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WO2025168125A1 - Agoniste du récepteur 5-ht2a de la sérotonine, son procédé de préparation et son utilisation - Google Patents

Agoniste du récepteur 5-ht2a de la sérotonine, son procédé de préparation et son utilisation

Info

Publication number
WO2025168125A1
WO2025168125A1 PCT/CN2025/076535 CN2025076535W WO2025168125A1 WO 2025168125 A1 WO2025168125 A1 WO 2025168125A1 CN 2025076535 W CN2025076535 W CN 2025076535W WO 2025168125 A1 WO2025168125 A1 WO 2025168125A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
hydrogen
straight chain
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/076535
Other languages
English (en)
Chinese (zh)
Inventor
程建军
汪胜
张金凤
唐凌杰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
Original Assignee
ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ShanghaiTech University, Center for Excellence in Molecular Cell Science of CAS filed Critical ShanghaiTech University
Publication of WO2025168125A1 publication Critical patent/WO2025168125A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P25/24—Antidepressants
    • 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
    • C07D215/16—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/12—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00

Definitions

  • SSRIs selective serotonin reuptake inhibitors
  • tricyclic antidepressants monoamine oxidase inhibitors
  • monoamine oxidase inhibitors etc.
  • SSRIs are widely used in clinical practice and include sertraline, citalopram, escitalopram, fluoxetine, paroxetine, vilazodone, and vortioxetine.
  • SSRIs are believed to work by inhibiting the reabsorption of the central neurotransmitter serotonin and increasing the concentration of serotonin in the synaptic cleft.
  • D is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N;
  • the C1-6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.
  • the halogen is independently fluorine, chlorine, bromine or iodine.
  • the C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C 1-6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • each “plurality” is independently 2, 3, 4 or 5, for example 2 or 3.
  • A is CH or N.
  • B is CH or N.
  • T is CR a .
  • D is a carbon atom or CH.
  • D is N.
  • n 1 or 2.
  • Ra is hydrogen or C1-6 alkoxy, such as hydrogen.
  • R b is hydrogen
  • X and Y are CH 2 .
  • Z is a single bond, a C 1-4 straight chain alkylene group or a C 2-4 straight chain alkenylene group.
  • Z is a single bond, a C 3-4 straight chain alkylene group or a C 2-4 straight chain alkenylene group.
  • Z is a C 3-4 straight chain alkylene group.
  • R b is C 1-6 alkyl; for example
  • the carbon atom marked with “*” is a chiral carbon atom, and its configuration is R configuration or S configuration; for example The carbon atom marked with “*” is a chiral carbon atom, and its configuration is R configuration or S configuration.
  • a and B are independently CH or N, T is CR a or N;
  • D is a carbon atom or CH
  • X and Y are O or CH 2 ;
  • R a is independently hydrogen or C 1-6 alkoxy
  • D is N
  • R d is hydrogen
  • Z is a C 3-4 straight chain alkylene group.
  • n 1, 2, or 3;
  • R b is hydrogen or C 1-6 alkyl
  • D is N
  • n 1 or 2;
  • n 1, 2, or 3;
  • R b is hydrogen or C 1-6 alkyl
  • R d is hydrogen
  • Z is a C 3-4 straight chain alkylene group or a C 2-4 straight chain alkenylene group.
  • D is a double bond or a single bond; When it is a double bond, D is a carbon atom; When it is a single bond, D is CH or N;
  • X and Y are independently O or CH 2 ;
  • n 1 or 2;
  • n 1, 2, or 3;
  • R a is hydrogen or C 1-6 alkyl
  • the carbon atom marked with "*" is a chiral carbon atom, and its configuration is R configuration.
  • the present invention provides a cyclic compound or a pharmaceutically acceptable salt thereof, wherein the cyclic compound is any one of the following compounds:
  • the annular compound is any one of the following compounds:
  • the present invention provides a use of a substance A, the pharmaceutical composition, a compound F, or a pharmaceutically acceptable salt thereof, in the preparation of a 5- HT2A receptor agonist.
  • the substance A is a compound represented by formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a cyclic compound as described above, or a pharmaceutically acceptable salt thereof; and the compound F is selected from any one of the following compounds:
  • the present invention provides a use of a substance A, the pharmaceutical composition, the compound F, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and/or preventing a disease associated with the 5-HT 2A receptor.
