WO2021098732A1 - 1',2'-dihydro-3'h-spiro[cyclobutane 1,4'-isoquinoline]-3'-one derivative and application thereof - Google Patents

1',2'-dihydro-3'h-spiro[cyclobutane 1,4'-isoquinoline]-3'-one derivative and application thereof Download PDF

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WO2021098732A1
WO2021098732A1 PCT/CN2020/129826 CN2020129826W WO2021098732A1 WO 2021098732 A1 WO2021098732 A1 WO 2021098732A1 CN 2020129826 W CN2020129826 W CN 2020129826W WO 2021098732 A1 WO2021098732 A1 WO 2021098732A1
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compound
group
alkyl
general formula
independently
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PCT/CN2020/129826
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French (fr)
Chinese (zh)
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张玲
蒋钰
唐演
周珺
金雪梅
万泽红
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江苏恩华药业股份有限公司
苏州恩华生物医药科技有限公司
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Priority to CN202080053796.0A priority Critical patent/CN114269747B/en
Publication of WO2021098732A1 publication Critical patent/WO2021098732A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a new 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivative, and its Preparation method, composition containing the compound, and application in the field of medicine.
  • NMDAR N-methyl-D-aspartate receptor
  • Glycine and glutamate a kind of glutamate ion receptor, which is mainly permeable to Ca 2+ ions. It can be activated after combining with glycine and glutamate. Excitatory synaptic plasticity plays an important role. Physiologically, they activate and trigger the opening of ion channels and generate input currents that only slowly inactivate. Under pathological conditions, it can cause excessive activation of NMDAR, which is an important pathogenesis of receptor excitotoxicity. NMDAR is widely distributed throughout the central nervous system and also exists in the peripheral nervous system, such as neurons, astrocytes and oligodendrocytes ([J].Nature,2005,438(7071):1162.).
  • NMDAR is a heteromeric complex that interacts with a variety of intracellular proteins through three different subunits NR1, NR2 and NR3.
  • NR2 has four different subunits: NR2A, NR2B, NR2C and NR2D ([J ]. Pharmacology&therapeutics, 2003, 97(1):55-85.).
  • NMDAR neurodegenerative diseases
  • Overactivation of NMDAR is related to acute neurological diseases, such as stroke or head injury, and chronic stress conditions, such as neurodegenerative diseases. Many pathologies are considered It is related to overactive NMDAR, so it is potentially sensitive to NMDA antagonists ([J].Journal of neurochemistry,2006,97(6):1611-1626.).
  • NMDAR neurodepressin
  • NMDA antagonists may treat opioid-induced incurable pain, postoperative pain, and cancer pain.
  • typical antidepressants change the affinity of the glycine site of the NMDA receptor.
  • Reduced NMDAR function contributes to the antidepressant response.
  • a single subanaesthetic dose of ketamine is administered intravenously to patients with refractory depression.
  • NMDAR non-competitive (or allosteric) antagonists
  • ATD sites such as ifendil, RGH-896, EVT101
  • competitive antagonists such as GLYX-13, NRX-1074
  • non-competitive antagonists channel hole blockers (TMD site)
  • TMD site channel hole blockers
  • CN106957285A discloses an aminocyclobutane derivative, which is an NMDAR antagonist, used for the potential treatment of depression and chronic pain, and its structure is as follows:
  • the invention provides a compound or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, racemate Or its mixture form, characterized in that the compound is represented by general formula (A):
  • R 1 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxy, amino substituted or unsubstituted by one or more alkyl groups, alkoxy, thioalkyl, cyano, haloalkyl, ring Alkyl, heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
  • R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and heterocyclic groups;
  • R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, thioalkyl, halogen and cyano;
  • R 7 is independently selected from hydrogen, alkyl, haloalkyl and
  • the alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more Rx substituents are substituted, the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more selected from halogen, Rx, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Substituents of C1-C6 thioalkyl are substituted; wherein each occurrence of Rx is independently selected from -OH, -NH 2 , -NO 2 and -CN.
  • one (species) or more (species) can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).
  • mn used herein refers to the range from m to n and the sub-range composed of each point value therein and each point value.
  • C1-C6 or “C1-6” covers the range of 1-6 carbon atoms, and should be understood to also cover any subrange and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C2-C6, etc., and C1, C2, C3, C4, C5, C6, etc.
  • C3-C6 or “C3-6” should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C5, C4-C6, C5-C6, C4 -C5 etc. and C3, C4, C5, C6 etc.
  • the expression "three yuan to seven yuan” should be understood as covering any sub-range and each point value, such as three yuan to five yuan, three yuan to six yuan, four yuan to five yuan, four yuan to six yuan , Four yuan to seven yuan, five yuan to six yuan, five yuan to seven yuan, six yuan to seven yuan, etc., and three, four, five, six, seven yuan, etc.
  • n 2 is any integer between 0 and 3” includes, for example, any integer from 0 to 2, any integer from 2 to 3, and the like, such as 1, 2, 3.
  • the compounds of the present invention may be optionally substituted by one or more substituents, such as the above formula compounds or specific examples or subclasses in the examples.
  • substituents such as the above formula compounds or specific examples or subclasses in the examples.
  • substituents such as the above formula compounds or specific examples or subclasses in the examples.
  • substituents such as the above formula compounds or specific examples or subclasses in the examples.
  • substituents such as the above formula compounds or specific examples or subclasses in the examples.
  • substituents such as the above formula compounds or specific examples or subclasses in the examples.
  • each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group under the current situation is not exceeded, and a stable compound is formed.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • a bond of a substituent is shown as a bond connecting two atoms through a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.
  • variable such as R
  • a variable with a label such as R 3 , R 6, etc.
  • substituted means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is to form a stable valence state or compound.
  • non-substituted can also be understood as “unsubstituted”. It should be understood that when the substituent is hydrogen, this can also mean that the corresponding group is “unsubstituted” or “unsubstituted”.
  • hydrogen (H) means a single hydrogen atom. Such atomic groups can be connected to other groups, for example, to oxygen atoms to form a hydroxyl group.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • C1-C6 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), iso Propyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2- Butyl (-C(CH 3 ) 2
  • Subunit refers to a group obtained by removing one more hydrogen atom from a carbon atom containing free valence electrons, and having two connection sites to other parts of the molecule.
  • alkylene or “alkylene” refers to a saturated linear or branched divalent hydrocarbon group.
  • alkylene when used alone or in combination with other groups herein, refers to a linear or branched saturated divalent hydrocarbon group.
  • C1-C3 alkylene refers to an alkylene group having 1 to 3 carbon atoms, such as methylene, ethylene, and propylene.
  • the brackets in the structural formula herein indicate the repetition of the structural unit.
  • n 2 represents the repeating number of the structural unit in the brackets, and the structural unit in the brackets is a methylene group substituted with one R 6.
  • n 2 is 1, 2 or 3
  • the structural fragment obtained by repeating the structural unit in the brackets is a C1-C3 alkylene group, and each -(CH 2 )- structure of the alkylene group is substituted with one R 6.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Alkenyl group can have 2 to 8 carbon atoms, i.e., "C 2 - 8 alkenyl group", for example, C 2 - 4 alkenyl, C 3 - 4 alkenyl group.
  • alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.
  • alkynyl refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms.
  • An alkynyl group can have 2 to 8 carbon atoms, i.e., "C 2 - 8 alkynyl group", for example, C 2 - 4 alkynyl, C 3 - 4 alkynyl group.
  • alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cycloalkyl group may be a monocyclic ring, a fused polycyclic ring, a bridged ring or a spiro ring structure.
  • Cycloalkyl groups can have 3-10 carbon atoms, that is, "C3-C10 cycloalkyl", such as C3-C8 cycloalkyl, C3-C6 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl base.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group may contain 1-12 carbon atoms. According to an embodiment of the present invention, the alkoxy group may contain 1-6 carbon atoms. According to another embodiment of the invention, the alkoxy group may contain 1 to 5 or 1 to 4 carbon atoms. According to yet another embodiment of the present invention, the alkoxy group may contain 1 to 5 carbon atoms. The alkoxy group is optionally substituted or unsubstituted with one or more substituents described in the present invention.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ),
  • thioalkyl means that the alkyl group is connected to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the thioalkyl group may contain 1-12 carbon atoms. According to an embodiment of the present invention, the thioalkyl group may contain 1-6 carbon atoms. According to another embodiment of the present invention, the thioalkyl group may contain 1-5 or 1-4 carbon atoms. According to yet another embodiment of the present invention, the alkoxy group may contain 1 to 5 carbon atoms. The thioalkyl group is optionally substituted or unsubstituted with one or more substituents described in the present invention.
  • thioalkyl groups include, but are not limited to, methylthio (MeS, -SCH 3 ), ethylthio (EtS, -SCH 2 CH 3 ), 1-propylthio (n-PrS, n -Propylthio, -SCH 2 CH 2 CH 3 ), 2-propylthio (i-PrS, i-propylthio, -SCH(CH 3 ) 2 ), 1-butylthio (n-BuS, n -Butylthio, -SCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH 2 CH(CH 3 ) 2 ), 2- Butylthio (s-BuS, s-butylthio, -SCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC( CH
  • heterocyclic group or "heterocyclic hydrocarbon group” means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, Oxygen, the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 4 to 6 ring atoms, of which 1 to Three (e.g. 1, 2, and 3) are heteroatoms. "Heterocyclic group” or “heterocyclic hydrocarbon group” does not possess aromaticity.
  • the heterocyclic group may be, for example, a four-membered ring, such as azetidinyl, oxetanyl, or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, Pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidine-1-yl; or six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl , Thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithiaalkyl; or seven-membered ring, such as diaza Base ring.
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group can be bicyclic without limitation, for example, a five-membered five-membered ring, such as hexahydrocyclopentane [c]pyrrole-2(1H)-yl) ring; or a five-membered six-membered bicyclic ring, such as Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.
  • the heterocycle may be unsaturated, that is, it may contain one or more double bonds without limitation.
  • an unsaturated heterocycle containing a nitrogen atom may be 1,6-dihydropyrimidine , 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1H- Pyrrole, 3,4-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H -[1,4] Thiazinyl ring
  • the unsaturated heterocyclic ring containing oxygen atom can be 2H-pyran, 4H-pyran, 2,3-dihydrofuran
  • the unsaturated heterocyclic ring containing sulfur atom can be It is 2H-thio
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic .
  • the aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. Examples of aryl groups may include phenyl, naphthyl, and anthracene.
  • the aryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl should be understood to preferably mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5 to 10 membered hetero Aryl"), especially 5 or 6 or 9 or 10 ring atoms, and at least one of the ring atoms (suitably 1-4, more suitably 1, 2 or 3) may be the same or different Heteroatoms such as oxygen, nitrogen or sulfur. Furthermore, the heteroaryl group may be benzo-fused in each case.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc., and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazole Group, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, Isoquinolinyl, etc.; or azocinyl, indazinyl
  • pharmaceutically acceptable refers to contact with the patient's tissues within the scope of normal medical judgment without undue toxicity, irritation, allergic reactions, etc., has a reasonable ratio of advantages and disadvantages, and can be effectively used for the purpose.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • preferred compounds are those isomeric compounds that exhibit superior biological activity.
  • Purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present invention are also included in the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.
  • Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by using optically active acids or bases to form diastereomeric salts, or by forming covalent diastereomers .
  • a mixture of diastereomers can be separated into single diastereomers based on their physical and/or chemical differences by methods known in the art (for example, by chromatography or fractional crystallization). Then, the optically active enantiomeric base or acid is released from the separated diastereomeric salt.
  • Another method for separating racemic enantiomers can use chiral chromatography (such as a chiral HPLC column).
  • the separated chiral isomers can be subjected to conventional derivatization or non-derivatization before separation, depending on Which method can achieve more effective separation of chiral isomers? Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers.
  • the compounds of the present invention may exist in the form of tautomers.
  • the present invention includes all possible tautomers of the compounds of the present invention, and also includes a single tautomer or the form of any mixture of the tautomers in any ratio.
  • the present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number.
  • the metabolites of the compounds of the present invention are also included within the scope of the present invention, that is, substances formed in the body when the compounds of the present invention are administered.
  • the metabolites of compounds can be identified by techniques well known in the art, and their activity can be characterized by experimental methods. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method in which the compound of the present invention is contacted with a mammal for a time sufficient to produce its metabolite.
  • the present invention also encompasses the compounds of the present invention containing protecting groups.
  • protecting groups In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any related molecules may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention.
  • the protecting groups described herein can be implemented by conventional protecting groups, for example, those described in Protective Groups in Organic Synthesis (Greene et al., 4th edition, Wiley-Interscience (2006)). These references are passed Cite this article. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • pharmaceutically acceptable carrier refers to those substances that have no obvious stimulating effect on organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carriers” include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
  • administration refers to methods that enable the compound or composition to be delivered to the desired biological site of action. These methods include but are not limited to oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like. Especially injection or oral administration.
  • treatment includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, and promoting Relief of disease or symptom, or cessation of symptoms of disease or symptom, and extended to include prevention.
  • Treatment also includes achieving therapeutic benefits and/or preventive benefits.
  • Therapeutic benefit refers to eradicating or improving the condition being treated.
  • the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease.
  • Prophylactic benefit means that the patient uses the composition to prevent the risk of a certain disease, or when the patient has one or more physiological conditions of the disease, even though the disease has not been diagnosed.
  • the terms "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refer to a sufficient amount of a drug or medicament that has acceptable side effects but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general conditions of the individual, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • neuropsychiatric diseases refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
  • the present invention aims to provide a new NMDAR inhibitor, which belongs to the channel hole blocker (TMD site), which can inhibit the channel opening caused by excessive activation of NMDA in pathological conditions and avoid excessive Ca 2+ influx , Without affecting the normal function of NMDAR.
  • the NMDAR antagonist of the present invention is a reversible NMDAR antagonist, and it dissociates very quickly after being combined without affecting the normal function of the NMDA receptor.
  • the purpose of the present invention is to provide a 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivative with pharmaceutical activity and its use in Applications in the medical field.
  • the present invention provides a compound or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoisomer, racemic Body or its mixture form, wherein the compound is represented by general formula (A),
  • R 1 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxy, amino substituted or unsubstituted by one or more alkyl groups, alkoxy, thioalkyl, cyano, haloalkyl, ring Alkyl, heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
  • R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and heterocyclic groups;
  • R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, thioalkyl, halogen and cyano;
  • R 7 is independently selected from hydrogen, alkyl, haloalkyl and
  • n 1 is independently any integer between 0 and 1;
  • n 2 is independently any integer between 0 and 3;
  • n 3 is independently any integer between 1 and 2;
  • n 4 is independently any integer between 1 and 3;
  • n 5 is independently any integer between 1 and 3;
  • the alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more Rx Substituents, the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more selected from halogen, Rx, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1 -Substituent substitution of C6 thioalkyl;
  • each occurrence of Rx is independently selected from -OH, -NH 2 , -NO 2 and -CN.
  • n 1 is selected from 0, 1, preferably 1.
  • n 2 is selected from 0, 1, 2, 3, preferably 0, 1 or 2, especially 0 or 1.
  • n 3 is selected from 1, 2, preferably 1.
  • n 4 is selected from 1, 2, 3, preferably 1.
  • n 5 is selected from 1, 2, 3, preferably 1 or 2, especially 1.
  • the alkyl group is selected from C1-C6 alkyl groups; the cycloalkyl group is selected from C3-C6 cycloalkyl groups; the haloalkyl group is selected from C1-C6 haloalkyl groups; the alkane
  • the oxy group is selected from C1-C6 alkoxy groups; the thioalkyl group is selected from C1-C6 thioalkyl groups;
  • the heterocyclic group is preferably a N-containing heterocyclic group, and more preferably contains only one N atom
  • the heterocyclic group; the amino group substituted by one or more alkyl groups is selected from amino groups substituted by one or more C1-C6 alkyl groups; the aryl group is phenyl or naphthyl, wherein phenyl or naphthalene
  • the group is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 halo
  • the ring atoms of the heteroaryl group contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, preferably Its ring atoms contain 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and the heteroaryl group is optionally substituted by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1- Substituents of C6 alkoxy, C1-C6 thioalkyl and Rx are substituted.
  • the alkyl group, alkoxy group, thioalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are all unsubstituted, and the alkyl group in the haloalkyl group The group is not substituted by a group other than halogen.
  • the C1-C6 alkyl group is a C1-C3 alkyl group.
  • the alkyl group is selected from unsubstituted C1-C6 alkyl groups.
  • the cycloalkyl group is selected from unsubstituted C3-C6 cycloalkyl groups.
  • the haloalkyl group is selected from C1-C6 haloalkyl groups, wherein the alkyl group is not substituted by a group other than halogen.
  • the alkoxy group is selected from unsubstituted C1-C6 alkoxy groups.
  • the thioalkyl group is selected from unsubstituted C1-C6 thioalkyl groups.
  • the N-containing heterocyclic group is selected from heterocyclic groups containing only one N atom.
  • the amino group substituted with one or more alkyl groups is selected from amino groups substituted with one or more C1-C6 alkyl groups, wherein the alkyl group is a non-substituted alkyl group.
  • the aryl group is selected from unsubstituted phenyl or naphthyl.
  • the alkyl group is selected from non-substituted C1-C6 alkyl groups; the cycloalkyl group is selected from non-substituted C3-C6 cycloalkyl groups; and the halogenated alkyl group is selected from non-substituted C3-C6 cycloalkyl groups.
  • Substituted C1-C6 haloalkyl said alkoxy group is selected from unsubstituted C1-C6 alkoxy; said thioalkyl group is selected from unsubstituted C1-C6 thioalkyl; said containing The N heterocyclic group is selected from unsubstituted heterocyclic groups containing only one N atom; the amino group substituted by one or more alkyl groups is selected from the amino group substituted by one or more C1-C6 alkyl groups, the The alkyl group is an unsubstituted alkyl group; the aryl group is selected from unsubstituted phenyl or naphthyl; the halogen is selected from fluorine, chlorine, bromine or iodine.
  • the C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl and pentyl.
  • the C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 and -(CH 2 ) a CH(CX 3 ) 2 .
  • the C1-C6 alkoxy group is selected from -O-(CH 2 ) a CH 3 and -O-(CH 2 ) a CH(CH 3 ) 2 .
  • the C1-C6 thioalkyl group is selected from -S-(CH 2 ) a CH 3 and -S-(CH 2 ) a CH(CH 3 ) 2 .
  • the amino group substituted with one or more C1-C6 alkyl groups is selected from -NH-(CH 2 ) a CH 3 and -N[(CH 2 ) a -CH 3 ] 2 .
  • the heterocyclic group containing only one N atom is selected from (E.g Wait).
  • X represents halogen
  • a is independently selected from any integer between 0 and 3, for example selected from 0, 1, 2, 3, especially 0, 1, or 2.
  • the C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl and pentyl;
  • the C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 and- (CH 2 ) a CH(CX 3 ) 2 ;
  • C1-C6 alkoxy is selected from -O-(CH 2 ) a CH 3 and -O-(CH 2 ) a CH(CH 3 ) 2 ;
  • C1-C6 The thioalkyl group is selected from -S-(CH 2 ) a CH 3 and -S-(CH 2 ) a CH(CH 3 ) 2 ;
  • the amino group substituted by one or more C1-C6 alkyl groups is selected from- NH-(CH 2 ) a CH 3 and -N[(CH 2 ) a -CH 3 ] 2 ;
  • X represents halogen, the halogen is selected from fluorine, chlorine, bromine and iodine; a is independently selected from any integer between 0 and 3, for example selected from 0, 1, 2, 3, especially 0, 1. Or 2.
  • haloalkyl refers to an alkyl substituted with one or more halogens.
  • the propyl group is selected from n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) and isopropyl ((i-Pr, -CH(CH 3 ) 2 ); butyl Selected from n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH (CH 3 )CH 2 CH 3 ) and tert-butyl (t-Bu, -C(CH 3 ) 3 ); pentyl is selected from n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2- Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl(-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl
  • halogen is selected from fluorine, chlorine, bromine and iodine. In a preferred embodiment, halogen is selected from fluorine, chlorine and bromine.
  • R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl.
  • R 1 is selected from hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, C3-C6 cycloalkyl and phenyl, wherein the alkyl group and the alkoxy group are each independently optionally substituted with one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted with one or more Rx, and The cycloalkyl, heterocyclic and phenyl groups are each independently optionally substituted with one or more substituents selected from halogen, Rx and C1-C3 alkyl.
  • R 1 is independently selected from hydrogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, phenyl and C3-C4 Cycloalkyl. In a more preferred embodiment, R 1 is independently selected from C1-C3 alkyl, hydroxyl, C1-C2 alkoxy, cyano, C1-C3 haloalkyl, phenyl and C3-C4 ring alkyl.
  • the alkyl group, alkoxy group, cycloalkyl group and phenyl group are all unsubstituted; and the alkyl group in the haloalkyl group is not substituted by groups other than halogen.
  • R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and N-containing heterocyclic groups.
  • the alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more substituents.
  • Each Rx substitution, the cycloalkyl group and the N-containing heterocyclic group are each independently optionally substituted with one or more substituents selected from halogen, Rx and C1-C3 alkyl.
  • R 2 and each R 3 are the same or different, R 2 and each R 3 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1- C3 thioalkyl, C1-C3 haloalkyl, cyano, amino substituted or unsubstituted by one or more C1-C3 alkyl, C3-C6 cycloalkyl and C3-C6 only contain
  • a heterocyclic group with a N atom is preferably hydrogen, halogen or cyano.
  • R 2 is halogen, and each occurrence of R 3 is independently selected from halogen and hydrogen. In a specific embodiment, R 2 is halogen and R 3 is hydrogen. In a specific embodiment, R 2 and each R 3 are each independently selected from halogen.
  • the alkyl group, alkoxy group, cycloalkyl group, thioalkyl group and heterocyclic group containing only one N atom are all unsubstituted; and the alkyl group in the haloalkyl group Not substituted by groups other than halogen.
  • R 4 , R 5 and R 6 are the same or different, and are each independently selected from hydrogen and alkyl. In one embodiment, R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 4 , R 5 and each R 6 are hydrogen. In one embodiment, R 4 is hydrogen, R 5 and R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 5 is hydrogen, R 4 and R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 4 and R 5 are hydrogen, and each R 6 is independently selected from hydrogen and C1-C3 alkyl. In one embodiment, n 2 is 0 and R 6 is not present; in a more preferred embodiment, the alkyl group is unsubstituted.
  • R 7 is independently selected from hydrogen, alkyl and n4 is 1 or 2, preferably 1. In one embodiment, R 7 is selected from hydrogen, C1-C3 alkyl and n4 is 1 or 2, preferably 1. In one embodiment, R 7 is hydrogen. In one embodiment, R 7 is selected from C1-C3 alkyl groups and In a preferred embodiment, the C1-C3 alkyl group is unsubstituted. n 4 is 1 or 2, preferably 1.
  • R 1 is independently selected from hydrogen, methyl, ethyl, cyano, hydroxyl, phenyl, trifluoromethyl, trichloromethyl, cyclopropyl, cyclobutyl, ethoxy, methoxy, phenyl , Trifluoroethyl, trichloroethyl, isopropyl, n-propyl, hydroxyethyl, cyanomethyl and methoxyethyl. ;
  • R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, cyano, thiomethyl, methoxy, Trifluoromethyl, trichloromethyl, cyclopropyl and -N(CH 3 ) 2 ;
  • R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and methyl;
  • R 7 is independently selected from hydrogen, methyl and
  • R 1 is independently selected from methyl, ethyl, trifluoroethyl, trichloroethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, hydroxyethyl, cyano Methyl, phenyl, methoxyethyl and ethoxyethyl.
  • n 2 is 0, and the compound of the general formula (A) has the structure of the following formula (A*),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , n 1 , n 3 , and n 5 are as defined in the above general formula (A).
  • n 5 is 1, and the compound of general formula (A) has the structure of the following formula (A-1-1),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n 1 , n 2 , and n 3 are as defined in the general formula (A).
  • n 5 is 1, n 2 is 0, and the compound of general formula (A) has the structure of the following formula (A-1-2),
  • R 6 does not exist, and R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , n 1 and n 3 are as defined in the general formula (A).
  • the compound of general formula (A) is any compound shown in the following table:
  • the compound of general formula (A) is selected from any one of the compounds shown in Table 2 below:
  • the present invention further provides a method for preparing a compound of general formula (IV), including the following steps (A-1) and (A-2), or including steps (A-i):
  • Step (A-1) a compound of general formula (III) prepared by reacting a compound of general formula (II) with a compound of general formula SM-3; wherein R 9 is a protective group for hydroxyl;
  • Step (A-2) The compound of general formula (III) is prepared by deprotection reaction to obtain the compound of general formula (IV);
  • R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 and n 5 are as defined above.
  • R 9 is selected from monomethoxytriphenyl (MMT), bismethoxytriphenyl (DMT), triphenylmethyl (Trityl), tert-butyldimethylsilane (TBS ) And tert-butyldimethylsilyl (TBDMS).
  • MMT monomethoxytriphenyl
  • DMT bismethoxytriphenyl
  • Trityl triphenylmethyl
  • TBS tert-butyldimethylsilane
  • TDMS tert-butyldimethylsilyl
  • a compound of general formula (II) is reacted with a compound of general formula SM-3 in an organic solvent to prepare a compound of general formula (III).
  • a suitable solvent such as tetrahydrofuran (THF)
  • THF tetrahydrofuran
  • the compound of general formula (II) and hexamethylphosphoryl Add the n-butyl lithium n-hexane solution to the triamine dropwise.
  • a suitable solvent such as a THF solution
  • step (A-2) a compound of general formula (III) is reacted with tetrabutylammonium fluoride in an organic solvent to prepare a compound of general formula (IV).
  • a suitable solvent such as THF
  • the compound of general formula (III) is reacted with tetrabutylammonium fluoride for 0.5-2 hours to obtain the compound of general formula (IV).
  • a compound of general formula (II) is reacted with a compound of general formula SM-4 in an organic solvent to prepare a compound of general formula (IV).
  • a suitable solvent such as THF
  • add a THF solution of isopropyl magnesium chloride add a compound of general formula (II) and a compound of general formula SM-4, After that, it was raised to room temperature and reacted for 2-18 hours to obtain the compound of general formula (IV).
  • step (B) includes the following steps (B-1) and (B-2), or includes steps (B-i) and (B-ii):
  • Step (B-1) The compound of general formula (IV) is reacted with phthalimide to prepare the compound of general formula (V);
  • Step (B-2) The compound of general formula (V) is prepared by deprotection reaction to obtain the compound of general formula (A);
  • R 5 and R 7 are hydrogen; R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 and n 5 are as defined above.
  • step (B-1) the compound of formula (IV) is reacted with phthalimide, triphenylphosphine and diethyl azodicarboxylate in an organic solvent to prepare Compound of general formula (V).
