[go: up one dir, main page]

WO2025232878A1 - Composé amine contenant un phényle substitué, son procédé de préparation et son utilisation - Google Patents

Composé amine contenant un phényle substitué, son procédé de préparation et son utilisation

Info

Publication number
WO2025232878A1
WO2025232878A1 PCT/CN2025/093780 CN2025093780W WO2025232878A1 WO 2025232878 A1 WO2025232878 A1 WO 2025232878A1 CN 2025093780 W CN2025093780 W CN 2025093780W WO 2025232878 A1 WO2025232878 A1 WO 2025232878A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
alkoxy
compound
cycloalkyl
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/CN2025/093780
Other languages
English (en)
Chinese (zh)
Inventor
艾萨阿吉艾克拜尔
何洋
吴春晖
纪靖
公绪栋
王贯
朱维良
张勇
田广辉
胡天文
余斐斐
侯琼琼
潘利彪
沈敬山
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.)
Shanghai Institute of Materia Medica of CAS
Xinjiang Technical Institute of Physics and Chemistry of CAS
Vigonvita Life Sciences Co Ltd
Original Assignee
Shanghai Institute of Materia Medica of CAS
Xinjiang Technical Institute of Physics and Chemistry of CAS
Vigonvita Life Sciences Co Ltd
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 Shanghai Institute of Materia Medica of CAS, Xinjiang Technical Institute of Physics and Chemistry of CAS, Vigonvita Life Sciences Co Ltd filed Critical Shanghai Institute of Materia Medica of CAS
Publication of WO2025232878A1 publication Critical patent/WO2025232878A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 ring system
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to a amine compound containing a substituted phenyl group as shown in formula (I), its preparation method and pharmaceutical compositions comprising the same, and its use in the preparation of medicaments for the prevention or treatment of diseases associated with NMDA receptors and/or monoamine transporters, particularly central nervous system diseases.
  • Depression is a serious mental illness, primarily characterized by depressed mood, low self-esteem, and even suicidal tendencies.
  • SSRIs/SSNIs Selective Serotonin/Norepinephrine Reuptake Inhibitors
  • these drugs are ineffective for nearly one-third of patients and generally have drawbacks such as slow onset of action and even increasing suicidal tendencies. There is a significant unmet clinical need in this area.
  • NMDA receptors NMDARs
  • NMDA receptors or NMDARs are ligand-gated ion channels. In vivo, these receptors can be activated by glutamate, one of the most important excitatory neurotransmitters in the central nervous system, thereby mediating the transmission of excitatory signals between synapses.
  • glutamate one of the most important excitatory neurotransmitters in the central nervous system, thereby mediating the transmission of excitatory signals between synapses.
  • the NMDAR ion channel opens, its permeability to cations such as Ca2+ , K+ , and Na+ increases, generating excitatory postsynaptic potentials and triggering a series of physiological and biochemical reactions.
  • the NMDAR molecule has a complex structure, and its various subtypes exhibit specificity in spatiotemporal distribution and pharmacological properties.
  • NMDARs Their quantity, composition, and distribution dynamically change at different developmental stages and in different brain regions, participating in numerous physiological activities and providing the molecular basis for complex neural activities, thus ensuring the normal functioning of neural networks.
  • Monoamine transporters are a class of proteins found on the cell membranes of neurons in the central and peripheral nervous systems, responsible for transporting commonly used neurotransmitters in synaptic transmission. Monoamine transporter inhibitors are commonly used as antidepressants to treat depression and anxiety disorders, such as bupropion, which inhibits norepinephrine and dopamine transporters, and fluoxetine and citalopram, which inhibit 5-HT transporters.
  • the NMDA receptor antagonist ketamine has been used in medicine for over 50 years as a good anesthetic. Studies have found that intravenous administration of subanesthetic doses of the NMDAR antagonist ketamine can rapidly relieve symptoms of depression within hours, and the effect can last for at least a week. Eketamine, developed by Johnson & Johnson, was approved by the FDA in 2019 for the treatment of treatment-resistant depression. Given that the main molecular target of ketamine is NMDAR, many have proposed that inhibiting this target is also the reason for ketamine's antidepressant effect. This mechanism suggests that the antidepressant effect of ketamine and its dissociative side effects may be inseparable at the mechanistic level.
  • ketamine and ethacrylamide greatly limit their clinical application.
  • NMDAR antagonists have been developed, none have yet demonstrated rapid antidepressant efficacy similar to ketamine. Therefore, there remains a pressing need for novel antidepressants with potent clinical efficacy, low or no dissociative side effects, and good oral bioavailability.
  • a drug that retains rapid antidepressant activity similar to ketamine while possessing reduced dissociative side effects and good oral bioavailability would offer a new treatment option that is more manageable and potentially feasible for home use due to its reduced dissociative effects and the associated reduced likelihood of abuse.
  • the purpose of this invention is to provide a novel substituted phenyl amine compound with NMDA receptor and/or monoamine transporter regulatory function, its preparation method and uses.
  • One object of the present invention is to provide an amine compound of formula (I) containing a substituted phenyl group, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt, polymorph, solvate, hydrate or isotopically labeled compound thereof.
  • Another object of the present invention is to provide a method for preparing amine compounds containing substituted phenyl groups as shown in formula (I).
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound selected from the formula (I), including its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Another object of the present invention is to provide one or more of the following: compounds selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds, or the use of the above pharmaceutical compositions in the preparation of medicaments for regulating the activity of NMDA receptors and/or monoamine transporters.
  • Another object of the present invention is to provide one or more of the following: compounds selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, or the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and/or treatment of diseases associated with NMDA receptors and/or monoamine transporters, particularly diseases of the central nervous system.
  • a compound of formula (I) or a stereoisomer, geometric isomer, conformational isomer, tautomer thereof, pharmaceutically acceptable salt, polymorph, solvate, hydrate or isotopically labeled compound is provided:
  • R1 is selected from CN, -C(O) NH2 , halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C6-C12 aryl C1-C6 alkoxy; particularly selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, C3-
  • R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or, R2 and R3 together with the attached nitrogen atom form a 3-9 member (e.g., 4, 5, 6 member) heterocyclic alkyl ring, wherein the 3-9 member heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, and the 3-9 member heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups;
  • a 3-9 member e.g., 4, 5, 6 member
  • heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms
  • the 3-9 member heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups;
  • R4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, CN, and halogen; in particular, R4 is selected from hydrogen or halogen.
  • G ring is selected from Specifically, ring G is selected from wherein, each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylacyl, carbamoyl (-C(O) NH2 ), formylamino, C1-C3 alkylamino, halo-C1-C3 alkylamino, N,N-dimethylamino, C1-C3 alkoxycarbonyl, C1-C3 alkylaminocarbonyl, C3-C5 cycloalkyl, morpholinyl, phenyl, pyridine, pyrrolidinyl, or piperidinyl; each R6 is independently selected from hydrogen and C1-C3 alkyl; in particular, each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl (-COOH), C1-C
  • R1 is independently selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyl C1-C4 alkyl, C3-C5 cycloalkyloxy, C3-C5 cycloalkyl C1-C4 alkoxy, C6-C10 aryl C1-C4 alkoxy, CN, -C(O) NH2 , C1-C4 alkylthio; particularly, R 1 is independently selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyl, C3-C5
  • R1 is independently selected from F, Cl, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy, benzyloxy, methylthio, CN, -C(O) NH2 .