  • the substance A is a compound of Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a paracyclic compound as described above, or a pharmaceutically acceptable salt thereof.
  • the disease associated with the 5-HT 2A receptor may be a central nervous system disease, such as depression.
  • the present invention provides a use of a substance A, the pharmaceutical composition, the compound F, or a pharmaceutically acceptable salt thereof, in the preparation of a 5-HT 2A receptor agonist and/or a 5-HT 2B receptor antagonist.
  • the substance A is a compound of formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or the aforementioned cyclic compound or a pharmaceutically acceptable salt thereof.
  • the present invention provides a substance A for use as a treatment or medicine, the pharmaceutical composition, the compound F, or a pharmaceutically acceptable salt thereof, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or a cyclic compound as described above, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F or a pharmaceutically acceptable salt thereof for treating and/or preventing a central nervous system disease, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof or the aforementioned cyclic compound, a pharmaceutically acceptable salt thereof, and the central nervous system disease may be depression.
  • the present invention provides a method for treating and/or preventing a central nervous system disease, comprising administering to a subject a therapeutically effective amount of substance A, the above-mentioned pharmaceutical composition, the above-mentioned compound F, or a pharmaceutically acceptable salt thereof, wherein the substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, the aforementioned cyclic compound, or a pharmaceutically acceptable salt thereof, and the central nervous system disease may be depression.
  • the method 1 comprises the following steps: in an organic solvent, in the presence of a deprotection agent, subjecting the compound represented by formula II to a deprotection reaction as shown in the following formula to obtain a compound represented by formula I:
  • Rh is an amino protecting group
  • Rd is H.
  • the method 2 comprises the following steps: in an organic solvent, in the presence of a base and a catalyst, reacting a compound represented by formula III-1 with a compound represented by formula III-2 to obtain a compound represented by formula I.
  • A, B, T , X, Y, Z, n, m, Ra and Rb are as defined in any embodiment of the present invention; Re is halogen, Rd is C1-6 alkyl; and D is N.
  • the organic solvent is 1,4-dioxane or dichloromethane.
  • the deprotection reagent is hydrochloric acid or trifluoroacetic acid.
  • the organic solvent is 1,4-dioxane.
  • the catalyst is Pd 2 (dba) 3 .
  • A, B, T, D, X, Y, Z, n, m and R b are as defined in any embodiment of the present invention; R h is an amino protecting group.
  • the compound represented by formula II is any one of the following compounds:
  • A, B, T, X, Y, Z, n, m, R b , Re and R h are as defined in any embodiment of the present invention; is a double bond or a single bond; D is C or H;
  • A, B, T, X, Y, Z, n, m, R b , Re and R h are as defined in any embodiment of the present invention; is a single bond; D is N.
  • the method I further comprises the following post-treatment step after the reaction is completed: hydrogenating the product obtained in the method 1 in a solvent in the presence of a catalyst (e.g., 10% palladium carbon) and a hydrogen source (e.g., hydrogen gas).
  • a catalyst e.g., 10% palladium carbon
  • a hydrogen source e.g., hydrogen gas
  • the term “multiple” in the phrase “satisfies one or more of the following conditions” refers to 2, 3, 4, or more conditions.
  • the maximum value of “more” is the maximum number of conditions recited in each claim.
  • the term “one or more” in the phrase “satisfies one or more of the following conditions” in that claim can be any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7, or 8.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkoxy refers to a group -ORX , wherein RX is an alkyl group as defined above.
  • alkenylene refers to a substituent formed by eliminating two hydrogen atoms from a straight-chain or branched alkene having a specific number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds.
  • the carbon-carbon double bond can be located at any position within the alkenylene, and the two eliminated hydrogen atoms can be on the same carbon atom or on different carbon atoms (for example, the two eliminated hydrogen atoms are on carbon atoms at the two ends).
  • pharmaceutical excipients refers to excipients and additives used in the production of medicines and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations in addition to the active ingredients.
  • treatment refers to therapeutic treatment.
  • treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • subject refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.
  • the reagents and raw materials used in the present invention are commercially available.
  • a positive and advantageous effect of the present invention is that the compounds of the present invention can be used to treat and/or prevent diseases associated with the 5-HT 2A receptor, such as depression.