  • the compound of formula (IV), phthalimide, triphenylphosphine and azodicarboxylic acid are added in a suitable solvent such as THF at 0°C.
  • THF a suitable solvent
  • the diethyl ester is then raised to room temperature and reacted for 6-18 hours to obtain the compound of formula (V).
  • the compound of general formula (IV) and methanesulfonyl chloride are prepared under the conditions of organic base and organic solvent to prepare the corresponding methanesulfonyl ester compound, and then the compound is combined with phthalimide and inorganic base.
  • organic solvent a compound of general formula (V) can be prepared.
  • the compound of formula (A'), triethylamine and methanesulfonyl chloride are added in a suitable solvent such as methylene chloride at 0°C, and the temperature is raised to room temperature to react 0.5-
  • the corresponding methanesulfonyl ester compound is obtained in 3 hours, and it is dissolved in a suitable solvent such as dimethylformamide without separation, and phthalimide and inorganic base (such as potassium carbonate or cesium carbonate) are added to increase the temperature to 70-
  • the compound of general formula (V) was obtained by reacting at 140°C for 2-16 hours.
  • step (B-2) a compound of general formula (V) is reacted with a deprotection reagent, such as ethanolamine, to prepare a compound of general formula (A).
  • a deprotection reagent such as ethanolamine
  • ethanolamine a deprotection reagent
  • a compound of general formula (V) is reacted with ethanolamine at 60 to 70° C. for 0.5-1.5 hours to prepare a compound of general formula (A).
  • step (Bi) the compound of general formula (V) and methanesulfonyl chloride are prepared under the conditions of organic base and organic solvent to prepare the corresponding methanesulfonyl ester compound, which is then combined with sodium azide and inorganic base.
  • organic solvent the compound of general formula (VI) is prepared.
  • the compound of general formula (V), triethylamine and methanesulfonyl chloride are added to a suitable solvent such as dimethylformamide at 0°C, and the reaction temperature is raised to room temperature.
  • step (B-ii-1) the compound of formula (VI) is hydrogenated in an organic solvent to prepare the compound of formula (A').
  • a suitable solvent such as ethyl acetate, add the compound of formula (VI) and the catalyst palladium carbon, and react at room temperature for 1-2 hours to obtain the formula (A') Compound.
  • step (C) includes step (C-1), step (C-2), and step (C-3), or includes step (C-i) and step (C-ii):
  • Step (C-1) The compound of general formula (VII) is reacted with an amino protecting group reagent to prepare a compound of general formula (VIII);
  • Step (C-2) The compound of general formula (VIII) is alkylated to obtain the compound of general formula (IX);
  • Step (C-3) The compound of general formula (IX) is prepared by deprotection reaction to obtain the compound of general formula (A); wherein R 8 is an amino protecting group;
  • Step (C-ii) The compound of general formula (X) is prepared by deprotection reaction to obtain the compound of general formula (A);
  • R 5 is hydrogen;
  • R 7 is independently selected from alkyl and
  • R 8 is an amino protecting group;
  • R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 , n 4 and n 5 are as defined above.
  • the amino protecting group reagent is selected from benzyloxycarbonyl chloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc 2 O), triphenylchloromethane (Trt-Cl), 4-methyl Oxybenzyl chloride (PMBCl) and 9-fluorenyl methyl chloroformate (Fmoc-Cl).
  • the amino protecting group R 8 is selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), triphenylmethyl (Trt), 4-methoxybenzyl (PMB) And chloroformic acid-9-fluorenylmethylcarbonyl (Fmoc).
  • the compound of general formula (VII) is prepared by referring to the method (1) for preparing the compound of general formula (A) above.
  • step (C-1) a compound of general formula (VII) is reacted with triethylamine and di-tert-butyl dicarbonate in an organic solvent to prepare a compound of general formula (VIII).
  • a suitable solvent such as DCM, add the compound of formula (VII), triethylamine and di-tert-butyl dicarbonate, and react at room temperature for 1-3 hours to obtain formula (VIII) compound of.
  • step (C-2) a compound of general formula (VIII) and methyl iodide are prepared under conditions of an inorganic base and an organic solvent to obtain a compound of general formula (IX).
  • the compound of general formula (VIII) and sodium hydride (60%) are added in a suitable solvent such as tetrahydrofuran at 0°C, and methyl iodide is added for 0.5-1 hour at room temperature. , Continue to react at room temperature for 12-16 hours to obtain a compound of general formula (IX).
  • step (C-3) the compound of general formula (IX) is reacted with a deprotection reagent in an organic solvent, such as reacting with trifluoroacetic acid to prepare a compound of general formula (A).
  • a deprotection reagent such as reacting with trifluoroacetic acid
  • the compound of general formula (IX) is reacted with trifluoroacetic acid for 0.5-1 hour to prepare the compound of general formula (A) .
  • a compound of general formula (VII) is reacted with N-tert-butoxycarbonyl-glycine in an organic solvent to prepare a compound of general formula (X).
  • a compound of general formula (VII) under the protection of nitrogen, in a suitable solvent such as DMF and NMP (N-methylpyrrolidone), a compound of general formula (VII), triethylamine, O-(7-azabenzene) is added (Di-triazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate and a compound of general formula SM-5, react at room temperature for 3-5 hours to obtain a compound of general formula (X) .
  • step (C-ii) a compound of general formula (X) is reacted with a deprotection reagent in an organic solvent to obtain a compound of general formula (A).
  • a deprotection reagent in an organic solvent
  • the compound of general formula (IX) is reacted with trifluoroacetic acid for 0.5-1 hour to prepare the compound of general formula (A).
  • the compound of general formula (II) can be prepared by the following method, so the present invention further provides a preparation method (1'), including:
  • the compound of the general formula (I) is prepared by the ring-forming reaction to obtain the compound of the general formula (II);
  • R 1 , R 2 , R 3 , R 6 , n 1 , n 2 and n 5 are as defined above.
  • a compound of general formula (I) and paraformaldehyde are prepared under the action of Eaton's reagent to obtain a compound of general formula (II).
  • Eaton's reagent for example, under the protection of nitrogen, the compound of general formula (I) and paraformaldehyde, using Eaton's reagent as the solvent, are heated to a temperature of 60-80°C and reacted for 30 minutes to 2 hours to obtain the compound of general formula (II) Compound.
  • the compound of general formula (II) can be prepared by the following method, so the present invention further provides a preparation method (1"), including:
  • R 1 , R 2 , R 3 , R 6 , n 1 , n 2 and n 5 are as defined above.
  • a compound of general formula SM-1 and thionyl chloride are prepared under organic solvent conditions under conditions known to those skilled in the art to prepare the corresponding acid chloride, and then the corresponding acid chloride is prepared with the general formula SM-
  • the commercially available raw materials shown in 2 are prepared in an organic solvent to obtain a compound of general formula (I): for example, at a temperature in the range of 0°C to room temperature, in a suitable solvent such as dichloromethane, the compound of formula SM-1 and After the thionyl chloride reacts for 0.5-2 hours, the solvent is evaporated under reduced pressure and dissolved in a suitable solvent such as dichloromethane. At a temperature ranging from 0°C to room temperature, a compound of general formula SM-2 is added, reaction 2- After 12 hours, the compound of formula (I) is obtained.
  • the present invention provides intermediates for the preparation of compounds described by general formula (A), the intermediates selected from the group consisting of formula (II), formula (III), formula (IV), formula (V), Compounds of formula (VI), formula (VII), formula (VIII), formula (XI) and formula (X):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n 1 , n 2 , n 3 , n 4 and n 5 are as defined above.
  • n 5 is 1, and the preparation method of the compound of formula (IV) is shown in the figure below:
  • n 5 is 1, and the preparation method (1) is shown in the figure below:
  • n 5 is 1, and the preparation method (2) is shown in the figure below:
  • n 5 is 1, and the preparation method (1') is shown in the figure below:
  • n 5 is 1, and the preparation method (1") is shown in the figure below:
  • R 1 , R 2 , R 3 , R 6 , n 1 and n 2 are as defined in the preparation method (1").
  • compositions preparations and kits
  • the present invention provides a therapeutically effective amount of a compound of general formula (A) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer
  • a pharmaceutical composition comprising a construct, a mesosome, a racemate or a mixture thereof, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation.
  • the dosage form of the medicine can also be formulated as a sustained release dosage form.
  • the effective dose is.
  • the compounds of the present invention or their pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers, racemates or mixtures thereof The form can be taken orally with, for example, an inert diluent or some carrier.
  • the compound of the present invention can be encapsulated in a gelatin capsule or compressed into a tablet.
  • the compound of the present invention can be used together with excipients and used in the form of tablets, lozenges, capsules, suspensions, syrups and the like.
  • the above formulation should contain at least 0.5% (w/w) of the active compound of the present invention, but it can vary according to specific dosage forms, and it is convenient to account for 4% to about 70% of the unit weight.
  • the amount of active compound in such a pharmaceutical composition should reach an appropriate dose.
  • the active compound of the present invention when used for parenteral administration, can be combined with sterile water or an organic medium to form an injectable solution or suspension.
  • the active compound of the present invention can be formulated into rectal compositions, such as suppositories or retention enemas.
  • the present invention also provides compounds of general formula (A) or pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers,
  • the medicament optionally contains another one or more active agents that regulate the mammalian nervous system or alleviate mental illness.
  • the present invention also provides a method for modulating NMDA receptors, which comprises administering to an individual in need a compound of general formula (A) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, Enantiomers, diastereomers, mesoisomers, racemates, or mixtures thereof, or pharmaceutical compositions thereof.
  • the method optionally also includes administering another one or more active agents that modulate the mammalian nervous system or alleviate mental illness.
  • the present invention also provides compounds of general formula (A) or pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers,
  • the racemate or its mixture form or its pharmaceutical composition is used to regulate the NMDA receptor.
  • the application also optionally includes the administration of another one or more active agents that regulate the mammalian nervous system or alleviate mental illness.
  • the regulation includes inhibitory activity or antagonistic activity on the receptor.
  • the compound of general formula (A) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, internal The form of racemate, racemate or a mixture thereof acts on the TMD site of the NMDAR receptor.
  • the present invention also provides the compound of the general formula (A) of the present invention or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer
  • A general formula (A) of the present invention
  • a pharmaceutically acceptable salt cis-trans isomer, tautomer, enantiomer, diastereomer
  • the present invention also provides a method for treating neuropsychiatric diseases, which comprises administering a compound of general formula (A) or a pharmaceutically acceptable salt, cis, trans, and isoforms to an individual in need (for example, a mammalian individual, such as a human).
  • a mammalian individual such as a human
  • the present invention also provides compounds of general formula (A) or pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers,
  • the racemate or its mixture form or its pharmaceutical composition is used for the treatment of neuropsychiatric diseases.
  • the neuropsychiatric disease is pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, abstinence
  • amputation syndrome or attention deficit preferably any one or more of pain, depression, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder.
  • the neuropsychiatric disease is selected from pain, depression and neurodegenerative diseases.
  • the pain is selected from acute pain and chronic pain
  • the chronic pain includes but not limited to headache, maxillofacial pain, nape occipital pain, neck and shoulder pain, upper limb pain, chest pain , Abdominal pain, low back pain, genital tract pain, urinary tract pain, dysmenorrhea.
  • the pain includes, but is not limited to, traumatic pain, inflammatory pain, ischemic pain, pain caused by metabolic diseases, neurogenic pain, pain caused by deformity of tissues and organs, Labor pain, pain caused by malignant proliferative diseases.
  • the neurogenic pain includes but is not limited to phantom limb pain, stump pain, causalgia, postherpetic neuralgia, sympathetic nerve-related pain, and peripheral neuropathic pain. pain.
  • the pain caused by the metabolic disease includes, but is not limited to, pain caused by gout and pain caused by diabetes.
  • the pain caused by the malignant proliferative disease includes, but is not limited to, pain caused by tumors, such as leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer , Pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, brain tumors.
  • tumors such as leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer , Pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, brain tumors.
  • the pain is selected from moderate to severe pain.
  • the moderate to severe pain includes but is not limited to traumatic pain, labor pain, pain caused by tumor, and inflammatory pain.
  • the neurodegenerative diseases include but are not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease and Lewy body dementia, more preferably Alzheimer's disease.
  • the depression includes, but is not limited to, mild to severe depression, which generally conforms to WHO ICD-10 ("International Classification of Diseases"), American DSM-5 ("Manual of Diagnosis and Statistics of Mental Disorders") and The relevant diagnostic criteria of CCMD-3 ("Chinese Classification and Diagnostic Standards of Mental Disorders”), preferably moderate to severe depression.
  • WHO ICD-10 International Classification of Diseases
  • American DSM-5 Manual of Diagnosis and Statistics of Mental Disorders
  • CCMD-3 Choinese Classification and Diagnostic Standards of Mental Disorders
  • the depression includes but is not limited to mild depressive episodes, moderate depressive episodes, major depressive episodes with or without psychotic symptoms, and recurrent depressive episodes.
  • the present invention provides a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof,
  • R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
  • R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
  • R 4 , R 5 and R 6 are the same or different, and are each independently selected from hydrogen or alkyl;
  • R 7 is independently selected from hydrogen, alkyl or
  • a compound represented by the general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, wherein the alkyl group is selected from C1-C6 alkyl; the cycloalkyl group is selected from C3-C6 cycloalkyl; the haloalkyl group is selected from C1-C6 haloalkyl; the alkoxy group is selected from C1-C6 alkoxy; the thioalkyl group is selected from C1-C6 sulfur Alkyl; the N-containing heterocyclic group is selected from heterocyclic groups containing only one N atom; the amino group substituted by one or more alkyl groups is selected from the group substituted by one or more C1-C6 alkyl groups Amino; the aryl group is selected from phenyl or naphthyl; the halogen is selected from fluorine, chlorine, bromine or iodine.
  • a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, characterized in that the C1-C6 alkyl group is selected from methyl, ethyl, propyl , Butyl or pentyl; the C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 or -(CH 2 ) a CH(CX 3 ) 2 ; the C1-C6 alkoxy group is selected from -O-(CH 2 ) a CH 3 or -O-(CH 2 ) a CH(CH 3 ) 2 ; the C1-C6 thioalkyl group is selected from -S-(CH 2 ) a CH 3 or- S-(CH 2 ) a CH(CH 3 ) 2 ; the amino group substituted by one or more C1-C6 alkyl groups is selected from -NH-(CH 2 ) a CH 3 or -N[(CH 2 )
  • X represents halogen, and the halogen is selected from fluorine, chlorine, bromine or iodine; a is independently selected from any integer between 0-3.
  • a pharmaceutically acceptable salt of the compound represented by the general formula (A-1) is provided, which is characterized in that it is selected from any one of the compounds shown in Table 1.
  • a method for preparing a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, which is characterized in that it comprises:
  • Method 1 The compound of general formula (IV) is reacted with phthalimide to prepare the compound of general formula (V), and the compound of general formula (V) is prepared by deprotection reaction to obtain the compound of general formula (A-1) Compound
  • Method 2 The compound of general formula (IV) is prepared by substitution reaction to obtain the compound of general formula (VI), and the compound of general formula (VI) is prepared by hydrogenation reaction to obtain the compound of general formula (A-1);
  • R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
  • R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
  • R 5 and R 7 are hydrogen
  • R 4 and R 6 are each independently selected from hydrogen or alkyl
  • a method for preparing a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, which is characterized in that it comprises:
  • Method 1 The compound of general formula (VII) is reacted with di-tert-butyl dicarbonate to prepare the compound of general formula (VIII).
  • the compound of general formula (VIII) is alkylated to obtain the compound of general formula (IX).
  • the compound of formula (IX) is prepared by reduction reaction to obtain the compound of general formula (A-1);
  • Method 2 The compound of general formula (VII) is reacted with the compound of general formula SM-5 to prepare the compound of general formula (X), and the compound of general formula (X) is prepared by deprotection reaction to obtain the compound of general formula (A-1) Compound
  • R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
  • R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
  • R 5 is hydrogen
  • R 4 and R 6 are each independently selected from hydrogen or alkyl
  • R 7 is independently selected from alkyl or
  • a pharmaceutical composition which is characterized by comprising a therapeutically effective amount of a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.
  • the compound provided by the present invention is a reversible NMDAR antagonist with moderate affinity to NMDAR. It specifically acts on the TMD site and can inhibit the channel opening caused by excessive activation of NMDAR under pathological conditions, thereby avoiding Ca Excessive influx of 2+. Compared with the marketed NMDAR antagonists, the compound provided by the present invention can be quickly dissociated after being combined with NMDAR, thereby not affecting the normal function of NMDAR.
  • the compound provided by the present invention has basically the same activity as compound 1a1, but the compound provided by the present invention has a faster dissociation rate from NMDAR, which is significantly better than that of compound 1a1, and is comparable to the dissociation rate of memantine and NMDAR. It is suggested that the compound provided by the present invention not only has significant analgesic and antidepressant activities, but also has a more prominent therapeutic advantage of reducing psychiatric-like adverse reactions, and has greater clinical use value.
  • Step 1 Tert-butyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane (NH200002-int 1)
  • Step 2 3-((tert-butyldimethylsilyl)oxy)-5′-chlorospiro[cyclobutane-1,3′-indole]-2′-one (NH200002-int 2)
  • Step 3 3-((tert-butyldimethylsilyl)oxy)-5′-chloro-1′-ethylspiro[cyclobutane-1,3′-indole]-2′-one (NH200002-int 3)
  • Step 4 5′-chloro-1′-ethyl-3-hydroxyspiro[cyclobutane-1,3′-indoline]-2′-one (NH200002-int 4)
  • Step 5 2-(5'-Chloro-1'-ethyl-2'-oxospiro[cyclobutane-1,3'-indoline]-3-yl)isoindole-1,3 -Diketone (NH200002-int 5)
  • Step 6 3-Amino-5'-chloro-1'-ethylspiro[cyclobutane-1,3'-indoline]-2'-one (NH200002)
  • Step 2 6-Chloro-2-ethyl-1,4-dihydroisoquinoline-3(2H)-one (NH200003-int 2)
  • Step 3 3-((tert-butyldimethylsilyl)oxy)-6′-chloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane- 1,4′-isoquinoline]-3′-one (NH200003-int 3)
  • Step 4 6′-chloro-2′-ethyl-3-hydroxy-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200003-int 4)
  • Step 5 2-(6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline )-3-yl)isoindoline-1,3-dione (NH200003-int 5)
  • Step 6 3-Amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200003)
  • Example 2-2 trans-3-amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200003-1) and cis-3-amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1 ,4′-isoquinoline)-3′-one (NH200003-2)
  • NH200003 is separated by preparative HPLC (Mobile Phase A: H 2 O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL ⁇ min -1 ) to obtain NH200003-1 and NH200003, respectively -2.
  • Example 2 The ethylamine in step 1 of Example 2 was replaced with cyclopropylamine, and the target compound was prepared according to the method of Example 2.
  • Step 1 N-(2-(benzyloxy)ethyl)-2-(3-chlorophenyl)acetamide (NH200003T-int1)
  • the ethylamine was replaced with 2-benzyloxyethyl-1-amine, and the target compound was prepared according to the step 1 method of Example 2.
  • Step 2 6-Chloro-2-(2-hydroxyethyl)-1,4-dihydroisoquinolin-3(2H)-one (NH200003T-int2)
  • Step 3 2-(2-(((tert-butyldimethylsilyl)oxy)ethyl)-6-chloro-1,4-dihydroisoquinolin-3(2H)-one (NH200003T -int3)
  • Step 4 2'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6'-chloro-3-hydroxy-1',2'-dihydro-3'H- Spiro[cyclobutane-1,4′-isoquinoline]-3′-one (NH200003T-int4)
  • Step 5 2'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6'-chloro-3'-oxo-2',3'-dihydro-1' H-spiro[cyclobutane-1,4′-isoquinoline]methanesulfonate-3-yl ester (NH200003T-int5)
  • Step 6 3-azido-6′-chloro-2′-(2-hydroxyethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-iso Quinoline)-3′-one (NH200003T-int6)
  • Step 7 3-Amino-6′-chloro-2′-(2-hydroxyethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200003T)
  • the ethylamine was replaced with trifluoroethylamine, and the target compound was prepared according to the method of Example 2 with a purity of 92.5%.
  • the 3-chlorophenylacetic acid was replaced with 3-trifluoromethylphenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 95.13%.
  • the 3-chlorophenylacetic acid was replaced with 3-chloro-4-fluorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 94.02%.
  • the 3-chlorophenylacetic acid was replaced with 2,3-dichlorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 90.87%.
  • the 3-chlorophenylacetic acid was replaced with 2-fluoro-3-chlorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 98.60%.
  • the 3-chlorophenylacetic acid was replaced with 3-bromophenylacetic acid, and the target compound was prepared according to the steps in Example 2 with a purity of 99.0%.
  • Step 1 2-(6′-Bromo-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline ]-3-yl)isoindoline-1,3-dione (NH200099-int 1)
  • the 3-chlorophenylacetic acid was replaced with 3-bromophenylacetic acid, and the target compound was prepared according to the steps 1-5 of Example 2.
  • Step 2 2-(2′-Ethyl-6′-(methylthio)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′ -Isoquinoline)-3-yl)isoindoline-1,3-dione (NH200099-int 2)
  • Step 3 3-Amino-2′-ethyl-6′-(methylthio)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200099)
  • Step 1 2-(2′-Ethyl-6′-cyano-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquine (Linoline)-3-yl)isoindoline-1,3-dione (NH200088-int 1)
  • Step 2 3-Amino-2′-ethyl-6′-(cyano)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200088)
  • Step 1 6,7-Dichloro-2-ethyl-1,4-dihydroisoquinolin-3(2H)-one (NH200003H-int 1)
  • Step 2 6′,7′-Dichloro-2′-ethyl-3-hydroxy-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200003H-int 2)
  • Step 3 6′,7′-Dichloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquine Linyl]-3-yl methanesulfonate (NH200003H-int 3)
  • Step 4 6′,7′-Dichloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquine (Aline)-3-yl)isoindoline-1,3-dione (NH200003H-int 4)
  • Step 5 3-Amino-4',5'-dichloro-2'-ethyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline] -3′-ketone (NH200003H)
  • Example 15-2 Trans-3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200102-1) and cis-3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1 ,4′-isoquinoline)-3′-one (NH200102-2)
  • NH200102 is separated by preparative HPLC (Mobile Phase A: H 2 O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL ⁇ min -1 ) to obtain NH200102-1 and NH200102, respectively -2.
  • Example 16-2 trans-3-amino-6′-chloro-2′-n-propyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquine Morpholine]-3′-one (NH200003P-1) and cis-3-amino-6′-chloro-2′-n-propyl-1′,2′-dihydro-3′H-spiro[cyclobutane -1,4′-isoquinoline]-3′-one (NH200003P-2)
  • NH200003P is separated by preparative HPLC (Mobile Phase A: H 2 O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL ⁇ min -1 ) to obtain NH200003P-1 and NH200003P, respectively -2.
  • the ethylamine was replaced with aniline, and the target compound was prepared according to the method of Example 2 with a purity of 97.52%.
  • the 3-chlorophenylacetic acid was replaced with 3-fluorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 97.52%.
  • the ethylamine was replaced with cyclobutylamine, and the target compound was prepared according to the method of Example 2.
  • the purity was 91.0%
  • Step 1 2-(6′-Cyclopropyl-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-iso Quinoline)-3-yl)isoindoline-1,3-dione (NH2000105-int1)
  • Step 2 3-Amino-6′-cyclopropyl-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3 ′-Ketone (NH2000105)
  • Step 1 2-(2′-Ethyl-3′-oxo-6′-(pyrrolidin-1-yl)-2′,3′-dihydro-1′H-spiro[cyclobutane-1 ,4′-isoquinoline)-3-yl)isoindoline-1,3-dione (NH2000141-int1)
  • Step 2 3-Amino-2′-ethyl-6′-(pyrrolidin-1-yl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-iso Quinoline)-3′-one (NH2000141)
  • the pyrrolidine was replaced with dimethylamine, and the target compound was prepared according to the method of Example 23, with a purity of 98.0%.
  • Step 1 Tert-butyl (6'-chloro-2'-ethyl-3'-oxo 2', 3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline )-3-yl)carbamate (NH200074-int 1)
  • Step 2 Tert-butyl (6'-chloro-2'-ethyl-3'-oxo-2', 3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquine (Pholino)-3-yl)(methyl)carbamate (NH200074-int 2)
  • Step 3 6′-chloro-2′-ethyl-3-(methylamino)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200074)
  • Step 1 tert-butyl (2-(((6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1, 4′-Isoquinoline)-3-yl)amino)-2-oxoethyl)carbamate (NH200073-int1)
  • Step 2 2-Amino-N-(6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′ -Isoquinoline)-3-yl)acetamide (NH200073)
  • Step 1 6-Chloro-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (NH200193-int1)
  • Step 2 3-Amino-6′-chloro-2,2′-dimethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200193)
  • the 2-(chloromethyl)oxirane was replaced with 2-(chloromethyl)-3-methyloxirane, and the title compound was prepared according to the method 4-7 of Example 6, with a purity of 98.2%.
  • Test drug Compound 1a1 was prepared according to the method of CN106957285A, and its structure is as follows:
  • NH200003, NH200003P, NH200003H, NH200073, NH200088, NH200098, NH200099, NH200102, NH200105, NH200121, NH200123, NH200141 were prepared according to the above-mentioned examples.
  • Negative control Weigh an appropriate volume of DMSO as a stock solution.
  • Preparation method of working solution of drug delivery preparation before channel current test, dilute the negative control and test compound stock solution into an appropriate amount of extracellular fluid as the working solution. Dilute to an appropriate amount of extracellular fluid as a working fluid. See the table below for details:
  • the HEK293 cell line stably expressing the rat NR1/NR2B gene was used, and its gene number was NR1: NM_017010, NR2B: NM_012574.
  • the detection concentration of the test compound was 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, and 30 ⁇ M.
  • the negative control is 0.1% DMSO.
  • the electrode inner liquid used is prepared and divided into 1 mL per tube, and stored in a refrigerator at -20°C.
  • the newly melted electrode inner liquid is used in the experiment every day. All the electrode fluid is used up within one month. For more than one month, discard the inner liquid of the old electrode and reconfigure it.
  • the patch clamp test method is as follows:
  • the capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode with a microelectrode drawing instrument (P97, Sutter Instruments).
  • a microelectrode drawing instrument (P97, Sutter Instruments).
  • the microelectrode manipulator (Sutter instruments, MP285) was operated to contact the recording electrode on the cell, and negative pressure suction was applied to form a G ⁇ seal.
  • After forming the G ⁇ seal perform fast capacitance compensation, and then continue to give negative pressure to suck and break the cell membrane to form a whole-cell recording mode. Then perform slow capacitance compensation and record the film capacitance and series resistance. No leakage compensation is given.