  • R4 is independently selected from hydrogen or halogen; preferably selected from hydrogen, F, or Cl.
  • R4 is independently selected from hydrogen, F, Cl, methoxy, CF3 , methyl, and CN.
  • R2 and R3 are independently selected from hydrogen, C1-C4 alkyl or C3-C5 cycloalkyl, C1-C4 alkyl; or R2 and R3 together with the nitrogen atom attached thereto form a 4-7 membered heterocyclic alkyl; preferably, R2 and R3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropylmethyl; or R2 and R3 together with the nitrogen atom attached thereto form aziridine, 4-pyrrolidinyl, piperidinyl.
  • the compound represented by formula (I) is selected from the structures shown in formulas (I-1) to (I-16):
  • the compound represented by formula (I) is selected from the structures shown in formulas (I-1-1) to (I-16-2):
  • R1 , R2 , R3 , R4 , R5 , and R6 are as described above.
  • the compound represented by formula (I) is the compound represented by formula (I-1-a).
  • R 1 is selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C1-C6 alkylthio, CN, -C(O)NH 2 ; particularly selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy;
  • R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or, R2 , R3 and the nitrogen atom attached thereto form a 3-9 membered heterocyclic alkyl ring, wherein the 3-9 membered heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, and the 3-9 membered heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups.
  • R1 is independently selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, C3-C5 cycloalkylC1-C4 alkoxy; and/or
  • R2 and R3 are each independently selected from hydrogen, C1-C4 alkyl, or C3-C5 cycloalkyl; or, R2 , R3 and the nitrogen atom attached thereto form a 3-9 membered heterocyclic alkyl group, wherein the 3-9 membered heterocyclic alkyl group is optionally substituted by one or more C1-C4 alkyl groups, and preferably R2 , R3 and the nitrogen atom attached thereto form a 4-7 membered heterocyclic alkyl group.
  • R1 is independently selected from F, Cl, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy; and/or
  • R2 and R3 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropylmethyl; or R2 and R3 together with the nitrogen atom attached thereto form azircyclic butyl, pyrrolidinyl, piperidinyl, azircyclic heptyl, morpholinyl.
  • the compound represented by formula (I) is the compound represented by formula (I-1-b).
  • R 1 is selected from halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and C3-C6 cycloalkyl-C1-C6 alkoxy.
  • R2 and R3 are each independently selected from hydrogen and C1-C6 alkyl groups.
  • R1 is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, and C3-C5 cycloalkylC1-C4 alkoxy; more preferably, R1 is selected from C1, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, ethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy.
  • R2 and R3 are each independently selected from hydrogen and C1-C4 alkyl; more preferably, R2 and R3 are each independently selected from hydrogen and methyl.
  • the compound represented by formula (I) is a compound represented by formula (I-1-b1) or formula (I-1-b2).
  • R 1 is selected from halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and C3-C6 cycloalkyl-C1-C6 alkoxy.
  • R2 and R3 are each independently selected from hydrogen and C1-C6 alkyl groups.
  • R1 is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, and C3-C5 cycloalkyl-C1-C4 alkoxy; more preferably, R1 is selected from Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, ethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy.
  • R2 and R3 are each independently selected from hydrogen and C1-C4 alkyl; more preferably, R2 and R3 are each independently selected from hydrogen and methyl.
  • halogen generally refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, or bromine; more preferably fluorine or chlorine.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • C1-C6 alkyl refers to a straight-chain or branched saturated hydrocarbon group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl or isobutyl.
  • halogenated C1-C6 alkyl refers to a straight-chain or branched saturated hydrocarbon group containing 1-6 carbon atoms in which the hydrogen atom is replaced by one or more identical or different halogen atoms.
  • Halogenated C1-C4 alkyl follows the same pattern, such as trifluoromethyl, fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, dichlorofluoromethyl, chloroethyl, bromopropyl, 2-chlorobutyl, or pentafluoroethyl, etc.
  • C1-C6 alkoxy refers to a straight-chain or branched alkoxy group containing 1-6 carbon atoms
  • C1-C4 alkoxy “C1-C3 alkoxy”, and so on.
  • Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, isohexoxy, 3-methylpentoxy, or n-hexoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or isohexoxy.
  • halogenated C1-C6 alkoxy refers to a straight-chain or branched alkoxy group containing 1-6 carbon atoms in which the hydrogen atom is replaced by one or more identical or different halogen atoms.
  • Halogenated C1-C4 alkoxy follows the same pattern, such as -OCF 3 , -OCHF 2 , -OCH 2 CH 2 Cl, -OCHBrCH 2 Cl, or -OCF 2 CF 3 , etc.
  • C1-C6 alkoxy - C1-C6 alkyl refers to the oxygen atom of a C1-C6 alkoxy group being attached to a C1-C6 alkyl group , such as -CH2OCH2CH3 , -CH2CH2OCH2CH3 , or -CH2CH2OCH3 .
  • C3-C6 cycloalkyl refers to a saturated cycloalkyl group containing 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • C3-C6 cycloalkyloxy refers to oxygen-bridged C3-C6 cycloalkyl groups as defined herein, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.
  • C3-C6 cycloalkyl C1-C6 alkyl refers to C3-C6 cycloalkyl linked to C1-C6 alkyl, such as cyclopropylmethyl, cyclobutylmethyl, etc.
  • C3-C6 cycloalkyl C1-C6 alkoxy refers to oxygen-bridged C3-C6 cycloalkyl C1-C6 alkyl groups as defined herein, such as cyclopropylmethyloxy, cyclopropylethyloxy, etc.
  • heterocyclic alkyl refers to a saturated monocyclic or polycyclic group containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from N and O as ring members.
  • 3-9 membered heterocyclic alkyl groups include azirrocyclic butyl, pyrrolidinyl, piperidinyl, azirrocyclic heptyl, morpholinyl, etc.
  • the substituted phenyl amine compounds and their geometric isomers, conformational isomers, and tautomers represented by general formula (I) of this invention also include solvate forms, such as hydrates and alcohols, and these solvates are also included within the scope of this invention.
  • Pharmaceutically acceptable salts of the heterocyclic compounds and their geometric isomers, conformational isomers, and tautomers represented by general formula (I) of this invention refer to the substituted phenyl amine compounds or their stereoisomers represented by general formula (I) converted into therapeutically active, non-toxic addition salt forms by treatment with appropriate acids.
  • the salts mentioned include, for example, hydrobromide, hydroiodide, sulfate or hydrogen sulfate, nitrate, phosphate or acid phosphate, perchlorate, formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, maleate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, ascorbate, camphorate or camphorsulfonate, etc.
