO)δ9.73(s,1H),8.00(s,1H),7.76(d,J＝8.8Hz,1H),7.65(d,J＝7.9Hz,1H),7.31(d,J＝1.8Hz,1H),7.26–7.16(m,2H),7.08(dd,J＝8.8,2.2Hz,1H),3.38(s,1H),3.31(s,1H),3.04(t,J＝7.5Hz,2H),1.81(s,3H).
第二步：N-(2-(7-(噁丁环-3-氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000044
将底物N-(2-(7-羟基萘-1-基)乙基)乙酰胺(61.6mg，0.2mmol),KI(49.8mg，300μmol)和Cs 2CO 3(97.8mg，300μmol)溶于DMF(1.5mL)中，置于5.0mL微波管中，加入3-溴噁丁环(137mg，1.0mmol)。微波130℃，反应1.5小时。反应液用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层用无水Na 2SO 4干燥，浓缩，得到粗品，用快速柱层析纯化得到粗品，后用制备HPLC纯化得到N-(2-(7-(噁丁环-3-氧基)萘-1-基)乙基)乙酰胺(36mg，产率48％)，为白色固体。
MS m/z(ESI):286.2[M+H] +.
1H NMR(400MHz,DMSO)δ8.16(t,J＝5.6Hz,1H),7.87(d,J＝8.9Hz,1H),7.73(d,J＝7.6Hz,1H),7.34–7.26(m,3H),7.17(dd,J＝8.9,2.4Hz,1H),5.52(t,J＝ 5.5Hz,1H),5.11(t,J＝6.7Hz,2H),4.62(dd,J＝7.2,5.1Hz,2H),3.31–3.24(m,2H),3.09(dd,J＝9.6,6.2Hz,2H),1.87(s,3H).
实施例6
N-(2-(7-异丙氧基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000045
第一步：N-(2-(7-甲氧基-3-溴萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000046
将底物N-(2-(7-甲氧基-1-萘基)乙基)乙酰胺(5g，20.6mmol)溶于冰乙酸(50mL)中，加热到85℃(油浴温度)，滴加液溴(4.0g，25.0mmol)的AcOH(30mL)溶液。滴加完毕，继续加热搅拌3小时。反应液冷却到室温，将其倒入水(150mL)中，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，浓缩，得到粗品，柱层析纯化得到N-(2-(7-甲氧基-3-溴萘-1-基)乙基)乙酰胺(4.5g，产率68％)。
MS m/z(ESI):322.1[M+H] +,324.1[M+H+2] +.
第二步：N-(2-(7-甲氧基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000047
将N-(2-(7-甲氧基-3-溴萘-1-基)乙基)乙酰胺(200mg，0.62mmol)溶于无水THF(20mL)，氮气保护下，冷却至-78℃，滴加n-BuLi(1.6mL，1.6mmol)的THF溶液(10mL)，搅拌0.5小时。滴加D 2O(1mL)，继续搅拌1小时。加水淬灭，用稀盐酸调节至pH～6，用乙酸乙酯萃取。无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到N-(2-(7-甲氧基萘-1-基-3-d)乙基)乙酰胺(87mg，产率57％)。
MS m/z(ESI):245.1[M+H] +.
第三步：N-(2-(7-羟基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000048
将N-(2-(7-甲氧基萘-1-基-3-d)乙基)乙酰胺(80mg，0.33mmol)溶于二氯甲烷(10mL)，氮气保护下，冷却至0℃，滴加BBr 3(270mg，1.1mmol)，室温搅拌2小时。加NaHCO 3水溶液淬灭，二氯甲烷萃取。用水和10％碳酸氢钠水溶液洗涤。有机相用无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到N-(2-(7-羟基萘-1-基-3-d)乙基)乙酰胺(55mg，产率73％)。
MS m/z(ESI):231.1[M+H] +.
第四步：N-(2-(7-异丙氧基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000049
N 2下往N-(2-(7-羟基萘-1-基-3-d)乙基)乙酰胺(50mg，217.13umol)，2-碘丙烷(110.7mg,651.4umol)的DMF(3mL)中加入Cs 2CO 3(141.1mg，434.2umol)，碘化钾(18mg，108.56umol)，50℃下，搅拌12小时。反应液加入水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩后制备HPLC纯化得到N-(2-(7-异丙氧基萘-1-基-3-d)乙基)乙酰胺(3mg，产率5％)。
MS m/z(ESI):273.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝9.0Hz,1H),7.81(s,1H),7.75(s,1H),7.41(s,1H),7.35-7.26(m,1H),5.66(s,1H),4.75-4.70(m,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),2.05(s,3H),1.30-1.28(d,J＝8.0Hz,6H).
实施例7
N-(2-(7-(戊烷-3-氧基)萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000050
N-(2-(7-(戊烷-3-氧基)萘-1-基-3-d)乙基)乙酰胺的制备参考实施例6。
MS m/z(ESI):301.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝9.0Hz,1H),7.81(s,1H),7.75(s,1H),7.41(s,1H),7.35-7.26(m,1H),5.66(s,1H),4.75-4.70(m,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),2.05(s,3H),1.76-1.72(m,4H),1.01-0.98(m,6H).
实施例8
N-(2-(7-(叔-丁氧基)萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000051
第一步：N-(2-(3-溴-7-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000052
将底物N-(2-(7-甲氧基萘-1-基)乙基)乙酰胺(14.6g，60.0mmol)溶于AcOH(120mL)中，加热到85℃(油浴温度)，滴加液溴(11.5g，72.0mmol，3.69mL)的AcOH(30mL)溶液。滴加完毕，继续搅拌0.5小时。将反应液冷却到室温，将其倒入水(500mL)中，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层用无水硫酸纳干燥，浓缩，得到粗品，用反相制备柱纯化得到N-(2-(3-溴-7-甲氧基萘-1-基)乙基)乙酰胺(15g，产率66％)，为白色固体。
MS m/z(ESI):322.2[M+H] +.
1H NMR(400MHz,DMSO)δ8.16–8.10(m,1H),7.99(d,J＝1.4Hz,1H),7.83(d,J＝9.0Hz,1H),7.62(d,J＝1.8Hz,1H),7.47(dd,J＝11.0,1.8Hz,1H),7.22(dd,J＝9.0,2.3Hz,1H),3.95(s,3H),3.38(dd,J＝12.7,6.1Hz,1H),3.32(d,J＝6.0Hz,1H),3.18–3.09(m,2H),1.83(s,3H).
第二步：N-(2-(7-甲氧基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000053
将底物N-(2-(3-溴-7-甲氧基萘-1-基)乙基)乙酰胺(3.9g，12mmol)溶于THF(60mL)中，氮气保护下，冷却到-75℃到-70℃，滴加n-BuLi(30.0mmol，12.5mL)，后在-75℃搅拌1.5小时，滴加D 2O(1.20g，60.00mmol)，滴加完毕，升温到室温搅拌过夜。将反应液缓慢倒入200mL水中淬灭，乙酸乙酯萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，柱层析纯化得到目标化合物N-(2-(7-甲氧基萘-1-基-3-d)乙基)乙酰胺(1.2g，产率41％)，为黄色固体。
MS m/z(ESI):245.1[M+H] +.
第三步：N-(2-(7-羟基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000054
将底物N-(2-(7-甲氧基萘-1-基-3-d)乙基)乙酰胺(1.2g，4.91mmol)溶于无水二氯甲烷(60mL)，氮气保护下，冷却到0℃，滴加BBr 3(10mmol，10mL),滴加完毕，升到室温搅拌30min。将反应液缓慢倒入150mL饱和NaHCO 3溶液中淬灭反应。二氯甲烷萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，柱层析纯化得到白色固体产品N-(2-(7-羟基萘-1-基-3-d)乙基)乙酰胺(1.05g，产率93％)。
MS m/z(ESI):231.2[M+H] +.
1H NMR(400MHz,DMSO)δ9.73(s,1H),8.01(t,J＝5.2Hz,1H),7.76(d,J＝8.8Hz,1H),7.65(d,J＝4.3Hz,1H),7.31(d,J＝2.0Hz,1H),7.25(d,J＝3.7Hz,1H),7.09(dd,J＝8.8,2.3Hz,1H),3.35–3.29(m,2H),3.05(t,J＝7.5Hz,2H),1.81(d,J＝3.7Hz,3H).
第四步：N-(2-(7-(叔-丁氧基)萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000055
将底物N-(2-(7-羟基萘-1-基-3-d)乙基)乙酰胺(134mg，582umol)溶于无水二氯甲烷(5.0mL)中，加入(Boc) 2O(317.5mg，1.45mmol)和Mg(ClO 4) 2(26mg，116umol)，氮气置换保护下，加热到50℃回流状态下反应2小时。将反应液冷却到室温，缓慢加入100mL水中，后加入50mL饱和NaHCO 3水溶液。乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水Na 2SO 4干燥。浓缩，得到粗品，制备HPLC纯化得到目标化合物N-(2-(7-(叔-丁氧基)萘-1-基-3-d)乙基)乙酰胺(54.6mg，产率33％)，为白色固体。
MS m/z(ESI):287.2[M+H] +.
1H NMR(400MHz,DMSO)δ8.04(s,1H),7.84(d,J＝8.8Hz,1H),7.74(s,1H),7.67(d,J＝1.7Hz,1H),7.32(s,1H),7.19(dd,J＝8.8,2.1Hz,1H),3.34(d,J＝6.7Hz,1H),3.29(s,1H),3.13–3.07(m,2H),1.82(s,3H),1.39(s,9H).
实施例10
N-(2-(6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000056
第一步：4-(3-氯-4-甲氧苯基)-4-羰基丁酸的制备
Figure PCTCN2021108795-appb-000057
0℃，氮气保护下往二氯甲烷(300mL)中加入AlCl 3(71.4g，0.54mol)，1-氯-2-甲氧基苯(30mL，0.24mol),分批加入二氢呋喃-2,5-二酮(26.8g，0.27mol)，加热到50℃搅拌2小时。冷却至室温，反应液倒入剧烈搅拌的冰水中，加入浓盐酸(65mL)，搅拌0.5小时。过滤，滤饼水洗，再用乙醇-水打浆过滤得到粉红色固体4-(3-氯-4-甲氧苯基)-4-羰基丁酸(55g，产率98％)。
MS m/z(ESI):241.1[M-H] -.
第二步：4-(3-氯-4-甲氧苯基)丁酸的制备
Figure PCTCN2021108795-appb-000058
氮气保护下往4-(3-氯-4-甲氧苯基)-4-羰基丁酸(8g，33mmol)的TFA(20mL)中滴加Et 3SiH(12mL)，加热至120℃，搅拌5小时。反应液浓缩后加入DMF(10mL),缓慢倒入剧烈搅拌的水中，过滤，滤饼水洗，干燥得到白色固体4-(3-氯-4-甲氧苯基)丁酸(7g，产率93％)。
MS m/z(ESI):227.1[M-H] -.
第三步：6-氯-7-甲氧基-3,4-二氢萘-1(2H)-酮的制备
Figure PCTCN2021108795-appb-000059
氮气保护下往4-(3-氯-4-甲氧苯基)丁酸(7g，30.7mmol)的TFA(30mL)中滴加MeSO 3H(7mL)，加热至120℃，搅拌7小时。冷却至室温，反应液倒入冰水中，过滤，滤饼水洗，再用乙醇-水打浆过滤,干燥得到黄色固体6-氯-7-甲氧基-3,4-二氢萘-1(2H)-酮(3.6g，产率56％)。
1H NMR(400MHz,Chloroform-d)δ7.54(s,1H),7.27(s,1H),3.92(s,3H),2.89-2.85(m,2H),2.65-2.61(m,2H),2.13-2.10(m,2H)
第四步：2-(6-氯-7-甲氧基-3,4-二氢萘-1-基)乙酰腈的制备
Figure PCTCN2021108795-appb-000060
氮气保护下往6-氯-7-甲氧基-3,4-二氢萘-1(2H)-酮(3.6g，17mmol)的甲苯(140mL)溶液中加入2-氰基乙酸(3.6g，42.5mmol)，庚酸(1.12g，8.6mmol),苄胺(920mg，8.6mmol)，加热至140℃，搅拌12小时。冷却至室温，反应液加入盐水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩后再用乙醇-水在90℃下打浆，过滤,干燥得到黄色固体2-(6-氯-7-甲氧基-3,4-二氢萘-1-基)乙酰腈(3g，产率76％)。
1H NMR(400MHz,d-DMSO)δ7.27(s,1H),6.99(s,1H),6.24(s,1H),3.87(s,5H),2.68-2.64(m,2H),2.28-2.19(m,2H)
第五步：2-(6-氯-7-甲氧基萘-1-基)乙酰腈的制备
Figure PCTCN2021108795-appb-000061
-10℃，氮气保护下往2-(6-氯-7-甲氧基-3,4-二氢萘-1-基)乙酰腈(3g，12.9mmol)的二氯甲烷(30mL)中加入DDQ(3.2g，14.1mmol)，20℃下，搅拌0.5小时。反应液过滤，有机相用饱和Na 2CO 3水溶液洗涤，盐水洗，无水硫酸钠干燥，过滤，浓缩得到黄色固体2-(6-氯-7-甲氧基萘-1-基)乙酰腈(2.8g，产率94％)。
1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.69-7.67(d,J＝8.0Hz,1H),7.53-7.51(d,J＝8.0Hz,1H),7.36-7.32(m,1H),7.07(s,1H),4.03(s,5H).