  • the voltage stimulation scheme for whole-cell patch clamp recording of whole-cell NMDA current is as follows: when a whole-cell seal is formed, the cell membrane voltage is clamped at -70mV or -60mV.
  • the order of administration is as follows:
  • the first step extracellular fluid (NMDA 100 ⁇ M + glycine 10 ⁇ M);
  • Step 2 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M + test compound (0.3 ⁇ M));
  • Step 3 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M);
  • Step 4 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M + test compound (1 ⁇ M));
  • Step 5 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M);
  • Step 6 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M + test compound (3 ⁇ M));
  • Step 7 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M);
  • the eighth step extracellular fluid (NMDA 100 ⁇ M + glycine 10 ⁇ M + test compound (10 ⁇ M));
  • Step 9 Extracellular fluid (NMDA 100 ⁇ M + Glycine 10 ⁇ M);
  • the tenth step extracellular fluid (NMDA 100 ⁇ M + glycine 10 ⁇ M + test compound (30 ⁇ M)).
  • Test compound IC 50 ( ⁇ M) Compound 1a1 0.99 NH200003 3.7 NH200003P 2.2 NH200003H >10 NH200073 >30 NH200088 4.9 NH200098 >30 NH200099 >30 NH200102 1.1 NH200105 >30 NH200121 8.1 NH200123 >30 NH200141 >30
  • Test drugs Compound 1a1, NH200102, Ketamine, Memantine
  • N-methyl-D-aspartic acid purchased from Merck Life Sciences (Shanghai) Co., Ltd.
  • Glycine Glycine
  • Positive control Weigh an appropriate amount of NMDA and Glycine (glycine) to prepare a 100mM stock solution with ultrapure water. Store at -20°C after aliquoting.
  • the detection concentration of the test substance is diluted with DMSO into a diluent, and then the diluent is diluted with extracellular fluid to the concentration of the working solution.
  • concentration of DMSO in each working solution is 0.1%.
  • test product stock solution and the positive control substance stock solution are stored at -20°C, and the test product working solution and the positive control substance working solution are prepared on the day of the test and stored at room temperature.
  • HEK cell line stably expressing rNR2B channel, gene information: rNR1: Grin1, NM_017010; rNR2B: Grin2b, NM_012574
  • Cells were cultured in DMEM medium containing 10% fetal bovine serum and 10 ⁇ g/mL Blasticidin (blasticidin), 100 ⁇ g/mL Zeocin (bleomycin), 200 ⁇ g/mL Hygromycin B (hygromycin B), The culture temperature is 37°C, and the carbon dioxide concentration is 5%.
  • Cell passage Remove the old medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution, and incubate at 37°C for 1 min. When the cells detach from the bottom of the dish, add 5 mL of complete medium pre-warmed at 37°C. The cell suspension was gently pipetted to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 min. To expand or maintain the culture, inoculate the cells in a 6 cm cell culture dish, each cell culture dish, the amount of cells inoculated is 2.5 ⁇ 10 5 cells (final volume: 5 mL).
  • the cell density In order to maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.
  • the cells were separated with 0.25%-Trypsin-EDTA before the experiment, 2 ⁇ 10 4 cells were spread on a cover glass, tetracycline and DAP-5 were added, and cultured in a 24-well plate (final volume: 500 ⁇ L). After 18 hours, an experimental test was carried out.
  • cesium methanesulfonate 10mM NaCl
  • 2mM MgCl 2 ⁇ 6H 2 O 10mM EGTA (ethylene glycol bis(2-aminoethyl ether)tetraacetic acid)
  • 2mM Na 2 -ATP 2mM Na 2 -ATP
  • 0.2mM Na 2 -GTP 0.2mM Na 2 -GTP
  • 10mM HEPES 10mM HEPES
  • intracellular solution After the intracellular solution is prepared, aliquot into 1 mL per tube and store it in a refrigerator at -20°C. Use the newly thawed intracellular solution for daily experiments. All intracellular fluids are used up within one month. For more than one month, discard the old intracellular fluid and reconstitute it.
  • the capillary glass tube is drawn into a recording electrode with a microelectrode drawing instrument. Operate the microelectrode manipulator under the inverted microscope to touch the recording electrode to the cell, and apply negative pressure suction to form a G ⁇ seal. After the G ⁇ seal is formed, fast capacitance compensation (pF) is performed, and then negative pressure is continued to suck and break the cell membrane to form a whole-cell recording mode. Then perform slow capacitance compensation and record the film capacitance (pF) and series resistance. No leakage compensation is given.
  • pF fast capacitance compensation
  • the voltage stimulation scheme for whole-cell patch clamp recording of NR2B current is as follows: when a whole-cell seal is formed, the cell membrane voltage is clamped to -70mV. Record 600s in Gap-free mode.
  • the specific administration method is as follows: first administer NMDA+Glycine until the current is stable, then give the test product and the mixture of NMDA and Glycine until the current is stable, and finally rinse with NMDA+Glycine for 3-5 min.
  • the test data is collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
  • Test drugs Compound 1a1, NH200003, NH200102 were prepared according to the above examples.
  • Negative control Weigh a suitable volume of solvent as a stock solution.
  • Test compound When preparing the test product, calculate the theoretical weighing amount according to the design concentration and the required volume. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
  • Theoretical weighing amount (mg) theoretical concentration of test product (mg/mL) ⁇ preparation volume (mL)
  • Administration method use 20% PEG+80% water as the vehicle, and perform IP administration respectively.
  • the administration volume of each group was 10 mL/kg, and the administration time of the test drug was 30 minutes before the test.
  • Rats were anesthetized by intraperitoneal injection of 7% chloral hydrate (350 mg/kg), then the right lower limb was shaved with a shaver, and routinely iodophor disinfected, and a vertical line of about 0.5-1 cm in length was cut on the outer femur with a surgical blade. Make an incision, cut the skin and subcutaneous tissues, bluntly separate the muscles, find the main sciatic nerve behind the femur, expose the sciatic nerve, free the surrounding tissues, and free the nerve about 7mm before approaching its bifurcation, separated by four 4.0 surgical lines. 1mm for loose ligation.
  • the ligation thread should be based on the slight twitching and contraction of the rat's leg or toe caused by the first or a certain silk thread, and should not affect the blood supply of the epineurium and make the epineurium slightly sunken. , And then stitched layer by layer.
  • the operation time was 5-8 minutes, and each rat was intramuscularly injected with penicillin 3 times, 40,000 units each time.
  • the behavioral testing uses an inter-group control.
  • the mechanical pain threshold is measured before and 14 days after the operation.
  • the pain threshold on the 14th day is used to determine whether the model is successful (generally, the pain threshold is reduced by more than 25%), and
  • the experimental grouping was carried out to detect the mechanical pain threshold 30min after a single administration.
  • Paw withdrawal threshold (PWT) measurement Place rats in a transparent plexiglass box, and place one rat in each box, with a 0.5cm ⁇ 0.5cm pore size barbed wire at the bottom. Allow them to adapt for 10 minutes before the experiment.
  • Each stimulation is completed in 10 seconds, the maximum The value is 40g, measured 2-3 times, in order to avoid or reduce the influence of the previous stimulation on the subsequent stimulation effect, the interval of stimulation of the same part is 10min, and the average value is taken.
  • the PWT at 30min and 60min after the first day of administration were detected respectively, and the maximum analgesic effect after the drug was calculated.
  • the maximum analgesic effect% (PWT after administration-PWT before administration) * 100% / (50-PWT before administration).
  • the model group is compared with the sham operation group by T test, ## P ⁇ 0.01 is the difference is significant; each drug group is compared with the model group by T test, with * P ⁇ 0.05, **P ⁇ 0.01 is a significant difference. .
  • Test drug Imipramine (commercially available); Compound 1a1, NH200003, NH200102 were prepared according to the above examples.
  • Negative control Weigh a suitable volume of solvent as a stock solution.
  • Test compound When preparing the test product, calculate the theoretical sample weight according to the design concentration and the required volume. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
  • Theoretical concentration (mg/mL) dose (mg/kg) / administration volume (mL/kg)
  • Theoretical weighing amount (mg) theoretical concentration of test product (mg/mL) ⁇ preparation volume (mL)
  • mice All rats were pre-swimmed for 15 minutes (water temperature 23-25°C, water depth 17cm). On the next day (24 hours later), perform a formal swim for 5 minutes (water temperature and water depth are the same as the pre-swim).
  • the NH200102 group and the vehicle group were given the vehicle (30 or 60 mg/kg) by IP once 30 minutes before the formal swimming.
  • the positive control drug imipramine has two ways of administration, one is administered 23.5, 17 and 0.5 hours before the formal swimming (30mg/kg each time, 3 times in total); the other is 30 minutes before the formal swimming Before administration 1 time (30mg/kg). Rats in each group were tested for immobility time 30 minutes, 1 hour, 3 hours and 24 hours after administration.
  • the compound of the present invention can significantly reduce the immobility time of rats.
  • imipramine and NH200102 (30mg/kg) at the same dose, it can be seen that this The compound of the present invention has a better effect of improving immobility time for a long time; at high doses, the compound of the present invention (60mg/kg) is significantly better than imipramine (3*30mg/kg) in duration of efficacy. Imidazine (3h, 24h), suggesting that the compound of the present invention has a good antidepressant effect.
  • mice After stratified by body weight, rats were randomly divided into blank group (vehicle), MK-801 administration group, compound 1a1 administration group, and NH200003 administration group. After 30 minutes of intraperitoneal injection of the drug (or vehicle), the rat was put into the shock reflex test box for testing. The first is an adaptation time of 5 minutes (62dB of background sound). After the adaptation period, 5 separate shock reflex stimuli are given (block1, the results are not included in the analysis to reduce the animal’s initial response to a plateau level), and then 4 Two different types of tests (block2) appear in a pseudo-random manner.
  • shock reflex stimulation alone or the pre-pulse combined shock reflex stimulation response amplitude is expressed in AVG (special unit of the instrument) value.
  • AVG value indirectly reflects the shrinking response of the rat body.
  • Evaluation index: PPI% (1-prepulse combined shock reflex stimulus response amplitude/single shock reflex stimulus response amplitude) ⁇ 100. The larger the value, the deeper the degree of inhibition.

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Abstract

A 1',2'-dihydro-3'H-spiro[cyclobutane 1,4'-isoquinoline]-3'-one derivative and an application thereof; the derivative has the structure represented by formula (A), and said class of compound can be used to prepare a drug for treating neuropsychiatric diseases.

Description

一种1′,2′-二氢-3′H-螺[环丁烷1,4′-异喹啉]-3′-酮衍生物及其应用A 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivative and application thereof
本申请要求要求2019年11月18日提交的题为“一种1′,2′-二氢-3′H-螺[环丁烷1,4′-异喹啉]-3′-酮衍生物及其应用”的201911133562.2号中国申请的优先权，以及2020年3月20日提交的题为“一种1′,2′-二氢-3′H-螺[环丁烷1,4′-异喹啉]-3′-酮衍生物及其应用”的202010198664.9号中国申请的优先权，其内容整体援引加入本文。This application requires a submission entitled "A 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivative submitted on November 18, 2019 The priority of the Chinese application No. 201911133562.2, and its application on March 20, 2020, entitled “A 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′ -Isoquinoline]-3'-ketone derivatives and their applications" is the priority of the Chinese application No. 202010198664.9, the content of which is incorporated herein by reference in its entirety.
技术领域Technical field
本发明属于药物化学领域，具体涉及一种新的1′,2′-二氢-3′H-螺[环丁烷1,4′-异喹啉]-3′-酮类衍生物、其制备方法和包含该化合物的组合物，以及在医药领域的应用。The invention belongs to the field of medicinal chemistry, and specifically relates to a new 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivative, and its Preparation method, composition containing the compound, and application in the field of medicine.
背景技术Background technique
NMDAR(N-甲基-D-天冬氨酸受体)是一种谷氨酸离子型受体，主要对Ca 2+离子有渗透性，与甘氨酸和谷氨酸结合后可被激活，在兴奋性突触可塑性中起着重要作用。生理学上，它们激活和触发离子通道的开放并产生仅缓慢失活的输入电流。在病理状态下可导致NMDAR过度激活，是受体兴奋毒性的重要发病机制。NMDAR广泛分布于整个中枢神经***，并且在外周神经***中也存在，如神经元、星形胶质细胞和少突细胞([J].Nature,2005,438(7071):1162.)。NMDAR是一种异聚复合物，它通过三个不同的亚基NR1，NR2和NR3，与多种胞内蛋白相互作用，NR2有NR2A、NR2B、NR2C和NR2D四个不同的亚基([J].Pharmacology&therapeutics,2003,97(1):55-85.)。 NMDAR (N-methyl-D-aspartate receptor) is a kind of glutamate ion receptor, which is mainly permeable to Ca 2+ ions. It can be activated after combining with glycine and glutamate. Excitatory synaptic plasticity plays an important role. Physiologically, they activate and trigger the opening of ion channels and generate input currents that only slowly inactivate. Under pathological conditions, it can cause excessive activation of NMDAR, which is an important pathogenesis of receptor excitotoxicity. NMDAR is widely distributed throughout the central nervous system and also exists in the peripheral nervous system, such as neurons, astrocytes and oligodendrocytes ([J].Nature,2005,438(7071):1162.). NMDAR is a heteromeric complex that interacts with a variety of intracellular proteins through three different subunits NR1, NR2 and NR3. NR2 has four different subunits: NR2A, NR2B, NR2C and NR2D ([J ]. Pharmacology&therapeutics, 2003, 97(1):55-85.).
NMDAR的生理活性对于正常的神经功能是必需的，NMDAR的过度活化涉及到急性神经疾病，例如中风或颅脑损伤，并且涉及到慢性应激病症，例如神经退行性疾病，有许多病理学被认为与NMDAR活跃过度相关，因此其潜在地对NMDA拮抗剂敏感([J].Journal of neurochemistry,2006,97(6):1611-1626.)。The physiological activity of NMDAR is necessary for normal nerve function. Overactivation of NMDAR is related to acute neurological diseases, such as stroke or head injury, and chronic stress conditions, such as neurodegenerative diseases. Many pathologies are considered It is related to overactive NMDAR, so it is potentially sensitive to NMDA antagonists ([J].Journal of neurochemistry,2006,97(6):1611-1626.).
越来越多的证据表明NMDAR在疼痛状态下诱导和维持中枢敏化的重要性。此外NMDAR也可能介导外周致敏和内脏痛([J].Nature,2005,438(7071):1162.)。大量临床前数据支持NMDA拮抗剂可能治疗阿片诱导的难治愈性的疼痛，术后疼痛，癌痛。另有研究表明典型的抗抑郁药改变了NMDA受体甘氨酸位点的亲和力，NMDAR功能降低有助于抗抑郁反应，向具有难治性抑郁症的患者通过静脉内途径施用单一亚麻醉剂量的***显著改善他们的病情，而且获得的抗抑郁效果持续一个星期([J].Archives of general psychiatry,2006,63(8):856-864.)，目前S-***鼻喷剂
Figure PCTCN2020129826-appb-000001
已于2019年3月在美国获批上市，用于辅助治疗治疗抵抗性抑郁。 More and more evidences show the importance of NMDAR in inducing and maintaining central sensitization in painful conditions. In addition, NMDAR may also mediate peripheral sensitization and visceral pain ([J].Nature,2005,438(7071):1162.). A large amount of preclinical data supports that NMDA antagonists may treat opioid-induced incurable pain, postoperative pain, and cancer pain. Other studies have shown that typical antidepressants change the affinity of the glycine site of the NMDA receptor. Reduced NMDAR function contributes to the antidepressant response. A single subanaesthetic dose of ketamine is administered intravenously to patients with refractory depression. Significantly improve their condition, and the antidepressant effect obtained lasts for a week ([J].Archives of general psychiatry,2006,63(8):856-864.), the current S-ketamine nasal spray
Figure PCTCN2020129826-appb-000001
It has been approved for marketing in the United States in March 2019 and is used as an adjuvant therapy for the treatment of resistant depression.
根据NMDAR的作用位点，它们可以被大致归类为三类，包括非竞争性(或变构)拮抗剂(ATD位点)，例如艾芬地尔，RGH-896，EVT101；竞争性拮抗剂(LBD位点)，例如GLYX- 13，NRX-1074；非竞争性拮抗剂，通道孔阻断剂(TMD位点)，例如***，右美沙芬，美金刚(memantine)等。但目前上市的NMDAR拮抗剂中依然普遍存在多种副作用限制其使用，如幻觉、混乱、人格障碍、梦魇、激动、注意力衰退、情绪改变、抽搐、镇静等([J].Biochemical pharmacology,2003,66(6):877-886.)。与NMDAR通道孔拮抗剂的亲和力越高，其与NMDAR的结合越慢，较慢的结合速度导致了Ca 2+的持续内流，则需达到很高的药物浓度才能完全结合受体，如MK-801，其对NMDAR的解离速度较慢，导致较大的拟精神副作用。 According to the site of action of NMDAR, they can be roughly classified into three categories, including non-competitive (or allosteric) antagonists (ATD sites), such as ifendil, RGH-896, EVT101; competitive antagonists (LBD site), such as GLYX-13, NRX-1074; non-competitive antagonists, channel hole blockers (TMD site), such as ketamine, dextromethorphan, memantine, etc. However, there are still many side effects in the currently marketed NMDAR antagonists that restrict their use, such as hallucinations, confusion, personality disorders, nightmares, agitation, attention decline, mood changes, convulsions, sedation, etc. ([J].Biochemical pharmacology,2003 ,66(6):877-886.). The higher the affinity with the NMDAR channel hole antagonist, the slower its binding to NMDAR. The slower binding speed results in the continuous influx of Ca 2+. A high drug concentration is required to fully bind the receptor, such as MK. -801, which has a slower dissociation rate of NMDAR, leading to greater psychiatric side effects.
目前已有研究证实，像MK-801这样的高亲和力非竞争性NMDA受体拮抗剂虽然能够阻止NMDAR的激活，阻止Ca 2+内流，但因显著的拟精神样不良反应限制其应用。相反，低亲和力、非竞争性NMDAR拮抗剂(如美金刚)可降低毒性，这归功于美金刚阻断和离去NMDAR的速度更快([J].European journal of pharmacology,1996,317(2-3):377-381)。另有研究表明，美金刚在阿尔茨海默氏病治疗中的临床良好耐受性和症状作用归因于其对NMDA受体通道的中等亲和力以及与NMDAR的快速解离([J].Neuropharmacology,2009,56(5):866-875.)；还有研究认为，美金刚比地佐西平(dizocilpine)具有更好的抑制恢复动力学，被认为是美金刚临床耐受性更好的主要决定因素([J].ACS chemical neuroscience,2018,9(11):2722-2730.)。因此能够与NMDAR快速解离是NMDAR拮抗剂的研发关键之一。 At present, studies have confirmed that, although high-affinity non-competitive NMDA receptor antagonists like MK-801 can prevent the activation of NMDAR and prevent Ca 2+ influx, their application is limited due to significant psychiatric-like adverse reactions. On the contrary, low-affinity, non-competitive NMDAR antagonists (such as memantine) can reduce toxicity, thanks to the fact that memantine blocks and leaves NMDAR faster ([J].European journal of pharmacology,1996,317(2 -3):377-381). Other studies have shown that the clinically well tolerated and symptomatic effects of memantine in the treatment of Alzheimer’s disease are due to its moderate affinity for NMDA receptor channels and rapid dissociation from NMDAR ([J].Neuropharmacology ,2009,56(5):866-875.); There are also studies that suggest that memantine has better inhibition and recovery kinetics than dizocilpine, and is considered to be the main reason for the better clinical tolerance of memantine Determinants ([J].ACS chemical neuroscience,2018,9(11):2722-2730.). Therefore, the ability to quickly dissociate from NMDAR is one of the keys to the development of NMDAR antagonists.
CN106957285A公开了一种氨基环丁烷衍生物，为NMDAR拮抗剂，用于抑郁和慢性疼痛的潜在治疗，其结构如下所示：CN106957285A discloses an aminocyclobutane derivative, which is an NMDAR antagonist, used for the potential treatment of depression and chronic pain, and its structure is as follows:
Figure PCTCN2020129826-appb-000002
Figure PCTCN2020129826-appb-000002
发明内容Summary of the invention
本发明提供了一种化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，其中化合物如通式(A)所示：The invention provides a compound or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, racemate Or its mixture form, characterized in that the compound is represented by general formula (A):
Figure PCTCN2020129826-appb-000003
Figure PCTCN2020129826-appb-000003
其中：among them:
R 1独立地选自氢、烷基、烯基、炔基、羟基、被一个或多个烷基取代的或非取代的氨基、烷氧基、硫代烷基、氰基、卤代烷基、环烷基、杂环基、取代或非取代的杂芳基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxy, amino substituted or unsubstituted by one or more alkyl groups, alkoxy, thioalkyl, cyano, haloalkyl, ring Alkyl, heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
R 2和每个R 3相同或不同，且各自独立地选自氢、卤素、烷基、烯基、炔基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及杂环基； R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and heterocyclic groups;
R 4、R 5和每个R 6相同或不同，且各自独立地选自氢、烷基、卤代烷基、羟基、烷氧基、硫代烷基、卤素和氰基； R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, thioalkyl, halogen and cyano;
R 7独立地选自氢、烷基、卤代烷基和
Figure PCTCN2020129826-appb-000004
R 7 is independently selected from hydrogen, alkyl, haloalkyl and
Figure PCTCN2020129826-appb-000004
n 1独立地为0～1之间的任意一个整数；n 2独立地为0～3之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1～3之间的任意一个整数；n 5独立地为1～3之间的任意一个整数； n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 3; n 3 is independently any integer between 1 and 2; n 4 is independently Any integer between 1 and 3; n 5 is independently any integer between 1 and 3;
所述烷基、烷氧基和硫代烷基各自独立地任选地被一个或多个选自卤素和Rx的取代基取代，所述卤代烷基中的烷基任选地被一个或多个Rx取代基取代，所述环烷基和杂环基各自独立地任选地被一个或多个选自卤素、Rx、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6硫代烷基的取代基取代；其中，Rx每次出现时独立选自-OH、-NH 2、-NO 2和-CN。 The alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more Rx substituents are substituted, the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more selected from halogen, Rx, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Substituents of C1-C6 thioalkyl are substituted; wherein each occurrence of Rx is independently selected from -OH, -NH 2 , -NO 2 and -CN.
具体实施方案Specific implementation plan
一般术语和定义General terms and definitions
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art to which the present invention belongs. If there is a conflict, the definition provided in this application shall prevail. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解， 上述术语如“包括”可以涵盖封闭式的含义，即“由…组成”。The terms "including", "comprising", "having", "containing" or "involving" and other variants herein are inclusive or open-ended, and do not exclude other unlisted elements or method steps . Those skilled in the art should understand that the above-mentioned terms such as "including" can encompass the closed meaning, that is, "consisting of".
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。The term "one (species) or more (species)" or similar expressions "at least one (species)" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。When the lower limit and the upper limit of a numerical range are disclosed, any numerical value and any included range falling within the range are specifically disclosed. In particular, each value range of the value disclosed herein should be understood to mean each value and range covered in a wider range.
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C1-C6”或“C1-6”涵盖1-6个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C2-C6等，以及C1、C2、C3、C4、C5、C6等。例如，表述“C3-C6”或“C3-6”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C3-C5、C4-C6、C5-C6、C4-C5等以及C3、C4、C5、C6等。又例如，表述“三元至七元”应理解为涵盖其中的任意亚范围以及每个点值，例如三元至五元、三元至六元、四元至五元、四元至六元、四元至七元、五元至六元、五元至七元、六元至七元，等，以及三、四、五、六、七元，等。本文中其他类似的表述也应当以类似的方式理解。表述“n 2为0～3之间的任意一个整数”包括例如0～2的任意一个整数、2～3的任意一个整数等，例如1、2、3。 The expression mn used herein refers to the range from m to n and the sub-range composed of each point value therein and each point value. For example, the expression "C1-C6" or "C1-6" covers the range of 1-6 carbon atoms, and should be understood to also cover any subrange and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C2-C6, etc., and C1, C2, C3, C4, C5, C6, etc. For example, the expression "C3-C6" or "C3-6" should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C5, C4-C6, C5-C6, C4 -C5 etc. and C3, C4, C5, C6 etc. For another example, the expression "three yuan to seven yuan" should be understood as covering any sub-range and each point value, such as three yuan to five yuan, three yuan to six yuan, four yuan to five yuan, four yuan to six yuan , Four yuan to seven yuan, five yuan to six yuan, five yuan to seven yuan, six yuan to seven yuan, etc., and three, four, five, six, seven yuan, etc. Other similar expressions in this article should also be understood in a similar way. The expression "n 2 is any integer between 0 and 3" includes, for example, any integer from 0 to 2, any integer from 2 to 3, and the like, such as 1, 2, 3.
术语“任选”、“任选地”或“任选存在”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况和不出现的情况。例如，“任选存在的键”是指该键可以存在或可以不存在，并且该描述包括单键、双键或三键等。The term "optional", "optionally" or "optionally present" means that the event or situation described later can but does not necessarily occur, and the description includes situations in which the event or situation occurs and situations in which it does not occur. For example, "optionally present bond" means that the bond may or may not exist, and the description includes single, double, or triple bonds, and the like.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物或者像实施例中特定的实例、子类。应了解术语“任选取代的”与术语“取代或未取代的”可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被特定取代基所取代。除非其他方面表明，任选取代的基团可以在该基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自特定基团的一个或多个取代基所取代时，那么取代基可以相同或不同地在各个位置取代。As described in the present invention, the compounds of the present invention may be optionally substituted by one or more substituents, such as the above formula compounds or specific examples or subclasses in the examples. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" can be used interchangeably. Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optionally substituted group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be substituted at each position with the same or different substitutions.
取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。Combinations of substituents and/or variables are only permissible when such combinations form stable compounds. When it is described that a certain substituent does not exist, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure can make the compound reach a stable state.
当描述基团中的每个碳原子可以任选地被杂原子代替时，条件是未超过基团中的所有原子在当前情况下的正常原子价，并且形成稳定的化合物。When it is described that each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group under the current situation is not exceeded, and a stable compound is formed.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent. When a bond of a substituent is shown as a bond connecting two atoms through a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.
当任何变量(例如R)，以及带有标记的变量(例如R 3、R 6等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独立的。 When any variable (such as R), as well as a variable with a label (such as R 3 , R 6, etc.) occurs more than once in the composition or structure of a compound, its definition in each case at each occurrence Is independent.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“独立地为”应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless it is clearly indicated in other ways, the description method used in the present invention should be understood in a broad sense, which can mean the expression between the same symbols in different groups The specific options do not affect each other, and it can also mean that the specific options expressed by the same symbol do not affect each other in the same group.