  • the salt form can be converted to a free base form by alkali treatment.
  • solvates include, for example, hydrates, alcohols, etc.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or two main categories: enantiomers and diastereomers.
  • Enantiomers are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. Where appropriate, this term is used to refer to racemic mixtures.
  • a single stereoisomer with known relative and absolute configurations e.g., (1S,2S)
  • a single stereoisomer with a known relative configuration but an unknown absolute configuration is indicated by an asterisk (e.g., (1R*,2R*));
  • a racemic mixture with two letters e.g., (1RS,2RS) is a racemic mixture of (1R,2R) and (1S,2S);
  • (1RS,2SR is a racemic mixture of (1R,2S) and (1S,2R)).
  • Diarrhetomers are stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is indicated according to the Cahn-Lngold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be described by R or S.
  • the resolved compounds with unknown absolute configurations can be designated as (+) or (-) based on the direction (dextrorotatory or levorotatory) of their rotational plane-polarized light at the sodium D line wavelength. Alternatively, the resolved compounds can be defined by the respective retention times of the corresponding enantiomers/diastereomers via chiral HPLC.
  • Geometric isomerism can occur when a compound contains a double bond or other features that give the molecule a certain degree of structural rigidity. If the compound contains a double bond, the substituent can be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration.
  • Conformation isomers are isomers that differ by rotation of one or more valence bonds.
  • a tautomer is an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule.
  • the following structures are a set of tautomers that interconvert with each other. All tautomer forms of the compounds of this invention are also included within the scope of this invention.
  • Polymorphic refers to a crystalline form having the same chemical structure/composition but different spatial arrangements of the molecules and/or ions forming the crystals.
  • the compounds of this invention can be provided as amorphous solids or crystalline solids. Freeze-drying can be used to provide solid compounds of this invention.
  • Solvate refers to a physical combination of the compound of the present invention with one or more organic or inorganic solvent molecules. Such physical combination includes hydrogen bonds. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate may be present in a regular and/or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate” includes solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.
  • This invention also includes all suitable isotopic variants of the compounds of the invention or pharmaceutically acceptable salts thereof.
  • An isotopic variant of the compounds of the invention or pharmaceutically acceptable salts thereof is defined as one in which at least one atom is replaced by an atom having the same number of atoms but a different atomic mass than those commonly found in nature.
  • Isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, such as 2H , 3H , 11C , 13C , 14C , 15N , 17O , 18O , 35S , 18F , 36Cl , and 125I .
  • Isotopic variants of the compounds of the invention or pharmaceutically acceptable salts thereof can be prepared using conventional techniques and appropriate isotopic variants with suitable reagents.
  • the amine compounds containing substituted phenyl groups represented by formula (I) have structures selected from the following:
  • the amine compound containing substituted phenyl groups represented by formula (I) has a structure selected from the following shown above: A2, A4, A6, A8, A10, A12, A14, A16, A18, A20, A22, A24, A26, A28, A30, A32, A34, A36, A38, A40, A42, A44, A46, A48, A50, A52, A54, A56, A58, A 60, A62, A64, A66, A68, A70, A72, A74, A76, A78, A79, A80, A81, A82, A83, A85, A86, A87, A89, A 90, A91, A93, A94, A96, A97, A99, A100, A102, A103, A105, A106, A108, A109, A111, A112, A114, A115, A117, A118, A120, A121, A123, A124, A125, A127, A
  • the amine compound containing substituted phenyl groups shown in formula (I) has a structure selected from the following: A2, A4, A6, A8, A10, A12, A14, A22, A24, A30, A32, A34, A36, A50, A52, A54, A56, A58, A60, A62, A64, A66, A68, A70, A72, A74, A76, A78, A85, A89, A108, A111, A1 14.
  • a method for preparing amine compounds containing substituted phenyl groups as shown in formula (I-1-a) is provided, said method being carried out by a process comprising the steps shown in the following reaction formula:
  • R2 and R3 are the same and are both C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl
  • the compound shown in formula (VI) undergoes deprotection and alkylation reactions, or undergoes deprotection and reductive amination reactions to generate the compound shown in formula (VII).
  • R2 and R3 are C1-C6 alkyl or C3-C6 cycloalkyl, and the two are different, the compound shown in formula (VI) undergoes a three-step reaction of alkylation or reductive amination, deprotection, and alkylation or reductive amination to generate the compound shown in formula (VII).
  • R1 and R2 are the same as defined and preferred above;
  • G represents a leaving group, such as C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, or benzyl, wherein the aforementioned C1-C6 alkylsulfinyl, benzenesulfinyl, or naphthyl may optionally be further substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, hydroxyl, amino, C1-C6 alkylacyl, C1-C6 alkoxy, or phenyl; G is preferably C1-C4 alkylsulfinyl, benzenesulfinyl, or naphthyl...
  • sulfonyl benzyl, the above-mentioned C1-C4 alkyl sulfinyl, benzene sulfinyl, naphthyl sulfinyl, benzyl are optionally further substituted by one or more groups selected from halogen, C1-C4 alkyl, nitro, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, phenyl; G is more preferably tert-butyl sulfinyl, p-toluene sulfinyl, trifluoromethyl sulfinyl, p-bromosulfinyl, benzyl, p-methoxybenzyl or triphenylmethyl;
  • M represents a leaving group, such as a metal element, halogen, metal compound, borane, silane, diazonium salt, etc., preferably -MgBr, -MgCl, or -Li.
  • a method for preparing amine compounds containing substituted phenyl groups as shown in formula (I-1-b) is provided, said method being carried out by a process comprising the steps shown in the following reaction formula:
  • R2 and R3 are different and are independently C1-C6 alkyl or C3-C6 cycloalkyl
  • the compound shown in formula (VI-2) undergoes a three-step reaction of alkylation or reductive amination, deprotection, and alkylation or reductive amination to generate the compound shown in formula (VII-2).
  • R1 , R2 and R3 are as defined in claim 5;
  • G represents a leaving group selected from C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups, wherein the C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups may optionally be further substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, hydroxyl, amino, C1-C6 alkylacyl, C1-C6 alkoxy, and phenyl groups; G is preferably C1-C4 alkylsulfinyl, benzenesulfinyl, or naphthyl groups.
  • Sulphinyl, benzyl, C1-C4 alkyl sulfinyl, benzene sulfinyl, naphthyl sulfinyl, benzyl are optionally further substituted by one or more groups selected from halogen, C1-C4 alkyl, nitro, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, phenyl;
  • G is more preferably tert-butyl sulfinyl, p-toluene sulfinyl, trifluoromethyl sulfinyl, p-bromosulfinyl, benzyl, p-methoxybenzyl or triphenylmethyl;
  • M represents a leaving group, such as a metal element, halogen, metal compound, borane, silane, diazonium salt, etc., preferably -MgBr, -MgCl, or -Li.
  • Step a) can be carried out in the presence or absence of acid in a solvent, which may be selected from ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; other types such as dimethyl sulfoxide, acetonitrile, etc.,
  • the acid can be selected from organic acids, inorganic acids, or Lewis acids.