第六步：N-(2-(6-氯-7-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000062
-10℃，氮气保护下往2-(6-氯-7-甲氧基萘-1-基)乙酰腈(2.8g，12mmol)的CH 2Cl 2-MeOH(100mL-50mL)中加入NiCl 2.6H 2O(1.8g，0.8mmol)，醋酸酐(2.72mL，0.8mmol)，分批加入NaBH 4(2.1g，54mmol)，20℃下，搅拌12小时。冷却至0℃，反应液加入盐酸(3M/L，40mL)，搅拌1小时，浓缩，加入乙酸乙酯萃取，饱和NaHCO 3水溶液洗涤，盐水洗，无水硫酸钠干燥，过滤，柱层析纯化得到黄色固体N-(2-(6-氯-7-甲氧基萘-1-基)乙基)乙酰胺(1g，产率30％)。
MS m/z(ESI):278.1[M+H] +.
1H NMR(400MHz,d-DMSO)δ8.15(s,1H),8.08(s,1H),7.79(s,1H),7.72-7.70(d,J＝8.0Hz,1H),7.37-7.30(m,2H),4.06(s,3H),3.34(s,2H),3.16-3.12(m,2H)，1.84(s,3H).
第七步：N-(2-(6-氯-7-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000063
0℃，氮气保护下往N-(2-(6-氯-7-甲氧基萘-1-基)乙基)乙酰胺(500mg，1.8mmol)的二氯甲烷(30mL)中加入BBr 3(3.6mL，3.6mmol)，20℃下，搅拌12小时。反应液加入二氯甲烷萃取，加入饱和NaHCO 3水溶液洗涤，盐水洗，无水硫酸钠干燥，过滤浓缩后得N-(2-(6-氯-7-羟基萘-1-基)乙基)乙酰胺(400mg，产率85％)。
MS m/z(ESI):264.1[M+H] +.
1H NMR(400MHz,d-DMSO)δ10.56(s,1H),8.01-7.98(m,2H),7.67-7.65(m,1H),7.50(s,1H),7.28-7.23(m,2H),3.39-3.34(m,2H),3.07-3.03(m,2H),1.81(s,3H).
第八步：N-(2-(6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000064
氮气保护下往N-(2-(6-氯-7-羟基萘-1-基)乙基)乙酰胺(100mg，0.4mmol)，溴环丙烷(100mg，0.8mmol)的NMP(3mL)中加入Cs 2CO 3(160mg，0.5mmol)，碘化钾(30mg，0.2mmol)，170℃下，微波搅拌2小时。反应液加入水，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩后制备HPLC纯化得到N-(2-(6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺(10mg，产率8％)。
MS m/z(ESI):304.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.89-7.82(m,1H),7.67(s,1H),7.51-7.46(m,2H),7.15-7.11(m,1H),5.54(s,1H),3.75-3.71(m,1H),3.60(t,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).
实施例11
N-(2-(6-溴-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000065
N-(2-(6-溴-7-环丙氧基萘-1-基)乙基)乙酰胺的制备参考实施例10。
MS m/z(ESI):348.1[M+H] +,350.1[M+H+2] +.
1H NMR(400MHz,Chloroform-d)δ7.92-7.85(m,1H),7.71(s,1H),7.53-7.47(m,2H),7.16-7.14(m,1H),5.56(s,1H),3.75-3.71(m,1H),3.60(t,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).
实施例12
N-(2-(7-环丙氧基萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000066
N-(2-(7-环丙氧基萘-1-基-3-d)乙基)乙酰胺的制备参考实施例6。
MS m/z(ESI):271.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.01(s,1H),7.93(dd,J＝9.9,2.3Hz,1H),7.80(m,J＝13.3,5.4Hz,1H),7.72(d,J＝3.1Hz,1H),7.44(s,1H),7.01-6.94(m,1H),4.05–3.99(m,1H),3.37(d,J＝8.0Hz,2H),3.14(t,J＝7.4Hz,2H),1.81(s,3H),0.91(q,J＝5.7Hz,2H),0.72(d,J＝7.1Hz,2H).
实施例13
N-(2-(7-环丙氧基-3-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000067
第一步：N-(2-(7-甲氧基-3-溴萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000068
将底物N-(2-(7-甲氧基-1-萘基)乙基)乙酰胺(14.6g，60.0mmol)溶于冰乙酸(120mL)中，加热到85℃(油浴温度)，滴加液溴(11.51g，72.0mmol，3.69mL)的AcOH(30mL)溶液。滴加完毕，继续加热搅拌3小时。反应液冷却到室温，将其倒入水(500mL)中，乙酸乙酯(200mL×3)萃取，合并有机层，饱和NaCl(150mL×3)洗涤，有机层Na 2SO 4干燥，浓缩，得到粗品，用反相纯化得到白色固体N-(2-(7-甲氧基-3-溴萘-1-基)乙基)乙酰胺(12.0g，产率62％)。
MS m/z(ESI):322.1[M+H] +,324.1[M+H+2] +.
第二步：N-(2-(7-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧硼酸-2-基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000069
将底物N-[2-(3-溴-7-甲氧基-1-萘基)乙基]乙酰胺(1.61g，5.0mmol)，嚬哪醇硼酸酯(2.54g，7.9mmol)和乙酸钾(1.47g，15.0mmol)溶于无水二氧六环(45mL)中，氮气置换三次，加入Pd(dppf)Cl 2(731mg，1.0mmol)，加热到90℃反应2小时。将反应液浓缩，得粗品，柱层析纯化得到目标化合物N-(2-(7-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧硼酸-2-基)萘-1-基)乙基)乙酰胺(1.6g，产率87％)，为黄色固体。
MS m/z(ESI):370.1[M+H] +.
第三步：N-(2-(7-甲氧基-3-(硼酸)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000070
将底物N-(2-(7-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧硼酸-2-基)萘-1-基)乙基)乙酰胺(1.4g，3.8mmol)溶于丙酮(40mL)和水(40mL)中，加入乙酸铵(1.46g，19.0mmol)和NaIO 4(4.05g，19.0mmol)。加热到25℃，反应4小时。将反应液浓缩，得粗品，混合溶剂(THF：EA＝1：1)萃取，合并有机相，无水硫酸钠干燥，浓缩得到粗品，柱层析纯化得到目标化合物N-(2-(7-甲氧基-3-(硼酸)萘-1-基)乙基)乙酰胺(766mg，产率70％)，为黄色固体。
MS m/z(ESI):286.1[M-H] -.
第四步：N-[2-(3-氟-7-甲氧基-1-萘基)乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000071
室温下，将试剂NaOH(121mg，3.0mmol)溶于MeOH(10mL)中，后加入底物N-(2-(7-甲氧基-3-(硼酸)萘-1-基)乙基)乙酰胺(722mg，2.5mmol)，然后在25℃搅拌15分钟。然后，将反应液冷却到0℃，加入试剂AgOTf(1.94g，7.5mmol)，在0℃条件下，搅拌30分钟。然后，用油泵在低温0℃条件下，将反应液溶剂浓缩，用丙酮(5mL×3)通过溶剂共沸除去残留的甲醇，得到粗品。将粗品溶于丙酮(10mL)中，加入活化的3A分子筛(350mg)，后加入F-TEDA-BF 4(935mg，2.6 mmol)。然后在0℃条件下搅拌1小时。将反应液缓慢加入到100mL水中，乙酸乙酯(150mL×3)萃取，合并有机相，无水硫酸钠干燥，浓缩，得到粗品，柱层析纯化得到N-[2-(3-氟-7-甲氧基-1-萘基)乙基]乙酰胺(214mg，产率33％)。
MS m/z(ESI):262.1[M+H] +.
第五步：N-[2-(3-氟-7-羟基-1-萘基)乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000072
将底物N-[2-(3-氟-7-甲氧基-1-萘基)乙基]乙酰胺(241mg，922.3μmol)溶于无水二氯甲烷(10mL)中，氮气置换保护下，冷却到0℃，滴加BBr 3(1.84mmol，3.0mL)，滴加完毕，继续搅拌30分钟。将反应液滴加到100mL水中淬灭，然后加入100mL饱和NaHCO 3水溶液，二氯甲烷(100mL×3)萃取，合并有机相，无水硫酸钠干燥，浓缩得到粗品。柱层析纯化得到目标化合物N-[2-(3-氟-7-羟基-1-萘基)乙基]乙酰胺(204mg，产率89％)。
MS m/z(ESI):248.1[M+H] +.
第六步：N-(2-(7-环丙基-3-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000073
将底物N-[2-(3-氟-7-羟基-1-萘基)乙基]乙酰胺(49mg，0.2mmol)和环丙基溴(121mg，1.0mmol)溶于NMP(1mL)中，置于5.0mL微波管中，加入Cs 2CO 3(98mg，300μmol)和KI(50mg，300μmol)。微波180℃反应2小时。将反应液浓缩，除去溶剂得到粗品N-(2-(7-环丙基-3-氟萘-1-基)乙基)乙酰胺(10mg，产率17％)，黄色液体。
MS m/z(ESI):288.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.07(s,1H),7.82(dd,J＝13.3,5.4Hz,2H),7.52(dd,J＝9.9,2.3Hz,1H),7.28–7.21(m,2H),4.05–3.99(m,1H),3.37(d,J＝8.0Hz,2H),3.14(t,J＝7.4Hz,2H),1.81(s,3H),0.91(q,J＝5.7Hz,2H),0.72(d,J＝7.1Hz,2H).
实施例14
N-(2-(7-环丙氧基-3-氯萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000074
第一步：N-(2-(7-环丙基-3-氯萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000075
氮气保护下往N-(2-(7-环丙基-3-溴萘-1-基)乙基)乙酰胺(20mg，57μmol)的DMF(2mL)溶液中加入CuCl(113mg，1.14mmol)，微波140℃下搅拌3小时，反应完全。反应液加饱和食盐水，二氯甲烷(3*10mL)萃取。合并有机层，无水硫酸钠干燥，浓缩后送酸法制备得到N-(2-(7-环丙基-3-氯萘-1-基)乙基)乙酰胺(7mg，产率38％)。
MS m/z(ESI):304.1[M+H] +,306.1[M+H+2] +.
1H NMR(400MHz,DMSO)δ8.07(s,1H),7.84(dd,J＝5.4,3.4Hz,2H),7.80(s,1H),7.35(d,J＝2.0Hz,1H),7.26(dd,J＝9.0,2.3Hz,1H),4.07–4.00(m,1H),3.37(s,2H),3.16–3.09(m,2H),1.81(s,3H),0.92(d,J＝7.3Hz,2H),0.73(d,J＝7.1Hz,2H).
实施例15
N-(2-(7-环丙氧基-3-溴萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000076
第一步：N-(2-(7-羟基-3-溴萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000077
0℃，氮气保护下往N-(2-(7-甲氧基-3-溴萘-1-基)乙基)乙酰胺(3.3g，10.24mmol)的二氯甲烷(30mL)溶液中滴加BBr 3(1M，20.48mL)，30℃下，搅拌1小时，反应完全。0℃下，把混合物倒入饱和NaHCO 3水溶液中，二氯甲烷-甲醇(10/1)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩后得到N-(2-(7-羟基-3-溴萘-1-基)乙基)乙酰胺(3g，产率95％)。
MS m/z(ESI):308.1[M+H] +,310.1[M+H+2] +.
第二步：N-(2-(7-环丙基-3-溴萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000078
氮气保护下往N-(2-(7-羟基-3-溴萘-1-基)乙基)乙酰胺(2.5g，8.11mmol)，碘化钾(134mg，0.81mmol)和Cs 2CO 3(5.27g，16.2mmol)的DMF(10mL)中加溴代环丙烷(1.96g，16.22mmol)，170℃下，微波搅拌4小时，反应完全。把反应液倒入水中，用乙酸乙酯萃取，有机层用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩，柱层析纯化[二氯甲烷/甲醇＝1/0到50/1]得到N-(2-(7-环丙基-3-溴萘-1-基)乙基)乙酰胺(1.3g，产率46％)黄色油状物。
MS m/z(ESI):348.1[M+H] +,350.1[M+H+2] +.
1H NMR(400MHz,DMSO)δ8.08(s,1H),8.00(s,1H),7.86–7.78(m,2H),7.46(s,1H),7.25(dd,J＝8.9,2.0Hz,1H),4.08–3.99(m,1H),3.35(d,J＝7.6Hz,2H),3.16–3.07(m,2H),1.81(s,3H),0.92(q,J＝6.1Hz,2H),0.72(s,2H).
实施例18
N-(2-(4-氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000079
N-(2-(4-氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备参考实施例2。
MS m/z(ESI):304.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.14(d,J＝9.0Hz,1H),7.72(t,J＝2.2Hz,1H),7.32–7.19(m,2H),6.99(dd,J＝10.4,7.8Hz,1H),5.59(s,1H),3.98(tt,J＝6.2,3.0Hz,1H),3.65(q,J＝6.8Hz,2H),3.24(t,J＝7.2Hz,2H),1.98(s,3H),0.98–0.76(m,4H).
实施例19
N-(2-(7-环丙氧基-2-氟萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000080
N-(2-(7-环丙氧基-2-氟萘-1-基-3-d)乙基)乙酰胺的制备参考实施例6。
MS m/z(ESI):289.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝9.0Hz,1H),7.79(s,1H),7.32-7.28(d,J＝6.0Hz,1H),6.98(dd,J＝10.6,7.8Hz,1H),5.54(s,1H),3.94(tt,J＝6.2,3.0Hz,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).
实施例20
N-(2-(7-环丙氧基-4-氟萘-1-基-3-d)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000081
N-(2-(7-环丙氧基-4-氟萘-1-基-3-d)乙基)乙酰胺的制备参考实施例6。
MS m/z(ESI):289.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝9.0Hz,1H),7.79(s,1H),7.38-7.34(d,J＝6.0Hz,1H),6.92(dd,J＝10.6,7.8Hz,1H),5.54(s,1H),3.94(tt,J＝6.2,3.0Hz,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).