术语“取代”表示化合物或基团上的一个或多个氢原子被其他原子或基团代替。条件是形成稳定的价态或化合物。表述“非取代”又可以理解为“未被取代”的。应当理解，取代基为氢时，这也可以表示对应的基团为“非取代”或者“未被取代”的。The term "substituted" means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is to form a stable valence state or compound. The expression "non-substituted" can also be understood as "unsubstituted". It should be understood that when the substituent is hydrogen, this can also mean that the corresponding group is "unsubstituted" or "unsubstituted".
术语“氢(H)”表示单个氢原子。这样的原子团可以与其他基团连接，譬如与氧原子相连，形成羟基基团。The term "hydrogen (H)" means a single hydrogen atom. Such atomic groups can be connected to other groups, for example, to oxygen atoms to form a hydroxyl group.
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。烷基基团的实例包括但不限于甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)、异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)、异丁基(i-Bu、-CH 2CH(CH 3) 2)、仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)、叔丁基(t-Bu、-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)、正庚基、正辛基，等等。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), iso Propyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2- Butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl ( -CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl Base-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4 -Methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-Methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl(-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and so on.
“亚基”是指在含有自由价电子的碳原子上再去掉一个氢原子而得到的，具有两个与分子其他部分连接的连接位点的基团。例如“亚烷基”或“烷基亚基”指饱和的直链或支链的二价烃基。"Subunit" refers to a group obtained by removing one more hydrogen atom from a carbon atom containing free valence electrons, and having two connection sites to other parts of the molecule. For example, "alkylene" or "alkylene" refers to a saturated linear or branched divalent hydrocarbon group.
术语“亚烷基”，在本文中单独或与其他基团组合使用时，指直链或支链的饱和的二价烃基。例如，术语“C1-C3亚烷基”指具有1-3个碳原子的亚烷基，例如亚甲基、亚乙基、亚丙基。本文结构式中的括号表示结构单元的重复。例如，n 2表示括号中的结构单元的重复数目，所述括号中的结构单元为被一个R 6取代的亚甲基。当n 2为1、2或3时，括号中的结构单元重复而得到的结构片段为C1-C3亚烷基，并且亚烷基的每个-(CH 2)-结构被一个R 6取代。 The term "alkylene", when used alone or in combination with other groups herein, refers to a linear or branched saturated divalent hydrocarbon group. For example, the term "C1-C3 alkylene" refers to an alkylene group having 1 to 3 carbon atoms, such as methylene, ethylene, and propylene. The brackets in the structural formula herein indicate the repetition of the structural unit. For example, n 2 represents the repeating number of the structural unit in the brackets, and the structural unit in the brackets is a methylene group substituted with one R 6. When n 2 is 1, 2 or 3, the structural fragment obtained by repeating the structural unit in the brackets is a C1-C3 alkylene group, and each -(CH 2 )- structure of the alkylene group is substituted with one R 6.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基可以具有2-8个碳原子，即“C 2- 8烯基”，例如C 2- 4烯基、C 3- 4烯基。烯基的非限制性实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯 基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基等。 The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Alkenyl group can have 2 to 8 carbon atoms, i.e., "C 2 - 8 alkenyl group", for example, C 2 - 4 alkenyl, C 3 - 4 alkenyl group. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基可以具有2-8个碳原子，即“C 2- 8炔基”，例如C 2- 4炔基、C 3- 4炔基。炔基的非限制性实例包括但不限于乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基等。 The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms. An alkynyl group can have 2 to 8 carbon atoms, i.e., "C 2 - 8 alkynyl group", for example, C 2 - 4 alkynyl, C 3 - 4 alkynyl group. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
术语“环烷基”是指由碳原子和氢原子组成的饱和的环状烃基，优选包含1或2个环。所述环烷基可以是单环、稠合多环、桥环或螺环结构。环烷基可以具有3-10个碳原子，即“C3-C10环烷基”，例如C3-C8环烷基、C3-C6环烷基、C5环烷基、C6环烷基、C7环烷基。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.2.1]庚基和螺[3.3]庚基等。该术语还涵盖这样的情况，其中的C原子可以被氧代(＝O)取代。The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group may be a monocyclic ring, a fused polycyclic ring, a bridged ring or a spiro ring structure. Cycloalkyl groups can have 3-10 carbon atoms, that is, "C3-C10 cycloalkyl", such as C3-C8 cycloalkyl, C3-C6 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl base. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like. The term also covers situations where the C atom can be replaced by oxo (=O).
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团可以含有1-12个碳原子。根据本发明的一个实施方案，烷氧基基团可以含有1-6个碳原子。根据本发明的另一个实施方案，烷氧基基团可以含有1-5或1-4个碳原子。根据本发明的又一个实施方案，烷氧基基团可以含有1-5个碳原子。所述烷氧基基团任选地被一个或多个本发明描述的取代基所取代或不取代。The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group may contain 1-12 carbon atoms. According to an embodiment of the present invention, the alkoxy group may contain 1-6 carbon atoms. According to another embodiment of the invention, the alkoxy group may contain 1 to 5 or 1 to 4 carbon atoms. According to yet another embodiment of the present invention, the alkoxy group may contain 1 to 5 carbon atoms. The alkoxy group is optionally substituted or unsubstituted with one or more substituents described in the present invention.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)、乙氧基(EtO、-OCH 2CH 3)、1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)、2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)、1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)、2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)、2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)、2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)、1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)、2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)、3-戊氧基(-OCH(CH 2CH 3) 2)、2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)、3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)、3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)、2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentoxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy Group (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), etc.
术语“硫代烷基”表示烷基基团通过硫原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述硫代烷基基团可以含有1-12个碳原子。根据本发明的一个实施方案，硫代烷基基团可以含有1-6个碳原子。根据本发明的另一个实施方案，硫代烷基基团可以含有1-5或1-4个碳原子。根据本发明的又一个实施方案，烷氧基基团可以含有1-5个碳原子。所述硫代烷基基团任选地被一个或多个本发明描述的取代基所取代或不取代。The term "thioalkyl" means that the alkyl group is connected to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the thioalkyl group may contain 1-12 carbon atoms. According to an embodiment of the present invention, the thioalkyl group may contain 1-6 carbon atoms. According to another embodiment of the present invention, the thioalkyl group may contain 1-5 or 1-4 carbon atoms. According to yet another embodiment of the present invention, the alkoxy group may contain 1 to 5 carbon atoms. The thioalkyl group is optionally substituted or unsubstituted with one or more substituents described in the present invention.
硫代烷基基团的实例包括，但并不限于，甲硫基(MeS、-SCH 3)、乙硫基(EtS、-SCH 2CH 3)、1-丙硫基(n-PrS、n-丙硫基、-SCH 2CH 2CH 3)、2-丙硫基(i-PrS、i-丙硫基、-SCH(CH 3) 2)、1-丁硫基(n-BuS、n-丁硫基、-SCH 2CH 2CH 2CH 3)、2-甲基-l-丙硫基(i-BuS、i-丁硫基、-SCH 2CH(CH 3) 2)、2-丁硫基(s-BuS、s-丁硫基、-SCH(CH 3)CH 2CH 3)、2-甲基-2- 丙硫基(t-BuS、t-丁硫基、-SC(CH 3) 3)、1-戊硫基(n-戊硫基、-SCH 2CH 2CH 2CH 2CH 3)、2-戊硫基(-SCH(CH 3)CH 2CH 2CH 3)、3-戊硫基(-SCH(CH 2CH 3) 2)、2-甲基-2-丁硫基(-SC(CH 3) 2CH 2CH 3)、3-甲基-2-丁硫基(-SCH(CH 3)CH(CH 3) 2)、3-甲基-l-丁硫基(-SCH 2CH 2CH(CH 3) 2)、2-甲基-l-丁硫基(-SCH 2CH(CH 3)CH 2CH 3)，等等 Examples of thioalkyl groups include, but are not limited to, methylthio (MeS, -SCH 3 ), ethylthio (EtS, -SCH 2 CH 3 ), 1-propylthio (n-PrS, n -Propylthio, -SCH 2 CH 2 CH 3 ), 2-propylthio (i-PrS, i-propylthio, -SCH(CH 3 ) 2 ), 1-butylthio (n-BuS, n -Butylthio, -SCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH 2 CH(CH 3 ) 2 ), 2- Butylthio (s-BuS, s-butylthio, -SCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC( CH 3 ) 3 ), 1-pentylthio (n-pentylthio, -SCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentylthio (-SCH(CH 3 )CH 2 CH 2 CH 3 ) , 3-pentylthio (-SCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butylthio (-SC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butane Sulfuryl (-SCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l-butylsulfanyl (-SCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l-butylsulfide Base (-SCH 2 CH(CH 3 )CH 2 CH 3 ), etc.
术语“杂环基”或“杂环烃基”表示饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含4至6个环原子，其中1～3个(例如1、2和3个)是杂原子。“杂环基”或“杂环烃基”不具备芳香性。该术语还涵盖这样的情况，其中的C原子可以被氧代(＝O)取代和/或环上的S原子可以被1个或2个氧代(＝O)取代和/或环上的P原子可以被1个或2个氧代(＝O)取代。The term "heterocyclic group" or "heterocyclic hydrocarbon group" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, Oxygen, the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 4 to 6 ring atoms, of which 1 to Three (e.g. 1, 2, and 3) are heteroatoms. "Heterocyclic group" or "heterocyclic hydrocarbon group" does not possess aromaticity. The term also covers situations in which the C atom can be replaced by oxo (=O) and/or the S atom on the ring can be replaced by 1 or 2 oxo (=O) and/or the P on the ring Atoms can be substituted with 1 or 2 oxo (=O).
杂环基可以是例如四元环，如氮杂环丁烷基、氧杂环丁烷基；或者五元环，如四氢呋喃基、二噁烷基(dioxolinyl)、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、氧代吡咯烷基、2-氧代咪唑烷-1-基；或者六元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、1,1-二氧代-1,2-噻嗪烷-2-基或三噻烷基；或者七元环，如二氮杂
Figure PCTCN2020129826-appb-000005
基环。任选地，杂环基可以是苯并稠和的。 The heterocyclic group may be, for example, a four-membered ring, such as azetidinyl, oxetanyl, or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, Pyrazolidinyl, pyrrolinyl, oxopyrrolidinyl, 2-oxoimidazolidine-1-yl; or six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl , Thiomorpholinyl, piperazinyl, 1,1-dioxo-1,2-thiazin-2-yl or trithiaalkyl; or seven-membered ring, such as diaza
Figure PCTCN2020129826-appb-000005
Base ring. Optionally, the heterocyclic group may be benzo-fused.
杂环基可以是双环的，不受其限制，例如五元并五元环，如六氢环戊烷[c]吡咯-2(1H)-基)环；或者五元并六元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。The heterocyclic group can be bicyclic without limitation, for example, a five-membered five-membered ring, such as hexahydrocyclopentane [c]pyrrole-2(1H)-yl) ring; or a five-membered six-membered bicyclic ring, such as Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.
如上文所提到的，杂环可以是不饱和的，即其可以包含一个或多个双键，不受其限制，例如包含氮原子的不饱和的杂环可以是1,6-二氢嘧啶、1,2-二氢嘧啶、1,4-二氢嘧啶、1,6-二氢吡啶、1,2-二氢吡啶、1,4-二氢吡啶、2,3-二氢-1H-吡咯、3,4-二氢-1H-吡咯、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基环，包含氧原子的不饱和的杂环可以是2H-吡喃、4H-吡喃、2,3-二氢呋喃，包含硫原子的不饱和的杂环可以是2H-噻喃、4H-噻喃。杂环可以是苯并稠和的，不受其限制，例如二氢异喹啉基环。As mentioned above, the heterocycle may be unsaturated, that is, it may contain one or more double bonds without limitation. For example, an unsaturated heterocycle containing a nitrogen atom may be 1,6-dihydropyrimidine , 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1H- Pyrrole, 3,4-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H -[1,4] Thiazinyl ring, the unsaturated heterocyclic ring containing oxygen atom can be 2H-pyran, 4H-pyran, 2,3-dihydrofuran, the unsaturated heterocyclic ring containing sulfur atom can be It is 2H-thiopyran and 4H-thiopyran. The heterocyclic ring may be benzo-fused without limitation, such as a dihydroisoquinolinyl ring.
术语“芳基”表示含有6-14个环原子、或6-12个环原子、或6-10个环原子的单环、双环和三环的碳环体系，其中至少一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic . The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group is optionally substituted with one or more substituents described in the present invention.
术语“杂芳基”应理解为优选表示一价的单环、双环或三环芳族环***，其具有5、6、7、8、9或10个环原子(“五元至十元杂芳基”)，特别是5或6或9或10个环原子，并且环原子中包含至少一个(适合地为1-4个，更适合地为1、2或3个)可以相同或不同的杂原子，所述杂原子是例如氧、氮或硫。此外，在每种情况下杂芳基可以是苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等，以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲 唑基、吲哚基、异吲哚基等；或者吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或者吖辛因基(azocinyl)、吲嗪基、嘌呤基等，以及它们的苯并衍生物；或者噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、咔唑基、吖啶基等。The term "heteroaryl" should be understood to preferably mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms ("5 to 10 membered hetero Aryl"), especially 5 or 6 or 9 or 10 ring atoms, and at least one of the ring atoms (suitably 1-4, more suitably 1, 2 or 3) may be the same or different Heteroatoms such as oxygen, nitrogen or sulfur. Furthermore, the heteroaryl group may be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc., and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazole Group, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, Isoquinolinyl, etc.; or azocinyl, indazinyl, purinyl, etc., and their benzo derivatives; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, Naphthyridinyl, carbazolyl, acridinyl, etc.
术语“药学上可接受的”是指在正常的医学判断范围内与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比且能有效用于目的用途。The term "pharmaceutically acceptable" refers to contact with the patient's tissues within the scope of normal medical judgment without undue toxicity, irritation, allergic reactions, etc., has a reasonable ratio of advantages and disadvantages, and can be effectively used for the purpose.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present invention are also included in the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.
根据常规方法通过拆分外消旋混合物可获得光学纯对映异构体，例如通过使用具有光学活性的酸或碱形成非对映异构体盐，或者通过形成共价非对映异构体。非对映异构体的混合物可基于它们的物理和/或化学差异，通过本领域已知的方法(例如通过色谱法或分级结晶)分离成单一的非对映异构体。然后，从分离的非对映异构体盐中释放具有光学活性的对映体碱或酸。另一种分离消旋对映异构体的方法可使用手性色谱法(例如手性HPLC柱)，被分离的手性异构体可以在分离前进行常规衍生化处理或不衍生化，取决于何种方法可以实现更有效地分离手性异构体。还可以使用酶法来分离衍生化的或没被衍生化的手性异构体。Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by using optically active acids or bases to form diastereomeric salts, or by forming covalent diastereomers . A mixture of diastereomers can be separated into single diastereomers based on their physical and/or chemical differences by methods known in the art (for example, by chromatography or fractional crystallization). Then, the optically active enantiomeric base or acid is released from the separated diastereomeric salt. Another method for separating racemic enantiomers can use chiral chromatography (such as a chiral HPLC column). The separated chiral isomers can be subjected to conventional derivatization or non-derivatization before separation, depending on Which method can achieve more effective separation of chiral isomers? Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers.
另外，本发明的化合物可以互变异构体的形式存在。本发明包括本发明的化合物所有可能的互变异构体，也包括单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。In addition, the compounds of the present invention may exist in the form of tautomers. The present invention includes all possible tautomers of the compounds of the present invention, and also includes a single tautomer or the form of any mixture of the tautomers in any ratio.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number.
在本发明的范围内还包括本发明的化合物的代谢产物，即在给药本发明的化合物时体内形成的物质。化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过试验的方法进行表征。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are the metabolites of the compounds of the present invention, that is, substances formed in the body when the compounds of the present invention are administered. The metabolites of compounds can be identified by techniques well known in the art, and their activity can be characterized by experimental methods. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method in which the compound of the present invention is contacted with a mammal for a time sufficient to produce its metabolite.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中， 保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。本文所述的保护基可以通过常规的保护基实现，例如，在Protective Groups in Organic Synthesis(Greene等人，第4版，Wiley-Interscience(2006))中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The present invention also encompasses the compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any related molecules may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. The protecting groups described herein can be implemented by conventional protecting groups, for example, those described in Protective Groups in Organic Synthesis (Greene et al., 4th edition, Wiley-Interscience (2006)). These references are passed Cite this article. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些物质。“药学上可接受的载体”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。The term "pharmaceutically acceptable carrier" refers to those substances that have no obvious stimulating effect on organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carriers" include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服或肠胃外(包括脑室内、静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。特别是注射或口服。The terms "administration" or "administration" and the like refer to methods that enable the compound or composition to be delivered to the desired biological site of action. These methods include but are not limited to oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like. Especially injection or oral administration.
如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。As used herein, the term "treatment" includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, and promoting Relief of disease or symptom, or cessation of symptoms of disease or symptom, and extended to include prevention. "Treatment" also includes achieving therapeutic benefits and/or preventive benefits. Therapeutic benefit refers to eradicating or improving the condition being treated. In addition, the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease. Although the patient may still have the underlying disease, the improvement of the patient's disease can be observed. Prophylactic benefit means that the patient uses the composition to prevent the risk of a certain disease, or when the patient has one or more physiological conditions of the disease, even though the disease has not been diagnosed.
针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量”是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With regard to drugs, drug units or active ingredients, the terms "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refer to a sufficient amount of a drug or medicament that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general conditions of the individual, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"Individual" as used herein includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
术语“神经精神类疾病”是指神经类疾病与精神类疾病的总称，包含神经类疾病和/或精神类疾病。The term "neuropsychiatric diseases" refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。The following detailed description of the invention is intended to illustrate non-limiting embodiments, so that other skilled in the art can more fully understand the technical solution of the present invention, its principle and its practical application, so that other skilled in the art can modify and modify in many forms. The present invention is implemented so that it can be optimally adapted to the requirements of a specific application.
本发明的化合物Compound of the present invention
本发明旨在提供一种全新的NMDAR抑制剂，属于通道孔阻断剂(TMD位点)，可抑 制在病理性条件的NMDA过度激活而导致的通道开放而避免Ca 2+的过多内流，而不影响NMDAR的正常功能。本发明所述的NMDAR拮抗剂是一种可逆性的NMDAR拮抗剂，结合后解离非常迅速，而不影响NMDA受体的正常功能。 The present invention aims to provide a new NMDAR inhibitor, which belongs to the channel hole blocker (TMD site), which can inhibit the channel opening caused by excessive activation of NMDA in pathological conditions and avoid excessive Ca 2+ influx , Without affecting the normal function of NMDAR. The NMDAR antagonist of the present invention is a reversible NMDAR antagonist, and it dissociates very quickly after being combined without affecting the normal function of the NMDA receptor.
本发明的目的在于提供一种具有药物活性的1′,2′-二氢-3′H-螺[环丁烷1,4′-异喹啉]-3′-酮类衍生物及其在医疗领域的应用。The purpose of the present invention is to provide a 1′,2′-dihydro-3′H-spiro[cyclobutane 1,4′-isoquinoline]-3′-one derivative with pharmaceutical activity and its use in Applications in the medical field.
在一方面，本发明提供化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其中化合物如通式(A)所示，In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoisomer, racemic Body or its mixture form, wherein the compound is represented by general formula (A),
Figure PCTCN2020129826-appb-000006
Figure PCTCN2020129826-appb-000006
其中：among them:
R 1独立地选自氢、烷基、烯基、炔基、羟基、被一个或多个烷基取代的或非取代的氨基、烷氧基、硫代烷基、氰基、卤代烷基、环烷基、杂环基、取代或非取代的杂芳基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxy, amino substituted or unsubstituted by one or more alkyl groups, alkoxy, thioalkyl, cyano, haloalkyl, ring Alkyl, heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
R 2和每个R 3相同或不同，且各自独立地选自氢、卤素、烷基、烯基、炔基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基和杂环基； R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and heterocyclic groups;
R 4、R 5和每个R 6相同或不同，且各自独立地选自氢、烷基、卤代烷基、羟基、烷氧基、硫代烷基、卤素和氰基； R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, thioalkyl, halogen and cyano;
R 7独立地选自氢、烷基、卤代烷基和
Figure PCTCN2020129826-appb-000007
R 7 is independently selected from hydrogen, alkyl, haloalkyl and
Figure PCTCN2020129826-appb-000007
n 1独立地为0～1之间的任意一个整数； n 1 is independently any integer between 0 and 1;
n 2独立地为0～3之间的任意一个整数； n 2 is independently any integer between 0 and 3;
n 3独立地为1～2之间的任意一个整数； n 3 is independently any integer between 1 and 2;
n 4独立地为1～3之间的任意一个整数； n 4 is independently any integer between 1 and 3;
n 5独立地为1～3之间的任意一个整数； n 5 is independently any integer between 1 and 3;
所述烷基、烷氧基和硫代烷基各自独立地任选地被一个或多个选自卤素和Rx取代基取代，所述卤代烷基中的烷基任选地被一个或多个Rx取代基取代，所述环烷基和杂环基各自独立地任选地被一个或多个选自卤素、Rx、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6硫代烷基的取代基取代；The alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more Rx Substituents, the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more selected from halogen, Rx, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1 -Substituent substitution of C6 thioalkyl;
其中，Rx每次出现时独立选自-OH、-NH 2、-NO 2和-CN。 Wherein, each occurrence of Rx is independently selected from -OH, -NH 2 , -NO 2 and -CN.
在一实施方案中，n 1选自0、1，优选1。 In one embodiment, n 1 is selected from 0, 1, preferably 1.
在一实施方案中，n 2选自0、1、2、3，优选0、1或2，特别是0或1。 In one embodiment, n 2 is selected from 0, 1, 2, 3, preferably 0, 1 or 2, especially 0 or 1.
在一实施方案中，n 3选自1、2，优选1。 In one embodiment, n 3 is selected from 1, 2, preferably 1.
在一实施方案中，n 4选自1、2、3，优选1。 In one embodiment, n 4 is selected from 1, 2, 3, preferably 1.
在一实施方案中，n 5选自1、2、3，优选1或2，特别是1。 In one embodiment, n 5 is selected from 1, 2, 3, preferably 1 or 2, especially 1.
在本发明优选的实施方案中，n 1选自0、1；n 2选自0、1、2、3；n 3选自1、2；n 4选自1、2、3；n 5为1。 In a preferred embodiment of the present invention, n 1 is selected from 0, 1; n 2 is selected from 0, 1, 2, 3; n 3 is selected from 1, 2; n 4 is selected from 1, 2, 3; n 5 is 1.
在一实施方案中，所述烷基选自C1-C6的烷基；所述环烷基选自C3-C6的环烷基；所述卤代烷基选自C1-C6的卤代烷基；所述烷氧基选自C1-C6的烷氧基；所述硫代烷基选自C1-C6的硫代烷基；所述杂环基优选为含N杂环基，更优选为仅含有一个N原子的杂环基；所述被一个或多个烷基取代的氨基选自被一个或多个C1-C6的烷基取代的氨基；所述芳基为苯基或萘基，其中苯基或萘基任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6硫代烷基和Rx的取代基取代；所述杂芳基为五元至十元杂芳基，优选为五元至六元杂芳基，所述杂芳基的环原子中包含1、2或3个选自氧、氮和硫的杂原子，优选其环原子中包含1或2个选自氧、氮和硫的杂原子，并且杂芳基任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6硫代烷基和Rx的取代基取代。在一优选的实施方案中，所述烷基、烷氧基、硫代烷基、环烷基、杂环基、芳基、杂芳基均为非取代的，并且所述卤代烷基中的烷基未被卤素之外的基团取代。In one embodiment, the alkyl group is selected from C1-C6 alkyl groups; the cycloalkyl group is selected from C3-C6 cycloalkyl groups; the haloalkyl group is selected from C1-C6 haloalkyl groups; the alkane The oxy group is selected from C1-C6 alkoxy groups; the thioalkyl group is selected from C1-C6 thioalkyl groups; the heterocyclic group is preferably a N-containing heterocyclic group, and more preferably contains only one N atom The heterocyclic group; the amino group substituted by one or more alkyl groups is selected from amino groups substituted by one or more C1-C6 alkyl groups; the aryl group is phenyl or naphthyl, wherein phenyl or naphthalene The group is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl and Rx; the heteroaryl The group is a five-membered to ten-membered heteroaryl group, preferably a five-membered to six-membered heteroaryl group. The ring atoms of the heteroaryl group contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, preferably Its ring atoms contain 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and the heteroaryl group is optionally substituted by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1- Substituents of C6 alkoxy, C1-C6 thioalkyl and Rx are substituted. In a preferred embodiment, the alkyl group, alkoxy group, thioalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are all unsubstituted, and the alkyl group in the haloalkyl group The group is not substituted by a group other than halogen.
在一优选的实施方案中，其中所述C1-C6烷基为C1-C3烷基。In a preferred embodiment, wherein the C1-C6 alkyl group is a C1-C3 alkyl group.
在通式(A)的化合物的一实施方案中，烷基选自非取代的C1-C6烷基。在通式(A)的化合物的一实施方案中，环烷基选自非取代的C3-C6的环烷基。在通式(A)的化合物的一实施方案中，卤代烷基选自C1-C6卤代烷基，其中烷基未被卤素之外的基团取代。在通式(A)的化合物的一实施方案中，烷氧基选自非取代的C1-C6烷氧基。在通式(A)的化合物的一实施方案中，硫代烷基选自非取代的C1-C6硫代烷基。在通式(A)的化合物的一实施方案中，含N杂环基选自仅含有一个N原子的杂环基。在通式(A)的化合物的一实施方案中，被一个或多个烷基取代的氨基选自被一个或多个C1-C6烷基取代的氨基，其中烷基为非取代烷基。在通式(A)的化合物的一实施方案中，芳基选自非取代的苯基或萘基。In one embodiment of the compound of general formula (A), the alkyl group is selected from unsubstituted C1-C6 alkyl groups. In one embodiment of the compound of general formula (A), the cycloalkyl group is selected from unsubstituted C3-C6 cycloalkyl groups. In one embodiment of the compound of the general formula (A), the haloalkyl group is selected from C1-C6 haloalkyl groups, wherein the alkyl group is not substituted by a group other than halogen. In one embodiment of the compound of general formula (A), the alkoxy group is selected from unsubstituted C1-C6 alkoxy groups. In one embodiment of the compound of general formula (A), the thioalkyl group is selected from unsubstituted C1-C6 thioalkyl groups. In one embodiment of the compound of general formula (A), the N-containing heterocyclic group is selected from heterocyclic groups containing only one N atom. In one embodiment of the compound of general formula (A), the amino group substituted with one or more alkyl groups is selected from amino groups substituted with one or more C1-C6 alkyl groups, wherein the alkyl group is a non-substituted alkyl group. In one embodiment of the compound of general formula (A), the aryl group is selected from unsubstituted phenyl or naphthyl.