  • Step 1 Preparation of tert-butyl 3-(5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate ZJF-07-115)
  • Step 1 Preparation of tert-butyl 5-(5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-2-yl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate ZJF-07-125)
  • Step 2 Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctane[d]pyrimidin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-08-104)
  • Step 1 Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctane[d]pyrimidin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-107)
  • Step 1 Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrocyclooctan-2-ylpyrimidine)-1,4-diazacyclopentane-1-carboxylate (Intermediate ZJF-08-109)
  • Step 2 Preparation of 2-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctane pyrimidine (Compound I-20)
  • Step 2 Preparation of 3-(1,4-diazepan-1-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridazine (Compound I-22)
  • Step 3 Preparation of 2-chloro-5,6,7,8,9,10-hexahydrocyclooctane[b]pyridin-3-amine (Intermediate ZJF-08-017)
  • step 1 of Example 7 The compound A1 in step 1 of Example 7 was replaced by compound A5.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a colorless oily intermediate (ZJF-08-040) (50 mg, yield 29%).
  • step 1 of Example 4 The compound A1 in step 1 of Example 4 was replaced by compound A5.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 4 to obtain a colorless oily intermediate (ZJF-08-042) (166 mg, yield 83%).
  • step 2 of Example 4 The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-042.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain a colorless oily intermediate (ZJF-08-043) (34 mg, yield 34%).
  • Step 3 Preparation of 3-methoxy-2-(piperidin-4-yl)-5,6,7,8,9,10-hexahydrocyclooctylpyridine (Compound I-27)
  • compound A6 was synthesized according to patent (CN112574183).
  • a solution of compound A6 (654 mg, 2.71 mmol) in DMF (24 mL) was treated with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (300 mg, 0.969 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (91 mg, 0.126 mmol), and then a solution of K2CO3 (670 mg, 4.84 mmol) in H2O (4 mL) was added. The mixture was stirred at 90°C for 2 hours.
  • reaction solution was diluted with water and extracted three times with ethyl acetate.
  • organic phases were combined and dried once over anhydrous Na2SO4 .
  • the solvent was evaporated under reduced pressure.
  • Step 2 Preparation of tert-butyl 4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperidine-1-carboxylate (Intermediate ZJF-08-077)
  • step 2 of Example 4 The intermediate ZJF-07-116 in step 2 of Example 4 was replaced with the intermediate ZJF-08-073.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 4 to obtain a colorless oily intermediate (ZJF-08-077) (72 mg, yield 71%).
  • step 2 of Example 1 The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-077.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a colorless oil (I-28) (22 mg, yield 44%).
  • Step 1 Preparation of (R,Z)-tert-butyl 4-(2,5-dihydrobenzo[b][1,4]dioxol-8-yl)-3-methylpiperazine-1-carboxylate (Intermediate ZJF-09-090)
  • step 1 of Example 29 The tert-butyl 1,4-diazepane-1-carboxylate in step 1 of Example 29 was replaced with tert-butyl (R)-3-methylpiperazine-1-carboxylate.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 29 to obtain a yellow oily intermediate (ZJF-09-090) (203 mg, yield 17%).
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-090.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-30) (30 mg, yield 52%).
  • Step 1 Preparation of (R)-tert-butyl 3-methyl-4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperazine-1-carboxylate (Intermediate ZJF-09-093)
  • step 2 of Example 2 The ZJF-07-115 in step 2 of Example 2 was replaced by ZJF-09-090.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 2 to obtain a colorless oily intermediate (ZJF-09-093) (110 mg, yield 73%).
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with the intermediate ZJF-09-093.
  • the remaining raw materials, reagents, and preparation method were the same as those in step 3 of Example 4 to obtain a yellow oil (I-31) (36 mg, yield 49%).
  • Step 1 Preparation of tert-butyl 4-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxol-8-yl)piperazine-1-carboxylate (Intermediate ZJF-09-096)
  • step 2 of Example 2 The ZJF-07-115 in step 2 of Example 2 was replaced by ZJF-09-012.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 2 to obtain a colorless oily intermediate (ZJF-09-096) (190 mg, yield 54%).
  • ZJF-08-097 The starting material, ZJF-08-097, was synthesized according to the literature (Zhang, Burgess et al., J. Med. Chem., 2008, 51, 3526–3539). ZJF-08-097 (558 mg, 2.65 mmol) was dissolved in a solution of TFA (4.53 g, 39.72 mmol) and triethylsilane (462 mg, 3.97 mmol). The mixture was stirred at 60°C overnight. The solvent was removed under vacuum. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and dried once over anhydrous Na2SO4 .