实施例21
N-(2-(7-环丙氧基-3,6-二氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000082
N-(2-(7-环丙氧基-3,6-二氟萘-1-基)乙基)乙酰胺的制备参考实施例10。
MS m/z(ESI):306.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.0Hz,1H),7.32-7.25(m,2H),6.92(d,J＝12.0,1H),5.54(s,1H),3.94(tt,J＝6.2,3.0Hz,1H),3.60(q,J＝6.8Hz,2H),3.20(t,J＝7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).
实施例22
N-(2-(7-环丙氧基-3,8-二氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000083
N-(2-(7-环丙氧基-3,8-二氟萘-1-基)乙基)乙酰胺的制备参考实施例10。
MS m/z(ESI):306.1[M+H] +.
1H NMR(400MHz,Chloroform)δ7.70(dd,J＝14.9,3.0Hz,1H),7.14(dt,J＝16.1,3.1Hz,1H),7.06(dd,J＝16.0,3.0Hz,1H),6.91(dd,J＝15.0,10.1Hz,1H),5.54(s,1H),3.53(p,J＝16.3Hz,1H),3.43–3.34(m,2H),3.31–3.23(m,2H),1.80(s,3H),0.87–0.67(m,2H),0.41–0.19(m,2H).
实施例23
N-(2-(3-氯-7-环丙氧基-6-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000084
N-(2-(3-氯-7-环丙氧基-6-氟萘-1-基)乙基)乙酰胺的制备参考实施例10。
MS m/z(ESI):322.1[M+H] +,324.1[M+H+2] +.
1H NMR(400MHz,Chloroform)δ7.57(s,1H),7.39(s,1H),7.17(s,1H),6.85(s,1H),5.70(s,1H),3.53(s,1H),3.38(s,2H),3.26(s,2H),1.79(s,3H),0.74(s,2H),0.28(s,2H).
实施例24
N-(2-(6-氯-7-环丙氧基-3-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000085
N-(2-(6-氯-7-环丙氧基-3-氟萘-1-基)乙基)乙酰胺的制备参考实施例10。
MS m/z(ESI):322.1[M+H] +,324.1[M+H+2] +.
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.77-7.73(m,2H),7.37(d,J＝4Hz,1H),5.63(s,1H),4.06–3.97(m,1H),3.62–3.55(m,2H),3.25–3.21(m,2H),1.81(s,3H),0.96–0.87(m,2H),0.75–0.68(m,2H).
实施例25
N-(2-(3,6-二氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000086
第一步：N-(2-(3-溴-6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000087
60℃，N 2下往N-(2-(6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺(0.2g，658.37μmol)的AcOH(5mL)中滴加液溴(126mg，790μmol，40.47μL)的AcOH(1mL)溶液，60℃下，搅拌2小时。冷却至0℃，加入饱和食盐水，乙酸乙酯萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到N-(2-(3-溴-6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺(25mg，产率10％)。
MS m/z(ESI):382.1[M+H] +.
第二步：N-(2-(3,6-二氯-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000088
N 2下往N-(2-(3-溴-6-氯-7-环丙氧基萘-1-基)乙基)乙酰胺(10mg，26.13μmol)的DMF(3mL)中加入CuCl(26mg，261.32μmol)，微波140℃下，搅拌2小时。反应液加入饱和食盐水，二氯甲烷萃取。合并有机层，无水硫酸钠干燥，浓缩，制备HPLC纯化得到N-(2-(3,6-二氯-7-环丙氧基萘-1-基)乙基)乙酰胺白色固体(4.5mg，产率47％)。
MS m/z(ESI):338.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.75(s,1H),7.68(s,1H),7.24(s,1H),5.54(s,1H),4.02(s,1H),3.61(q,J＝6.8Hz,2H),3.25(t,J＝7.2Hz,2H),1.98(s,3H),1.02–0.96(m,4H).
实施例26
N-(1-(7-环丙氧基-3-氟萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000089
第一步：1-(7-甲氧基萘-1-基)丙烷-2-胺的制备
Figure PCTCN2021108795-appb-000090
将底物N-(2-(7-甲氧基萘-1-基)乙基)乙酰胺(3.94g，0.02mol)溶于无水THF(15mL)中，氮气置换保护下，滴加MeMgI(30.0mmol，10.0mL，3M in THF)，滴加完毕，室温搅拌3小时。将反应液冷却到0℃，缓慢滴加MeOH(40mL)，加毕，加入NaBH 4(2.26g，60.00mmol)。室温搅拌24小时。将反应液缓慢倒入200mL水中淬灭，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层用无水Na 2SO 4干燥，浓缩，得到粗品，1-(7-甲氧基萘-1-基)丙烷-2-胺(368mg，产率8％)，为黄色液体。
MS m/z(ESI):216.2[M+H] +.
第二步：N-(1-(7-甲氧基萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000091
将底物1-(7-甲氧基萘-1-基)丙烷-2-胺(368mg，1.7mmol)溶于二氯甲烷(30mL)中，加入TEA(519mg，5.12mmol，0.72mL)，室温搅拌10分钟，冷却到0℃，滴加乙酸酐(262mg，2.56mmol)。滴加完毕，室温搅拌2小时。将反应液倒入100mL水中淬灭，二氯甲烷萃取，合并有机层，无水Na 2SO 4干燥，浓缩，得到粗品。用柱层析纯化得到目标化合物N-(1-(7-甲氧基萘-1-基)丙烷-2-基)乙酰胺(300mg，产率82％)，为白色固体。
MS m/z(ESI):258.0[M+H] +.
1H NMR(400MHz,CDCl3)δ7.78–7.72(m,2H),7.69–7.65(m,1H),7.24(d,J＝4.9Hz,2H),7.15(dd,J＝8.9,2.1Hz,1H),4.42(s,1H),4.05(s,3H),3.64(dd,J＝13.2,3.4Hz,1H),2.76(dd,J＝13.0,9.5Hz,1H),2.00(s,3H),1.10(d,J＝6.5Hz,3H).
第三步：N-(1-(3-溴-7-甲氧基萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000092
将底物N-(1-(7-甲氧基萘-1-基)丙烷-2-基)乙酰胺(230mg，0.89mmol)溶于AcOH(5mL)中，加热到85℃(油浴温度)，滴加液溴(144mg，0.9mmol)的AcOH(1mL)溶液。滴加完毕，继续加热搅拌0.5小时。将反应液冷却到室温，将其倒入水(50mL)中，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层用无水Na 2SO 4干燥，浓缩，得到粗品，柱层析纯化得到N-(1-(3-溴-7-甲氧基萘-1-基)丙烷-2-基)乙酰胺(270mg，产率87％)，为白色固体。
MS m/z(ESI):336.2[M+H] +.
1H NMR(400MHz,Chloroform)δ7.97–7.91(m,2H),7.54(dd,J＝20.6,2.9Hz,2H),6.99(dd,J＝14.8,3.0Hz,1H),5.53(s,1H),4.28–4.14(m,1H),3.81(s,3H),3.37(dd,J＝24.8,13.5Hz,1H),3.12(dd,J＝24.8,13.6Hz,1H),1.99(s,3H),1.14(d,J＝12.0Hz,3H).
第四步：N-(1-(7-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000093
将底物N-(1-(3-溴-7-甲氧基萘-1-基)丙烷-2-基)乙酰胺(270mg，0.8mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(406mg，10.0mmol)和KOAc(157mg，1.6mmol)溶于无水二氧六环(5mL)中，氮气置换三次，保护下加入Pd(dppf)Cl 2(117mg，0.16mmol)，加热到90℃(外温)反应2小时。将反液应浓缩干，得粗品，柱层析纯化得到目标化合物N-(1-(7-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)丙烷-2-基)乙酰胺(276mg，产率90％)，为黄色固体。
MS m/z(ESI):384.2[M+H] +.
第五步：(4-(2-乙酰氨基丙基)-6-甲氧基萘-2-基)硼酸的制备
Figure PCTCN2021108795-appb-000094
将底物N-(1-(7-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)丙烷-2-基)乙酰胺(276mg，0.72mmol)溶于丙酮(10mL)和水(10mL)中，加NH 4OAc(280mg，3.6mmol)和NaIO 4(770mg，3.6mmol)。加热到25℃(外温)，反应1.5小时。将反液应浓缩干，得粗品，加水，乙酸乙酯萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，柱层析纯化得到目标化合物(4-(2-乙酰氨基丙基)-6-甲氧基萘-2-基)硼酸(130mg，产率60％)，为黄色固体。
MS m/z(ESI):302.2[M+H] +.
第六步：N-(1-(3-氟-7-甲氧基萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000095
室温下，将试剂NaOH(21mg，525μmol)溶于MeOH(1mL)中，后加入底物(4-(2-乙酰氨基丙基)-6-甲氧基萘-2-基)硼酸(130mg，432μmol)，然后在25℃(外 温，油浴温度)，搅拌15分钟。将反应液冷却到0℃，加入试剂AgOTf(334mg，1.3mmol)，在0℃条件下，搅拌30分钟。然后，用油泵在0℃条件下，将反应液溶剂浓缩干，用丙酮通过溶剂共沸除去残留的甲醇，得到粗品。将粗品溶于丙酮(3mL)中，加入活化的3A分子筛(350mg),后加入F-TEDA-BF 4(161mg，454μmol)。然后在室温条件下搅拌1小时。将反应液缓慢加入到10mL水中，乙酸乙酯萃取，合并有机层，无水Na 2SO 4干燥，浓缩，得到粗品，柱层析纯化得到目标化合物N-(1-(3-氟-7-甲氧基萘-1-基)丙烷-2-基)乙酰胺(86mg，产率60％)，白色固体。
MS m/z(ESI):276.1[M+H] +.
第七步：N-(1-(3-氟-7-羟基萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000096
将底物N-(1-(3-氟-7-羟基萘-1-基)丙烷-2-基)乙酰胺(86mg，310.8μmol)溶于二氯甲烷(15mL)，氮气保护下，冷却到0℃，滴加BBr 3(3mL，1M in CH 2Cl 2)，滴加完毕，升到室温搅拌30分钟。将反应液缓慢倒入100mL饱和NaHCO 3溶液中淬灭反应。二氯甲烷萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，柱层析纯化得到白色固体产品N-(1-(3-氟-7-羟基萘-1-基)丙烷-2-基)乙酰胺(77mg，产率95％)，为白色固体。
MS m/z(ESI):262.1[M+H] +.
第八步：N-(1-(7-环丙氧基-3-氟萘-1-基)丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000097
将底物N-(1-(3-氟-7-羟基萘-1-基)丙烷-2-基)乙酰胺(39mg，0.15mmol)和溴环丙烷(91mg，0.75mmol)溶于NMP(2mL)中，置于5.0mL微波管中，加入Cs 2CO 3(73mg，225μmol)和KI(37mg，225μmol)。微波180℃，反应4小时。将反应液浓缩，除去溶剂得到粗品，制备HPLC(碱法)纯化得到目标化合物N-(1-(7-环丙氧基-3-氟萘-1-基)丙烷-2-基)乙酰胺(9.5mg，产率21％)，白色固体。
MS m/z(ESI):302.1[M+H] +.
1H NMR(500MHz,Chloroform)δ7.93(dd,J＝15.0,2.9Hz,1H),7.72(d,J＝2.9Hz,1H),7.14(dt,J＝16.1,3.0Hz,1H),7.01(dd,J＝15.0,3.1Hz,1H),6.72(dd,J＝15.9,2.9Hz,1H),5.87(s,1H),4.21(dd,J＝24.1,12.1Hz,1H),3.53(p,J＝16.5Hz,1H),3.37(dd,J＝24.8,12.2Hz,1H),3.12(dd,J＝24.7,12.3Hz,1H),1.99(s,3H), 1.14(d,J＝12.0Hz,3H),0.83–0.67(m,2H),0.35–0.14(m,2H).
实施例27
N-(1-(7-环丙氧基-3-氟萘-1-基)-2-甲基丙烷-2-基)乙酰胺的制备
Figure PCTCN2021108795-appb-000098
N-(1-(7-环丙氧基-3-氟萘-1-基)-2-甲基丙烷-2-基)乙酰胺的制备参考实施例26。
MS m/z(ESI):316.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.78-7.70(m,3H),7.36(d,J＝4Hz,1H),5.63(s,1H),4.07–3.97(m,1H),3.25(s,2H),1.81(s,3H),1.47(s,6H),0.94–0.87(m,2H),0.75–0.66(m,2H).
实施例28
N-(1-((7-环丙氧基-3-氟萘-1-基)甲基)环丙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000099
第一步：1-((7-环丙氧基-3-氟萘-1-基)甲基)环丙烷-1-胺的制备
Figure PCTCN2021108795-appb-000100
30℃,N 2下往2-(7-环丙氧基-3-氟萘-1-基)乙酰腈(610mg，2.54mmol)和四异丙氧钛(790mg，2.79mmol，583.30uL)的THF(10mL)中滴加乙基溴化镁(676mg，5.07mmol)，30℃下，搅拌1小时。加入BF 3.Et 2O(1M，5.07mL)，混合物搅拌1小时。0℃下，把混合物倒入NaOH(10％)中，二氯甲烷萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到1-((7-环丙氧基-3-氟萘-1-基)甲基)环丙烷-1-胺(150mg，产率26％)。
MS m/z(ESI):272.1[M+H] +.
第二步：N-(1-((7-环丙氧基-3-氟萘-1-基)甲基)环丙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000101
0℃，N 2下往1-((7-环丙氧基-3-氟萘-1-基)甲基)环丙烷-1-胺(0.15g，550μmol)和DIEA(256mg，1.98mmol，344.84μL)的DCM(10mL)中滴加醋酸酐(135mg，1.32mmol)，30℃下，搅拌1小时。浓缩后反应液过滤，制备HPLC纯化得到N-(1-((7-环丙氧基-3-氟萘-1-基)甲基)环丙基)乙酰胺(77mg，产率43％)白色固体。
MS m/z(ESI):314.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.68-7.65(m,2H),7.38(s,1H),7.22-7.20(d,J＝8.0Hz,1H),6.44(s,1H),4.02(s,1H),3.59(s,2H),1.98(s,3H),0.95-0.80(m,4H),0.79-0.76(m,4H).