  • Inorganic acids may include: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; organic acids may include: formic acid, acetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid, glutamic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, camphoric acid, or camphorsulfonic acid; Lewis acids include: aluminum chloride, ferric chloride, boron trifluoride, e
  • Step b) can be carried out in a solvent, which may be selected from ethers, such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics, such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; ketones, such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; esters, such as ethyl acetate, ethyl formate, methyl acetate
  • the deprotection can be carried out in a solvent under acid or base catalysis.
  • the acid may include: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, acetic acid, etc.
  • the base may include: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydrogen phosphate, etc.
  • the reaction solvent can be water; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatics such as benzene, toluene, nitrobenzene, and chlorobenzene; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate; other solvents such
  • the deprotection or reductive amination reaction can be carried out in a solvent under reducing agent conditions.
  • the reducing agent system includes: Pd/C catalyst-catalyzed hydrogenation, Pd/ BaSO4 catalyst-catalyzed hydrogenation, PtO2 catalyst-catalyzed hydrogenation, Raney Ni catalyst-catalyzed hydrogenation, PPh3- THF- H2O system, LAH, etc.
  • the reaction solvent can be selected from water; ethers, such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics, such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; esters, such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; other types, such as dimethyl sulfoxide, acetonitrile, acetic acid, formic acid, tertvalerate, etc., or mixtures of the above solvents.
  • ethers such as dioxane, tetrahydro
  • the alkylation reaction can be carried out in the presence of an alkylating agent, which includes, but is not limited to, iodomethane, iodoethane, 2-bromopropane, bromocyclopropane, tert-butyl bromide, etc.
  • an alkylating agent which includes, but is not limited to, iodomethane, iodoethane, 2-bromopropane, bromocyclopropane, tert-butyl bromide, etc.
  • the reaction solvent can be selected from ethers, such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics, such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; ketones, such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; other types, such as dimethyl sulfoxide, acetonitrile, etc., or mixtures of the above solvents.
  • ethers such
  • Step d) can be carried out in a solvent, selected from water, ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, etc., or mixtures of the above solvents; the halogenation reaction is, for example, chlorination, bromination, or iodination.
  • a solvent selected from water, ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl
  • the halogenating reagents used include: N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, thioyl chloride, liquid bromine, tribromopyridinium, dibromohydantoin, elemental iodine, etc.
  • Step e) can be carried out in a solvent, wherein the chiral acid includes: D- or L-type tartaric acid, mandelic acid, camphorsulfonic acid, gluconic acid, methionine, aspartic acid, proline, phenylalanine, lactic acid, malic acid, and citric acid; in particular, L-tartaric acid can be used for salt formation and separation of R-configured compounds, and D-tartaric acid can be used for salt formation and separation of S-configured compounds.
  • the chiral acid includes: D- or L-type tartaric acid, mandelic acid, camphorsulfonic acid, gluconic acid, methionine, aspartic acid, proline, phenylalanine, lactic acid, malic acid, and citric acid; in particular, L-tartaric acid can be used for salt formation and separation of R-configured compounds, and D-tartaric acid can be used for salt formation and separation of S-configured compounds.
  • the required solvent is selected from water, ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, etc., or mixtures of the above solvents;
  • ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.
  • aromatics such as benzene, toluene, nitrobenzene, chlorobenzene
  • the starting compounds used in the above reaction formulas can be suitable salts, including alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, calcium salts, magnesium salts, etc.; organic base salts, such as pyridinium salts, triethylamine salts, etc.; inorganic acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; and organic acid salts, such as formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, bis(trimethylammonium salt), picrate, glutamate, methanesulfonate, benzenesulfonate, etc.
  • alkali metal salts and alkaline earth metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, etc.
  • organic base salts such
  • the starting compounds used in the above reaction formulas may include solvates, such as hydrates, alcohols, etc.
  • the target compounds obtained from each reaction can be separated and purified from the reaction mixture by methods such as filtration, extraction or concentration after cooling of the reaction mixture to obtain crude products, which are then purified by conventional methods such as column chromatography, pulping or recrystallization.
  • any atom (including heteroatoms) having an unsatisfied valence bond is considered to have a hydrogen atom sufficient to satisfy the valence bond, unless otherwise indicated.
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of this invention have multi-target effects on NMDA receptors and/or monoamine transporters, and can be used to treat various central nervous system diseases, especially depression, bipolar disorder, schizophrenia, anxiety disorder, phobia, autism, Alzheimer's disease, bipolar disorder, hysteria, obsessive-compulsive disorder, ADHD, epilepsy, and other diseases.
  • one or more of the following are provided: compounds selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds; or the use of the above pharmaceutical compositions in the preparation of medicaments for regulating the activity of NMDA receptors and/or monoamine transporters, specifically, in the preparation of NMDA receptor antagonists, and in the preparation of monoamine transporter inhibitors.
  • amine compounds containing substituted phenyl groups as shown in formula (I) above their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds, or the use of the above pharmaceutical compositions in the preparation of medicaments for the prevention and/or treatment of diseases associated with NMDA receptors and/or monoamine transporters, particularly diseases of the central nervous system.
  • the central nervous system diseases mentioned are selected from: cerebral ischemia; stroke; cerebral infarction; traumatic brain injury; anti-NMDA receptor encephalitis; epilepsy; amyotrophic lateral sclerosis (ALS); schizophrenia; uncontrollable, refractory, or chronic schizophrenia; affective disorders; mental disorders; mood disorders; type I bipolar disorder; type II bipolar disorder; depression; endogenous depression; major depressive disorder; uncontrollable depression; dysphoric disorder; cyclothymic disorder; panic attacks; panic disorder; social phobia; obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; hysteria; anorexia nervosa; sleep disorders; adjustment disorder; cognitive impairment; autism; neuropathic pain; mania; Parkinson's disease; Huntington's disease; Alzheimer's disease; various dementias; memory impairment; ADHD; attention deficit/hyperactivity disorder; tic disorders; and other neurological events or neurodegenerations caused by NMDA receptor activation
  • the neuropathic pain includes peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain.
  • the central nervous system disorders are selected from: type I bipolar disorder; type II bipolar disorder; depression; endogenous depression; major depressive disorder; uncontrollable depression; dysphoric disorder; cyclothymic affective disorder; panic attack; panic disorder; social phobia; obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; Parkinson's disease; peripheral diabetic neuropathy; postherpetic neuralgia; complex regional pain syndrome; attention deficit hyperactivity disorder.
  • a method for treating and/or preventing diseases associated with NMDA receptors and/or monoamine transporters, particularly central nervous system diseases comprising administering to a human or animal an amine compound containing a substituted phenyl group, its stereoisomer, or a pharmaceutically acceptable salt thereof, as shown in formula (I) above.
  • a method for preparing the above-described pharmaceutical composition comprising mixing a substituted phenyl amine compound, its stereoisomer or a pharmaceutically acceptable salt thereof, as shown in formula (I) above, with a pharmaceutically acceptable carrier.