  • Step 2 Preparation of tert-butyl 4-(5,6,7,8,9,10-hexahydrobenzo[8]cyclopent-2-yl)piperazine-1-carboxylate (Intermediate ZJF-09-007)
  • Step 1 Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-142)
  • Compound A8 was synthesized by replacing the starting material cyclooctanone with cycloheptanone according to patent (WO2008083353).
  • step 1 of Example 7 Compound A1 was replaced with Compound A8, and tert-butyl 1,4-diazepane-1-carboxylate was replaced with tert-butyl piperazine-1-carboxylate.
  • the remaining raw materials, reagents, and preparation method were the same as those in step 1 of Example 7 to obtain the intermediate (ZJF-08-142) as a yellow oil (101 mg, 62% yield).
  • step 2 of Example 1 The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with the intermediate ZJF-08-142.
  • the remaining raw materials, reagents, and preparation method were the same as those in step 2 of Example 1 to obtain a yellow oil (I-34) (55 mg, yield 81%).
  • Step 1 Preparation of tert-butyl R-3-methyl-4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-09-083)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-083.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-35) (37 mg, yield 72%).
  • Example 35 by changing the corresponding starting materials, the compounds listed in Examples 36-38 can be prepared using the same method, as shown in Table 2 for details.
  • Step 1 Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)-1,4-diazepine-1-carboxylate (Intermediate ZJF-08-145)
  • step 1 of Example 7 The compound A1 in step 1 of Example 7 was replaced by compound A8.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a yellow oily intermediate (ZJF-08-145) (60 mg, yield 32%).
  • step 2 of Example 1 The intermediate ZJF-07-115 in step 2 of Example 1 was replaced with intermediate ZJF-08-145.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 2 of Example 1 to obtain a white solid (I-39) (40 mg, yield 94%).
  • Step 1 Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cycloheptane-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (Intermediate ZJF-08-147)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-147.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-40) (38 mg, yield 48%).
  • Step 1 Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cycloheptane-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (Intermediate ZJF-08-147) was carried out in the same manner as in Step 1 of Example 37.
  • Step 2 Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate ZJF-08-149)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-08-149.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow solid (I-41) (18 mg, yield 17%).
  • Step 1 Preparation of tert-butyl 4-(6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yl)piperazine-1-carboxylate (Intermediate LHQ-08-145)
  • step 1 of Example 7 The compound A1 in step 1 of Example 7 was replaced by compound A9, and tert-butyl 1,4-diazepane-1-carboxylate was replaced by tert-butyl piperazine-1-carboxylate.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 1 of Example 7 to obtain a yellow solid intermediate (LHQ-04-113) (187 mg, yield 51%).
  • Example 42 the compounds listed in Examples 43 and 44 can be prepared by changing the corresponding starting materials using the same method, as shown in Table 3 for details.
  • Step 1 Preparation of tert-butyl 4-(5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate (Intermediate ZJF-08-137)
  • the starting material, compound A10 is commercially available.
  • a stirred solution of compound A10 (108 mg, 0.509 mmol) in toluene (20 mL) at room temperature was purged with nitrogen for 30 minutes.
  • BINAP 63 mg, 0.102 mmol
  • Pd 2 (dba) 3 0.019 g, 0.020 mmol
  • sodium tert-butoxide 98 mg, 1.02 mmol
  • reaction solution was extracted with ethyl acetate.
  • organic phases were combined, dried once over anhydrous Na 2 SO 4 , and the solvent was evaporated under reduced pressure.
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with the intermediate ZJF-08-137.
  • the remaining raw materials, reagents, and preparation method were the same as those in step 3 of Example 4 to obtain a white solid (I-45) (41 mg, yield 69%).
  • Example 45 by changing the corresponding starting materials, the compounds listed in Examples 46-49 can be prepared using the same method, as shown in Table 4 for details.
  • Step 1 Preparation of tert-butyl 4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-042)
  • Step 1 Preparation of (S)-tert-butyl 2-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-048)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-048.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-51) (27 mg, yield 73%).
  • Step 1 Preparation of (R)-tert-butyl 2-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-050)
  • Step 1 Preparation of (R)-tert-butyl 3-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-086)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-086.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-53) (30 mg, yield 49%).