实施例31
N-(2-(7-环丙氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000102
N-(2-(7-环丙氧基异喹啉-1-基)乙基)乙酰胺的制备参考实施例2。
MS m/z(ESI):271.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.28(d,J＝4Hz,1H),8.14–8.02(m,1H),7.88(d,J＝8Hz,1H),7.69–7.58(m,2H),7.45–7.38(m,1H),4.05–3.92(m,1H),3.58–3.45(m,2H),3.40–3.31(m,2H),1.81(s,3H),0.95–0.87(m,2H),0.75–0.66(m,2H).
实施例32
N-(2-(7-环丙氧基萘-1-基)乙基)-2,2,2-三氟乙酰胺的制备
Figure PCTCN2021108795-appb-000103
N-(2-(7-环丙氧基萘-1-基)乙基)-2,2,2-三氟乙酰胺的制备参考实施例1。
MS m/z(ESI):324.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.72(d,J＝8Hz,1H),7.67(d,J＝8Hz,1H),7.59(s,1H),7.30-7.24(m,2H),7.15–7.12(m,1H),5.66(s,1H),4.06–3.94(m,1H),3.57–3.44(m,2H),3.40–3.30(m,2H),0.95–0.88(m,2H),0.76–0.65(m,2H).
实施例33
N-(2-(7-环丙氧基萘-1-基)乙基)环丙甲酰胺的制备
Figure PCTCN2021108795-appb-000104
N-(2-(7-环丙氧基萘-1-基)乙基)环丙甲酰胺的制备参考实施例1。
MS m/z(ESI):296.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ7.73-7.66(m,2H),7.59(s,1H),7.30-7.24(m,2H),7.14(dd,J＝12Hz,4Hz,1H),5.63(s,1H),4.04-4.01(m,1H),3.62-3.57(m,2H),3.25-3.21(m,2H),1.43-1.38(m,1H),1.01-0.79(m,8H).
实施例34
N-(2-(7-环丙氧基萘-1-基)乙基)丙酰胺的制备
Figure PCTCN2021108795-appb-000105
N-(2-(7-环丙氧基萘-1-基)乙基)丙酰胺的制备参考实施例1。
MS m/z(ESI):284.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ7.74-7.65(m,2H),7.58(s,1H),7.31-7.23(m,2H),7.14(dd,J＝12Hz,4Hz,1H),5.60(s,1H),4.03-4.00(m,1H),3.64-3.59(m,2H),3.26-3.22(m,2H),1.42-1.39(m,2H),1.01-0.81(m,7H).
实施例35
N-(2-(7-环丙氧基萘-1-基)乙基)异丁酰胺的制备
Figure PCTCN2021108795-appb-000106
N-(2-(7-环丙氧基萘-1-基)乙基)异丁酰胺的制备参考实施例1。
MS m/z(ESI):298.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ7.73-7.66(m,2H),7.59(s,1H),7.30-7.24(m,2H),7.14(dd,J＝12Hz,4Hz,1H),5.63(s,1H),4.04-4.01(m,1H),3.62-3.57(m,2H),3.25-3.21(m,2H),1.43-1.38(m,1H),1.01-0.79(m,10H).
实施例36
N-(2-(7-环丙氧基-3-甲基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000107
第一步：N-(2-(7-环丙基-3-甲基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000108
底物N-(2-(7-环丙基-3-溴萘-1-基)乙基)乙酰胺(104mg，0.3mmol)，Cs 2CO 3(293mg，900μmol)和硼酸三甲酯(75mg，720μmol，83.87μL)溶于无水二氧六环(5mL)和水(1mL)中，氮气置换三次，加入Pd(dppf)Cl 2(44mg，60μmol)，加热至110℃反应4小时。将反应液浓缩，得粗品，加水，乙酸乙酯(80mL×3)萃取，合并有机相，无水硫酸钠干燥，浓缩得到粗品，柱层析纯化得到粗产物，后再用制备HPLC纯化得到白色固体产物N-(2-(7-环丙基-3-甲基萘-1-基)乙基)乙酰胺(24mg,产率27％)。
MS m/z(ESI):284.1[M+H] +.
1H NMR(400MHz,CDCl3)δ7.65(dd,J＝17.5,5.3Hz,2H),7.46(s,1H),7.16(dd,J＝10.7,3.9Hz,2H),3.93–3.87(m,1H),3.64(dd,J＝13.2,6.7Hz,2H),3.22(t,J＝7.0Hz,2H),2.46(s,3H),1.94(s,3H),0.92–0.87(m,2H),0.82(t,J＝6.3Hz,2H).
实施例37
N-[2-[3-溴-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000109
第一步：1,1-二氘-2-(7-甲氧基-1-萘)乙胺的制备
Figure PCTCN2021108795-appb-000110
0℃，氮气保护下往2-(7-甲氧基-1-萘基)乙腈(3g，15.2mmol)的THF(30mL)中加LiAlD 4(1.83g，44.6mmol)，30℃下搅拌1小时。冷却到0℃，向反应液中加入Na 2SO 4·10H 2O，加入乙酸乙酯萃取，有机相用无水硫酸钠干燥后浓缩得到粗品1,1-二氘-2-(7-甲氧基-1-萘)乙胺(2g，产率65％)。直接用于下一步。
MS m/z(ESI):204.1[M+H] +.
第二步：N-[1,1-二氘-2-(7-甲氧基-1-萘)乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000111
0℃，氮气保护下往1,1-二氘-2-(7-甲氧基-1-萘)乙胺(2g，9.8mmol)，和三乙胺(2.99g，29.5mmol，4.1mL)的二氯甲烷(6.7mL)中加乙酸酐(2.01g，19.7mmol)，30℃下搅拌2小时。冷却到0℃下，加入盐水，二氯甲烷萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得到N-[1,1-二氘-2-(7-甲氧基-1-萘)乙基]乙酰胺(2g，产率83％)黄色油状物。
MS m/z(ESI):246.1[M+H] +.
第三步：N-[1,1-二氘-2-(7-羟基-1-萘基)乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000112
0℃，氮气保护下往N-[1,1-二氘-2-(7-甲氧基-1-萘)乙基]乙酰胺(2g，8.2mmol)的二氯甲烷(20mL)溶液中，加入BBr 3(1M，16.31mL)，逐渐升温至30℃搅拌1小时。冷却到0℃，反应液加入饱和NaHCO 3水溶液淬灭，加入二氯甲烷萃取，有机相用盐水洗，无水硫酸钠干燥，过滤，浓缩得到N-[1,1-二氘-2-(7-羟基-1-萘基)乙基]乙酰胺(1.5g，产率80％)黄色固体。
MS m/z(ESI):232.1[M+H] +.
第四步：N-(2-(7-环丙氧基萘-1-基)乙基-1,1-二氘)乙酰胺的制备
Figure PCTCN2021108795-appb-000113
氮气保护下往N-[1,1-二氘-2-(7-羟基-1-萘基)乙基]乙酰胺(1.5g，6.5mmol)，KI(108mg，648μmol)和Cs 2CO 3(4.2g，13mmol)的DMF(8mL)溶液中加溴代环丙烷(2.35g，19.5mmol)，170℃下，微波搅拌2小时。冷却至室温，加入盐水，二氯甲烷萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到N-(2-(7-环丙氧基萘-1-基)乙基-1,1-二氘)乙酰胺(0.9g，产率51％)棕色油状物。
MS m/z(ESI):272.1[M+H] +.
第五步：N-[2-[3-溴-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000114
70℃,氮气保护下往N-(2-(7-环丙氧基萘-1-基)乙基-1,1-二氘)乙酰胺(0.2g，737μmol)的AcOH(5mL)溶液中，滴加液溴(141mg，884μmol)的AcOH(2mL)溶液，70℃下搅拌7小时。冷却至0℃，加入盐水，乙酸乙酯萃取。合并有机层，水洗，无水硫酸钠干燥，过滤，浓缩后柱层析纯化，再用制备HPLC纯化得到N-[2-[3-溴-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺(20mg，产率7％)。
MS m/z(ESI):350.1[M+H] +,352.1[M+H+2] +.
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.68–7.64(m,2H),7.37(s,1H),7.21-7.18(dd,J＝8.0,4.0Hz,1H),5.62(s,1H),3.94-3.91(m,1H),3.20(s,2H),1.96(s,3H),0.97–0.90(m,2H),0.83-0.79(m,2H).
实施例38
N-[2-[3-氯-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000115
第一步：N-[2-[3-氯-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000116
氮气保护下往N-[2-[3-溴-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺(20mg，57μmol)的DMF(2mL)中，加入CuCl(113mg，1.14mmol)，微波140℃下搅拌3小时。反应液加饱和食盐水，二氯甲烷萃取。合并有机层，无水硫酸钠干燥，浓缩后制备HPLC纯化得到N-[2-[3-氯-7-(环丙氧基)-1-萘基]-1,1-二氘-乙基]乙酰胺(7mg，产率38％)。
MS m/z(ESI):306.1[M+H] +,308.1[M+H+2] +.
1H NMR(400MHz,DMSO-d 6)δ8.07(s,1H),7.86–7.81(m,3H),7.35(s,1H),7.27-7.24(dd,J＝8.0,2.0Hz,1H),4.06-4.03(m,1H),3.12(s,2H),1.81(s,3H),0.95-0.90(m,2H),0.74-0.70(m,2H).
实施例39
N-(2-(3-溴-7-环丙氧基萘-1-基)乙基)-2,2-二氟乙酰胺的制备
Figure PCTCN2021108795-appb-000117
N-(2-(3-溴-7-环丙氧基萘-1-基)乙基)-2,2-二氟乙酰胺的制备参考实施例15。
MS m/z(ESI):384.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.68-7.65(m,2H),7.38(s,1H),7.22-7.20(d,J＝8.0Hz,1H),6.44(s,1H),6.03-5.75(t,J＝56Hz,1H),4.02(s,1H),3.61(q,J＝6.8Hz,2H),3.25(t,J＝7.2Hz,2H),0.95-0.80(m,4H).
实施例40
N-(2-(7-环丙氧基-3-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000118
第一步：N-(2-(3-溴-7-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000119
将底物N-(2-(3-溴-7-甲氧基萘-1-基)乙基)乙酰胺(1.29g，4.0mmol),溶于二氯甲烷(40mL)，氮气保护下，冷却到0℃，滴加BBr 3(40mL，1M二氯甲烷溶液)，滴加完毕，升到室温搅拌30分钟。将反应液缓慢倒入200mL饱和NaHCO 3溶液中淬灭反应。二氯甲烷萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，柱层析纯化得到白色固体产品N-(2-(3-溴-7-羟基萘-1-基)乙基)乙酰胺(1.05g，产率85％)，为白色固体。
MS m/z(ESI):309.2[M+H] +.
第二步：N-(2-(3-溴-7-环丙氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000120
将底物N-(2-(3-溴-7-羟基萘-1-基)乙基)乙酰胺(616mg，2.0mmol)，Cs 2CO 3(977mg，3.0mmol)和碘化钾(498mg，3.0mmol)溶于DMA(5.0mL)中，置于25mL 微波管中，加入溴环丙烷(1.21g，10mmol)。微波180℃，反应4小时。加水，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层无水Na 2SO 4干燥，浓缩，得到粗品，柱层析纯化得到黄色固体产品N-(2-(3-溴-7-环丙氧基萘-1-基)乙基)乙酰胺(1.05g，产率85％)。
MS m/z(ESI):348.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.08(s,1H),8.00(s,1H),7.87–7.77(m,2H),7.46(s,1H),7.25(dd,J＝8.9,2.0Hz,1H),4.10–3.97(m,1H),3.37–3.32(m,2H),3.17–3.08(m,2H),1.81(s,3H),0.92(q,J＝6.1Hz,2H),0.72(s,2H).
第三步：N-(2-(7-环丙氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000121
将底物N-(2-(3-溴-7-环丙氧基萘-1-基)乙基)乙酰胺(700mg，2.01mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(1.02g，4.02mmol)和KOAc(591mg，6.03mmol)溶于无水二氧六环(10mL)中，氮气保护下，加入Pd(dppf)Cl 2(294mg，402μmol)，加热100℃(外温)反应10小时。将反液应浓缩干，得粗品，柱层析纯化得到目标化合物N-(2-(7-环丙氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙基)乙酰胺(760mg，产率79％)，为黄色固体。
MS m/z(ESI):396.2[M+H] +.
第四步：(4-(2-乙酰氨基乙基)-6-环丙氧基萘-2-基)硼酸的制备
Figure PCTCN2021108795-appb-000122
将底物N-(2-(7-环丙氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙基)乙酰胺(760mg，1.92mmol)溶于丙酮(15mL)和H 2O(15mL)中，加入NH 4OAc(741mg，9.61mmol)和NaIO 4(2.06g，9.61mmol)。加热到25℃(外温)，反应1.5小时。将反液应浓缩干，得粗品，加水，乙酸乙酯萃取，合并有机层，无水Na 2SO 4干燥，浓缩得到粗品，柱层析纯化得到目标化合物(4-(2-乙酰氨基乙基)-6-环丙氧基萘-2-基)硼酸(245mg，产率33％)，为黄色固体。
MS m/z(ESI):314.1[M+H] +.