  • compositions of the present invention various pharmaceutical formulations may be selected according to the therapeutic purpose, including but not limited to: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections (e.g., lipid-soluble or oil-soluble injections).
  • the “therapeutic effective amount” of the compounds of this invention refers to the amount of the compounds of this invention that can induce a biological or medical response in an individual, or improve symptoms, slow or delay disease progression, or prevent disease, etc.
  • the “therapeutic effective amount” can be determined by the participating physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the individual's age and related health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.
  • “individual” refers to an animal. Preferably, the animal is a mammal. “Individual” also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the individual is a human being.
  • primates e.g., humans
  • cattle, sheep, goats horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.
  • the individual is a human being.
  • inhibition refers to the reduction or suppression of a specific patient, symptom, condition, or disease, or a significant reduction in biological activity or baseline activity of a process.
  • treatment refers to improving a disease or condition (i.e., halting or slowing the development of the disease or at least one of its clinical symptoms).
  • treatment refers to improving at least one bodily parameter, which may not be perceptible to the patient.
  • treatment refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both.
  • prevention means administering one or more pharmaceutical substances, particularly the compounds of the present invention and/or their pharmaceutically acceptable salts, to an individual with a predisposition to the disease in order to prevent the individual from contracting the disease.
  • This invention provides a novel NMDAR antagonist, belonging to the category of channel pore blockers, which can inhibit channel opening caused by excessive NMDA activation under pathological conditions, thereby preventing excessive Ca2 + influx without affecting the normal function of NMDAR.
  • the NMDAR antagonist described in this invention is a reversible NMDAR antagonist, exhibiting very rapid dissociation after binding without affecting the normal function of the NMDA receptor.
  • the compounds of the present invention have modulatory NMDA receptor activity, and can therefore be used to treat and/or prevent diseases associated with NMDA receptors.
  • the compounds of this invention exhibit good inhibitory effects on monoamine transporters (5-HT transporters and/or norepinephrine transporters and/or dopamine transporters), and can improve comorbidities such as anxiety and depression in anxiety disorders, depression, or other central nervous system diseases.
  • monoamine transporters 5-HT transporters and/or norepinephrine transporters and/or dopamine transporters
  • comorbidities such as anxiety and depression in anxiety disorders, depression, or other central nervous system diseases.
  • Specific configurations of certain compounds of this invention, relative to their racemic or isomer forms, have achieved unexpected effects in inhibiting specific monoamine transporters (dopamine transporters), and have greater potential in treating and/or preventing diseases associated with specific monoamine transporters.
  • the compounds of this invention have the characteristics of high oral bioavailability, low effective dose and few toxic side effects, and are effective for diseases of the central nervous system, especially for central nervous system diseases related to NMDA receptors and/or dopamine transporters.
  • Figure 1 shows the results of the forced swimming experiment in pharmacological example 4; *p ⁇ 0.05, ***p ⁇ 0.001 (unpaired T-test).
  • Figure 2 shows the X-ray crystal structure of compound A3 crystals grown in a methanol-ethyl acetate mixed solvent.
  • Figure 3 shows the ADHD experiment results (total activity distance within 60 min) in pharmacological example 5.
  • the Wistar group consisted of normal rats, and the SHR group consisted of spontaneously hypertensive rats; *p ⁇ 0.05, ***p ⁇ 0.001 (one-way ANOVA, Dunnett's multiple comparison test).
  • Figure 4 shows the ADHD experimental results (object recognition index) in pharmacological example 5.
  • the Wistar group consisted of normal rats, and the SHR group consisted of spontaneously hypertensive rats; **p ⁇ 0.01 (one-way ANOVA, Dunnett's multiple comparison test).
  • the raw materials, reagents, and methods used in the examples and pharmacological examples are all conventional raw materials, reagents, and methods in the art.
  • HPLC high-performance liquid chromatography
  • A1-b (63g) was dissolved in 620mL of tetrahydrofuran (THF), and 72.6g of boron trifluoride ether was added dropwise with stirring at low temperature (-60°C). After the addition was completed, the mixture was stirred at low temperature for 60min to obtain an imine solution.
  • THF tetrahydrofuran
  • n-Bromoanisole (86.4 g, 1.5 eq) was dissolved in tetrahydrofuran (320 mL), and n-butyllithium (2.5 M, 160 mL) was added dropwise with stirring at low temperature (-60 °C). After the addition was complete, the mixture was stirred at low temperature for 60 min to obtain a phenyllithium solution.
  • a phenyllithium solution was added dropwise to the imine solution at low temperature. After the addition was complete, the mixture was stirred at low temperature (-60°C) for 1 hour and allowed to naturally rise to room temperature. After the reaction was monitored by TLC, 20.5 mL of 20% NaOH aqueous solution was added to quench the reaction. Water (400 mL) was added, and the mixture was extracted with EA (400 mL ⁇ 2). The organic phase was washed once with 400 mL of water and once with 400 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily substance. The concentrate was dissolved in 100 g of ethanol and heated to 0–5°C. The mixture was then stirred for 2 hours and filtered to obtain compound A1-c (56.5 g white solid).
  • 3-bromoanisole (9.46 g, 50.58 mmol, 2.45 eq) was dissolved in THF.
  • a 2.5 M n-butyllithium solution (21 mL, 52.50 mmol, 2.54 eq) was slowly added dropwise at -78 °C, and the mixture was stirred at -75 °C for approximately 0.5 h.
  • a THF solution of compound A3-b (5.36 g, 20.67 mmol, 1 eq) was then slowly added dropwise to the above system. After the addition was complete, the mixture was stirred at -70 °C for 3–4 h, and then slowly heated to room temperature. The reaction was monitored by TLC until completion.
  • reaction mixture was poured into a saturated ammonium chloride aqueous solution, extracted three times with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-c (2.94 g yellow solid, yield 38.7%).
  • compound A3-c (2.94 g, 8 mmol, 1 eq) was dissolved in methanol, and 4 M dioxane hydrochloride solution (11 mL, 44 mmol, 5.5 eq) was slowly added. The mixture was stirred at 35 °C for 4–5 h. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted three times with DCM, and the organic phase was passed through anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-d (1.21 g, yield 57.3%).
  • A3-d (1.21 g, 4.58 mmol, 1 eq) was dissolved in methanol and stirred at -5 to 0 °C for 5 min.
  • Acetic acid (1.1 g, 18.32 mmol, 4 eq) and sodium cyanoborohydride (662 mg, 10.53 mmol, 2.3 eq) were then added, and the mixture was stirred for 5 min.
  • a 37% aqueous solution of formaldehyde (1.04 g, 12.82 mmol, 2.8 eq) was added. The mixture was slowly heated to room temperature. After the reaction was complete as monitored by TLC, the reaction was quenched with a saturated sodium bicarbonate solution.
  • A3-e (4.58 mmol, 1 eq) was dissolved in a mixture of acetone and water (1:1, v/v), and p-toluenesulfonic acid monohydrate (871 mg, 4.58 mmol, 1 eq) and 4.6 mL of 2 M HCl (aq) were added.