本发明进一步优选的实施方案中，所述烷基选自非取代的C1-C6的烷基；所述环烷基选自非取代的C3-C6的环烷基；所述卤代烷基选自非取代的C1-C6的卤代烷基；所述烷氧基选自非取代的C1-C6的烷氧基；所述硫代烷基选自非取代的C1-C6的硫代烷基；所述含N杂环基选自仅含有一个N原子的非取代的杂环基；所述被一个或多个烷基取代的氨基选自被一个或多个C1-C6的烷基取代的氨基，所述烷基为非取代烷基；所述芳基选自非取代的苯基或萘基；所述卤素选自氟、氯、溴或碘。In a further preferred embodiment of the present invention, the alkyl group is selected from non-substituted C1-C6 alkyl groups; the cycloalkyl group is selected from non-substituted C3-C6 cycloalkyl groups; and the halogenated alkyl group is selected from non-substituted C3-C6 cycloalkyl groups. Substituted C1-C6 haloalkyl; said alkoxy group is selected from unsubstituted C1-C6 alkoxy; said thioalkyl group is selected from unsubstituted C1-C6 thioalkyl; said containing The N heterocyclic group is selected from unsubstituted heterocyclic groups containing only one N atom; the amino group substituted by one or more alkyl groups is selected from the amino group substituted by one or more C1-C6 alkyl groups, the The alkyl group is an unsubstituted alkyl group; the aryl group is selected from unsubstituted phenyl or naphthyl; the halogen is selected from fluorine, chlorine, bromine or iodine.
在一更优选的实施方案中，C1-C6的烷基选自甲基、乙基、丙基、丁基和戊基。在另一更优选的实施方案中，C1-C6的卤代烷基选自-(CH 2) aCX 3和-(CH 2) aCH(CX 3) 2。在又一更优选的实施方案中，C1-C6的烷氧基选自-O-(CH 2) aCH 3和-O-(CH 2) aCH(CH 3) 2。在另一更优选的实施方案中，C1-C6的硫代烷基选自-S-(CH 2) aCH 3和-S-(CH 2) aCH(CH 3) 2。在又一更优选的实施方案中，被一个或多个C1-C6的烷基取代的氨基选自-NH-(CH 2) aCH 3和-N[(CH 2) a-CH 3] 2。在另一更优选的实施方案中，仅含有一个N原子的杂环基选自
Figure PCTCN2020129826-appb-000008
(例如
Figure PCTCN2020129826-appb-000009
等)。其中：X代表卤素；a独立地选自0～3之间的任意一个整数，例如选自0、1、2、3，特别是0、1或2。 In a more preferred embodiment, the C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl and pentyl. In another more preferred embodiment, the C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 and -(CH 2 ) a CH(CX 3 ) 2 . In yet another more preferred embodiment, the C1-C6 alkoxy group is selected from -O-(CH 2 ) a CH 3 and -O-(CH 2 ) a CH(CH 3 ) 2 . In another more preferred embodiment, the C1-C6 thioalkyl group is selected from -S-(CH 2 ) a CH 3 and -S-(CH 2 ) a CH(CH 3 ) 2 . In yet another more preferred embodiment, the amino group substituted with one or more C1-C6 alkyl groups is selected from -NH-(CH 2 ) a CH 3 and -N[(CH 2 ) a -CH 3 ] 2 . In another more preferred embodiment, the heterocyclic group containing only one N atom is selected from
Figure PCTCN2020129826-appb-000008
(E.g
Figure PCTCN2020129826-appb-000009
Wait). Wherein: X represents halogen; a is independently selected from any integer between 0 and 3, for example selected from 0, 1, 2, 3, especially 0, 1, or 2.
本发明进一步优选的实施方案中，C1-C6的烷基选自甲基、乙基、丙基、丁基和戊基；C1-C6的卤代烷基选自-(CH 2) aCX 3和-(CH 2) aCH(CX 3) 2；C1-C6的烷氧基选自-O-(CH 2) aCH 3和-O-(CH 2) aCH(CH 3) 2；C1-C6的硫代烷基选自-S-(CH 2) aCH 3和-S-(CH 2) aCH(CH 3) 2；被一个或多个C1-C6的烷基取代的氨基选自-NH-(CH 2) aCH 3和-N[(CH 2) a-CH 3] 2；仅含有一个N原子的杂环基选自
Figure PCTCN2020129826-appb-000010
(例如
Figure PCTCN2020129826-appb-000011
Figure PCTCN2020129826-appb-000012
等)； In a further preferred embodiment of the present invention, the C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl and pentyl; the C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 and- (CH 2 ) a CH(CX 3 ) 2 ; C1-C6 alkoxy is selected from -O-(CH 2 ) a CH 3 and -O-(CH 2 ) a CH(CH 3 ) 2 ; C1-C6 The thioalkyl group is selected from -S-(CH 2 ) a CH 3 and -S-(CH 2 ) a CH(CH 3 ) 2 ; the amino group substituted by one or more C1-C6 alkyl groups is selected from- NH-(CH 2 ) a CH 3 and -N[(CH 2 ) a -CH 3 ] 2 ; the heterocyclic group containing only one N atom is selected from
Figure PCTCN2020129826-appb-000010
(E.g
Figure PCTCN2020129826-appb-000011
Figure PCTCN2020129826-appb-000012
Wait);
其中：X代表卤素，所述卤素选自氟、氯、溴和碘；a独立地选自0～3之间的任意一个整数，例如选自0、1、2、3，特别是0、1或2。Wherein: X represents halogen, the halogen is selected from fluorine, chlorine, bromine and iodine; a is independently selected from any integer between 0 and 3, for example selected from 0, 1, 2, 3, especially 0, 1. Or 2.
在本发明的实施方案中，卤代烷基指被一个或多个卤素取代的烷基。In an embodiment of the present invention, haloalkyl refers to an alkyl substituted with one or more halogens.
本发明优选的其他实施方案中，丙基选自正丙基(n-Pr、-CH 2CH 2CH 3)和异丙基((i-Pr、-CH(CH 3) 2)；丁基选自正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)和叔丁基(t-Bu、-C(CH 3) 3)；戊基选自正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)和2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)。 In other preferred embodiments of the present invention, the propyl group is selected from n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) and isopropyl ((i-Pr, -CH(CH 3 ) 2 ); butyl Selected from n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH (CH 3 )CH 2 CH 3 ) and tert-butyl (t-Bu, -C(CH 3 ) 3 ); pentyl is selected from n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2- Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl(-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ) and 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ).
在一实施方案中，卤素选自氟、氯、溴和碘。在一优选的实施方案中，卤素选自氟、氯和溴。In one embodiment, halogen is selected from fluorine, chlorine, bromine and iodine. In a preferred embodiment, halogen is selected from fluorine, chlorine and bromine.
在一实施方案中，R 1独立地选自氢、烷基、羟基、烷氧基、氰基、卤代烷基、环烷基以及取代或非取代的芳基。在一实施方案中，R 1选自氢、C1-C3的烷基、羟基、C1-C3的烷氧基、氰基、C1-C3的卤代烷基、C3-C6的环烷基和苯基，其中所述烷基和烷氧基各自独立地任选地被一个或多个选自卤素和Rx的取代基取代，所述卤代烷基中的烷基任选地被一个或多个Rx取代，所述环烷基、杂环基和苯基各自独立地任选地被一个或多个选 自卤素、Rx和C1-C3烷基的取代基取代。在一优选的实施方案中，R 1独立地选自氢、C1-C3的烷基、羟基、C1-C3的烷氧基、氰基、C1-C3的卤代烷基，苯基和C3-C4的环烷基。在一更优选的实施方案中，R 1独立地选自C1-C3的烷基、羟基、C1-C2的烷氧基、氰基、C1-C3的卤代烷基、苯基和C3-C4的环烷基。在一优选的实施方案中，所述烷基、烷氧基、环烷基和苯基均为非取代的；并且所述卤代烷基中的烷基未被卤素之外的基团取代。 In one embodiment, R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl. In one embodiment, R 1 is selected from hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, C3-C6 cycloalkyl and phenyl, Wherein the alkyl group and the alkoxy group are each independently optionally substituted with one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted with one or more Rx, and The cycloalkyl, heterocyclic and phenyl groups are each independently optionally substituted with one or more substituents selected from halogen, Rx and C1-C3 alkyl. In a preferred embodiment, R 1 is independently selected from hydrogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, cyano, C1-C3 haloalkyl, phenyl and C3-C4 Cycloalkyl. In a more preferred embodiment, R 1 is independently selected from C1-C3 alkyl, hydroxyl, C1-C2 alkoxy, cyano, C1-C3 haloalkyl, phenyl and C3-C4 ring alkyl. In a preferred embodiment, the alkyl group, alkoxy group, cycloalkyl group and phenyl group are all unsubstituted; and the alkyl group in the haloalkyl group is not substituted by groups other than halogen.
在一实施方案中，R 2和每个R 3相同或不同，且各自独立地选自氢、卤素、烷基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及含N杂环基。其中所述烷基、烷氧基和硫代烷基各自独立地任选地被一个或多个选自卤素和Rx的取代基取代，所述卤代烷基中的烷基任选地被一个或多个Rx取代，所述环烷基和含N杂环基各自独立地任选地被一个或多个选自卤素、Rx和C1-C3烷基的取代基取代。在一实施方案中，R 2和每个R 3相同或不同，R 2和每个R 3各自独立地选自氢、卤素、C1-C3的烷基、C1-C3的烷氧基、C1-C3的硫代烷基、C1-C3的卤代烷基、氰基、被一个或多个C1-C3的烷基取代的或非取代的氨基、C3-C6的环烷基以及C3-C6的仅含一个N原子的杂环基，优选氢、卤素或氰基。在一优选的实施方案中，R 2为卤素，R 3每次出现时各自独立地选自卤素和氢。在一具体的实施方案中，R 2为卤素，R 3为氢。在一具体的实施方案中，R 2和每个R 3各自独立地选自卤素。在一优选的实施方案中，所述烷基、烷氧基、环烷基、硫代烷基和仅含一个N原子的杂环基均为非取代的；并且所述卤代烷基中的烷基未被卤素之外的基团取代。 In one embodiment, R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and N-containing heterocyclic groups. Wherein the alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more substituents. Each Rx substitution, the cycloalkyl group and the N-containing heterocyclic group are each independently optionally substituted with one or more substituents selected from halogen, Rx and C1-C3 alkyl. In one embodiment, R 2 and each R 3 are the same or different, R 2 and each R 3 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1- C3 thioalkyl, C1-C3 haloalkyl, cyano, amino substituted or unsubstituted by one or more C1-C3 alkyl, C3-C6 cycloalkyl and C3-C6 only contain A heterocyclic group with a N atom is preferably hydrogen, halogen or cyano. In a preferred embodiment, R 2 is halogen, and each occurrence of R 3 is independently selected from halogen and hydrogen. In a specific embodiment, R 2 is halogen and R 3 is hydrogen. In a specific embodiment, R 2 and each R 3 are each independently selected from halogen. In a preferred embodiment, the alkyl group, alkoxy group, cycloalkyl group, thioalkyl group and heterocyclic group containing only one N atom are all unsubstituted; and the alkyl group in the haloalkyl group Not substituted by groups other than halogen.
在一实施方案中，R 4、R 5和R 6相同或不同，且各自独立地选自氢和烷基。在一实施方案中，R 4、R 5和每个R 6相同或不同，且各自独立地选自氢和C1-C3的烷基。在一实施方案中，R 4、R 5和每个R 6为氢。在一实施方案中，R 4为氢，R 5和R 6相同或不同，且各自独立地选自氢和C1-C3的烷基。在一实施方案中，R 5为氢，R 4和R 6相同或不同，且各自独立地选自氢和C1-C3的烷基。在一实施方案中，R 4和R 5为氢，每个R 6各自独立地选自氢和C1-C3的烷基。在一实施方案中，n 2为0，R 6不存在；在更优选的实施方案中，所述烷基为非取代的。 In one embodiment, R 4 , R 5 and R 6 are the same or different, and are each independently selected from hydrogen and alkyl. In one embodiment, R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 4 , R 5 and each R 6 are hydrogen. In one embodiment, R 4 is hydrogen, R 5 and R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 5 is hydrogen, R 4 and R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl. In one embodiment, R 4 and R 5 are hydrogen, and each R 6 is independently selected from hydrogen and C1-C3 alkyl. In one embodiment, n 2 is 0 and R 6 is not present; in a more preferred embodiment, the alkyl group is unsubstituted.
在一实施方案中，R 7独立地选自氢、烷基和
Figure PCTCN2020129826-appb-000013
n4为1或2，优选为1。在一实施方案中，R 7选自氢、C1-C3的烷基和
Figure PCTCN2020129826-appb-000014
n4为1或2，优选为1。在一实施方案中，R 7为氢。在一实施方案中，R 7选自C1-C3的烷基和
Figure PCTCN2020129826-appb-000015
在一优选的实施方案中，所述C1-C3的烷基为非取代的。n 4为1或2，优选为1。 In one embodiment, R 7 is independently selected from hydrogen, alkyl and
Figure PCTCN2020129826-appb-000013
n4 is 1 or 2, preferably 1. In one embodiment, R 7 is selected from hydrogen, C1-C3 alkyl and
Figure PCTCN2020129826-appb-000014
n4 is 1 or 2, preferably 1. In one embodiment, R 7 is hydrogen. In one embodiment, R 7 is selected from C1-C3 alkyl groups and
Figure PCTCN2020129826-appb-000015
In a preferred embodiment, the C1-C3 alkyl group is unsubstituted. n 4 is 1 or 2, preferably 1.
在一更优选的实施方案中，通式(A)的化合物中：In a more preferred embodiment, in the compound of general formula (A):
R 1独立地选自氢、甲基、乙基、氰基、羟基、苯基、三氟甲基、三氯甲基、环丙基、 环丁基、乙氧基、甲氧基、苯基、三氟乙基、三氯乙基、异丙基、正丙基、羟基乙基、氰基甲基和甲氧基乙基。； R 1 is independently selected from hydrogen, methyl, ethyl, cyano, hydroxyl, phenyl, trifluoromethyl, trichloromethyl, cyclopropyl, cyclobutyl, ethoxy, methoxy, phenyl , Trifluoroethyl, trichloroethyl, isopropyl, n-propyl, hydroxyethyl, cyanomethyl and methoxyethyl. ；
R 2和每个R 3相同或不同，且各自独立地选自氢、氟、氯、溴、甲基、氰基、硫代甲基、甲氧基、
Figure PCTCN2020129826-appb-000016
三氟甲基、三氯甲基、环丙基和-N(CH 3) 2； R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, cyano, thiomethyl, methoxy,
Figure PCTCN2020129826-appb-000016
Trifluoromethyl, trichloromethyl, cyclopropyl and -N(CH 3 ) 2 ;
R 4、R 5和每个R 6相同或不同，且各自独立地选自氢和甲基； R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and methyl;
R 7独立地选自氢、甲基和
Figure PCTCN2020129826-appb-000017
R 7 is independently selected from hydrogen, methyl and
Figure PCTCN2020129826-appb-000017
n 1独立地为0～1之间的任意一个整数；n 2独立地为0～1之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1；n 5独立地为1～2之间的任意一个整数，n 5优选为1。 n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 1; n 3 is independently any integer between 1 and 2; n 4 is independently 1; n 5 is independently any integer between 1 and 2, and n 5 is preferably 1.
在一实施方案中，R 1独立地选自甲基、乙基、三氟乙基、三氯乙基、异丙基、正丙基、环丙基、环丁基、羟基乙基、氰基甲基、苯基、甲氧基乙基和乙氧基乙基。 In one embodiment, R 1 is independently selected from methyl, ethyl, trifluoroethyl, trichloroethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, hydroxyethyl, cyano Methyl, phenyl, methoxyethyl and ethoxyethyl.
在一实施方案中，n 2为0，通式(A)的化合物具有如下式(A*)的结构， In one embodiment, n 2 is 0, and the compound of the general formula (A) has the structure of the following formula (A*),
Figure PCTCN2020129826-appb-000018
Figure PCTCN2020129826-appb-000018
R 1、R 2、R 3、R 4、R 5、R 7、n 1、n 3、n 5如上述通式(A)所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , n 1 , n 3 , and n 5 are as defined in the above general formula (A).
在一优选的实施方案中，n 5为1，通式(A)的化合物具有如下式(A-1-1)的结构， In a preferred embodiment, n 5 is 1, and the compound of general formula (A) has the structure of the following formula (A-1-1),
Figure PCTCN2020129826-appb-000019
Figure PCTCN2020129826-appb-000019
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、n 1、n 2、和n 3如通式(A)所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n 1 , n 2 , and n 3 are as defined in the general formula (A).
在一优选的实施方案中，n 5为1，n 2为0，通式(A)的化合物具有如下式(A-1-2)的结构， In a preferred embodiment, n 5 is 1, n 2 is 0, and the compound of general formula (A) has the structure of the following formula (A-1-2),
Figure PCTCN2020129826-appb-000020
Figure PCTCN2020129826-appb-000020
此时R 6不存在，R 1、R 2、R 3、R 4、R 5、R 7、n 1和n 3如通式(A)所定义。 At this time, R 6 does not exist, and R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , n 1 and n 3 are as defined in the general formula (A).
本发明优选的其他实施方案中，所述通式(A)的化合物为如下表所示任意一个化合物：In other preferred embodiments of the present invention, the compound of general formula (A) is any compound shown in the following table:
表1通式(A)的化合物的示例化合物Table 1 Exemplary compounds of the compound of general formula (A)
Figure PCTCN2020129826-appb-000021
Figure PCTCN2020129826-appb-000021
Figure PCTCN2020129826-appb-000022
Figure PCTCN2020129826-appb-000022
Figure PCTCN2020129826-appb-000023
Figure PCTCN2020129826-appb-000023
Figure PCTCN2020129826-appb-000024
Figure PCTCN2020129826-appb-000024
Figure PCTCN2020129826-appb-000025
Figure PCTCN2020129826-appb-000025
Figure PCTCN2020129826-appb-000026
Figure PCTCN2020129826-appb-000026
本发明优选的其他实施方案中，所述通式(A)的化合物选自如下表2所示任意一个化合物：In other preferred embodiments of the present invention, the compound of general formula (A) is selected from any one of the compounds shown in Table 2 below:
表2通式(A)的化合物的示例化合物Table 2 Exemplary compounds of the compound of general formula (A)
Figure PCTCN2020129826-appb-000027
Figure PCTCN2020129826-appb-000027
Figure PCTCN2020129826-appb-000028
Figure PCTCN2020129826-appb-000028
制备方法Preparation
在一方面，本发明进一步提供如通式(IV)的化合物的制备方法，包括以下步骤(A-1)和步骤(A-2)，或者包括步骤(A-i)：In one aspect, the present invention further provides a method for preparing a compound of general formula (IV), including the following steps (A-1) and (A-2), or including steps (A-i):
Figure PCTCN2020129826-appb-000029
Figure PCTCN2020129826-appb-000029
步骤(A-1)：通式(II)的化合物与通式SM-3的化合物反应制备得到的通式(III)的化合物；其中，R 9是羟基的保护基团； Step (A-1): a compound of general formula (III) prepared by reacting a compound of general formula (II) with a compound of general formula SM-3; wherein R 9 is a protective group for hydroxyl;
步骤(A-2)：通式(III)的化合物通过脱保护反应制备得到通式(IV)的化合物；Step (A-2): The compound of general formula (III) is prepared by deprotection reaction to obtain the compound of general formula (IV);
步骤(A-i)：通式(II)的化合物与通式SM-4的化合物反应制备得到的通式(IV)的化合物；Step (A-i): a compound of general formula (IV) prepared by reacting a compound of general formula (II) with a compound of general formula SM-4;
其中R 1、R 2、R 3、R 4、R 6、n 1、n 2、n 3和n 5如上文所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 and n 5 are as defined above.
在一实施方案中，R 9选自单甲氧基三苯基(MMT)，双甲氧基三苯基(DMT)，三苯基甲基(Trityl)，叔丁基二甲基硅烷(TBS)和叔丁基二甲硅基(TBDMS)。 In one embodiment, R 9 is selected from monomethoxytriphenyl (MMT), bismethoxytriphenyl (DMT), triphenylmethyl (Trityl), tert-butyldimethylsilane (TBS ) And tert-butyldimethylsilyl (TBDMS).
在一实施方案中，步骤(A-1)中将通式(II)的化合物在有机溶剂中与通式SM-3的化合物反应，制备得到通式(III)的化合物。在一具体的实施方案中，在氮气保护下，在-78至-40℃的温度下，在合适溶剂中，如四氢呋喃(THF)中，向通式(II)的化合物与六甲基磷酰三胺中滴加正丁基锂的正己烷溶液，反应0.5-1小时后，滴加通式SM-3的化合物，使其溶于合适溶剂中，如THF的溶液，升至室温，反应12-18小时得到通式(III)的化合物。在一实施方案中，步骤(A-2)中将通式(III)的化合物在有机溶剂中，与四丁基氟化铵反应，制备得到通式(IV)的化合物。例如，在室温温度下，在合适溶剂如THF中，通式(III)的化合物与四丁基氟化铵反应0.5-2小时得到通式(IV)的化合物。In one embodiment, in step (A-1), a compound of general formula (II) is reacted with a compound of general formula SM-3 in an organic solvent to prepare a compound of general formula (III). In a specific embodiment, under the protection of nitrogen, at a temperature of -78 to -40°C, in a suitable solvent, such as tetrahydrofuran (THF), the compound of general formula (II) and hexamethylphosphoryl Add the n-butyl lithium n-hexane solution to the triamine dropwise. After reacting for 0.5-1 hour, add the compound of general formula SM-3 dropwise to dissolve it in a suitable solvent, such as a THF solution, and raise it to room temperature. Reaction 12. The compound of general formula (III) is obtained in -18 hours. In one embodiment, in step (A-2), a compound of general formula (III) is reacted with tetrabutylammonium fluoride in an organic solvent to prepare a compound of general formula (IV). For example, at room temperature, in a suitable solvent such as THF, the compound of general formula (III) is reacted with tetrabutylammonium fluoride for 0.5-2 hours to obtain the compound of general formula (IV).
在另一实施方案中，步骤(A-i)中将通式(II)的化合物在有机溶剂中与通式SM-4的化合物反应，制备得到通式(IV)的化合物。如在氮气保护下，在-20至-0℃的温度下，在合适溶剂如THF中，加入异丙基氯化镁的THF溶液，加入通式(II)的化合物和通式SM-4的化合物，之后升至室温反应2-18小时得到通式(IV)的化合物。In another embodiment, in step (A-i), a compound of general formula (II) is reacted with a compound of general formula SM-4 in an organic solvent to prepare a compound of general formula (IV). For example, under the protection of nitrogen, at a temperature of -20 to -0°C, in a suitable solvent such as THF, add a THF solution of isopropyl magnesium chloride, add a compound of general formula (II) and a compound of general formula SM-4, After that, it was raised to room temperature and reacted for 2-18 hours to obtain the compound of general formula (IV).
在一方面，本发明进一步提供如通式(A)的化合物的制备方法(1)，包括步骤(B)。在一实施方案中，步骤(B)包括以下步骤(B-1)和步骤(B-2)，或包括步骤(B-i)和步骤(B-ii)：In one aspect, the present invention further provides a preparation method (1) of a compound of general formula (A), including step (B). In one embodiment, step (B) includes the following steps (B-1) and (B-2), or includes steps (B-i) and (B-ii):
Figure PCTCN2020129826-appb-000030
Figure PCTCN2020129826-appb-000030
步骤(B-1)：通式(IV)的化合物与邻苯二甲酰亚胺反应制备得到通式(V)的化合物；Step (B-1): The compound of general formula (IV) is reacted with phthalimide to prepare the compound of general formula (V);
步骤(B-2)：通式(V)的化合物通过脱保护反应制备得到通式(A)的化合物；Step (B-2): The compound of general formula (V) is prepared by deprotection reaction to obtain the compound of general formula (A);
步骤(B-i)：通式(IV)的化合物通过取代反应制备得到通式(VI)的化合物；Step (B-i): The compound of general formula (IV) is prepared by substitution reaction to obtain the compound of general formula (VI);
步骤(B-ii)：通式(VI)的化合物通过加氢反应制备得到通式(A)的化合物；Step (B-ii): The compound of general formula (VI) is prepared by hydrogenation reaction to obtain the compound of general formula (A);
其中R 5和R 7为氢；R 1、R 2、R 3、R 4、R 6、n 1、n 2、n 3和n 5如上文所定义。 Wherein R 5 and R 7 are hydrogen; R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 and n 5 are as defined above.
当R 5和R 7为氢时，通式(A)的化合物可以表示为通式(VII)
Figure PCTCN2020129826-appb-000031
When R 5 and R 7 are hydrogen, the compound of general formula (A) can be represented as general formula (VII)
Figure PCTCN2020129826-appb-000031
在一实施方案中，步骤(B-1)中将通式(IV)的化合物在有机溶剂中与邻苯二甲酰亚胺、 三苯基膦和偶氮二甲酸二乙酯反应，制备得到通式(V)的化合物。在一具体的实施方案中，在氮气保护下，在0℃下，在合适溶剂例如THF中，加入式(IV)的化合物、邻苯二甲酰亚胺、三苯基膦和偶氮二甲酸二乙酯，之后升至室温反应6-18小时得到式(V)的化合物。在另一实施方案中，将通式(IV)的化合物与甲磺酰氯在有机碱及有机溶剂条件下制备得相应的甲磺酰酯化合物，之后与邻苯二甲酰亚胺和无机碱在有机溶剂中，制备得到通式(V)的化合物。在一具体的实施方案中，在氮气保护下，在0℃下，在合适溶剂例如二氯甲烷中加入式(A’)的化合物、三乙胺和甲基磺酰氯，升至室温反应0.5-3小时得到相应的甲磺酰酯化合物，不经分离溶于合适溶剂例如二甲基甲酰胺中，加入邻苯二甲酰亚胺、无机碱(例如碳酸钾或者碳酸铯)，升至70-140℃，反应2-16小时得到通式(V)的化合物。In one embodiment, in step (B-1), the compound of formula (IV) is reacted with phthalimide, triphenylphosphine and diethyl azodicarboxylate in an organic solvent to prepare Compound of general formula (V). In a specific embodiment, under the protection of nitrogen, the compound of formula (IV), phthalimide, triphenylphosphine and azodicarboxylic acid are added in a suitable solvent such as THF at 0°C. The diethyl ester is then raised to room temperature and reacted for 6-18 hours to obtain the compound of formula (V). In another embodiment, the compound of general formula (IV) and methanesulfonyl chloride are prepared under the conditions of organic base and organic solvent to prepare the corresponding methanesulfonyl ester compound, and then the compound is combined with phthalimide and inorganic base. In an organic solvent, a compound of general formula (V) can be prepared. In a specific embodiment, under the protection of nitrogen, the compound of formula (A'), triethylamine and methanesulfonyl chloride are added in a suitable solvent such as methylene chloride at 0°C, and the temperature is raised to room temperature to react 0.5- The corresponding methanesulfonyl ester compound is obtained in 3 hours, and it is dissolved in a suitable solvent such as dimethylformamide without separation, and phthalimide and inorganic base (such as potassium carbonate or cesium carbonate) are added to increase the temperature to 70- The compound of general formula (V) was obtained by reacting at 140°C for 2-16 hours.