第五步：N-(2-(7-环丙氧基-3-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000123
将(4-(2-乙酰氨基乙基)-6-环丙氧基萘-2-基)硼酸(245mg，780μmol)溶于四氢呋喃(2mL)和水(4mL)中，冷却到0℃，加入NH 4HCO 3(75mg，950μmol)，然后滴加H 2O 2(64.6mg，1.9mmol，2.2mL)。室温搅拌1小时。向反应液中缓慢加入饱和Na 2SO 3水溶液淬灭反应，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层用无水Na 2SO 4干燥，浓缩，得到粗品，柱层析纯化得到N-(2-(7-环丙氧基-3-羟基萘-1-基)乙基)乙酰胺(209mg，产率71％)，为淡黄色固体。
MS m/z(ESI):286.1[M+H] +.
第六步：N-(2-(7-环丙氧基-3-甲氧基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000124
将底物N-(2-(7-环丙氧基-3-羟基萘-1-基)乙基)乙酰胺(57mg，0.2mmol)，MeI(142mg，1.0mmol)和K 2CO 3(55mg，400μmol)溶于乙腈(10mL)中，氮气保护下，室温搅拌过夜。反应液用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，有机层用无水Na 2SO 4干燥，浓缩，得到粗品，然后用制备HPLC(酸法，后用碱法)纯化得到N-(2-(7-环丙氧基-3-甲氧基萘-1-基)乙基)乙酰胺(25mg，产率41.70％)，为白色固体。
MS m/z(ESI):300.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.07(t,J＝5.3Hz,1H),7.72(dd,J＝13.6,5.3Hz,2H),7.17(dd,J＝8.5,1.9Hz,2H),7.00(d,J＝2.2Hz,1H),4.01–3.95(m,1H),3.83(s,3H),3.36–3.33(m,2H),3.08(t,J＝7.5Hz,2H),1.82(s,3H),0.89(q,J＝5.9Hz,2H),0.73–0.66(m,2H).
实施例41
N-(2-(3-溴-7-(2-甲氧基乙氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000125
N-(2-(3-溴-7-(2-甲氧基乙氧基)萘-1-基)乙基)乙酰胺的制备参考实施例15。
MS m/z(ESI):366.1[M+H] +,368.1[M+H+2] +。
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.64(d,J＝9.0Hz,1H),7.46(s,1H),7.35(d,J＝1.4Hz,1H),7.22(dd,J＝8.9,2.0Hz,1H),5.77(s,1H),4.33–4.28(m,2H),3.86–3.81(m,2H),3.55(dd,J＝13.0,6.4Hz,2H),3.47(s,3H),3.18(t,J＝7.2Hz,2H),1.96(s,3H).
实施例42
N-(2-(3-氯-7-(3-甲氧基丙氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000126
N-(2-(3-氯-7-(3-甲氧基丙氧基)萘-1-基)乙基)乙酰胺的制备参考实施例14。
MS m/z(ESI):336.1[M+H] +,338.1[M+H+2] +。
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.66(d, J＝9.0Hz,1H),7.38(d, J＝12.6Hz,2H),7.17(d, J＝8.9Hz,1H),4.23(t, J＝6.1Hz,2H),3.61(t, J＝6.1Hz,4H),3.38(s,3H),3.20(t, J＝7.0Hz,2H),2.16–2.10(m,2H),1.97(s,3H).
实施例43
N-(2-(3-氯-7-(2-乙氧基乙氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000127
N-(2-(3-氯-7-(3-甲氧基丙氧基)萘-1-基)乙基)乙酰胺的制备参考实施例14。
MS m/z(ESI):336.1[M+H] +,338.1[M+H+2] +.
1H NMR(400MHz,CDCl 3)δ7.91(dd,J＝15.0,2.9Hz,1H),7.61(d,J＝3.1Hz,1H),7.49(t,J＝3.0Hz,1H),7.21(d,J＝3.1Hz,1H),6.97(dd,J＝15.0,2.9Hz,1H),5.60(s,1H),4.40(t,J＝14.6Hz,2H),3.76(t,J＝14.6Hz,2H),3.49–3.34(m,4H),3.30–3.21(m,2H),1.80(s,3H),1.13(t,J＝11.8Hz,3H).
实施例44
N-(2-(6-环丙氧基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000128
第一步：2-(6-甲氧基-4-喹啉基)-N,N-二甲基-乙烯胺的制备
Figure PCTCN2021108795-appb-000129
6-甲氧基-4-甲基-喹啉(970mg，5.6mmol)的叔-丁氧基二(二甲氨基)甲烷(9mL)溶液在110℃搅拌60小时。浓缩反应液得到2-(6-甲氧基-4-喹啉基)-N,N-二甲基-乙烯胺(1.28g，产率100％)黑色油，直接用于下一步反应。
MS m/z(ESI):229.1[M+H] +。
第二步：2-(6-甲氧基-4-喹啉基)乙酰腈的制备
Figure PCTCN2021108795-appb-000130
往2-(6-甲氧基-4-喹啉基)-N,N-二甲基-乙烯胺(1.28g，5.6mmol)的乙腈(60mL)和水(40mL)溶液里加羟胺磺酸(1.9g，16.8mmol)，有大量固体析出。加热至50℃搅拌5小时。往反应液加水(60mL)，用碳酸钠固体调节至pH～9，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，浓缩后柱层析纯化得到2-(6-甲氧基-4-喹啉基)乙酰腈(1g，产率90％)黄色固体。
MS m/z(ESI):199.1[M+H] +。
第三步：N-[2-(6-甲氧基-4-喹啉基)乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000131
-10℃下往2-(6-甲氧基-4-喹啉基)乙酰腈(800mg，4mmol)的二氯甲烷(20mL)和甲醇(10mL)溶液里加六水合氯化镍(576mg，2.4mmol)，醋酸酐(989mg，9.7mmol)，再分批加硼氢化钠(611mg，16.1mmol)，溶液变黑色，加完室温搅拌3小时。在冰水浴下滴加浓盐酸(3mL)，室温搅拌1小时。加水(100mL)，用乙酸乙酯洗涤，水相再用碳酸钠调节至pH～9，乙酸乙酯萃取，有机相浓缩后柱层析纯化得到N-[2-(6-甲氧基-4-喹啉基)乙基]乙酰胺(700mg，产率67％)粉色固体。
MS m/z(ESI):245.1[M+H] +.
第四步：N-(2-(6-羟基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000132
0℃下往N-[2-(6-甲氧基-4-喹啉基)乙基]乙酰胺(200mg，819μmol)的二氯甲烷(15mL)的溶液里加三溴化硼的二氯甲烷溶液(1.0M，8mL)，加完搅拌1小时。反应用水(30mL)淬灭，用碳酸钠固体调节至pH～9，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，浓缩后柱层析纯化得到N-(2-(6-羟基喹啉-4-基)乙基)乙酰胺(100mg，产率53％)黄色固体。
MS m/z(ESI):231.1[M+H] +。
第五步：N-(2-(6-环丙氧基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000133
往N-(2-(6-羟基喹啉-4-基)乙基)乙酰胺(100mg，0.43mmol)，溴环丙烷(100mg，0.8mmol)的N-甲基吡咯烷酮(3mL)中加入碳酸铯(160mg，0.5mmol)，碘化钾(30mg，0.2mmol)，微波170℃搅拌2小时。反应液加入水(40mL)中，二氯甲烷萃取，浓缩后经过高效液相色谱分离，冻干得到N-(2-(6-环丙氧基喹啉-4-基)乙基)乙酰胺(10mg，产率8％)。
MS m/z(ESI):271.1[M+H] +。
1H NMR(400MHz,DMSO)δ8.63(d,J＝4Hz,1H),8.17–8.04(m,1H),7.92(d,J＝8Hz,1H),7.60(d,J＝4Hz,1H),7.44–7.36(m,1H),7.32(d,J＝4Hz,1H),4.06–3.93(m,1H),3.43–3.37(m,2H),3.17(t,J＝8Hz,2H),1.81(s,3H),0.95–0.87(m,2H),0.77–0.65(m,2H).
实施例45
N-(2-(2-氯-6-环丙氧基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000134
第一步：4-(2-乙酰氨基乙基)-6-环丙氧基喹啉1-氧化制备
Figure PCTCN2021108795-appb-000135
N-(2-(6-环丙氧基喹啉-4-基)乙基)乙酰胺(100mg，0.37mol)和间氯过氧苯甲酸(149mg，0.74mol，85％)在二氯甲烷(15mL)中室温搅拌13小时。浓缩，柱层析纯化得到4-(2-乙酰氨基乙基)-6-环丙氧基喹啉1-氧化(95mg，产率90％)黄色固体。
MS m/z(ESI):287.1[M+H] +。
第二步：N-(2-(2-氯-6-环丙氧基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000136
4-(2-乙酰氨基乙基)-6-环丙氧基喹啉1-氧化(95mg，0.33mol)在三氯氧磷(5mL)中100℃搅拌1小时。慢慢倒入碳酸钠水溶液(100mL)里，用乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后经过高效液相色谱分离，冻干得到N-(2-(2-氯-6-环丙氧基喹啉-4-基)乙基)乙酰胺(12mg，产率11％)白色固体。
MS m/z(ESI):305.1[M+H] +，307.1[M+H+2] +。
1H NMR(400MHz,DMSO)δ8.19–8.05(m,1H),7.86(d,J＝8Hz,1H),7.63(d,J＝4Hz,1H),7.48–7.43(m,1H),7.41(s,1H),4.06–3.93(m,1H),3.47–3.40(m,2H),3.38–3.32(m,2H),1.80(s,3H),0.95–0.85(m,2H),0.77–0.65(m,2H).
实施例46
N-(2-(2-溴-6-环丙氧基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000137
N-(2-(2-溴-6-环丙氧基喹啉-4-基)乙基)乙酰胺的制备参考实施例45。
MS m/z(ESI):349.1[M+H] +，351.1[M+H+2] +。
1H NMR(400MHz,DMSO)δ8.19–8.05(m,1H),7.87(d,J＝8Hz,1H),7.63(d,J＝4Hz,1H),7.48–7.43(m,1H),7.45(s,1H),4.06–3.95(m,1H),3.46–3.44(m,2H),3.37–3.32(m,2H),1.81(s,3H),0.95–0.86(m,2H),0.75–0.65(m,2H).
实施例47
N-(2-(6-环丙氧基-2-氟喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000138
N-(2-(6-环丙氧基-2-氟喹啉-4-基)乙基)乙酰胺的制备参考实施例45。
MS m/z(ESI):289.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.86(d,J＝8Hz,1H),7.64(d,J＝4Hz,1H),7.47-7.41(m,2H),4.04-4.01(m,1H),3.62-3.57(m,2H),3.25-3.21(m,2H),1.43(s,3H),1.01-0.89(m,4H).
实施例48
N-(2-(6-环丙氧基-2-甲基喹啉-4-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000139
N-(2-(6-环丙氧基-2-甲基喹啉-4-基)乙基)乙酰胺的制备参考实施例36。
MS m/z(ESI):285.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.19–8.04(m,1H),7.84(d,J＝8Hz,1H),7.63(d,J＝4Hz,1H),7.48–7.43(m,1H),7.31(s,1H),4.06–3.93(m,1H),3.47–3.40(m,2H),3.38–3.32(m,2H),2.50(s,3H),1.80(s,3H),0.95–0.88(m,2H),0.76–0.65(m,2H).
实施例49
N-(2-(7-甲氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000140
第一步：7-甲氧基-1-甲基异喹啉的制备
Figure PCTCN2021108795-appb-000141
1-(3-甲氧苯基)乙烷-1-胺(5g，33.1mmol)，2,2-二乙氧基乙醛(6.6g，50mmol)溶于甲苯(100mL)中，加热至回流搅拌5小时。浓缩反应液，加入三氯氧磷(50mL)，加热回流15小时。浓缩反应液，加入冰水，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，有机相浓缩，柱层析纯化得到7-甲氧基-1-甲基异喹啉(1.9g，产率33％)。
MS m/z(ESI):174.1[M+H] +.
第二步：(Z)-2-(7-甲氧基异喹啉-1-基)-N,N-二甲基乙烯-1-胺的制备
Figure PCTCN2021108795-appb-000142
7-甲氧基-1-甲基异喹啉(1.8g，10.3mmol)加入1-叔-丁氧基-N,N,N',N'-四甲基甲二胺(2.7g，15.5mmol)中，加热至110℃搅拌60小时。反应液浓缩，得到(Z)-2-(7-甲氧基异喹啉-1-基)-N,N-二甲基乙烯-1-胺黑色油状产物，直接用于下一步反应(2.8g，粗品)。
MS m/z(ESI):229.1[M+H] +.
第三步：2-(7-甲氧基异喹啉-1-基)乙酰腈的制备
Figure PCTCN2021108795-appb-000143
(Z)-2-(7-甲氧基异喹啉-1-基)-N,N-二甲基乙烯-1-胺(2.8g)溶于乙腈/水(50mL/30mL)中，加入(氨基氧代)磺酸(3.4g，30.1mmol)，加热至50℃搅拌13小时。反应液用碳酸钠固体调节至pH～9，加水(60mL)，乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相浓缩，柱层析纯化得到2-(7-甲氧基异喹啉-1-基)乙酰腈(1.7g，两步产率83％)。
MS m/z(ESI):199.1[M+H] +.
第四步：N-(2-(7-甲氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000144
2-(7-甲氧基异喹啉-1-基)乙酰腈(1.5g，7.5mmol)溶于MeOH/CH 2Cl 2(20mL/50mL)，加入NiCl 2.6H 2O(1.1g，4.6mmol)，搅拌溶解，加入乙酸酐(1.9g，18.6mmol)，分批加入NaBH 4(1.1g，28.9mmol)，室温搅拌3小时。用入浓盐酸(1mL)淬灭，室温搅拌1小时。往反应液里加水(50mL)，用碳酸钠调至pH～9，二氯甲烷萃取，无水硫酸钠干燥，过滤，有机相浓缩，柱层析纯化得到N-(2-(7-甲氧基异喹啉-1-基)乙基)乙酰胺(380mg,产率21％)。
MS m/z(ESI):245.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.28(d,J＝4Hz,1H),8.15–8.04(m,1H),7.88(d,J＝12Hz,1H),7.67–7.64(m,1H),7.62(d,J＝4Hz,1H),7.46–7.37(m,1H),3.96(s,3H),3.54–3.47(m,2H),3.38–3.32(m,2H),1.81(s,3H).