  • Step 1 Preparation of (S)-tert-butyl 3-methyl-4-(5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-126)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-126.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-54) (48 mg, yield 46%).
  • the starting material, Compound A11 is commercially available. Substitute Compound A12 for Compound A11 in Step 1 of Example 7, and replace tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods are the same as those in Step 1 of Example 7 to obtain the intermediate (ZJF-08-114) as a yellow oil (98 mg, 50% yield).
  • Step 1 Preparation of tert-butyl 4-(6,7-dihydro-5H-cyclopentyl[c]pyridin-3-yl)piperazine-1-carboxylate (Intermediate ZJF-09-141)
  • the starting material, compound A13 is commercially available. Substitute compound A13 for compound A1 in step 1 of Example 7, and replace tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl piperazine-1-carboxylate. The remaining raw materials, reagents, and preparation methods are the same as those in step 1 of Example 7 to obtain a yellow solid intermediate (ZJF-09-141) (102 mg, 52% yield).
  • Step 1 Preparation of (S)-tert-butyl 4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-2-methylpiperazine-1-carboxylate (Intermediate ZJF-09-034)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-034.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-63) (8 mg, yield 22%).
  • Step 1 Preparation of (R)-tert-butyl 4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-2-methylpiperazine-1-carboxylate (Intermediate ZJF-09-036)
  • step 3 of Example 4 The intermediate ZJF-07-120 in step 3 of Example 4 was replaced with intermediate ZJF-09-036.
  • the remaining raw materials, reagents and preparation methods were the same as those in step 3 of Example 4 to obtain a yellow oil (I-64) (57 mg, yield 31%).
  • the first step is to prepare cell membrane fractions containing specific 5- HT2A or 5- HT2B receptors.
  • a 10 cm dish filled with HEK-293T cells (ATCC, CRL-11268) was transfected with 10 ng of the 5- HT2A or 5- HT2B receptor plasmid and 40 ⁇ L of PEI. After 48 hours, the 10 cm dish containing cells expressing the 5- HT2A or 5- HT2B receptor was removed. The culture medium was removed using a vacuum pump, and 3 mL of lysis buffer was added to each well. The cells were placed in a 4°C refrigerator and allowed to stand for 10 minutes.
  • the cells After the cells detached, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm for 5 minutes at 4°C. The supernatant was discarded. The cell pellet was transferred to a tissue homogenizer, and 3 mL of lysis buffer was added. The cells were thoroughly ground until the cells were broken. The cell suspension was then aliquoted into EP tubes and centrifuged at 12000 rpm for 5 minutes at 4°C. The supernatant was discarded. The precipitate is the cell membrane fraction containing 5-HT 2A receptors or 5-HT 2B receptors.
  • ligand-receptor binding assays were performed on 293T membrane fractions transiently expressing 5- HT2A or 5- HT2B receptors.
  • standard binding buffer was added to the cell membrane fractions containing 5- HT2A or 5- HT2B receptors, and the cell membranes were disrupted and resuspended using an electric tissue homogenizer.
  • 30 ⁇ L of membrane protein suspension was added to each well of a 96-well plate.
  • 30 ⁇ L of different drugs were added to the 96-well plate from left to right, ensuring that the final drug concentrations from bottom to top were 10-5 M, 10-6 M, 10-7 M, 10-8 M, 10-9 M, and 0 M, respectively. Each treatment was repeated in duplicate.
  • the compounds of the present invention have a medium affinity for the 5-HT 2A receptor and a high affinity for the 5-HT 2B receptor.
  • Biological Test Example 2 Testing of the functional activity of the compounds of the present invention on 5-hydroxytryptamine receptors.
  • BRET method was used to determine the functional activity of compounds on 5-HT receptors: To detect the downstream G protein signaling pathway mediated by 5-HT 2A receptor, on the first day, 6 cm culture dishes filled with HEK-293T cells (ATCC, CRL-11268) were transfected with 1 ⁇ g 5-HT 2A receptor plasmid, 1 ⁇ g G ⁇ q containing C-terminal algal luciferase (G ⁇ q-Rluc), 1 ⁇ g G ⁇ 3, 1 ⁇ g G ⁇ 9 containing C-terminal green fluorescent protein (G ⁇ 9-GFP) and 16 ⁇ L PEI.