  • the mixture was refluxed, and after TLC monitoring of the reaction, the pH was adjusted to 9-10 with 5% sodium hydroxide aqueous solution. After three extractions with EA, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-f (0.682 g of yellow oil, yield 60%).
  • A3-f (682 mg, 2.76 mmol, 1 eq) was dissolved in 1,4-dioxane, and elemental iodine (772 mg, 3.04 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 1–2 h, followed by the addition of thiourea (241 mg, 3.17 mmol, 1.15 eq). The mixture was refluxed overnight and monitored by TLC. After the reaction was complete, the reaction solution was concentrated. Sodium thiosulfate aqueous solution, sodium bicarbonate aqueous solution, and EA were added. The mixture was extracted three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-g (322 mg of yellow oil, yield 38.5%).
  • A3-g (322 mg, 1.06 mmol, 1 eq) was dissolved in 5 mL of DCM and stirred at -20 °C for 20 min. Then, a commercially available 1 M boron tribromide solution in dichloromethane (10 mL, 10 mmol, 10 eq) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 15 min, and the reaction was monitored by TLC. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution, extracted 2-3 times with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound A3-h (154 mg pale yellow solid).
  • HPLC detection conditions are the same as above.
  • the concentrate was dissolved in MTBE and salted with 1.5 equivalents of 4M HCl-EA solution under ice bath conditions. After stirring for 1 hour, the mixture was filtered, and the filter cake was dried to obtain 1.67 g of compound B3-e, a pale yellow solid.
  • HPLC detection conditions are the same as above.
  • Example 5 6-(2-fluoro-3-isopropoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, (R)-6-(2-fluoro-3-isopropoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and (S)-6-(2-fluoro-3-isopropoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine
  • 3-Isopropoxy-2-fluorobromobenzene (5.584 g, 2.0 eq) was dissolved in 50 mL of tetrahydrofuran under nitrogen protection and cooled to -60 °C.
  • 2.5 M n-butyllithium (10.5 mL, 2.2 eq) was slowly added dropwise. After the addition was complete, the reaction was maintained at -55 °C for approximately 1 h. Then, it was slowly added to a tetrahydrofuran solution of B6-a (3.107 g, 1.0 eq). After the addition was complete, the mixture was allowed to naturally warm to room temperature and reacted for 2 h.
  • B6-b (6 g, 1.0 eq) was dissolved in 60 mL of tetrahydrofuran by stirring. Then, 6 mL of water and 6 mL of 6N hydrochloric acid were added, and the mixture was heated and stirred at 60 °C for 6 h. Post-treatment: Tetrahydrofuran was removed by concentration under reduced pressure. A suitable amount of water was added to the concentrate, and the pH was adjusted to weakly alkaline using a saturated sodium bicarbonate aqueous solution. The solution was then extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 1.123 g of a yellow oily liquid.
  • HPLC detection conditions are the same as above.
  • a phenyllithium solution was added dropwise to the imine solution at low temperature. After the addition was complete, the mixture was stirred at low temperature (-60°C) for 1 hour, allowed to rise naturally to room temperature, and monitored by TLC. After the reaction was complete, 20% NaOH aqueous solution (20.5 mL) was added to quench the reaction. Water (400 mL) was added, and the mixture was extracted with EA (400 mL ⁇ 2). The organic phase was washed once with 400 mL of water and once with 400 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily substance. The concentrate was dissolved in 100 g of ethanol by heating, then cooled to 0–5°C, stirred for 2 hours, and filtered to obtain compound B39-c (50 g white solid).
  • HPLC detection conditions are the same as above.
  • NMDA Receptor Antagonistic Activity Assay The effect of the compound on the channel current of NMDA receptor (N-methyl-D-aspartate receptor, NR1/2A subtype) was tested using the electrophysiological whole-cell manual patch-clamp method.
  • Electrode drawing apparatus P-97, Sutter, USA
  • Vibration damping platform and shielding mesh (63-534, TMC, USA)
  • HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N’-(2-ethanesulfonic acid) (abbreviated as HEPES) (Sigma, Cat: H3375)
  • Ethylene glycol bis(2-aminoethyl ether)tetraacetic acid (Sigma, Cat: E3889)
  • Lipofectamine 3000 Transfection Kit (Gibco, Cat: L3000015) (includes both Lipofectamine 3000 and P3000 reagents)
  • Fetal bovine serum (FBS) (Gibco, Cat: 10099141)
  • Extracellular fluid formulation 140 NaCl, 2.8 KCl, 1 CaCl2, 10 HEPES and 20 Sucrose, pH adjusted to 7.4 with NaOH.
  • Intracellular fluid formulation 10 CsCl, 115 CsF, 10 EGTA and 10 HEPES, pH adjusted to 7.2 with CsOH.
  • HEK293 cell lines were cultured in DMEM medium containing 10% fetal bovine serum at a temperature of 37°C and a carbon dioxide concentration of 5%.
  • Cell passage Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25% Trypsin-EDTA solution and incubate at room temperature for 1 minute. When the cells detach from the bottom of the dish, add 3 mL of pre-warmed 37°C complete culture medium (90% DMEM + 10% FBS). Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 800 rpm for 3 minutes to collect the cells. Seed the cells at a 1:5 ratio in T25 cell culture flasks (final volume: 6 mL) for expansion or maintenance culture.
  • Transient transfection 24 hours before transient transfection, HEK-293 cells with a cell density of about 80% were reseeded into 35 mm2 cell culture dishes, with an inoculation amount of 3 ⁇ 105 cells per cell culture dish.
  • HEK293 cells transiently expressing NMDA receptor channels were used to record the current induced by 100 ⁇ M glutamic acid (containing 100 ⁇ M glycine) at room temperature using whole-cell patch-clamp technique.
  • the glass microelectrode was fabricated from a glass electrode blank (BF150-86-10, Sutter) using a stretching instrument. The tip resistance after perfusion with electrode fluid was approximately 2-5 M ⁇ .
  • the glass microelectrode was connected to the patch-clamp amplifier by inserting it into the amplifier probe. Clamping voltage and data recording were controlled and recorded via computer using pClamp software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz.
  • cells were clamped at -70 mV.
  • a rapid drug delivery system was used to administer 100 ⁇ M glutamic acid (containing 100 ⁇ M glycine) via gravity to induce channel currents. Once the current stabilized, 100 ⁇ M glutamic acid (containing 100 ⁇ M glycine) containing the compound was administered to observe changes in current amplitude. The compound was administered continuously from low to high concentrations, with a final administration of 100 ⁇ M glutamic acid (containing 100 ⁇ M glycine). Each test concentration of the compound was administered for at least 20 seconds, and at least two cells (n ⁇ 2) were tested for each concentration.
  • Inhibition% represents the percentage of NMDA channel current inhibited by the compound
  • I and Io represent the current amplitude induced by 100 ⁇ M Glutamic acid (containing 100 ⁇ M Glycine) before and after drug administration.