实施例50
N-(2-(3-氯-7-甲氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000145
第一步：1-(2-乙酰氨基乙基)-7-甲氧基异喹啉2-氧化制备
Figure PCTCN2021108795-appb-000146
N-(2-(6-环丙氧基喹啉-4-基)乙基)乙酰胺(60mg，0.25mol)和间氯过氧苯甲酸(100mg，0.5mol，85％)在二氯甲烷(15mL)中室温搅拌3小时。直接浓缩，柱层析纯化得到1-(2-乙酰氨基乙基)-7-甲氧基异喹啉2-氧化(60mg，产率94％)黄色固体。
MS m/z(ESI):261.1[M+H] +。
第二步：N-(2-(3-氯-7-甲氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000147
4-(2-乙酰氨基乙基)-6-环丙氧基喹啉1-氧化(60mg，0.23mol)在三氯氧磷(5mL)中100℃搅拌1小时。慢慢倒入碳酸钠水溶液(100mL)里，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，浓缩后经过高效液相色谱分离，冻干得到N-(2-(3-氯-7-甲氧基异喹啉-1-基)乙基)乙酰胺(15mg，产率22％)黄色固体。
MS m/z(ESI):279.1[M+H] +，281.1[M+H+2] +。
1H NMR(400MHz,DMSO)δ8.39(s,1H),8.13–8.02(m,2H),7.75–7.67(m,1H),7.62–7.55(m,1H),4.00(s,3H),3.53–3.47(m,2H),3.35–3.30(m,2H),1.80(s,3H).
实施例51
N-(2-(7-甲氧基-3-甲基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000148
N-(2-(7-甲氧基-3-甲基异喹啉-1-基)乙基)乙酰胺的制备参考实施例36。
MS m/z(ESI):259.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.10–8.02(m,2H),7.71–7.64(m,1H),7.60–7.52(m,1H),4.00(s,3H),3.53–3.47(m,2H),3.35–3.30(m,2H),2.51(s,3H),1.80(s,3H).
实施例52
N-(2-(7-环丙氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000149
N-(2-(7-环丙氧基异喹啉-1-基)乙基)乙酰胺的制备参考实施例1。
MS m/z(ESI):271.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝4Hz,1H),8.09(s,1H),7.88(d,J＝12Hz,1H),7.66-7.62(m,2H),7.42(dd,J＝8Hz,4Hz,1H),4.04-4.01(m,1H),3.53-3.48(m,2H),3.36-3.33(m,2H),1.81(s,3H),1.01-0.89(m,4H).
实施例53
N-(2-(3-氯-7-环丙氧基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000150
N-(2-(3-氯-7-环丙氧基异喹啉-1-基)乙基)乙酰胺的制备参考实施例45。
MS m/z(ESI):305.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.08(d,J＝8Hz,1H),7.71(d,J＝4 Hz,1H),7.58(dd,J＝8Hz,4Hz,1H),5.63(s,1H),4.04-4.01(m,1H),3.52-3.47(m,2H),3.36-3.33(m,2H),1.80(s,3H),1.01-0.89(m,4H).
实施例54
N-(2-(7-环丙氧基-3-甲基异喹啉-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000151
N-(2-(7-环丙氧基-3-甲基异喹啉-1-基)乙基)乙酰胺的制备参考实施例36。
MS m/z(ESI):285.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.10(d,J＝8Hz,1H),7.72(d,J＝4Hz,1H),7.60(dd,J＝8Hz,4Hz,1H),5.63(s,1H),4.03-4.01(m,1H),3.53-3.47(m,2H),3.37-3.33(m,2H),2.53(s,3H),1.80(s,3H),1.01-0.89(m,4H).
实施例55
N-[2-[3-溴-7-(氰基甲氧基)-1-萘基]乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000152
第一步：N-[2-[3-溴-7-(氰基甲氧基)-1-萘基]乙基]乙酰胺的制备
Figure PCTCN2021108795-appb-000153
N-[2-(3-溴-7-羟基-1-萘基)乙基]乙酰胺(50mg，162.25μmol)，溴乙腈(58mg，486μmol)和碳酸钾(67mg，486μmol)在乙腈(5mL)中80℃搅拌1小时。反应液过滤，乙酸乙酯洗涤，有机相浓缩，快速柱层析纯化(二氯甲烷/甲醇＝15/1)得到N-[2-[3-溴-7-(氰基甲氧基)-1-萘基]乙基]乙酰胺白色固体(40mg，产率68％)。
MS m/z(ESI):347.0[M+H] +，349.0[M+H+2] +.
1H NMR(400MHz,DMSO)δ8.18–8.10(m,1H),8.06(s,1H),7.93(d,J＝9.0Hz,1H),7.83-7.82(m,1H),7.52-7.51(m,1H),7.38–7.29(m,1H),5.39(s,2H),3.36–3.25(m,2H),3.14(t,J＝8Hz,2H),1.83(s,3H).
实施例56
N-(2-(3-氯-7-(氰基甲氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000154
第一步：N-(2-(3-氯-7-羟基萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000155
N-[2-(3-溴-7-羟基-1-萘基)乙基]乙酰胺(130mg，422μmol)和氯化亚铜(418mg，4.22mmol)在N,N-二甲基甲酰胺(3mL)中微波140℃搅拌1小时。往反应液中加水30mL)和乙酸乙酯(20mL)，过滤，再用乙酸乙酯(20mL×2)萃取，有机相用饱和食盐水(15mL)洗，无水硫酸钠干燥，浓缩得到N-(2-(3-氯-7-羟基萘-1-基)乙基)乙酰胺黄色油(70mg，产率63％)。
MS m/z(ESI):264.1[M+H] +，266.1[M+H+2] +.
第二步：N-(2-(3-氯-7-(氰基甲氧基)萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000156
N-[2-(3-氯-7-羟基-1-萘基)乙基]乙酰胺(70mg，265μmol)，溴乙腈(95mg，796μmol)和碳酸钾(110mg，796μmol)在乙腈(3mL)中80℃搅拌1小时。反应液过滤，乙酸乙酯洗涤，有机相浓缩，快速柱层析纯化(二氯甲烷/甲醇＝15/1)得到N-(2-(3-氯-7-(氰基甲氧基)萘-1-基)乙基)乙酰胺白色固体(30mg，产率35％)。
MS m/z(ESI):303.1[M+H] +,305.1[M+H+2] +.
1H NMR(400MHz,DMSO)δ8.20–8.09(m,1H),7.96–7.88(m,2H),7.86–7.80(m,1H),7.43–7.38(m,1H),7.37–7.30(m,1H),5.39(s,2H),3.43–3.33(m,2H),3.15(t,J＝8Hz,2H),1.83(s,3H).
实施例57
N-(2-(7-(氰基甲氧基)-3-甲基-1-萘基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000157
第一步：N-(2-(7-羟基-3-甲基-萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000158
N-[2-(3-溴-7-羟基-1-萘基)乙基]乙酰胺(100mg，324μmol),三甲基环三硼氧烷(122mg，973μmol)，Cs 2CO 3(211mg，649μmol)，Pd(dppf)Cl 2-DCM(27mg，32μmol)在二氧六环(3mL)和水(0.3mL)中，氮气保护下，100℃微波搅拌1小时。LC-MS显示反应完。反应液直接用于下一步反应。
MS m/z(ESI):244.1[M+H] +.
第二步：N-(2-(7-(氰基甲氧基)-3-甲基-1-萘基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000159
在上一步反应液中，加入溴乙腈(117mg，974μmol)和碳酸钾(135mg，974μmol)，80℃搅拌1小时。反应液过滤，乙酸乙酯洗涤，有机相浓缩，快速柱层析纯化(二氯甲烷/甲醇＝0％-3％)得到粗品，制备HPLC纯化得到N-(2-(7-(氰基甲氧基)-3-甲基-1-萘基)乙基)乙酰胺白色固体(23mg，产率24％)。
MS m/z(ESI):283.1[M+H] +.
1H NMR(400MHz,DMSO)δ8.18–8.07(m,1H),7.82(d,J＝8Hz,1H),7.79–7.74(m,1H),7.54(s,1H),7.29–7.18(m,2H),5.35(s,2H),3.47–3.27(m,2H),3.18–3.01(m,2H),2.42(s,3H),1.85(s,3H).
实施例59
N-(2-(7-(氰基甲氧基)-4-氟萘-1-基)乙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000160
N-(2-(7-(氰基甲氧基)-4-氟萘-1-基)乙基)乙酰胺的制备参考实施例57。
MS m/z(ESI):287.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝9.0Hz,1H),7.68(t,J＝2.2Hz,1H),7.26–7.14(m,2H),6.92(dd,J＝10.3,7.8Hz,1H),5.54(s,1H),,5.35(s,2H),3.35-3.31(m,2H),3.12-3.08(m,2H),2.42(s,3H).
实施例60
N-(2-(3-溴-7-环丙氧基萘-1-基)-3-羟基丙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000161
第一步:乙基2-氰基-2-(7-甲氧基-1-萘基)乙酸酯的制备
Figure PCTCN2021108795-appb-000162
将2-(7-甲氧基-1-萘基)乙酰腈(2.5g，12.7mmol)，NaH(1.1g，25.4mmol，60％purity)加入四氢呋喃(40mL)中，混合均匀后，在70℃下反应2小时，向反应液加入碳酸二乙酯(3g，25.4mmol)，继续反应1小时，淬灭，乙酸乙酯萃取，减压浓缩，粗品用快速层析柱分离纯化，得目标化合物乙基2-氰基-2-(7-甲氧基-1-萘基)乙酸酯(2g，产率58％)，黄色油状。
MS m/z(ESI):270.1[M+H] +.
第二步:3-氨基-2-(7-甲氧基-1-萘基)丙烷-1-醇的制备
Figure PCTCN2021108795-appb-000163
将LiAlH 4(113mg，2.97mmol)加入THF(10mL)，混合均匀后，在0℃下搅拌，向反应液加入乙基2-氰基-2-(7-甲氧基-1-萘基)乙酸酯(200mg，742.68μmol)，继续反应1小时，淬灭，二氯甲烷萃取，减压浓缩，粗品3-氨基-2-(7-甲氧基-1-萘基)丙烷-1-醇(100mg，432.36μmol，产率58％)直接用于下一步反应。
MS m/z(ESI):232.1[M+H] +.
第三步:3-乙酰氨基-2-(7-甲氧基萘-1-基)丙基乙酸酯
Figure PCTCN2021108795-appb-000164
将3-氨基-2-(7-甲氧基-1-萘基)丙烷-1-醇(100mg，432.36μmol，粗品)，K 2CO 3(179mg，1.30mmol)加入EtOAc/H 2O(20mL)中，混合均匀后，在0℃下滴加乙酰氯(51mg，648.54μmol)，反应1小时，乙酸乙酯萃取，减压浓缩，粗品用Pre-HPLC分离纯化，得目标化合物3-乙酰氨基-2-(7-甲氧基萘-1-基)丙基乙酸酯(40mg，产率33％)。
MS m/z(ESI):316.1[M+H] +.
第四步:[3-乙酰氨基-2-(3-溴-7-甲氧基-1-萘基)丙基]乙酸酯的制备
Figure PCTCN2021108795-appb-000165
将3-乙酰氨基-2-(7-甲氧基萘-1-基)丙基乙酸酯(40mg，0.15mmol)，Br 2(35mg，0.22mmol)加入乙酸(5mL)中，在70℃下反应3小时，减压浓缩，粗品用快速层析柱分离纯化，得目标化合物[3-乙酰氨基-2-(3-溴-7-甲氧基-1-萘基)丙基]乙酸酯(40mg,产率80％)。
MS m/z(ESI):394.1[M+H] +.
第五步:N-(2-(3-溴-7-羟基萘-1-基)-3-羟基丙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000166
将[3-乙酰氨基-2-(3-溴-7-甲氧基-1-萘基)丙基]乙酸酯(40mg，0.1mmol)，BBr 3(1M，2mL)加入二氯甲烷(5mL)中，在室温下反应1小时，加水淬灭，二氯甲烷萃取，减压浓缩，粗品用快速层析柱分离纯化，得目标化合物N-(2-(3-溴-7-羟基萘-1-基)-3-羟基丙基)乙酰胺(20mg，产率60％)。
MS m/z(ESI):338.1[M+H] +.
第六步:N-[2-[3-溴-7-(环丙氧基)-1-萘基]-3-羟基-丙基]乙酰胺
Figure PCTCN2021108795-appb-000167
将N-(2-(3-溴-7-羟基萘-1-基)-3-羟基丙基)乙酰胺(20mg，59μmol)，溴环丙烷(31.8mg，263.0μmol)，KI(1.1mg，6.57μmol)，Cs 2CO 3(42.7mg，131.5μmol)加入DMF(2mL)中，混合均匀后，在170℃下反应4小时，减压浓缩，粗品用Pre-HPLC分离纯化，得目标化合物N-[2-[3-溴-7-(环丙氧基)-1-萘基]-3-羟基-丙基]乙酰胺(4mg，产率16％)。
MS m/z(ESI):378.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.93-7.87(m,3H),7.50(d,J＝2Hz, 1H)7.35(dd,J＝8.8,2Hz,1H),4.82(brs,1H),4.03-4.01(m,1H),3.85-3.70(m,3H),3.52-3.49(m,1H),3.29-3.27(m,1H),1.81(s,3H),1.01-0.90(m,4H).