  • a 6-cm dish containing confluent HEK-293T cells was transfected with 500 ⁇ g of 5- HT2A or 5- HT2B receptor plasmids containing C-terminal algal luciferase (5- HT2A -Rluc or 5- HT2B- Rluc), 500 ⁇ g of G protein-coupled receptor kinase 2 (GRK2), 2500 ⁇ g of ⁇ -arrestin2 containing N-terminal green fluorescent protein (GFP2-ARRB2), and 14 ⁇ L of PEI on day 1.
  • 5- HT2A or 5- HT2B receptor plasmids containing C-terminal algal luciferase 5- HT2A -Rluc or 5- HT2B- Rluc
  • GRK2 G protein-coupled receptor kinase 2
  • GFP2-ARRB2 N-terminal green fluorescent protein
  • the former characterizes the degree of activation of the ⁇ -arrestin2 signaling pathway downstream of the 5-HT 2A receptor or 5-HT 2B receptor
  • the latter characterizes the degree of activation of the G protein signaling pathway downstream of the 5-HT 2A receptor.
  • the culture medium was removed from the 384-well plate, and 15 ⁇ L of the dye Fluo-4 (4 ⁇ M, Invitrogen) was added.
  • the cells were then incubated at 37°C in a 5% CO2 incubator for 1 h.
  • Drugs were dispensed in a drug buffer containing 2.5 mM probenecid (Sigma) to a 384-well plate.
  • the final concentrations of drug added to the plate were 10-4.5 M, 10-5 M, 10-5.5 M, 10-6 M, 10-6.5 M, 10-7 M, 10-7.5 M, 10-8 M, 10-8.5 M, 10-9 M, 10-9.5 M, 10-10 M, 10-10.5 M, 10-11 M , 10-11.5 M, and 0 M, with three replicates per treatment.
  • Drugs were added (7.5 ⁇ L per well) and the plate was read using a FLIPR Penta high -throughput real-time fluorescence detector. Fluorescence readings at 520 nm reflect the amount of intracellular calcium released upon Gq protein activation; an increase in readings indicates receptor activation.
  • the EC50 values for activation of the 5- HT2A receptor Gq protein by different compounds were calculated using the Graphpad Prism "log (agonist) vs. response -- Variable slope (four parameters)" formula. Following the completion of the assay, for compounds that did not exhibit agonist activity, 7.5 ⁇ L of serotonin (Sigma) was added to the wells, ensuring a final concentration of 10-9 M serotonin in all wells treated with the compound.
  • the plate was then read and the IC50 values for inhibition of the 5- HT2A and 5- HT2B receptor Gq proteins by different compounds were calculated using the Graphpad Prism "log (inhibitor) vs. response -- Variable slope ( four parameters)" formula.
  • Method (2) For male C57BL/6 mice (8 weeks old, purchased from Shanghai Lingchang Biotechnology Co., Ltd.), corticosterone was dissolved in the drinking water of mice at a concentration of 25 ⁇ g/mL. The corticosterone solution was administered to the mice using a drinking water bottle for 21 days. The mice were maintained in a 12-hour light cycle. Fresh drinking water containing corticosterone was replaced every other day for the first two weeks, and the amount was gradually halved every two days in the last week and replaced with normal drinking water without corticosterone.
  • mice After 21 days of corticosterone exposure, the mice were injected with 1 mg/kg of the compound every day for one week, and the antidepressant activity of the compound was tested by tail suspension test at two time periods, 7 days and 14 days later.
  • Tail suspension test The mice in the control group and the treatment group were respectively suspended by tape on their tails for 6 minutes, and the time was recorded by a camera. The final 4 minutes of immobility were manually timed and evaluated by an uninformed observer.
  • the compounds of the present invention have antidepressant effects.

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Abstract

L'invention concerne un agoniste du récepteur de la sérotonine 5-HT2A, son procédé de préparation et son utilisation. L'invention concerne un composé représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci. L'agoniste du récepteur de la sérotonine 5-HT2A selon l'invention peut être utilisé pour traiter et/ou prévenir des maladies associées à des récepteurs 5-HT2A, tels que la dépression.
PCT/CN2025/076535 2024-02-08 2025-02-08 Agoniste du récepteur 5-ht2a de la sérotonine, son procédé de préparation et son utilisation Pending WO2025168125A1 (fr)

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