  • the IC 50 of the compound was calculated using GraphPad Prism 8 software by fitting the following equation:
  • Bovine Serum Albumin (Sigma,Cat:B2064-100G)
  • HEK-293 cells overexpressing human SERT the inhibitory effect of the test compound on the human SERT transporter was detected using a Neurotransmitter transporter uptake assay kit (Molecular devices).
  • the assay was performed according to the kit instructions, with citalopram used as a positive control. The specific procedures are as follows:
  • test solutions for citalopram and the compounds of the present invention were prepared in 384-well plates using experimental buffer (HBSS solution containing 0.1% BSA and 20 mM HEPES).
  • the initial test concentration of citalopram was 1 ⁇ M, diluted 3X, and the initial test concentration of the test compound was 10 ⁇ M or 100 ⁇ M, diluted 3X. Each concentration was repeated twice.
  • the inhibitory effect of the compound on transporters expressing human DAT and NET in HEK-293 cells was detected using a Neurotransmitter transporter uptake assay kit (Molecular devices).
  • the assay was performed according to the kit instructions, with Centanafadine used as a positive control. The specific procedures are as follows:
  • HEK 293T cells were digested with trypsin, centrifuged, resuspended in culture medium, counted, and seeded in 6cm culture dishes at a density of 3 ⁇ 106 cells/well.
  • HEK 293T cells were changed in medium, and then two tubes (A and B) were prepared to be transfected with the NET-pcDNA5/FRT plasmid.
  • tube A 200 ⁇ L of Opti-MEM was added, followed by 10 ⁇ L of Lipofectamine TM 3000, and mixed thoroughly.
  • tube B 200 ⁇ L of Opti-MEM was added, followed by 5 ⁇ g of NET-pcDNA5/FRT plasmid, and mixed thoroughly.
  • 10 ⁇ L of P3000 TM was added to tube B and mixed thoroughly (plasmid to transfection reagent ratio: 1 ⁇ g: 2 ⁇ L).
  • the diluted solution from tube A was added to the diluted solution from tube B, mixed thoroughly, and incubated at room temperature for 15 minutes. Finally, the mixture was gently added to the cells after the medium was changed, gently shaken to mix, and then incubated overnight at 37°C with 5% CO2. Cells were used for compound functional activity assays 18-20 hours after transfection.
  • DAT stable culture The DAT-HEK cell line was cultured in DMEM medium containing 10% fetal bovine serum and 0.2 mg/mL Hygromycin B at a temperature of 37°C and a carbon dioxide concentration of 5%.
  • DAT stable cell passage Remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Express solution and incubate at 37°C for approximately 2 minutes. When the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes. To maintain cell physiological viability, the cell confluence should be controlled at approximately 80%.
  • step d) Take 16 ⁇ L of the compound prepared in step b) and add it to the corresponding experimental wells. Add the first concentration of 2 ⁇ positive control compound to the positive control well and add 0.2% DMSO buffer to the negative control well. After centrifugation, incubate at 37°C for 30 min.
  • test reagent Prepare the test reagent with 1 ⁇ HBSS, add 16 ⁇ L of the test reagent to each well, centrifuge, and incubate at 37°C for 60min;
  • the compounds in the embodiments of the present invention have certain antagonistic activity against monoamine transporters, and are expected to have therapeutic effects on central nervous system diseases associated with monoamine transporters.
  • the 5-HTT inhibitory activity of compound B1 is significantly better than that of B2
  • the 5-HTT inhibitory activity of compound B4 is significantly better than that of B5
  • the 5-HTT inhibitory activity of compound B39 is significantly better than that of B40, with IC50 values ⁇ 200 nM, and are expected to have therapeutic effects on central nervous system diseases associated with 5-HT transporters.
  • the DAT inhibitory activity of the S-configuration compounds is significantly better than that of the R-configuration compounds.
  • the DAT inhibitory activity of compound A2 is significantly better than that of A1
  • the DAT inhibitory activity of compound A4 is significantly better than that of A3.
  • the IC50 values of some S-configuration compounds are ⁇ 500 nM, and they are expected to have therapeutic effects on dopamine transporter-related central nervous system diseases, such as attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • Drug The compound of this invention is mixed with 5% DMSO and then added with 5% Mix HS15 thoroughly, then add 90% physiological saline to prepare a solution of appropriate concentration. Prepare and use immediately.
  • mice Male C57 mice, approximately 22g. Animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Mice in each group were administered either the solvent prescription or the test drug via intraperitoneal injection (ip).
  • ip intraperitoneal injection
  • mice were subjected to forced swimming tests 0.5 h or 24 h after drug administration.
  • the water level in the forced swimming device was 45 cm, and the water temperature was 25 °C.
  • the mice were placed in the experimental room for 1 h to acclimatize.
  • the mice were placed in the device for 6 minutes. The entire process was recorded by a camera, and only the immobile time of the mice in the last 4 minutes was counted when analyzing the data.
  • Table 3 0.5 h time point
  • Table 4 24 h time point
  • Drug The compound of this invention is mixed with 5% DMSO and then added with 5% Mix HS15 thoroughly, then add 90% physiological saline to prepare a solution of appropriate concentration. Prepare and use immediately.
  • mice Male C57 mice, approximately 22g. Animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Mice in each group were administered either the solvent prescription or the test drug via intraperitoneal injection (ip).
  • ip intraperitoneal injection
  • mice were subjected to forced swimming tests 1 hour or 24 hours after drug administration.
  • the water level in the forced swimming device was 45 cm, and the water temperature was 25°C.
  • the mice were placed in the experimental room for 1 hour to acclimatize to the environment.
  • the mice were placed in the device for 6 minutes. The entire process was recorded by a camera, and only the immobile time of the mice in the last 4 minutes was counted when analyzing the data.
  • LMA Locomotor Activity
  • mice were first placed in a spontaneous incubator to adapt for 15 minutes, and their spontaneous activities were recorded within 15 minutes. Then, the mice were removed from the spontaneous incubator, and after intraperitoneal administration of the drug, they were immediately placed in a spontaneous incubator (25cm long, 25cm wide, and 45cm high). The activity trajectory of the mice within 60 minutes after drug administration was recorded using the Nordas video analysis system, and the data was analyzed and statistically analyzed.
  • compounds A2 and A4 significantly increased spontaneous activity (total distance of movement within 60 min) in mice in a dose-dependent manner within the dose range of 10-40 mg/kg (10, 20, 40 mg/kg), demonstrating psychostimulant effects. They can be used to treat diseases related to dopamine reuptake, such as ADHD.
  • Pharmacological Example 5 Experimental drug for ADHD in rats: The compound of the present invention was mixed with 5% DMSO and then 90% physiological saline to prepare a solution of appropriate concentration, which was prepared and used immediately.
  • SHR spontaneously hypertensive rats
  • Wistar rats weighing between 200g and 400g
  • All rats were 1-3 months old.
  • SHR rats were randomly divided into a model group and each test drug group, with 6-8 animals in each group. Mice in each group received an intraperitoneal injection of either the solvent formulation or the test drug, while Wistar rats received the same solvent formulation via intraperitoneal injection.