实施例61
N-(2-(3-氯-7-环丙氧基萘-1-基)-3-羟基丙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000168
N-(2-(3-氯-7-环丙氧基萘-1-基)-3-羟基丙基)乙酰胺的制备参考实施例14。
MS m/z(ESI):334.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.94-7.86(m,3H),7.49(d,J＝2Hz,1H)7.34(dd,J＝8.8,2Hz,1H),4.81(brs,1H),4.04-4.01(m,1H),3.84-3.71(m,3H),3.52-3.49(m,1H),3.29-3.27(m,1H),1.80(s,3H),1.01-0.89(m,4H).
实施例62
N-(2-(7-环丙氧基-3-甲基萘-1-基)-3-羟基丙基)乙酰胺的制备
Figure PCTCN2021108795-appb-000169
N-(2-(7-环丙氧基-3-甲基萘-1-基)-3-羟基丙基)乙酰胺的制备参考实施例36。
MS m/z(ESI):314.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.83-7.78(m,2H),7.54(s,1H),7.25-7.22(m,2H),4.81(brs,1H),4.04-4.01(m,1H),3.84-3.71(m,3H),3.52-3.49(m,1H),3.29-3.27(m,1H),2.40(s,3H),1.80(s,3H),1.01-0.89(m,4H).
其他化合物信息如下表1：
表1化合物信息
Figure PCTCN2021108795-appb-000170
Figure PCTCN2021108795-appb-000171
Figure PCTCN2021108795-appb-000172
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
一、细胞功能实验
测试例1、本发明化合物在稳定表达MT1/MT2受体细胞对钙流影响的测定
1.实验目的：
检测化合物对HEK293-MT1/HEK293-MT2细胞活性的激动作用。
2.实验仪器和试剂：
2.1仪器：
384孔-试验板(Corning：3764)；
384孔-Echo化合物板(Labcyte：LP-0200)；
384孔-化合物板(PE：6008590)；
Bravo Tip(Agilent：10734-202)；
FLIPR Tip(Molecular Device：9000-0764)；
读板仪FLIPR Tetra(Molecular Device)；
移液工作站Bravo(Agilent)和ECHO 550(LABCYTE)；
液体加样器Multidrop Combi(ThermoFisher)。
2.2试剂：
DMEM,high glucose(Gibco：12100)；
胎牛血清(Biosera：FB-1058/500)；
P/S(Biosera：XC-A4122)；
5X Matrigel(Corning：354230)；
HBSS(Sigma：H1387)；
HEPES(Invitrogen：15630080)；
Fluo-8 AM(AAT Bioquest：21080)；
Probenecid(Sigma：P8761)；
Pluronic F-127(Sigma：P2443-250G)；
1000X Fluo-8 AM(2mM)：Fluo-8 AM溶于DMSO，振荡1-2min，分装后于-20℃保存；
完全培养基：DMEM+10％FBS+1X P/S；
细胞接种培养基：DMEM+10％FBS+1X PS；
实验缓冲液1：1X HBSS+20mM HEPES+1mM Probenecid+0.025％Pluronic F-127；
实验缓冲液2：1X HBSS+20mM HEPES+0.075％Pluronic F-127；1X Matrigel：用DMEM稀释5X Matrigel；
细胞株：
HDB HEK293-MT1；
HDB HEK293-MT2。
3.实验方法：
1)HEK293-MT1/HEK293-MT2细胞株培养于完全培养基中，37℃5％CO 2至70％～90％融合度。
2)用1X Matrigel包被384孔-细胞板，每孔包被5uL，室温10-30分钟。
3)将细胞消化处理重悬于细胞接种培养基中，接种8,000个细胞/孔/20μL至384孔-细胞培养板中，于37℃5％CO 2培养24小时。
4)将细胞培养板从CO2培养箱取出，于室温平衡10分钟。
5)取出1000X Fluo-8 AM，用平衡至室温的实验缓冲液1稀释成1X Fluo-8 AM，浓度2μM。
6)去除细胞培养板的培养基，每孔加入20μL 1X Fluo-8 AM，室温300rpm离心60秒后，于室温避光孵育1小时。
7)配制阳性对照化合物和待测化合物工作液(3X)：
①用仪器Bravo在384孔-Echo化合物板(LABCYTE：LP-0200)上稀释化合物11个浓度点；
②然后用仪器ECHO转移每孔90nL化合物(化合物储存浓度,比如最高浓度点10mM)至384孔-化合物板(PE：6008590)；
③用Multidrop Combi加入30μL实验缓冲液2至384孔-化合物板(PE：6008590)，将阳性对照化合物和待测化合物稀释至30μM(3X)，置于室温待用。
8)用FLIPR Tetra将10μL稀释的3X化合物加入相应384-孔细胞板的实验孔中，同时读取收集数据。
4.实验数据处理方法：
FLIPR Tetra读取收集荧光信号值(RFU)，取最大RFU值，根据Low control(DMSO对照物)和High control(100nM阳性化合物)实验组的读值，计算百分比激活的数据{％激活率＝(RFUsample-RFUlow control)/(RFUhigh control- RFUlow control)×100}，待测化合物的浓度经过反应体系稀释3倍后的11个浓度为10μM至0.17nM，使用XLFit拟合百分比激活率和11个点浓度数据至参数非线性逻辑公式计算出化合物的EC 50值。
5.实验结果：
表2化合物对HEK293-MT1/HEK293-MT2细胞的EC 50值
Figure PCTCN2021108795-appb-000173
注：“NA”表示未检测。
6.实验结论：
本发明所示的实施例化合物在稳定表达MT1和MT2受体细胞对钙流影响实验中显示出良好的激动活性。
测试例2、本发明化合物在稳定表达5-HT 2C受体细胞对钙流影响的测定
1.实验目的：
检测化合物对HEK293-5HT 2C细胞活性的拮抗作用。
2.实验仪器和试剂：
2.1仪器：
384孔-试验板(Corning：3764)；
384孔-Echo化合物板(Labcyte：LP-0200)；
384孔-化合物板(PE：6008590)；
Bravo Tip(Agilent：10734-202)；
FLIPR Tip(Molecular Device：9000-0764)；
读板仪FLIPR Tetra(Molecular Device)；
移液工作站Bravo(Agilent)和ECHO 550(LABCYTE)；
液体加样器Multidrop Combi(ThermoFisher)。
2.2试剂：
DMEM,high glucose(Gibco：12100)；
胎牛血清(Biosera：FB-1058/500)；
P/S(Biosera：XC-A4122)；
5X Matrigel(Corning：354230)；
HBSS(Sigma：H1387)；
HEPES(Invitrogen：15630080)；
Fluo-8 AM(AAT Bioquest：21080)；
Probenecid(Sigma：P8761)；
Pluronic F-127(Sigma：P2443-250G)
1000X Fluo-8 AM(2mM)：Fluo-8 AM溶于DMSO，振荡1-2min，分装后于-20℃保存；
完全培养基：DMEM+10％FBS+1X P/S；
细胞接种培养基：DMEM+10％FBS+1X PS；
换液培养基：DMEM+1X P/S；
实验缓冲液1：1X HBSS+20mM HEPES+1mM Probenecid+0.025％Pluronic F-127；
实验缓冲液2：1X HBSS+20mM HEPES+0.075％Pluronic F-127；1X Matrigel：用DMEM稀释5X Matrigel；
细胞株：HDB HEK293-5HT 2C。
3.实验方法：
1)HEK293-5HT 2C细胞株培养于完全培养基中，37℃，5％CO 2至70％～90％融合度。
2)用1X Matrigel包被384孔-细胞板，每孔包被5μL，室温10-30分钟。
3)将细胞消化处理重悬于细胞接种培养基中，接种8,000个细胞/孔/20μL至384孔-细胞培养板中，于37℃5％CO 2培养24小时。
4)显微镜下观察，细胞已贴壁。去除接种培养基，每孔加入20μL预热至37℃的无血清的换液培养基，于37℃5％CO 2培养过夜(18小时)。
5)将细胞培养板从CO 2培养箱取出，于室温平衡10分钟。
6)取出1000X Fluo-8 AM，用平衡至室温的实验缓冲液1稀释成1X Fluo-8 AM，浓度2μM。
7)去除细胞培养板的培养基，每孔加入20μL 1X Fluo-8 AM，室温300rpm离心60秒后，于室温避光孵育1小时。
8)配制阳性对照化合物和待测化合物工作液(3X)：
①用仪器Bravo在384孔-Echo化合物板(LABCYTE：LP-0200)上稀释化合物11个浓度点；
②然后用仪器ECHO转移每孔90nL化合物(化合物储存浓度，比如最高浓度点10mM)至384孔-化合物板(PE：6008590)；
③用Multidrop Combi加入30μL实验缓冲液2至384孔-化合物板(PE：6008590)，将阳性对照化合物和待测化合物稀释至30μM(3X)，置于室温待用。
9)用FLIPR Tetra将10μL稀释的3X化合物加入相应384-孔细胞板的实验孔中，同时读取收集数据。
4.实验数据处理方法：
FLIPR Tetra读取收集荧光信号值(RFU)，取最大RFU值，根据Low control(DMSO对照物)和High control(100nM阳性化合物)实验组的读值，计算百分比激活的数据{％激活率＝(RFUsample-RFUlow control)/(RFUhigh control-RFUlow control)×100}，待测化合物的浓度经过反应体系稀释3倍后的11个浓度为10μM至0.17nM，使用XLFit拟合百分比激活率和11个点浓度数据至参数非线性逻辑公式计算出化合物的IC 50值。
5.实验结果：
表3化合物对HEK293-5HT 2C细胞的IC 50值
Figure PCTCN2021108795-appb-000174
6.实验结论：
本发明所示的实施例化合物在稳定表达5HT 2C受体细胞对钙流影响实验中显示出一定的拮抗作用。
测试例3、大鼠药代动力学测定
3.1.研究目的：
以SD大鼠为受试动物，研究本发明化合物在静脉和口服给药在大鼠体内(血浆)的药代动力学行为。
3.2.试验方案
3.2.1试验药品：
本发明实施例化合物，自制。
3.2.2试验动物：
SD大鼠每组3只，雄性。上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006N0.311620400001794)。
3.2.3药物配制：
静脉给药药物配制：(5％DMSO+10％Solutol HS15+85％PBS配制方法)
称取实施例化合物，先加入5％DMSO，涡旋、超声2min，使其完全溶解，再加入10％Solutol HS15，涡旋、超声2min，使其完全溶解，最后加入85％PBS，涡旋、超声5min得到无色透明澄清溶液，浓度为0.2mg/mL。
口服给药药物配制：(0.5％CMC-Na(1％吐温80))
称取5g羧甲基纤维素钠(CMC-Na，粘度：800-1200Cps)，溶于1000mL纯净水，加入10g Tween80。混合搅拌均匀成澄清溶液。
称取实施例化合物，溶于该溶液中，摇匀，超声15分钟，得到无色澄清溶液，浓度为0.5mg/mL。
3.2.4给药：
静脉给药:
SD大鼠每组3只，雄性，禁食一夜后分别IV，剂量为1mg/kg，给药体积5mL/kg。
口服给药:
SD大鼠每组3只，雄性，禁食一夜后分别PO，剂量为5mg/kg，给药体积10mL/kg。
3.2.5样品采集：
静脉给药:
于给药前和给药后0h，0.083h，0.25h，0.5h，1.0h，2.0h，4.0h颈静脉采血0.2mL，置于EDTA-2K试管中，4℃6000rpm离心6min分离血浆，于-80℃保存；给药后4h进食。
口服给药:
于给药前和给药后0.25h，0.5h，1.0h，2.0h，4.0h颈静脉采血0.2mL，置于EDTA-2K试管中，4℃6000rpm离心6min分离血浆，于-80℃保存；给药后4h进食。
3.3实验结果：
应用LCMS/MS方法得到最后测定结果，见表4和表5
表4：本发明化合物的大鼠静脉给药药代动力学参数
Figure PCTCN2021108795-appb-000175
表5：本发明化合物的大鼠口服给药药代动力学参数
Figure PCTCN2021108795-appb-000176
3.4实验结论：
表中数据显示，在口服给药剂量为5mg/kg时，本发明实施例化合物在大鼠血浆中的暴露量和生物利用度良好。
测试例4、CYP酶表型鉴定实验
4.1实验目的
采用CYPs重组酶孵育体系，根据不同亚型CYPs重组酶对化合物的代谢情况，初步判断化合物在人体内代谢过程中的主要代谢酶。
4.2实验步骤
4.2.1溶液配制：
10.0mM NADPH，称重16.7mg NADPH(还原型烟酰胺腺嘌呤二核苷酸磷酸)加100mM磷酸缓冲液至2mL。用100mM磷酸缓冲液，将各CYPs重组酶稀释至12.5pmol/L，混匀。
待测化合物反应液的配制：
称取待测实施例化合物，用DMSO稀释至10mM,再用100mM磷酸缓冲液稀释至10μM。
4.2.2实验流程：
1.在96孔板中，加入400μL重组酶、50μL待测化合物，预孵育10min。
2.加入NADPH 50μL。
3.在0,5,10,15,20和30min时分别取出50μL，加入200μL含有内标的乙腈终止液。
4.离心进样。
4.3实验结果：
表6：实施例化合物CYP酶表型鉴定结果
Figure PCTCN2021108795-appb-000177
Figure PCTCN2021108795-appb-000178
4.4实验结论：
以上数据显示，本发明实施例化合物对CYP1A2的代谢依赖性降低，其他CYP酶亚型对本实施例化合物的代谢比例增加，可以降低化合物的变异性。
测试例5、CYP酶单点抑制试验
5.1实验目的
采用人肝微粒体孵育体系，利用单点法快速预测化合物对CYP450酶亚型的抑制情况。
5.2实验步骤
5.2.1溶液配制：
2.5mM NADPH，称重4.165mg NADPH(还原型烟酰胺腺嘌呤二核苷酸磷酸)加100mM磷酸缓冲液至2mL。0.25mg/mL微粒体，50μL 20mg/mL微粒体，加4mL 100mM磷酸缓冲液，混匀。
待测化合物反应液的配制：
称取待测实施例化合物，用DMSO稀释至10mM,再用100mM磷酸缓冲液稀释至100μM。
5.2.2实验流程：
1.在96孔板中，加入40μL肝微粒体、10μL底物、10μL待测化合物，预孵育3min。
2.加入NADPH 40μL。
3.在20min时加入300μL含有内标的乙腈终止液。
4.离心进样。
5.3实验结果：
表7：实施例化合物CYP酶单点抑制结果
Figure PCTCN2021108795-appb-000179
注：
强抑制：IC 50<1μM；中等抑制：1μM<IC 50<10μM；弱抑制：IC 50>10μM
5.4实验结论：
以上数据显示，本发明实施例化合物对CYP1A2有强抑制，对其他CYP酶亚型没有强抑制，DDI(药物相互作用)风险小。
测试例6、血浆蛋白结合率实验
6.1实验目的：
本实验方法的目的是检测实施例化合物在血浆中的血浆蛋白结合情况。
6.2实验仪器及材料：
液相质谱联用仪、离心机、涡旋仪、移液枪、连续加液器、96孔板、组织匀浆机(组织样品分析时使用)、50％的甲醇水溶液，加入内标的乙腈溶液、空白基质(血浆、尿液或组织匀浆液等)。
6.3实验步骤：
6.3.1待测物储备液的配制A
用DMSO将实施例化合物配制成1mM溶液A.