在一实施方案中，步骤(B-2)中将通式(V)的化合物与脱保护试剂反应，例如乙醇胺制备得到通式(A)的化合物。例如，在60至70℃下通式(V)的化合物与乙醇胺反应0.5-1.5小时制备得到通式(A)的化合物。In one embodiment, in step (B-2), a compound of general formula (V) is reacted with a deprotection reagent, such as ethanolamine, to prepare a compound of general formula (A). For example, a compound of general formula (V) is reacted with ethanolamine at 60 to 70° C. for 0.5-1.5 hours to prepare a compound of general formula (A).
在一实施方案中，步骤(B-i)中将通式(V)的化合物与甲磺酰氯在有机碱及有机溶剂条件下制备得相应的甲磺酰酯化合物，之后与叠氮化钠和无机碱在有机溶剂中，制备得到通式(VI)的化合物。在一具体的实施方案中，在氮气保护下，在0℃下，在合适溶剂例如二甲基甲酰胺中加入通式(V)的化合物、三乙胺和甲基磺酰氯，升至室温反应0.5-3小时得到相应的甲磺酰酯化合物，不经分离溶于合适溶剂例如二甲基甲酰胺中，加入叠氮化钠、无机碱(例如碳酸钾或者碳酸铯)，升至70-120℃中反应2-16小时得到通式(VI)的化合物。In one embodiment, in step (Bi), the compound of general formula (V) and methanesulfonyl chloride are prepared under the conditions of organic base and organic solvent to prepare the corresponding methanesulfonyl ester compound, which is then combined with sodium azide and inorganic base. In an organic solvent, the compound of general formula (VI) is prepared. In a specific embodiment, under the protection of nitrogen, the compound of general formula (V), triethylamine and methanesulfonyl chloride are added to a suitable solvent such as dimethylformamide at 0°C, and the reaction temperature is raised to room temperature. Obtain the corresponding methanesulfonyl ester compound in 0.5-3 hours, dissolve it in a suitable solvent such as dimethylformamide without separation, add sodium azide, inorganic base (such as potassium carbonate or cesium carbonate), and increase to 70-120 The compound of general formula (VI) is obtained by reacting at ℃ for 2-16 hours.
在一实施方案中，步骤(B-ii-1)中将通式(VI)的化合物在有机溶剂中通过氢化反应，加氢制备得到式(A’)的化合物。在一具体的实施方案中，在一个大气压的氢气下，在合适溶剂例如乙酸乙酯中，加入通式(VI)的化合物和催化剂钯碳，室温反应1-2小时得到式(A’)的化合物。In one embodiment, in step (B-ii-1), the compound of formula (VI) is hydrogenated in an organic solvent to prepare the compound of formula (A'). In a specific embodiment, under one atmosphere of hydrogen, in a suitable solvent such as ethyl acetate, add the compound of formula (VI) and the catalyst palladium carbon, and react at room temperature for 1-2 hours to obtain the formula (A') Compound.
在一方面，本发明进一步提供通式(A)的化合物的制备方法(2)，包括步骤(C)。在一实施方案中，步骤(C)包括步骤(C-1)、步骤(C-2)和步骤(C-3)，或包括步骤(C-i)和步骤(C-ii)：In one aspect, the present invention further provides a preparation method (2) of the compound of general formula (A), including step (C). In one embodiment, step (C) includes step (C-1), step (C-2), and step (C-3), or includes step (C-i) and step (C-ii):
Figure PCTCN2020129826-appb-000032
Figure PCTCN2020129826-appb-000032
步骤(C-1)：通式(VII)的化合物与氨基保护基试剂反应制备得到通式(VIII)的化合物；Step (C-1): The compound of general formula (VII) is reacted with an amino protecting group reagent to prepare a compound of general formula (VIII);
步骤(C-2)：通式(VIII)的化合物通过烷基化反应得到通式(IX)的化合物；Step (C-2): The compound of general formula (VIII) is alkylated to obtain the compound of general formula (IX);
步骤(C-3)：通式(IX)的化合物通过脱保护反应制备得到通式(A)的化合物；其中，R 8为氨基保护基； Step (C-3): The compound of general formula (IX) is prepared by deprotection reaction to obtain the compound of general formula (A); wherein R 8 is an amino protecting group;
步骤(C-i)：通式(VII)的化合物与通式SM-5的化合物反应制备得到通式(X)的化合物；Step (C-i): a compound of general formula (VII) is reacted with a compound of general formula SM-5 to prepare a compound of general formula (X);
步骤(C-ii)：通式(X)的化合物通过脱保护反应制备得到通式(A)的化合物；Step (C-ii): The compound of general formula (X) is prepared by deprotection reaction to obtain the compound of general formula (A);
其中R 5为氢；R 7独立地选自烷基和
Figure PCTCN2020129826-appb-000033
R 8为氨基保护基；R 1、R 2、R 3、R 4、R 6、n 1、n 2、n 3、n 4和n 5如上文所定义。 Where R 5 is hydrogen; R 7 is independently selected from alkyl and
Figure PCTCN2020129826-appb-000033
R 8 is an amino protecting group; R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 , n 4 and n 5 are as defined above.
在一实施方案中，氨基保护基试剂选自苯甲氧基甲酰氯(Cbz-Cl)、二碳酸二叔丁酯(Boc 2O)、三苯基氯甲烷(Trt-Cl)、4-甲氧基氯苄(PMBCl)和氯甲酸-9-芴基甲酯(Fmoc-Cl)。在另一实施方案中，氨基保护基R 8选自苯甲氧羰基(Cbz)、叔丁基氧羰基(Boc)、三苯基甲基(Trt)、4-甲氧基苄基(PMB)和氯甲酸-9-芴基甲基羰基(Fmoc)。 In one embodiment, the amino protecting group reagent is selected from benzyloxycarbonyl chloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc 2 O), triphenylchloromethane (Trt-Cl), 4-methyl Oxybenzyl chloride (PMBCl) and 9-fluorenyl methyl chloroformate (Fmoc-Cl). In another embodiment, the amino protecting group R 8 is selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), triphenylmethyl (Trt), 4-methoxybenzyl (PMB) And chloroformic acid-9-fluorenylmethylcarbonyl (Fmoc).
在一实施方案中，所述通式(VII)的化合物参照上述通式(A)的化合物的制备方法(1)制备。在一实施方案中，步骤(C-1)中将通式(VII)的化合物在有机溶剂中与三乙胺和二碳酸二叔丁酯反应，制备得到通式(VIII)的化合物。在一具体的实施方案中，在氮气保护下，在合适溶剂如DCM中，加入式(VII)的化合物、三乙胺和二碳酸二叔丁酯，室温反应1-3小时得到式(VIII)的化合物。在一实施方案中，步骤(C-2)中将通式(VIII)的化合物与碘甲烷在无机碱及有机溶剂条件下制备得到通式(IX)的化合物。在一具体的实施方案中，在氮气保护下，在0℃下，在合适溶剂如四氢呋喃中加入通式(VIII)的化合物、氢化钠(60％)，在室温反应0.5-1小时候加入碘甲烷，继续室温反应12-16小时得到通式(IX)的化合物。在一实施方案中，步骤(C-3)中将通式(IX)的化合物在有机溶剂中，与脱保护试剂反应，如与三氟乙酸反应制备得到通式(A)的化合物。在一具体的实施方案中，在室温下，在合适溶剂如DCM(二氯甲烷)中，将通式(IX)的化合物与三氟乙酸反应0.5-1小时制备得到通式(A)的化合物。In one embodiment, the compound of general formula (VII) is prepared by referring to the method (1) for preparing the compound of general formula (A) above. In one embodiment, in step (C-1), a compound of general formula (VII) is reacted with triethylamine and di-tert-butyl dicarbonate in an organic solvent to prepare a compound of general formula (VIII). In a specific embodiment, under the protection of nitrogen, in a suitable solvent such as DCM, add the compound of formula (VII), triethylamine and di-tert-butyl dicarbonate, and react at room temperature for 1-3 hours to obtain formula (VIII) compound of. In one embodiment, in step (C-2), a compound of general formula (VIII) and methyl iodide are prepared under conditions of an inorganic base and an organic solvent to obtain a compound of general formula (IX). In a specific embodiment, under the protection of nitrogen, the compound of general formula (VIII) and sodium hydride (60%) are added in a suitable solvent such as tetrahydrofuran at 0°C, and methyl iodide is added for 0.5-1 hour at room temperature. , Continue to react at room temperature for 12-16 hours to obtain a compound of general formula (IX). In one embodiment, in step (C-3), the compound of general formula (IX) is reacted with a deprotection reagent in an organic solvent, such as reacting with trifluoroacetic acid to prepare a compound of general formula (A). In a specific embodiment, at room temperature, in a suitable solvent such as DCM (dichloromethane), the compound of general formula (IX) is reacted with trifluoroacetic acid for 0.5-1 hour to prepare the compound of general formula (A) .
在一实施方案中，步骤(C-i)中将通式(VII)的化合物在有机溶剂中与N-叔丁氧羰基-甘氨酸反应制备得到通式(X)的化合物。在一具体的实施方案中，在氮气保护下，在合适溶剂如DMF和NMP(N-甲基吡咯烷酮)中，加入通式(VII)的化合物，三乙胺，O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯和通式SM-5的化合物，室温反应3-5小时得到通式(X)的化合物。在一实施方案中，步骤(C-ii)中将通式(X)的化合物在有机溶剂中与脱保护试剂反应得到通式(A)的化合物。在一具体的实施方案中，在室温下，在合适溶剂如DCM中，将通式(IX)的化合物与三氟乙酸反应0.5-1小时制备得到通式(A)的化合物。In one embodiment, in step (C-i), a compound of general formula (VII) is reacted with N-tert-butoxycarbonyl-glycine in an organic solvent to prepare a compound of general formula (X). In a specific embodiment, under the protection of nitrogen, in a suitable solvent such as DMF and NMP (N-methylpyrrolidone), a compound of general formula (VII), triethylamine, O-(7-azabenzene) is added (Di-triazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate and a compound of general formula SM-5, react at room temperature for 3-5 hours to obtain a compound of general formula (X) . In one embodiment, in step (C-ii), a compound of general formula (X) is reacted with a deprotection reagent in an organic solvent to obtain a compound of general formula (A). In a specific embodiment, at room temperature, in a suitable solvent such as DCM, the compound of general formula (IX) is reacted with trifluoroacetic acid for 0.5-1 hour to prepare the compound of general formula (A).
任选地，通式(II)的化合物可以通过如下方法制备，因此本发明进一步提供制备方法(1’)，包括：Optionally, the compound of general formula (II) can be prepared by the following method, so the present invention further provides a preparation method (1'), including:
Figure PCTCN2020129826-appb-000034
Figure PCTCN2020129826-appb-000034
通式(I)的化合物通过成环反应制备得到通式(II)的化合物；The compound of the general formula (I) is prepared by the ring-forming reaction to obtain the compound of the general formula (II);
其中R 1、R 2、R 3、R 6、n 1、n 2和n 5如上文所定义。 Wherein R 1 , R 2 , R 3 , R 6 , n 1 , n 2 and n 5 are as defined above.
本发明优选的实施例方案中，例如，通式(I)的化合物与多聚甲醛在Eaton′s试剂作用下，制备得到通式(II)的化合物。如在氮气保护下，通式(I)的化合物与多聚甲醛，以Eaton′s试剂为溶剂，加热至60-80℃的温度下反应30分钟到2小时后，得到通式(II)的化合物。In a preferred embodiment of the present invention, for example, a compound of general formula (I) and paraformaldehyde are prepared under the action of Eaton's reagent to obtain a compound of general formula (II). For example, under the protection of nitrogen, the compound of general formula (I) and paraformaldehyde, using Eaton's reagent as the solvent, are heated to a temperature of 60-80°C and reacted for 30 minutes to 2 hours to obtain the compound of general formula (II) Compound.
任选地，通式(II)的化合物可以通过如下方法制备，因此本发明进一步提供制备方法(1”)，包括：Optionally, the compound of general formula (II) can be prepared by the following method, so the present invention further provides a preparation method (1"), including:
Figure PCTCN2020129826-appb-000035
Figure PCTCN2020129826-appb-000035
通式SM-1的化合物与通式SM-2的化合物发生酰胺化反应，制备得到通式(1)的化合物；The compound of general formula SM-1 and the compound of general formula SM-2 undergo an amidation reaction to prepare a compound of general formula (1);
其中R 1、R 2、R 3、R 6、n 1、n 2和n 5如上文所定义。 Wherein R 1 , R 2 , R 3 , R 6 , n 1 , n 2 and n 5 are as defined above.
本发明优选的实施例方案中，例如，本领域技术人员已知的条件下将通式SM-1的化合物与二氯亚砜在有机溶剂条件下制备得相应的酰氯，之后与通式SM-2所示商业可得原料，在有机溶剂中，制备得到通式(I)的化合物：例如，在0℃至室温范围内的温度下，在合适溶剂如二氯甲烷中式SM-1的化合物与二氯亚砜反应0.5-2小时后，溶剂减压蒸除后溶于合适溶剂如二氯甲烷中，在0℃至室温范围内的温度下，加入通式SM-2的化合物，反应2-12小时后，得到式(I)的化合物。In the preferred embodiment of the present invention, for example, a compound of general formula SM-1 and thionyl chloride are prepared under organic solvent conditions under conditions known to those skilled in the art to prepare the corresponding acid chloride, and then the corresponding acid chloride is prepared with the general formula SM- The commercially available raw materials shown in 2 are prepared in an organic solvent to obtain a compound of general formula (I): for example, at a temperature in the range of 0°C to room temperature, in a suitable solvent such as dichloromethane, the compound of formula SM-1 and After the thionyl chloride reacts for 0.5-2 hours, the solvent is evaporated under reduced pressure and dissolved in a suitable solvent such as dichloromethane. At a temperature ranging from 0°C to room temperature, a compound of general formula SM-2 is added, reaction 2- After 12 hours, the compound of formula (I) is obtained.
在一方面，本发明提供用于制备如通式(A)所述的化合物的中间体，所述中间体选自式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(XI)和式(X)的化合物：In one aspect, the present invention provides intermediates for the preparation of compounds described by general formula (A), the intermediates selected from the group consisting of formula (II), formula (III), formula (IV), formula (V), Compounds of formula (VI), formula (VII), formula (VIII), formula (XI) and formula (X):
Figure PCTCN2020129826-appb-000036
Figure PCTCN2020129826-appb-000037
Figure PCTCN2020129826-appb-000038
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、n 1、n 2、n 3、n 4和n 5如上文所定义。
Figure PCTCN2020129826-appb-000036
Figure PCTCN2020129826-appb-000037
Figure PCTCN2020129826-appb-000038
Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n 1 , n 2 , n 3 , n 4 and n 5 are as defined above.
在一实施方案中，n 5为1，式(IV)的化合物的制备方法如下图所示： In one embodiment, n 5 is 1, and the preparation method of the compound of formula (IV) is shown in the figure below:
Figure PCTCN2020129826-appb-000039
Figure PCTCN2020129826-appb-000039
其中式(II)、式(III)、式(IV)的结构如图所示，R 1、R 2、R 3、R 4、R 6、R 9、n 1、n 2和n 3如上文所定义。 The structures of formula (II), formula (III), and formula (IV) are shown in the figure, and R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , n 1 , n 2 and n 3 are as above Defined.
在一实施方案中，n 5为1，制备方法(1)如下图所示： In one embodiment, n 5 is 1, and the preparation method (1) is shown in the figure below:
Figure PCTCN2020129826-appb-000040
Figure PCTCN2020129826-appb-000040
其中式(IV)、式(V)、式(VI)的结构如图所示，R 1、R 2、R 3、R 4、R 5、R 6、R 7、n 1、n 2和n 3如制备方法(1)所定义。 The structures of formula (IV), formula (V), and formula (VI) are shown in the figure, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n 1 , n 2 and n 3 As defined in the preparation method (1).
在一实施方案中，n 5为1，制备方法(2)如下图所示： In one embodiment, n 5 is 1, and the preparation method (2) is shown in the figure below:
Figure PCTCN2020129826-appb-000041
Figure PCTCN2020129826-appb-000041
其中式(VII)、式(VIII)、式(IX)、式(X)的结构如图所示，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、n 1、n 2、n 3和n 4如制备方法(2)所定义。 The structures of formula (VII), formula (VIII), formula (IX), and formula (X) are shown in the figure, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , N 1 , n 2 , n 3 and n 4 are as defined in the preparation method (2).
在一实施方案中，n 5为1，制备方法(1’)如下图所示： In one embodiment, n 5 is 1, and the preparation method (1') is shown in the figure below:
Figure PCTCN2020129826-appb-000042
Figure PCTCN2020129826-appb-000042
其中式(I)、式(II)的结构如图所示，R 1、R 2、R 3、R 6、n 1和n 2如制备方法(1’)所定义。 The structures of formula (I) and formula (II) are shown in the figure, and R 1 , R 2 , R 3 , R 6 , n 1 and n 2 are as defined in the preparation method (1′).
在一实施方案中，n 5为1，制备方法(1”)如下图所示： In one embodiment, n 5 is 1, and the preparation method (1") is shown in the figure below:
Figure PCTCN2020129826-appb-000043
Figure PCTCN2020129826-appb-000043
其中式(I)的结构如图所示，R 1、R 2、R 3、R 6、n 1和n 2如制备方法(1”)所定义。 The structure of formula (I) is shown in the figure, and R 1 , R 2 , R 3 , R 6 , n 1 and n 2 are as defined in the preparation method (1").
药物组合物、制剂和试剂盒Pharmaceutical compositions, preparations and kits
在一方面，本发明提供包含治疗有效量的通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式和至少一种药学上可接受的载体的药物组合物。In one aspect, the present invention provides a therapeutically effective amount of a compound of general formula (A) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer A pharmaceutical composition comprising a construct, a mesosome, a racemate or a mixture thereof, and at least one pharmaceutically acceptable carrier.
本发明优选的实施方案中，药物组合物可以利用一种或多种可药用的载体按照常规的方式加以配制。因此，本发明的活性化合物可以被配制成口服、口腔含化给药、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠给药的剂型，或者适用于通过吸入或吹入给药的剂型。本发明的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式也可以被配制成持续释放的剂型。In a preferred embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation. The dosage form of the medicine. The compounds of the present invention or their pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers, racemates or mixtures thereof The form can also be formulated as a sustained release dosage form.
本发明优选的实施方案中，有效剂量的。本发明的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式可与如惰性稀释剂或某种载体一起口服。根据本发明的一些实施例，可将本发明的化合物包裹于明胶胶囊中或压制成片。为口服治疗的目的，本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。根据本发明的实施例，上述制剂应含有至少0.5％(w/w)的本发明的活性化合物，但可根据特定的剂型变化，其中占单位重量的4％至约70％是便利的。在这样的药物组合物中活性化合物的量应达到适当的剂量。In a preferred embodiment of the present invention, the effective dose is. The compounds of the present invention or their pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers, racemates or mixtures thereof The form can be taken orally with, for example, an inert diluent or some carrier. According to some embodiments of the present invention, the compound of the present invention can be encapsulated in a gelatin capsule or compressed into a tablet. For the purpose of oral therapy, the compound of the present invention can be used together with excipients and used in the form of tablets, lozenges, capsules, suspensions, syrups and the like. According to an embodiment of the present invention, the above formulation should contain at least 0.5% (w/w) of the active compound of the present invention, but it can vary according to specific dosage forms, and it is convenient to account for 4% to about 70% of the unit weight. The amount of active compound in such a pharmaceutical composition should reach an appropriate dose.
本发明优选的实施方案中，当本发明的活性化合物用于胃肠外施用时，可将本发明提供的化合物与无菌水或有机介质组合形成可注射的溶液或悬液。In a preferred embodiment of the present invention, when the active compound of the present invention is used for parenteral administration, the compound provided by the present invention can be combined with sterile water or an organic medium to form an injectable solution or suspension.
本发明优选的实施方案中，本发明的活性化合物可以被配制成直肠组合物，例如栓剂或保留灌肠剂。In a preferred embodiment of the present invention, the active compound of the present invention can be formulated into rectal compositions, such as suppositories or retention enemas.
治疗方法和用途Treatment methods and uses
本发明还提供通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式或其药物组合物在制备调控NMDA受体的药物中的用途。其中所述药物任选包含另外一种或多种调节哺乳动物神经***或缓解精神疾病的活性剂。The present invention also provides compounds of general formula (A) or pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers, The use of the racemate or its mixture form or its pharmaceutical composition in the preparation of a medicine for regulating the NMDA receptor. The medicament optionally contains another one or more active agents that regulate the mammalian nervous system or alleviate mental illness.
本发明还提供一种调控NMDA受体的方法，其包括向有需要的个体给药通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、 内消旋体、外消旋体或其混合物形式或其药物组合物。所述方法还任选包括给药另外一种或多种调节哺乳动物神经***或缓解精神疾病的活性剂。The present invention also provides a method for modulating NMDA receptors, which comprises administering to an individual in need a compound of general formula (A) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, Enantiomers, diastereomers, mesoisomers, racemates, or mixtures thereof, or pharmaceutical compositions thereof. The method optionally also includes administering another one or more active agents that modulate the mammalian nervous system or alleviate mental illness.
本发明还提供通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式或其药物组合物，用于调控NMDA受体。其中所述应用还任选包含施用另外一种或多种调节哺乳动物神经***或缓解精神疾病的活性剂。The present invention also provides compounds of general formula (A) or pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers, The racemate or its mixture form or its pharmaceutical composition is used to regulate the NMDA receptor. Wherein, the application also optionally includes the administration of another one or more active agents that regulate the mammalian nervous system or alleviate mental illness.
本发明优选的实施方案中，所述调控包括对受体的抑制活性或拮抗活性。In a preferred embodiment of the present invention, the regulation includes inhibitory activity or antagonistic activity on the receptor.
本发明优选的实施方案中，通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式作用于NMDAR受体的TMD位点。In a preferred embodiment of the present invention, the compound of general formula (A) or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, internal The form of racemate, racemate or a mixture thereof acts on the TMD site of the NMDAR receptor.
在另一方面，本发明还提供本发明的通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式或本发明的药物组合物在制备治疗神经精神疾病的药物中的用途。In another aspect, the present invention also provides the compound of the general formula (A) of the present invention or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer The use of the structure, mesosome, racemate or mixture thereof or the pharmaceutical composition of the present invention in the preparation of drugs for treating neuropsychiatric diseases.
本发明还提供一种治疗神经精神疾病的方法，其包括向有需要的个体(例如哺乳动物个体，如人)给药通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式或其药物组合物。The present invention also provides a method for treating neuropsychiatric diseases, which comprises administering a compound of general formula (A) or a pharmaceutically acceptable salt, cis, trans, and isoforms to an individual in need (for example, a mammalian individual, such as a human). Conformers, tautomers, enantiomers, diastereomers, mesoisomers, racemates or mixtures thereof or pharmaceutical compositions thereof.
本发明还提供通式(A)的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式或其药物组合物，用于治疗神经精神疾病。The present invention also provides compounds of general formula (A) or pharmaceutically acceptable salts, cis-trans isomers, tautomers, enantiomers, diastereomers, mesoisomers, The racemate or its mixture form or its pharmaceutical composition is used for the treatment of neuropsychiatric diseases.
在一实施方案中，所述神经精神疾病为疼痛、精神***症、抑郁症、焦虑症、睡眠障碍、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选疼痛、抑郁症、焦虑症、精神***症、睡眠障碍、神经退行性疾病或双相情感障碍中的任意一种或多种。在一优选的实施方案中，所述神经精神疾病选自疼痛、抑郁和神经退行性疾病。In one embodiment, the neuropsychiatric disease is pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, abstinence One or more of amputation syndrome or attention deficit, preferably any one or more of pain, depression, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder. In a preferred embodiment, the neuropsychiatric disease is selected from pain, depression and neurodegenerative diseases.
本发明优选的实施方案中，所述的疼痛选自急性疼痛和慢性疼痛，所述的慢性疼痛包括但不限于头痛、颌面部痛、项枕部疼痛、颈肩痛、上肢痛、胸部痛、腹痛、腰腿痛、生殖道疼痛、泌尿道疼痛、痛经。In a preferred embodiment of the present invention, the pain is selected from acute pain and chronic pain, and the chronic pain includes but not limited to headache, maxillofacial pain, nape occipital pain, neck and shoulder pain, upper limb pain, chest pain , Abdominal pain, low back pain, genital tract pain, urinary tract pain, dysmenorrhea.
本发明进一步优选的实施方案中，所述的疼痛包括但不限于创伤性疼痛，炎性疼痛，缺血性疼痛，代谢性疾病引起的疼痛，神经源性疼痛，组织、器官畸形引起的疼痛，分娩疼痛，恶性增殖疾病引起的疼痛。In a further preferred embodiment of the present invention, the pain includes, but is not limited to, traumatic pain, inflammatory pain, ischemic pain, pain caused by metabolic diseases, neurogenic pain, pain caused by deformity of tissues and organs, Labor pain, pain caused by malignant proliferative diseases.
本发明进一步优选的实施方案中，所述的神经源性疼痛包括但不限于幻肢痛、残端痛、灼性神经痛、带状疱疹后遗神经痛、交感神经相关性疼痛、外周神经性疼痛。In a further preferred embodiment of the present invention, the neurogenic pain includes but is not limited to phantom limb pain, stump pain, causalgia, postherpetic neuralgia, sympathetic nerve-related pain, and peripheral neuropathic pain. pain.
本发明进一步优选的实施方案中，所述的代谢性疾病引起的疼痛包括但不限于痛风引起的疼痛、糖尿病引起的疼痛。In a further preferred embodiment of the present invention, the pain caused by the metabolic disease includes, but is not limited to, pain caused by gout and pain caused by diabetes.
本发明进一步优选的实施方案中，所述的恶性增殖疾病引起的疼痛包括但不限于肿 瘤引起的疼痛，例如白血病、淋巴瘤、骨髓瘤、乳腺癌、肺癌、食管癌、胃癌、大肠癌、肝癌、胰腺癌、头颈部癌、肾癌、膀胱癌、***癌、卵巢癌、子宫内膜癌、子***、骨肉瘤、软组织肉瘤、黑色素瘤、脑瘤引起的疼痛。In a further preferred embodiment of the present invention, the pain caused by the malignant proliferative disease includes, but is not limited to, pain caused by tumors, such as leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer , Pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, brain tumors.