  • mice were placed in the experimental room to acclimatize for 1 hour. Immediately after intraperitoneal injection of the drug, rats were placed in an open field for spontaneous activity testing, which lasted for 1 hour. Object recognition was then performed 3 hours after drug administration. Specific experimental procedures are as follows:
  • Rats were intraperitoneally injected with the test drug or solvent at a volume of 5 ml/kg. Immediately after injection, the rats were placed in an open enclosure (80cm*80cm*40cm, L*W*H) and allowed to explore freely for 1 hour. Anymaze software was used to record the movement distance and trajectory of each rat. The activity level of the animals was analyzed every 15 minutes and the total activity level over 60 minutes.
  • rats were placed in an open-field box containing two identical objects (cylinders with a base diameter of 6 cm and a height of 15 cm) and allowed to explore freely for 10 minutes; this was the training period.
  • One hour after the training period one of the objects was moved to a new location, and the rat was placed back in the same box and allowed to explore freely for another 10 minutes.
  • the exploration time for each object was manually timed by the experimenter, and the behavior of each rat was recorded using video software.
  • the 1-hour object recognition index of the rats was calculated using the following formula:
  • compounds A2, A4, A60, A83 maleate, A197, A204, A217 and A223 reduced total spontaneous activity in rats (Figure 3) and improved spatial memory (Figure 4) in the dose range of 10-40 mg/kg, and have anti-ADHD effects. They can be used to treat diseases related to dopamine or norepinephrine reuptake, such as ADHD.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé amine contenant un phényle substitué, son procédé de préparation et son utilisation. Le composé amine contenant un phényle substitué est tel que représenté par la formule (I), a pour fonction d'ajuster l'activité d'un récepteur NMDA et/ou d'un transporteur de monoamine, et peut être utilisé dans la préparation d'un médicament pour le traitement et/ou la prévention de maladies associées au récepteur NMDA et/ou au transporteur de monoamine, en particulier des maladies du système nerveux central.
PCT/CN2025/093780 2024-05-09 2025-05-09 Composé amine contenant un phényle substitué, son procédé de préparation et son utilisation Pending WO2025232878A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202410570887 2024-05-09
CN202410570887.1 2024-05-09
CN202410571730 2024-05-09
CN202410571730.0 2024-05-09
CN202510293027.2 2025-03-12
CN202510293027 2025-03-12

Publications (1)

Publication Number Publication Date
WO2025232878A1 true WO2025232878A1 (fr) 2025-11-13

Family

ID=97597083

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/093780 Pending WO2025232878A1 (fr) 2024-05-09 2025-05-09 Composé amine contenant un phényle substitué, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN120923442A (fr)
WO (1) WO2025232878A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4292323A (en) * 1980-03-31 1981-09-29 Schering Corporation Phenyl-1,2,3,4-tetrahydrocarbazoles and use thereof
CN1438996A (zh) * 2000-05-31 2003-08-27 沃尼尔·朗伯公司 二环环己胺类化合物及其作为nmda受体拮抗剂的应用
US20060128715A1 (en) * 2004-07-09 2006-06-15 Jennifer Sealy Oxime derivative hydroxyethylamine aspartyl-protease inhibitors
CN101686672A (zh) * 2007-05-31 2010-03-31 塞普拉柯公司 苯基取代的环烷胺作为一元胺再摄取抑制剂
WO2016133793A1 (fr) * 2015-02-16 2016-08-25 Merck Sharp & Dohme Corp. Inhibiteurs du facteur ixa
WO2024099393A1 (fr) * 2022-11-09 2024-05-16 中国科学院上海药物研究所 Composé amine contenant un aryle, son procédé de préparation et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4292323A (en) * 1980-03-31 1981-09-29 Schering Corporation Phenyl-1,2,3,4-tetrahydrocarbazoles and use thereof
CN1438996A (zh) * 2000-05-31 2003-08-27 沃尼尔·朗伯公司 二环环己胺类化合物及其作为nmda受体拮抗剂的应用
US20060128715A1 (en) * 2004-07-09 2006-06-15 Jennifer Sealy Oxime derivative hydroxyethylamine aspartyl-protease inhibitors
CN101686672A (zh) * 2007-05-31 2010-03-31 塞普拉柯公司 苯基取代的环烷胺作为一元胺再摄取抑制剂
WO2016133793A1 (fr) * 2015-02-16 2016-08-25 Merck Sharp & Dohme Corp. Inhibiteurs du facteur ixa
WO2024099393A1 (fr) * 2022-11-09 2024-05-16 中国科学院上海药物研究所 Composé amine contenant un aryle, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
CN120923442A (zh) 2025-11-11

Similar Documents

Publication Publication Date Title
TW201105677A (en) Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents
JP2021514963A (ja) ニューロトロフィンに関連する疾患を治療するためのトリアジン誘導体
AU2012327076B2 (en) Bicyclic heterocyclic compound
JP5822079B2 (ja) 疼痛治療剤
JP2024545931A (ja) Ｌｓｄ誘導体、合成、並びに疾患及び障害の治療のための方法
JP2025142197A (ja) 神経変性疾患及びミトコンドリア病の治療用の組成物ならびにその使用方法
CN113214140B (zh) 哌啶酰胺类衍生物、其药物组合物及其应用
US8530453B2 (en) Compounds and methods for the treatment of pain and other diseases
WO2025232878A1 (fr) Composé amine contenant un phényle substitué, son procédé de préparation et son utilisation
Zhou et al. Structure-based design of novel G-protein-coupled receptor TAAR1 agonists as potential antipsychotic drug candidates
WO2021149767A1 (fr) Dérivé hétérocyclique
EP1716867A1 (fr) Agents de pr vention pour la migraine
EP4617263A1 (fr) Composé amine contenant un aryle, son procédé de préparation et son utilisation
US8822688B2 (en) Imidazo[1,2-a]pyridine derivative
EP1852129A1 (fr) Remede pour le syndrome du colon irritable (sci)
JP4774436B2 (ja) ５ｈｔ５ａレセプターアンタゴニストとしての２−アニリノ−３，４−ジヒドロ−キナゾリンの使用
CN108276332B (zh) 一种双阿魏酰胺孪药类化合物及其制备方法和用途
CN107459510B (zh) 异恶唑类化合物及其应用
WO2023166351A1 (fr) Antagoniste du récepteur h3 de l'histamine et son utilisation médicale
HK40086209A (zh) 用於治疗神经退行性疾病和线粒体疾病的组合物及其使用方法
WO2024032530A1 (fr) Dérivé de cyclohexyl aminoalkyl pipéridine hétérocyclique aromatique, son procédé de préparation et son utilisation
HK40086209B (zh) 用於治疗神经退行性疾病和线粒体疾病的组合物及其使用方法
WO2023134673A1 (fr) Agoniste du canal potassique kcnq4 à haute sélectivité, son procédé de préparation et son utilisation
CN118284607A (zh) 用于治疗疾病和障碍的lsd衍生物、合成和方法
TW202000651A (zh) 治療性組成物及其使用方法