6.3.2血浆溶液的配制B
取溶液A加入到血浆溶液中,配制成5uM溶液B.
6.3.3处理流程
1)在膜内加入200uL溶液B.
2)在膜外加入350uLPBS.
3)在37℃水浴锅内孵育6h.
4)样品进行处理稀释并进质谱检测.
6.4色谱条件：
仪器：岛津LC-20AD；
色谱柱：Phenomenex
Figure PCTCN2021108795-appb-000180
C18(50*4.6mm，5μm粒径)；
流动相：A：乙腈，B:0.1％甲酸溶液，0～0.5min：5％A→90％A，2.0～2.1min：90％A→5％A；流速：0.8mL/min；运行时间：5.0min；进样体积：5μL。
6.5质谱条件：
仪器:API4000型液相色谱质谱联用仪，美国AB公司；
离子源为电喷雾离子化源(ESI)；
干燥气体(N 2)温度500℃；
电喷雾电压为5500V；
检测方式为正离子检测；
扫描方式为选择反应监测(MRM)方式；扫描时间为0.1s。
6.6实验结果：
表8：实施例化合物血浆蛋白结合率(％)
编号 人 大鼠 小鼠 犬
实施例2A 93.6 89.6 93.5 98.6
实施例14 99.9 99.4 / /
实施例15 100.0 99.7 / /
实施例56 97.6 97.1 94.8 99.2
6.7实验结论：
本发明实施例化合物显示出高血浆蛋白结合率，种属差异小。
测试例7.大鼠习得性无助和糖水偏好模型中的药效评价
7.1实验目的：
本实验的目的是评估待测化合物在SD大鼠习得性无助(LH模型)和糖水偏好模型中的抗抑郁作用。
7.2实验动物：
SD大鼠，雄性，7-8周龄，136只。
7.3实验仪器：
表9.实验主要仪器
Figure PCTCN2021108795-appb-000181
7.4实验方法过程：
7.4.1.适应
136只SD雄性大鼠到达实验设施后，在设施内适应一周后开始实验，在开始训练前在实验房间适应2天。
7.4.2.训练
动物放入穿梭箱中，动物被限制在穿梭箱的一侧，足底接受60次电流强度为0.8mA，持续时间为15秒的电流，每次电击开始前会有2秒的声音刺激，两次之间的间隔时间为20秒。
7.4.3.筛选
动物放入穿梭箱后，穿梭门打开，动物可以在箱体内自由穿梭，足底接受30次强度为0.6mA，持续时间为10秒的电流(如果动物在电流持续期间逃至另一侧，则电击停止)，每次电击开始前会有2秒的声音和光照刺激，两次之间的 间隔时间为20秒，记录：
主动逃避次数：声音和光照刺激下，主动逃避至非电击一侧
被动逃避次数：声音和光照刺激结束后，电击持续过程中逃至非电击一侧
逃避失败次数：电击结束后仍不逃避
逃避失败次数在20次以上的动物被认为是习得性无助，可用于药物筛选
7.4.4.分组
动物习得性无助筛选结束后立即进行分组，筛选出的习得性无助的动物根据逃避失败次数随机分组，用于化合物筛选测试。
7.4.5.给药
对照组和化合物组分组完毕后进行第一次给药，连续给药七天，给药体积为10mL/kg。阳性化合物(丙咪嗪组)从第一次习得性无助测试开始前进行给药，连续给药四天，给药体积为2mL/kg。
7.4.6.测试
7.4.6.1习得性无助测试(LH模型)
化合物给药第2天和第5天(阳性化合物给药第1天和第4天)进行习得性无助测试，阳性化合物给药0.5小时，待测化合物给药0.25或0.5小时后，对大鼠进行电击逃避测试，大鼠逃避失败和穿梭的次数将被记录用于分析。
实验结果：
表10：实施例化合物LH实验大鼠逃避失败次数和穿梭次数
编号 逃避失败次数 穿梭次数
Vehicle 24.2 5.8
丙米嗪(64mg/kg) 10.7 19.9
实施例2A(20mg/kg) 19.9 10.5
实施例2A(50mg/kg) 20.0 10.2
实施例56(20mg/kg) 24.8 5.2
实施例56(50mg/kg) 26.5 3.6
实验结论：
LH模型中，实施例化合物具有降低大鼠逃避失败率的趋势。
7.4.6.2糖水偏好测试
化合物给药第4天后，动物给予两瓶普通水适应；
化合物给药第5天，习得性无助测试结束后，其中一瓶普通水更换为1％糖 水，24小时内更换6次位置；
化合物第6天给药结束后，禁食禁水；
化合物第7天给药结束后1小时，添加一瓶糖水和一瓶普通水，并测试1，12和24小时的耗水量。
糖水偏好率＝糖水摄入量/(普通水摄入量+糖水摄入量)*100％
数据收集和分析:
使用Excel软件收集数据。使用Prism(GraphPad software,Inc.)软件进行数据分析，使用单因素方差分析(One-way ANOVA)附加Fisher’s LSD多重比较检验数据。p<0.05认为是有显著性差异。
实验结果：
表11：实施例化合物蔗糖嗜好实验12h和24h大鼠糖水偏好
编号 12h糖水偏好(％) 24h糖水偏好(％)
Vehicle 64.0 63.0
阿戈美拉汀(20mg/kg) 65.3 66.4
实施例2A(20mg/kg) 84.0 84.9**
实施例56(20mg/kg) 78.3 83.1*
注：*p<0.05；**p<0.01
实验结论：
在糖水偏好实验中，与vehicle组比，待测化合物能够显著增加大鼠12h和24h的糖水偏好率，实验中未发现明显副作用。

Claims (17)

  1. 通式(I)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2021108795-appb-100001
    其中：
    M 1为N或CR 1；
    M 2为N或CR 2；
    M 3为N或CR 3；
    Figure PCTCN2021108795-appb-100002
    选自
    Figure PCTCN2021108795-appb-100003
    Figure PCTCN2021108795-appb-100004
    R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；
    R选自氢、氘、卤素、氨基、硝基、羟基、氰基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选可以进一步被取代；
    R 4、R 5和R 6各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；
    R 7选自氢、氘、卤素、氨基、硝基、羟基、氰基、氧代基、硫代基、羧基、 烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选可以进一步被取代；
    R 8、R 8’、R 9和R 9’各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；
    或者，R 8、R 8’、R 9、R 9’中任意两个以及它们连接的碳原子形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选的可以进一步被取代。
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(II)所示：
    Figure PCTCN2021108795-appb-100005
    其中：
    R选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
    R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、 C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
    R 4、R 5和R 6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
    R 7选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
    R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
    或者，R 8和R 8’与它们所连接的碳原子一起形成一个C 3-12环烷基或3-12元杂环基，所述的C 3-12环烷基或3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代。
  3. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(II-A)所示：
    Figure PCTCN2021108795-appb-100006
    其中：
    M 1为N或CR 1，优选N或CH；
    R选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    R 9和R 9’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    或者，R 9和R 9’一起可形成氧代基或硫代基；
    或者，R 9和R 9’与它们所连接的碳原子一起形成C 3-12环烷基或3-12元杂环基，所述的C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14 芳基和5-14元杂芳基中的一个或多个取代基所取代。
  4. 根据权利要求1～3任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-12环烷基和3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    优选C 1-6烷基、C 1-6氘代烷基、C 3-8环烷基或3-8元杂环基，所述的C 1-6烷基、C 1-6氘代烷基、C 3-8环烷基或3-8元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-8环烷基或3-8元杂环基中的一个或多个取代基所取代；
    更优选甲基、氘代甲基、异丙基、叔丁基、叔戊基、3-戊基、环丙基或氧杂环丁烷基，所述的甲基、异丙基、叔丁基、叔戊基、3-戊基、环丙基或氧杂环丁烷基，进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基中的一个或多个取代基所取代。
  5. 根据权利要求1～3任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R 1、R 2和R 3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；
    优选氢、氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基；
    更优选氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基或叔丁基。
  6. 根据权利要求1～3任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R 4、R 5和R 6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；
    优选氢、氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟 烷基、C 3-8环烷基或3-8元杂环基；
    更优选氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基或叔丁基。
  7. 根据权利要求1～3任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R 7选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；
    优选C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基；
    更优选甲基、乙基、丙基、异丙基、叔丁基、环丙基或三氟甲基。
  8. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(III)所示：
    Figure PCTCN2021108795-appb-100007
    其中：
    M 3为N或CR 3；
    R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；优选氢、氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基；更优选氢、氘、氟、氯、溴、甲基、乙基、丙基、异丙基、叔丁基或甲氧基；
    R 3选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6羟烷基；优选氢；
    R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；优选氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基；更优选氢、氘、氟、氯、溴、甲基或乙基；
    或者，R 8和R 8’链接形成一个C 3-12环烷基或3-12元杂环基，所述的C 3-12环 烷基或3-12元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；优选形成C 3-12环烷基；
    当M 3为CH，R 8和R 8’为氢时，R 2不为氢。
  9. 根据权利要求1、2或8所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R 8和R 8’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基或3-12元杂环基；
    优选氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、氰基取代的C 1-3烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基；
    更优选氢、氘、氟、氯、溴、甲基或乙基；
    或者，R 8、R 8’和它们所连接的碳原子形成C 3-8环烷基或3-8元杂环基，任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基中的一个或多个取代基所取代。
  10. 根据权利要求3所述的化合物其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(IV-A)所示：
    Figure PCTCN2021108795-appb-100008
    R选自C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、氰基取代的C 1-3烷基或C 3-6环烷基；
    优选甲基、氘代甲基或环丙基。
  11. 根据权利要求3所述的化合物其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(IV-B)所示：
    Figure PCTCN2021108795-appb-100009
    R 2或R 3独立地选自氘、卤素、氰基或C 1-3烷基，优选氘、氟、氯、溴或甲基；
    n为1、2或3。
  12. 根据权利要求1～11任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物的具体结构如下：
    Figure PCTCN2021108795-appb-100010
    Figure PCTCN2021108795-appb-100011
    Figure PCTCN2021108795-appb-100012
  13. 制备权利要求10所述的化合物、其立体异构体或其药学上可接受的盐地方法，包括如下步骤：
    Figure PCTCN2021108795-appb-100013
    式(V-A)化合物在碱存在下与R-X反应得到通式(IV-A)化合物，
    其中：
    X为溴或碘；
    R如权利要求10所定义；
    或者，制备权利要求11所述的化合物、其立体异构体或其药学上可接受的盐地方法，包括如下步骤：
    Figure PCTCN2021108795-appb-100014
    通式(V-B)化合物在碱存在下与
    Figure PCTCN2021108795-appb-100015
    反应得到通式(IV-B)化合物，其中：
    X为溴或碘；
    R 2、R 3和n如权利要求11所定义。
  14. 一种药物组合物，其包括治疗有效剂量的权利要求1～12任一项所述的 化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
  15. 根据权利要求1～12任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求14所述的药物组合物在制备褪黑素受体激动剂药物中的用途。
  16. 根据权利要求1～12任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求14所述的药物组合物在制备MT1和MT2受体激动剂以及5-HT 2C受体拮抗剂药物中的用途。
  17. 根据权利要求1～12任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求14所述的药物组合物在制备治疗或预防心血管疾病、消化系统疾病、中枢神经系统疾病和/或精神疾病药物中的用途；优选地，所述中枢神经系统疾病和/或精神疾病选自褪黑素系统疾病、紧张、焦虑症、季节性情感障碍、精神分裂症、恐惧症、抑郁症、重度抑郁症、睡眠障碍、睡眠失调、飞行时差引起的失眠或疲劳、体重失调、心境障碍、精神分裂症谱系障碍、痉挛性障碍、记忆障碍和/或认知障碍、运动障碍、人格障碍、自闭症谱系障碍、疼痛、外伤性脑损伤、物质滥用障碍和/或戒断综合征、耳鸣、自闭症、阿尔兹海默症、癫痫发作、神经痛或戒毒症状重度抑郁症或狂躁症疾病。
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