本发明进一步优选的实施方案中，所述的疼痛选自中至重度疼痛，优选的，所述的中至重度疼痛包括但不限于创伤性疼痛、分娩疼痛、肿瘤引起的疼痛、炎性疼痛。In a further preferred embodiment of the present invention, the pain is selected from moderate to severe pain. Preferably, the moderate to severe pain includes but is not limited to traumatic pain, labor pain, pain caused by tumor, and inflammatory pain.
本发明优选的实施例方案中，所述神经退行性疾病包括但不限于阿尔兹海默症、帕金森症、亨丁顿舞蹈症和路易氏体失智症，更优选阿尔兹海默症。In a preferred embodiment of the present invention, the neurodegenerative diseases include but are not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease and Lewy body dementia, more preferably Alzheimer's disease.
本发明优选的实施方案中，所述的抑郁包括但不限于轻至重度抑郁，一般符合WHO ICD-10(《国际疾病分类》)、美国DSM-5(《精神障碍诊断与统计手册》)和CCMD-3(《中国精神疾病分类和诊断标准》)的相关诊断标准，优选中至重度抑郁。In a preferred embodiment of the present invention, the depression includes, but is not limited to, mild to severe depression, which generally conforms to WHO ICD-10 ("International Classification of Diseases"), American DSM-5 ("Manual of Diagnosis and Statistics of Mental Disorders") and The relevant diagnostic criteria of CCMD-3 ("Chinese Classification and Diagnostic Standards of Mental Disorders"), preferably moderate to severe depression.
本发明优选的实施方案中，所述的抑郁包括但不限于轻度抑郁发作、中度抑郁发作、重度抑郁发作伴有或不伴有精神病性症症状的抑郁以及复发性抑郁发作。In a preferred embodiment of the present invention, the depression includes but is not limited to mild depressive episodes, moderate depressive episodes, major depressive episodes with or without psychotic symptoms, and recurrent depressive episodes.
本发明的实施方案还可以表述如下：The embodiments of the present invention can also be expressed as follows:
本发明提供了一种如通式(A-1)所示的化合物或其可药用的盐，The present invention provides a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020129826-appb-000044
Figure PCTCN2020129826-appb-000044
其中：among them:
R 1独立地选自氢、烷基、羟基、烷氧基、氰基、卤代烷基、环烷基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
R 2和R 3相同或不同，且各自独立地选自氢、卤素、烷基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及含N杂环基； R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
R 4、R 5和R 6相同或不同，且各自独立地选自氢或烷基； R 4 , R 5 and R 6 are the same or different, and are each independently selected from hydrogen or alkyl;
R 7独立地选自氢、烷基或
Figure PCTCN2020129826-appb-000045
R 7 is independently selected from hydrogen, alkyl or
Figure PCTCN2020129826-appb-000045
n 1独立地为0～1之间的任意一个整数；n 2独立地为0～3之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1～3之间的任意一个整数。 n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 3; n 3 is independently any integer between 1 and 2; n 4 is independently Any integer between 1 and 3.
在一实施方案中，提供了通式(A-1)所示的化合物或其可药用的盐，其特征在于，所述烷基选自C1-C6的烷基；所述环烷基选自C3-C6的环烷基；所述卤代烷基选自C1-C6的 卤代烷基；所述烷氧基选自C1-C6的烷氧基；所述硫代烷基选自C1-C6的硫代烷基；所述含N杂环基选自仅含有一个N原子的杂环基；所述被一个或多个烷基取代的氨基选自被一个或多个C1-C6的烷基取代的氨基；所述芳基选自苯基或萘基；所述卤素选自氟、氯、溴或碘。In one embodiment, a compound represented by the general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, wherein the alkyl group is selected from C1-C6 alkyl; the cycloalkyl group is selected from C3-C6 cycloalkyl; the haloalkyl group is selected from C1-C6 haloalkyl; the alkoxy group is selected from C1-C6 alkoxy; the thioalkyl group is selected from C1-C6 sulfur Alkyl; the N-containing heterocyclic group is selected from heterocyclic groups containing only one N atom; the amino group substituted by one or more alkyl groups is selected from the group substituted by one or more C1-C6 alkyl groups Amino; the aryl group is selected from phenyl or naphthyl; the halogen is selected from fluorine, chlorine, bromine or iodine.
在又一实施方案中，提供了通式(A-1)所示的化合物或其可药用的盐，其特征在于，所述C1-C6的烷基选自甲基、乙基、丙基、丁基或戊基；所述C1-C6的卤代烷基选自-(CH 2) aCX 3或-(CH 2) aCH(CX 3) 2；所述C1-C6的烷氧基选自-O-(CH 2) aCH 3或-O-(CH 2) aCH(CH 3) 2；所述C1-C6的硫代烷基选自-S-(CH 2) aCH 3或-S-(CH 2) aCH(CH 3) 2；所述被一个或多个C1-C6的烷基取代的氨基选自-NH-(CH 2) aCH 3或-N[(CH 2) a-CH 3] 2；所述仅含有一个N原子的杂环基选自
Figure PCTCN2020129826-appb-000046
In another embodiment, a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, characterized in that the C1-C6 alkyl group is selected from methyl, ethyl, propyl , Butyl or pentyl; the C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 or -(CH 2 ) a CH(CX 3 ) 2 ; the C1-C6 alkoxy group is selected from -O-(CH 2 ) a CH 3 or -O-(CH 2 ) a CH(CH 3 ) 2 ; the C1-C6 thioalkyl group is selected from -S-(CH 2 ) a CH 3 or- S-(CH 2 ) a CH(CH 3 ) 2 ; the amino group substituted by one or more C1-C6 alkyl groups is selected from -NH-(CH 2 ) a CH 3 or -N[(CH 2 ) a -CH 3 ] 2 ; the heterocyclic group containing only one N atom is selected from
Figure PCTCN2020129826-appb-000046
其中：X代表卤素，所述卤素选自氟、氯、溴或碘；a独立地选自0～3之间的任意一个整数。Wherein: X represents halogen, and the halogen is selected from fluorine, chlorine, bromine or iodine; a is independently selected from any integer between 0-3.
在又一实施方案中，提供了所述的通式(A-1)所示的化合物其可药用的盐，其特征在于，选自表1所示任意一个化合物。In another embodiment, a pharmaceutically acceptable salt of the compound represented by the general formula (A-1) is provided, which is characterized in that it is selected from any one of the compounds shown in Table 1.
在又一实施方案中，提供了一种制备通式(A-1)所示的化合物或其可药用的盐的方法，其特征在于，包括：In yet another embodiment, a method for preparing a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, which is characterized in that it comprises:
Figure PCTCN2020129826-appb-000047
Figure PCTCN2020129826-appb-000047
方法一：通式(IV)的化合物与邻苯二甲酰亚胺反应制备得到通式(V)的化合物，通式(V)的化合物通过脱保护反应制备得到通式(A-1)的化合物；Method 1: The compound of general formula (IV) is reacted with phthalimide to prepare the compound of general formula (V), and the compound of general formula (V) is prepared by deprotection reaction to obtain the compound of general formula (A-1) Compound
或者or
方法二：通式(IV)的化合物通过取代反应制备得到通式(VI)的化合物，通式(VI)的化合物通过加氢反应制备得到通式(A-1)的化合物；Method 2: The compound of general formula (IV) is prepared by substitution reaction to obtain the compound of general formula (VI), and the compound of general formula (VI) is prepared by hydrogenation reaction to obtain the compound of general formula (A-1);
其中：among them:
R 1独立地选自氢、烷基、羟基、烷氧基、氰基、卤代烷基、环烷基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
R 2和R 3相同或不同，且各自独立地选自氢、卤素、烷基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及含N杂环基； R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
R 5和R 7为氢； R 5 and R 7 are hydrogen;
R 4和R 6各自独立地选自氢或烷基； R 4 and R 6 are each independently selected from hydrogen or alkyl;
n 1独立地为0～1之间的任意一个整数；n 2独立地为0～3之间的任意一个整数；n 3独立地为1～2之间的任意一个整数。 n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 3; n 3 is independently any integer between 1 and 2.
在又一实施方案中，提供了一种制备通式(A-1)所示的化合物或其可药用的盐的方法，其特征在于，包括：In yet another embodiment, a method for preparing a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof is provided, which is characterized in that it comprises:
Figure PCTCN2020129826-appb-000048
Figure PCTCN2020129826-appb-000048
方法一：通式(VII)的化合物与二碳酸二叔丁酯反应制备得到通式(VIII)的化合物，通式(VIII)的化合物通过烷基化反应得到通式(IX)的化合物，通式(IX)的化合物通过还原反应制备得到通式(A-1)的化合物；Method 1: The compound of general formula (VII) is reacted with di-tert-butyl dicarbonate to prepare the compound of general formula (VIII). The compound of general formula (VIII) is alkylated to obtain the compound of general formula (IX). The compound of formula (IX) is prepared by reduction reaction to obtain the compound of general formula (A-1);
或者or
方法二：通式(VII)的化合物与通式SM-5的化合物反应制备得到通式(X)的化合物，通式(X)的化合物通过脱保护反应制备得到通式(A-1)的化合物；Method 2: The compound of general formula (VII) is reacted with the compound of general formula SM-5 to prepare the compound of general formula (X), and the compound of general formula (X) is prepared by deprotection reaction to obtain the compound of general formula (A-1) Compound
其中：among them:
R 1独立地选自氢、烷基、羟基、烷氧基、氰基、卤代烷基、环烷基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
R 2和R 3相同或不同，且各自独立地选自氢、卤素、烷基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及含N杂环基； R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
R 5为氢； R 5 is hydrogen;
R 4和R 6各自独立地选自氢或烷基； R 4 and R 6 are each independently selected from hydrogen or alkyl;
R 7独立地选自烷基或
Figure PCTCN2020129826-appb-000049
R 7 is independently selected from alkyl or
Figure PCTCN2020129826-appb-000049
n 1独立地为0～1之间的任意一个整数；n 2独立地为0～3之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1～3之间的任意一个整数。 n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 3; n 3 is independently any integer between 1 and 2; n 4 is independently Any integer between 1 and 3.
在又一实施方案中，提供了一种药物组合物，其特征在于，包含治疗有效量的通式(A-1)所示的化合物或其可药用的盐和医学上可接受的载体。In another embodiment, a pharmaceutical composition is provided, which is characterized by comprising a therapeutically effective amount of a compound represented by general formula (A-1) or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.
在又一实施方案中，提供了通式(A-1)所示的化合物或其可药用的盐或上述的药物组合物在制备治疗神经精神类疾病的药物中的用途。In another embodiment, there is provided the use of the compound represented by the general formula (A-1) or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a medicament for the treatment of neuropsychiatric diseases.
在又一实施方案中，提供了通式(A-1)所示的化合物或其可药用的盐或上述的药物组合物在制备治疗神经精神类疾病的药物中的用途，其中所述神经精神类疾病选自抑郁或疼痛。In another embodiment, there is provided the use of the compound represented by the general formula (A-1) or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a medicament for the treatment of neuropsychiatric diseases, wherein the nerve The mental illness is selected from depression or pain.
有益效果Beneficial effect
本发明提供的化合物为一种可逆的NMDAR拮抗剂，对NMDAR具有中等的亲和力，其特定的作用于TMD位点，可抑制在病理性条件下的NMDAR过度激活而导致的通道开放，从而避免Ca 2+的过多内流。与已上市的NMDAR拮抗剂相比，本发明提供的化合物与NMDAR结合后能够快速解离，从而不影响NMDAR的正常功能。 The compound provided by the present invention is a reversible NMDAR antagonist with moderate affinity to NMDAR. It specifically acts on the TMD site and can inhibit the channel opening caused by excessive activation of NMDAR under pathological conditions, thereby avoiding Ca Excessive influx of 2+. Compared with the marketed NMDAR antagonists, the compound provided by the present invention can be quickly dissociated after being combined with NMDAR, thereby not affecting the normal function of NMDAR.
体外研究结果显示，本发明提供的化合物与化合物1a1的活性基本相当，但本发明提供的化合物与NMDAR的解离速度较快，明显优于化合物1a1，与美金刚和NMDAR的解离速度相当，提示本发明提供的化合物不仅具有显著的镇痛和抗抑郁活性，同时也具有更突出的降低拟精神样不良反应的治疗优势，具有较大的临床使用价值。The results of in vitro studies show that the compound provided by the present invention has basically the same activity as compound 1a1, but the compound provided by the present invention has a faster dissociation rate from NMDAR, which is significantly better than that of compound 1a1, and is comparable to the dissociation rate of memantine and NMDAR. It is suggested that the compound provided by the present invention not only has significant analgesic and antidepressant activities, but also has a more prominent therapeutic advantage of reducing psychiatric-like adverse reactions, and has greater clinical use value.
实施例Example
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。除非另外指明，本文所指的比例、百分比等均以重量计。The embodiments of the present invention are described in detail below. The embodiments described below are exemplary, and are only used to explain the present invention, but should not be construed as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.
合成实施例Synthesis Example
实施例1 3-氨基-5′-氯-1′-乙基螺[环丁烷-1,3′-吲哚啉]-2′-酮(NH200002)Example 1 3-Amino-5′-chloro-1′-ethylspiro[cyclobutane-1,3′-indoline]-2′-one (NH200002)
Figure PCTCN2020129826-appb-000050
Figure PCTCN2020129826-appb-000050
步骤1：叔丁基((1,3-二溴丙-2-基)氧基)二甲基硅烷(NH200002-int 1)Step 1: Tert-butyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane (NH200002-int 1)
在250mL单口瓶中，加入10g 1,3-二溴-2-丙醇(45.89mmol)、6.25g咪唑(91.78mmol)和二氯甲烷(100mL)，0℃下加入8.3g叔丁基二甲基氯硅烷(TBSCl，55.07mmol)，升至室温搅拌反应12小时。反应结束后，加入200mL水和100mL二氯甲烷，萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝30:1,v/v)得无色液体标题化合物14.96g，收率99.7％。In a 250mL single-mouth flask, add 10g 1,3-dibromo-2-propanol (45.89mmol), 6.25g imidazole (91.78mmol) and dichloromethane (100mL), add 8.3g tert-butyldimethyl at 0℃ Chlorosilane (TBSCl, 55.07mmol), warmed to room temperature and stirred for 12 hours. After the reaction, add 200 mL of water and 100 mL of dichloromethane, extract the organic phase, and concentrate the organic phase under reduced pressure to obtain a crude product, which is separated by column chromatography (petroleum ether: ethyl acetate = 30:1, v/v). The title compound was 14.96 g in color liquid, and the yield was 99.7%.
步骤2：3-((叔丁基二甲基硅烷基)氧基)-5′-氯螺[环丁烷-1,3′-吲哚]-2′-酮(NH200002-int 2)Step 2: 3-((tert-butyldimethylsilyl)oxy)-5′-chlorospiro[cyclobutane-1,3′-indole]-2′-one (NH200002-int 2)
在100mL单口瓶中，加入3g 5-氯氧化吲哚(17.8mmol)溶于60mL四氢呋喃(THF)和6mL六甲基磷酰三胺(HMPA)，-20℃下滴加15.7mL正丁基锂(39.38mmol)，1小时后，加入6.5g NH200002-int 1(19.69mmol)，室温下搅拌反应12小时。反应结束后，加入70mL水和25mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝10:1,v/v)得淡黄色固体标题化合物2g,收率33.1％。In a 100mL single-neck flask, add 3g 5-chloroindole (17.8mmol) dissolved in 60mL tetrahydrofuran (THF) and 6mL hexamethylphosphoric triamide (HMPA), add 15.7mL n-butyllithium dropwise at -20℃ (39.38mmol), 1 hour later, add 6.5g NH200002-int1 (19.69mmol), and stir for 12 hours at room temperature. After the reaction, add 70mL of water and 25mL of dichloromethane to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 10:1, v/v) to obtain a pale yellow The solid title compound was 2g, the yield was 33.1%.
步骤3：3-((叔丁基二甲基甲硅烷基)氧基)-5′-氯-1′-乙基螺[环丁烷-1,3′-吲哚]-2′-酮(NH200002-int 3)Step 3: 3-((tert-butyldimethylsilyl)oxy)-5′-chloro-1′-ethylspiro[cyclobutane-1,3′-indole]-2′-one (NH200002-int 3)
在50mL单口瓶中，加入600mg NH200002-int 2(1.78mmol)、232mg溴乙烷(2.13mmol)、1.15g碳酸铯(3.56mmol)和10mL N,N-二甲基甲酰胺(DMF)，70℃下搅拌反应1小时。反应结束后，加入40mL水和25mL乙酸乙酯萃取得有机相，有机相减压浓缩得黄色油状标题化合物710mg。In a 50mL single-mouth bottle, add 600mg NH200002-int 2 (1.78mmol), 232mg bromoethane (2.13mmol), 1.15g cesium carbonate (3.56mmol) and 10mL N,N-dimethylformamide (DMF), 70 The reaction was stirred at °C for 1 hour. After the reaction, 40 mL of water and 25 mL of ethyl acetate were added to extract the organic phase, and the organic phase was concentrated under reduced pressure to obtain 710 mg of the title compound as a yellow oil.
步骤4：5′-氯-1′-乙基-3-羟基螺[环丁烷-1,3′-二氢吲哚]-2′-酮(NH200002-int 4)Step 4: 5′-chloro-1′-ethyl-3-hydroxyspiro[cyclobutane-1,3′-indoline]-2′-one (NH200002-int 4)
在50mL单口瓶中，加入740mg NH200002-int 3(2.02mmol)溶于10mL四氢呋喃(THF)，加入2mL四丁基氟化铵(TBAF,3.03mmol)，室温下搅拌反应1小时。反应结束后，加入40mL水和25mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝3：1,v/v)得白色固体标题化合物400mg，收率78.7％。In a 50mL single-necked flask, add 740mg NH200002-int3 (2.02mmol) dissolved in 10mL tetrahydrofuran (THF), add 2mL tetrabutylammonium fluoride (TBAF, 3.03mmol), stir and react at room temperature for 1 hour. After the reaction, add 40 mL of water and 25 mL of ethyl acetate to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate=3:1, v/v) to obtain a white solid The title compound was 400 mg, and the yield was 78.7%.
步骤5：2-(5′-氯-1′-乙基-2′-氧代螺[环丁烷-1,3′-二氢吲哚]-3-基)异吲哚-1,3-二酮(NH200002-int 5)Step 5: 2-(5'-Chloro-1'-ethyl-2'-oxospiro[cyclobutane-1,3'-indoline]-3-yl)isoindole-1,3 -Diketone (NH200002-int 5)
在50mL单口瓶中，加入200mg NH200002-int 5(0.79mmol)、175mg邻苯二甲酰亚胺(1.19mmol)、208mg偶氮二甲酸二乙酯(DEAD,1.19mmol)、313mg三苯基膦(PPh 3, 1.19mmol)和2mL四氢呋喃(THF)，氮气保护下，从0℃到室温搅拌反应12小时。TLC检测，反应完毕，加入40mL水和25mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(石油醚：乙酸乙酯＝1:1,v/v)得75mg黄色固体标题化合物(粗产品)。 In a 50mL single-mouth flask, add 200mg NH200002-int 5 (0.79mmol), 175mg phthalimide (1.19mmol), 208mg diethyl azodicarboxylate (DEAD, 1.19mmol), 313mg triphenylphosphine (PPh 3 , 1.19mmol) and 2mL of tetrahydrofuran (THF), under nitrogen protection, the reaction was stirred from 0°C to room temperature for 12 hours. TLC detection, the reaction is complete, add 40mL water and 25mL ethyl acetate to extract the organic phase, the organic phase is concentrated under reduced pressure to obtain a crude product, separated by a pre-preparation plate (petroleum ether: ethyl acetate = 1:1, v/v) 75 mg yellow solid title compound (crude product).
步骤6：3-氨基-5′-氯-1′-乙基螺[环丁烷-1,3′-吲哚啉]-2′-酮(NH200002)Step 6: 3-Amino-5'-chloro-1'-ethylspiro[cyclobutane-1,3'-indoline]-2'-one (NH200002)
在50mL单口瓶中，加入75mg上一步产物(0.20mmol)和2mL乙醇胺，70℃下搅拌反应1小时。反应结束后，加入20mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(二氯甲烷：甲醇＝10:1,v/v)得白色固体标题化合物12mg，收率24.0％，纯度97.7％。In a 50 mL single-necked flask, 75 mg of the product from the previous step (0.20 mmol) and 2 mL of ethanolamine were added, and the reaction was stirred at 70° C. for 1 hour. After the reaction, add 20mL of water and 15mL of dichloromethane to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by a pre-preparation plate (dichloromethane: methanol = 10:1, v/v) to obtain a white solid title Compound 12mg, yield 24.0%, purity 97.7%.
1H NMR(400MHz,Methanol-d 4)δ7.67(s,1H),7.35(d,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,1H),4.23-4.19(m,1H),3.82-3.77(m,2H),2.87-2.82(m,2H),2.66-2.62(m,2H),1.26-1.22(m,3H)；[M+H] +251.0 1 H NMR(400MHz,Methanol-d 4 )δ7.67(s,1H), 7.35(d,J=8.0Hz,1H), 7.04(d,J=8.0Hz,1H), 4.23-4.19(m, 1H),3.82-3.77(m,2H),2.87-2.82(m,2H),2.66-2.62(m,2H),1.26-1.22(m,3H); [M+H] + 251.0
实施例2-1 3-氨基-6′-氯-2′-乙基-1′,2′-二氢-3′氢-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003)Example 2-1 3-Amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinoline]-3 ′-Ketone (NH200003)
Figure PCTCN2020129826-appb-000051
Figure PCTCN2020129826-appb-000051
步骤1：2-(3-氯苯基)-N-乙基乙酰胺(NH200003-int 1)Step 1: 2-(3-Chlorophenyl)-N-ethylacetamide (NH200003-int 1)
在100mL单口瓶中，加入5g 3-氯苯乙酸(29.31mmol)溶于50mL二氯甲烷中，0℃下加入4.53g二氯亚砜(38.10mmol)和1.07g N,N-二甲基甲酰胺(14.66mmol)，氮气保护下室温搅拌1小时。浓缩油泵拉干溶剂，再溶于25mL二氯甲烷，0℃下加入29.3mL乙胺(2M THF)(58.62mmol)，室温搅拌反应12小时。反应结束后，加入50mL水和40mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(二氯甲烷：甲醇＝30：1,v/v)得黄棕色固体标题化合物3.26g，收率56.3％。In a 100mL single-neck flask, add 5g 3-chlorophenylacetic acid (29.31mmol) dissolved in 50mL dichloromethane, add 4.53g thionyl chloride (38.10mmol) and 1.07g N,N-dimethylformaldehyde at 0℃ Amide (14.66 mmol), stirred at room temperature under nitrogen protection for 1 hour. The solvent was pulled dry by a concentrated oil pump and dissolved in 25 mL of dichloromethane. 29.3 mL of ethylamine (2M THF) (58.62 mmol) was added at 0°C, and the reaction was stirred at room temperature for 12 hours. After the reaction, add 50mL water and 40mL dichloromethane to extract the organic phase. The organic phase is concentrated under reduced pressure to obtain a crude product, which is separated by column chromatography (dichloromethane: methanol = 30:1, v/v) to obtain a yellow-brown solid The title compound was 3.26 g, and the yield was 56.3%.
步骤2：6-氯-2-乙基-1,4-二氢异喹啉-3(2H)-酮(NH200003-int 2)Step 2: 6-Chloro-2-ethyl-1,4-dihydroisoquinoline-3(2H)-one (NH200003-int 2)
在50mL单口瓶中，加入2.26g NH200003-int 1(11.43mmol)、412mg多聚甲醛(13.72mmol)和15mL Eaton′s试剂，氮气保护下，80℃搅拌反应2小时。反应结束后，加入70mL水和25mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝5：1,v/v)得黄色固体A 1.7g,收率70.8％。Add 2.26g NH200003-int 1 (11.43mmol), 412mg paraformaldehyde (13.72mmol) and 15mL Eaton's reagent to a 50mL single-necked flask. Under nitrogen protection, the reaction was stirred at 80°C for 2 hours. After the reaction, add 70mL of water and 25mL of dichloromethane to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v/v) to obtain a yellow solid A 1.7g, the yield is 70.8%.
步骤3：3-((叔丁基二甲基硅烷基)氧基)-6′-氯-2′-乙基-1′，2′-二氢-3′H-螺[环丁烷-1,4′- 异喹啉]-3′-酮(NH200003-int 3)Step 3: 3-((tert-butyldimethylsilyl)oxy)-6′-chloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane- 1,4′-isoquinoline]-3′-one (NH200003-int 3)
在100mL单口瓶中，加入1g NH200003-int 2(4.77mmol)溶于20mL四氢呋喃(THF)中，加入2mL六甲基磷酰三胺(HMPA)，氮气保护，-40℃下滴加4.2mL正丁基锂(10.49mmol)，此温度下搅拌1小时。再加入1.9g NH200002-int 1(5.72mmol)的THF(5mL)溶液，室温搅拌反应12小时。反应结束后，加入40mL水和25mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝5：1,v/v)得黄色油状物760mg，收率42.0％。In a 100mL single-neck flask, add 1g NH200003-int 2 (4.77mmol) dissolved in 20mL tetrahydrofuran (THF), add 2mL hexamethylphosphoric triamide (HMPA), nitrogen protection, drop 4.2mL normal Butyl lithium (10.49 mmol), stirring at this temperature for 1 hour. Then add 1.9 g of NH200002-int 1 (5.72 mmol) in THF (5 mL), and stir at room temperature for 12 hours. After the reaction, add 40 mL of water and 25 mL of ethyl acetate to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v/v) to obtain a yellow oil The compound is 760 mg, and the yield is 42.0%.
步骤4：6′-氯-2′-乙基-3-羟基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003-int 4)Step 4: 6′-chloro-2′-ethyl-3-hydroxy-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200003-int 4)
在50mL单口瓶中，加入760mg NH200003-int 3(2.0mmol)溶于10mL四氢呋喃(THF)，加入3mL四丁基氟化铵(TBAF,3.0mmol)，室温下搅拌反应1小时。反应结束后，加入40mL水和25mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝1:1,v/v)得黄色油状物460mg，收率86.6％。In a 50 mL single-neck flask, add 760 mg NH200003-int 3 (2.0 mmol) dissolved in 10 mL tetrahydrofuran (THF), add 3 mL tetrabutylammonium fluoride (TBAF, 3.0 mmol), and stir for reaction at room temperature for 1 hour. After the reaction, add 40 mL of water and 25 mL of ethyl acetate to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 1:1, v/v) to obtain a yellow oil 460mg, yield 86.6%.
步骤5：2-(6′-氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1,3-二酮(NH200003-int 5)Step 5: 2-(6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline )-3-yl)isoindoline-1,3-dione (NH200003-int 5)
在50mL单口瓶中，加入460mg NH200003-int 4(1.73mmol)、305mg邻苯二甲酰亚胺(2.08mmol)和545mg三苯基膦(PPh 3，2.08mmol)溶于5mL四氢呋喃(THF)中，0℃下加入362mg偶氮二甲酸二乙酯(DEAD,2.08mmol)，氮气保护下从0℃到室温搅拌反应12小时。反应结束后，加入40mL水和25mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(石油醚：乙酸乙酯＝1：1,v/v)得340mg粗品。 In a 50mL single-mouth flask, add 460mg NH200003-int 4 (1.73mmol), 305mg phthalimide (2.08mmol) and 545mg triphenylphosphine (PPh 3 , 2.08mmol) dissolved in 5mL tetrahydrofuran (THF) 362mg of diethyl azodicarboxylate (DEAD, 2.08mmol) was added at 0°C, and the reaction was stirred from 0°C to room temperature under nitrogen protection for 12 hours. After the reaction, add 40 mL of water and 25 mL of ethyl acetate to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by a pre-preparation plate (petroleum ether: ethyl acetate = 1:1, v/v) to obtain 340 mg of crude product. .
步骤6：3-氨基-6′-氯-2′-乙基-1′,2′-二氢-3′氢-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003)Step 6: 3-Amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′hydro-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200003)
在50mL单口瓶中，加入340mg上一步产物(0.86mmol)和5mL乙醇胺，70℃下搅拌反应1小时。反应结束后，加入20mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(二氯甲烷：甲醇＝10：1,v/v)得无色油状物30mg，收率13.2％，纯度97.3％。In a 50 mL single-mouth flask, 340 mg of the product from the previous step (0.86 mmol) and 5 mL ethanolamine were added, and the reaction was stirred at 70° C. for 1 hour. After the reaction, add 20mL water and 15mL dichloromethane to extract the organic phase. The organic phase is concentrated under reduced pressure to obtain a crude product, which is separated by a pre-preparation plate (dichloromethane: methanol = 10:1, v/v) to obtain a colorless oil 30mg, yield 13.2%, purity 97.3%.
1H NMR(400MHz,CDCl 3)δ7.44(s,1H),7.19(d,J＝8.0Hz,1H),7.08(d,J＝8.0Hz,1H),4.33(s,2H),3.85–3.81(m,1H),3.59-3.54(m,2H),3.07-3.02(m,2H),2.08-2.03(m,2H),1.18-1.15(m,3H)；[M+H] +265.1 1 H NMR(400MHz, CDCl 3 )δ7.44(s,1H), 7.19(d,J=8.0Hz,1H), 7.08(d,J=8.0Hz,1H), 4.33(s,2H), 3.85 –3.81(m,1H),3.59-3.54(m,2H),3.07-3.02(m,2H),2.08-2.03(m,2H),1.18-1.15(m,3H); [M+H] + 265.1
实施例2-2反式-3-氨基-6′-氯-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003-1)及顺式-3-氨基-6′-氯-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003-2)Example 2-2 trans-3-amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200003-1) and cis-3-amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1 ,4′-isoquinoline)-3′-one (NH200003-2)
NH200003经制备HPLC(Mobile Phase A:H 2O(0.1％TFA,Mobile Phase B:CAN,Column:C18,5um,4.6x250mm,Flow rate:15mL·min -1)分离可分别得到NH200003-1和NH200003-2。 NH200003 is separated by preparative HPLC (Mobile Phase A: H 2 O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL·min -1 ) to obtain NH200003-1 and NH200003, respectively -2.
NH200003-1: 1H NMR(400MHz,Methanol-d 4)δ7.61(s,1H),7.31–7.25(m,2H),4.49(s,2H),3.97-3.88(m,1H),3.61-3.56(m,2H),3.02-2.96(m,2H),2.45-2.38(m,2H),1.20(t,J＝7.2Hz,3H)；[M+H] +265.1 NH200003-1: 1 H NMR(400MHz,Methanol-d 4 )δ7.61(s,1H),7.31-7.25(m,2H),4.49(s,2H),3.97-3.88(m,1H),3.61 -3.56(m,2H),3.02-2.96(m,2H),2.45-2.38(m,2H),1.20(t,J=7.2Hz,3H); [M+H] + 265.1
NH200003-2: 1H NMR(400MHz,CDCl 3)δ7.66(d,J＝2.0Hz,1H),7.35–7.28(m,2H),4.53(s,2H),4.12–3.97(m,1H),3.64–3.56(m,2H),3.09–2.97(m,2H),2.60–2.45(m,2H),1.21(t,J＝7.2Hz,3H)；[M+H] +265.1 NH200003-2: 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J=2.0Hz,1H),7.35-7.28(m,2H),4.53(s,2H),4.12-3.97(m,1H ), 3.64–3.56(m,2H),3.09–2.97(m,2H),2.60–2.45(m,2H),1.21(t,J=7.2Hz,3H); [M+H] + 265.1
实施例3 3-氨基-6′-氯-2′-乙基-1′,2′-二氢-3′氢-螺[环戊烷-1,4′-异喹啉]-3′-酮(NH200020)Example 3 3-Amino-6′-chloro-2′-ethyl-1′,2′-dihydro-3′hydro-spiro[cyclopentane-1,4′-isoquinoline]-3′- Ketone (NH200020)
Figure PCTCN2020129826-appb-000052
Figure PCTCN2020129826-appb-000052
将1,3-二溴丙-2-醇换成1,4-二溴丁-2-醇，按实施例2的方法制备目标化合物。Replace 1,3-dibromopropan-2-ol with 1,4-dibromobutan-2-ol, and prepare the target compound according to the method of Example 2.
1H NMR(400MHz,CDCl 3)δ7.51(s,1H),7.16(d,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,1H),4.46–4.36(m,2H),3.85–3.82(m,1H),3.58-3.52(m,2H),2.77-2.72(m,1H),2.45-2.38(m,1H),2.27–2.19(m,1H),2.04-1.97(m,1H),1.79-1.68(m,2H),1.17-1.14(m,3H)；[M+H] +279.1 1 H NMR(400MHz,CDCl 3 )δ7.51(s,1H), 7.16(d,J=8.0Hz,1H), 7.04(d,J=8.0Hz,1H), 4.46–4.36(m,2H) , 3.85-3.82(m,1H),3.58-3.52(m,2H),2.77-2.72(m,1H),2.45-2.38(m,1H),2.27-2.19(m,1H),2.04-1.97( m,1H),1.79-1.68(m,2H),1.17-1.14(m,3H); [M+H] + 279.1
实施例4 3-氨基6′-氯-2′-环丙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003O)Example 4 3-Amino 6′-chloro-2′-cyclopropyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200003O)
将实施例2步骤1中的乙胺换成环丙基胺，按实施例2的方法制备目标化合物。The ethylamine in step 1 of Example 2 was replaced with cyclopropylamine, and the target compound was prepared according to the method of Example 2.
1H NMR(400MHz,CDCl 3)δ7.57(s,1H),7.12(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,1H),4.34(s,2H),4.06-4.02(m,1H),3.06-3.01(m,2H),2.80-2.77(m,1H),2.46-2.41(m,2H),0.88–0.85(m,2H),0.70–0.67(m,2H)；[M+H] +277.1 1 H NMR(400MHz,CDCl 3 )δ7.57(s,1H), 7.12(d,J=8.0Hz,1H), 7.01(d,J=8.0Hz,1H), 4.34(s,2H), 4.06 -4.02(m,1H),3.06-3.01(m,2H),2.80-2.77(m,1H),2.46-2.41(m,2H),0.88-0.85(m,2H),0.70-0.67(m, 2H); [M+H] + 277.1
实施例5 3-氨基-6′-氯-2′-(2-羟乙基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003T)Example 5 3-Amino-6′-chloro-2′-(2-hydroxyethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200003T)
Figure PCTCN2020129826-appb-000053
Figure PCTCN2020129826-appb-000053
步骤1：N-(2-(苄氧基)乙基)-2-(3-氯苯基)乙酰胺(NH200003T-int1)Step 1: N-(2-(benzyloxy)ethyl)-2-(3-chlorophenyl)acetamide (NH200003T-int1)
将乙胺换成2-苄氧基乙基-1-胺，按实施例2的步骤1方法制备目标化合物。The ethylamine was replaced with 2-benzyloxyethyl-1-amine, and the target compound was prepared according to the step 1 method of Example 2.
步骤2：6-氯-2-(2-羟乙基)-1,4-二氢异喹啉-3(2H)-酮(NH200003T-int2)Step 2: 6-Chloro-2-(2-hydroxyethyl)-1,4-dihydroisoquinolin-3(2H)-one (NH200003T-int2)
在100mL单口瓶中，加入上一步产物(13g，42.79mmol)、多聚甲醛(1.67g，55.63mmol)和39mL Eaton′s试剂，氮气保护下，80℃搅拌反应2小时。反应结束后，倒入冰水中，饱和NaHCO 3调pH至中性，加入2N NaOH调pH至9-10，加入80mL二氯甲烷萃取3次得有机相，有机相无水硫酸钠干燥、过滤、减压浓缩得粗品，直接用于下一步。 Add the product from the previous step (13g, 42.79mmol), paraformaldehyde (1.67g, 55.63mmol) and 39mL Eaton's reagent to a 100mL single-necked flask. Under nitrogen protection, the reaction was stirred at 80°C for 2 hours. After the reaction is over, pour into ice water, adjust the pH to neutral with saturated NaHCO 3 , add 2N NaOH to adjust the pH to 9-10, add 80 mL of dichloromethane to extract 3 times to obtain the organic phase, the organic phase is dried over anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to obtain the crude product, which was used directly in the next step.
步骤3：2-(2-(((叔丁基二甲基甲硅烷基)氧基)乙基)-6-氯-1,4-二氢异喹啉-3(2H)-酮(NH200003T-int3)Step 3: 2-(2-(((tert-butyldimethylsilyl)oxy)ethyl)-6-chloro-1,4-dihydroisoquinolin-3(2H)-one (NH200003T -int3)
在500mL单口瓶中，加入上一步产物(9.66g，42.79mmol)、咪唑(2.9g，42.79mmol)和100mL二氯甲烷，0℃下分批加入叔丁基二甲基氯硅烷(TBSCl，12.90g，85.58mmol)，转入室温搅拌反应12小时。反应结束后，加入100mL水和80mL二氯甲烷萃取得有机相，饱和NaCl洗涤有机相，有机相减压浓缩得粗产品，经过柱层析分离得1.6g。In a 500mL single-neck flask, add the product from the previous step (9.66g, 42.79mmol), imidazole (2.9g, 42.79mmol) and 100mL of dichloromethane. Add tert-butyldimethylchlorosilane (TBSCl, 12.90 g, 85.58 mmol), the reaction was stirred at room temperature for 12 hours. After the reaction, 100 mL of water and 80 mL of dichloromethane were added to extract the organic phase, the organic phase was washed with saturated NaCl, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain 1.6 g.
步骤4：2′-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-6′-氯-3-羟基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003T-int4)Step 4: 2'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6'-chloro-3-hydroxy-1',2'-dihydro-3'H- Spiro[cyclobutane-1,4′-isoquinoline]-3′-one (NH200003T-int4)
在50mL单口瓶中，加入i-PrMgCl(1.23mL，2.47mol)和10mL THF，冰水浴下加入上一步产物(200mg,0.588mmol)和环氧氯丙烷(98mg，1.06mmol)，室温反应2h。反应结束后，加入50mL水和30mL乙酸乙酯萃取得有机相，饱和NaCl洗涤有机相，有机相减压浓缩得粗产品，经过柱层析分离(PE：EA＝5：1,v/v)得75mg，收率32.2％。Add i-PrMgCl (1.23mL, 2.47mol) and 10mL THF to a 50mL single-necked flask, add the product from the previous step (200mg, 0.588mmol) and epichlorohydrin (98mg, 1.06mmol) under ice water bath, and react at room temperature for 2h. After the reaction, add 50mL water and 30mL ethyl acetate to extract the organic phase, wash the organic phase with saturated NaCl, and concentrate the organic phase under reduced pressure to obtain the crude product, which is separated by column chromatography (PE:EA=5:1, v/v) 75 mg was obtained, and the yield was 32.2%.
步骤5：2′-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-6′-氯-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]甲基磺酸-3-基酯(NH200003T-int5)Step 5: 2'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6'-chloro-3'-oxo-2',3'-dihydro-1' H-spiro[cyclobutane-1,4′-isoquinoline]methanesulfonate-3-yl ester (NH200003T-int5)
在50mL单口瓶中，加入上一步产物(500mg，1.26mmol)溶于10mL二氯甲烷，0℃下加入三乙胺(382.4mg，3.78mmol)和甲基磺酰氯(216.7mg，1.89mmol)，室温下搅拌反应2小时。反应结束后，加入40mL水和25mL二氯甲烷萃取2次得有机相，有机相减压浓缩得粗产品，经过柱层析分离(PE：EA＝5：1,v/v)得黄色油状物450mg，收率75.3％。In a 50mL single-neck flask, add the product from the previous step (500mg, 1.26mmol) dissolved in 10mL of dichloromethane, add triethylamine (382.4mg, 3.78mmol) and methanesulfonyl chloride (216.7mg, 1.89mmol) at 0°C, The reaction was stirred at room temperature for 2 hours. After the reaction, add 40mL water and 25mL dichloromethane and extract twice to obtain the organic phase. The organic phase is concentrated under reduced pressure to obtain a crude product, which is separated by column chromatography (PE:EA=5:1, v/v) to obtain a yellow oil 450mg, the yield was 75.3%.
步骤6：3-叠氮基-6′-氯-2′-(2-羟乙基)-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003T-int6)Step 6: 3-azido-6′-chloro-2′-(2-hydroxyethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-iso Quinoline)-3′-one (NH200003T-int6)
在50mL单口瓶中，加入上一步产物(450mg，0.95mmol)溶于10mL DMF中，加入NaN 3(247mg，3.80mmol)和KI(15.77mg，0.095mmol)，150℃搅拌反应3小时。反应结束后，加入50mL水和50mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(PE：EA＝1:1,v/v)得120mg，收率41.2％。 In a 50 mL single-neck flask, add the product from the previous step (450 mg, 0.95 mmol) and dissolve it in 10 mL DMF, add NaN 3 (247 mg, 3.80 mmol) and KI (15.77 mg, 0.095 mmol), stir and react at 150°C for 3 hours. After the reaction, add 50mL water and 50mL ethyl acetate to extract the organic phase. The organic phase is concentrated under reduced pressure to obtain the crude product, which is separated by column chromatography (PE:EA=1:1, v/v) to obtain 120mg, the yield is 41.2 %.
步骤7：3-氨基-6′-氯-2′-(2-羟乙基)-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003T)Step 7: 3-Amino-6′-chloro-2′-(2-hydroxyethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200003T)
在50mL单口瓶中，加入上一步产物(120mg，0.39mmol)溶于10mL EA，加入Pd/C(24mg，0.078mmol)，通入H 2，室温搅拌反应2小时。反应结束后，加入50mL水和30mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过p-TLC分离(DCM:MeOH＝5:1,v/v)得油状物60mg，纯度94.8％。 In a 50 mL single-neck flask, add the product from the previous step (120 mg, 0.39 mmol) and dissolve in 10 mL EA, add Pd/C (24 mg, 0.078 mmol), pass H 2 , and stir at room temperature to react for 2 hours. After the reaction, add 50mL water and 30mL ethyl acetate to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated by p-TLC (DCM:MeOH=5:1, v/v) to obtain 60 mg of oily substance with purity 94.8%.
1H NMR(400MHz,CDCl 3)δ7.48(s,1H),7.18-7.12(m,2H),4.47(s,2H),3.78-3.70(m,1H),3.65(t,J＝5.2Hz,2H),3.55(t,J＝5.2Hz,2H),2.94-2.89(m,2H),2.28-2.21(m,2H).[M+H] +281.1 1 H NMR(400MHz, CDCl 3 )δ7.48(s,1H), 7.18-7.12(m,2H), 4.47(s,2H), 3.78-3.70(m,1H), 3.65(t,J=5.2 Hz,2H),3.55(t,J=5.2Hz,2H),2.94-2.89(m,2H),2.28-2.21(m,2H).[M+H] + 281.1
实施例6 3-氨基-6′-氯-2′-(2,2,2-三氟-乙基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200087)Example 6 3-Amino-6′-chloro-2′-(2,2,2-trifluoro-ethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1, 4′-isoquinoline)-3′-one (NH200087)
将乙胺换成三氟乙胺，按实施例2的方法制备目标化合物，纯度92.5％。The ethylamine was replaced with trifluoroethylamine, and the target compound was prepared according to the method of Example 2 with a purity of 92.5%.
1H NMR(400MHz,CDCl 3)δ7.48(s,1H),7.24(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),4.49(s,2H),4.20-4.13(m,2H),4.05-4.01(m,1H),3.06–3.01(m,2H),2.78–2.73(m,2H)；[M+H] +319.1 1 H NMR(400MHz,CDCl 3 )δ7.48(s,1H), 7.24(d,J=8.0Hz,1H), 7.12(d,J=8.0Hz,1H), 4.49(s,2H), 4.20 -4.13(m,2H),4.05-4.01(m,1H),3.06–3.01(m,2H),2.78–2.73(m,2H); [M+H] + 319.1
实施例7 3-氨基-2′-乙基-6′-(三氟甲基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200098)Example 7 3-Amino-2′-ethyl-6′-(trifluoromethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200098)
将3-氯苯乙酸换成3-三氟甲基苯乙酸，按实施例2的方法制备目标化合物，纯度95.13％。The 3-chlorophenylacetic acid was replaced with 3-trifluoromethylphenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 95.13%.
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.46(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),4.42(s,2H),4.06–4.02(m,1H),3.59-3.54(m,2H),3.09-3.04(m,2H),2.47-2.42(m,2H),1.18-1.14(m,3H)；[M+H] +299.1 1 H NMR (400MHz, CDCl 3 ) δ 7.81 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.42 (s, 2H), 4.06 –4.02(m,1H),3.59-3.54(m,2H),3.09-3.04(m,2H),2.47-2.42(m,2H),1.18-1.14(m,3H); [M+H] + 299.1
实施例8 3-氨基-6′-氯-2′-乙基-7′-氟-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003J)Example 8 3-Amino-6′-chloro-2′-ethyl-7′-fluoro-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200003J)
将3-氯苯乙酸换成3-氯-4-氟苯乙酸，按实施例2的方法制备目标化合物，纯度94.02％。The 3-chlorophenylacetic acid was replaced with 3-chloro-4-fluorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 94.02%.
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),4.31(s,2H),3.86–3.78(m,1H),3.59-3.54(m,2H),3.07-3.01(m,2H),2.02-1.97(m,2H),1.18-1.15(m,3H)；[M+H] +283.1 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J=8.0Hz,1H), 6.95(d,J=8.0Hz,1H), 4.31(s,2H), 3.86–3.78(m,1H) ,3.59-3.54(m,2H),3.07-3.01(m,2H),2.02-1.97(m,2H),1.18-1.15(m,3H); [M+H] + 283.1
实施例9 3-氨基-5′,6′-二氯-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200043)Example 9 3-Amino-5′,6′-dichloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200043)
将3-氯苯乙酸换成2,3-二氯苯乙酸，按实施例2的方法制备目标化合物，纯度90.87％。The 3-chlorophenylacetic acid was replaced with 2,3-dichlorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 90.87%.
1H NMR(400MHz,CDCl 3)δ7.32(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),4.40(s,2H),4.13–4.05(m,1H),3.56-3.51(m,2H),3.316-3.31(m,,2H),3.11-3.06(m,2H),1.17-1.14(m,3H)；[M+H] +299.0 1 H NMR(400MHz,CDCl 3 )δ7.32(d,J=8.0Hz,1H), 6.97(d,J=8.0Hz,1H), 4.40(s,2H), 4.13–4.05(m,1H) ,3.56-3.51(m,2H),3.316-3.31(m,,2H),3.11-3.06(m,2H),1.17-1.14(m,3H); [M+H] + 299.0
实施例10 3-氨基-6′-氯-2′-乙基-5′-氟-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200043a)Example 10 3-Amino-6′-chloro-2′-ethyl-5′-fluoro-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200043a)
将3-氯苯乙酸换成2-氟-3-氯苯乙酸，按实施例2的方法制备目标化合物，纯度98.60％。The 3-chlorophenylacetic acid was replaced with 2-fluoro-3-chlorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 98.60%.
实施例11 3-氨基-6′-溴-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200133)Example 11 3-Amino-6′-bromo-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200133)
将3-氯苯乙酸换成3-溴苯乙酸，按实施例2的步骤方法制备目标化合物，纯度99.0％。The 3-chlorophenylacetic acid was replaced with 3-bromophenylacetic acid, and the target compound was prepared according to the steps in Example 2 with a purity of 99.0%.
1H NMR(400MHz,CDCl 3)δ7.77(d,J＝4.0Hz,1H),7.29(d,J＝8.0Hz,1H),6.96(d,J＝8.0Hz,1H),4.33(s,2H),4.11-4.02(m,1H),3.57-3.52(m,2H),3.07-3.01(m,2H),2.52-2.47(m,2H),1.17-1.13(m,3H)；[M+H] +309.0 1 H NMR (400MHz, CDCl 3 ) δ7.77 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.33 (s ,2H),4.11-4.02(m,1H),3.57-3.52(m,2H),3.07-3.01(m,2H),2.52-2.47(m,2H),1.17-1.13(m,3H);[ M+H] + 309.0
实施例12 3-氨基-2′-乙基-6′-(甲硫基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200099)Example 12 3-Amino-2′-ethyl-6′-(methylthio)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200099)
Figure PCTCN2020129826-appb-000054
Figure PCTCN2020129826-appb-000054
步骤1：2-(6′-溴-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1,3-二酮(NH200099-int 1)Step 1: 2-(6′-Bromo-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline ]-3-yl)isoindoline-1,3-dione (NH200099-int 1)
将3-氯苯乙酸换成3-溴苯乙酸，按实施例2的步骤1-5方法制备目标化合物。The 3-chlorophenylacetic acid was replaced with 3-bromophenylacetic acid, and the target compound was prepared according to the steps 1-5 of Example 2.
步骤2：2-(2′-乙基-6′-(甲硫基)-3′-氧代-2′,3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1,3-二酮(NH200099-int 2)Step 2: 2-(2′-Ethyl-6′-(methylthio)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′ -Isoquinoline)-3-yl)isoindoline-1,3-dione (NH200099-int 2)
在50mL单口瓶中，加入200mg NH200099-int 1(0.46mmol)和100mg甲硫醇钠(1.38mmol)溶于4mL甲苯中，再加入300mg碳酸铯(0.92mmol)、26mg三(二亚苄基丙酮)二钯(pd 2(dba) 3，0.046mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos，0.046mmol)，110℃搅拌反应12小时。反应结束后，加入50mL水和30mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(石油醚：乙酸乙酯＝2:1)得40mg。 In a 50mL single-neck flask, add 200mg NH200099-int 1 (0.46mmol) and 100mg sodium methyl mercaptan (1.38mmol) dissolved in 4mL toluene, then add 300mg cesium carbonate (0.92mmol), 26mg tris(dibenzylidene acetone) ) Dipalladium (pd 2 (dba) 3 , 0.046mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos, 0.046mmol), stirred at 110°C for 12 hours . After the reaction, 50 mL of water and 30 mL of dichloromethane were added to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by a pre-preparation plate (petroleum ether: ethyl acetate = 2:1) to obtain 40 mg.
步骤3：3-氨基-2′-乙基-6′-(甲硫基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200099)Step 3: 3-Amino-2′-ethyl-6′-(methylthio)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200099)
将NH200002-int 5换成NH200099-int 2，按实施例1的步骤6方法制备目标化合物，纯度98.49％。Replace NH200002-int 5 with NH200099-int 2, and prepare the target compound according to step 6 of Example 1, with a purity of 98.49%.
1H NMR(400MHz,CDCl 3)δ7.44(s,1H),7.10(d,J＝8.0Hz,1H),7.03(d,J＝8.0Hz,1H),4.32(s,2H),4.02–3.98(m,1H),3.58-3.52(m,2H),3.05-3.00(m,2H),2.51(s,3H),2.43-2.38(m,2H),1.17-1.14(m,3H)；[M+H] +277.1 1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H), 7.10(d,J=8.0Hz,1H), 7.03(d,J=8.0Hz,1H), 4.32(s,2H), 4.02 --3.98(m,1H),3.58-3.52(m,2H),3.05-3.00(m,2H),2.51(s,3H),2.43-2.38(m,2H),1.17-1.14(m,3H) ; [M+H] + 277.1
实施例13 3-氨基-2′-乙基-6′-(氰基)-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200088)Example 13 3-Amino-2′-ethyl-6′-(cyano)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200088)
Figure PCTCN2020129826-appb-000055
Figure PCTCN2020129826-appb-000055
步骤1：2-(2′-乙基-6′-氰基-3′-氧代-2′,3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1,3-二酮(NH200088-int 1)Step 1: 2-(2′-Ethyl-6′-cyano-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquine (Linoline)-3-yl)isoindoline-1,3-dione (NH200088-int 1)
在50mL单口瓶中，加入100mg NH200099-int 1(0.23mmol)溶于5mL DMA，加入41mg氰化亚铜(0.46mmol)和4.3mg碘化亚铜(0.023mmol)，升温至170℃，反应5小时。反应结束后，加入20mL水和30mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离得42mg标题化合物。In a 50mL single-necked flask, add 100mg NH200099-int 1 (0.23mmol) dissolved in 5mL DMA, add 41mg cuprous cyanide (0.46mmol) and 4.3mg cuprous iodide (0.023mmol), heat up to 170℃, react 5 hour. After the reaction, 20 mL of water and 30 mL of ethyl acetate were added to extract the organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain 42 mg of the title compound.
1H NMR(400MHz,CDCl 3)δ8.31(s,1H),7.80-7.78(m,2H),7.68-7.65(m,2H),7.50(d,J＝8.0Hz,1H),7.21-7.18(m,1H),5.31-5.23(m,1H),4.43(s,2H),3.56(q,J＝7.2Hz,2H),3.26-3.20(m,2H),3.01-2.95(m,2H),1.17(t,J＝7.6,3H). 1H NMR (400MHz, CDCl 3 ) δ 8.31 (s, 1H), 7.80-7.78 (m, 2H), 7.68-7.65 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.21-7.18 (m,1H),5.31-5.23(m,1H),4.43(s,2H),3.56(q,J=7.2Hz,2H),3.26-3.20(m,2H),3.01-2.95(m,2H) ), 1.17(t,J=7.6,3H).
步骤2：3-氨基-2′-乙基-6′-(氰基)-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200088)Step 2: 3-Amino-2′-ethyl-6′-(cyano)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200088)
将NH200002-int 5换成NH200088-int 1，按实施例1的步骤6方法制备目标化合物，纯度95.2％。Replace NH200002-int 5 with NH200088-int 1, and prepare the target compound according to the method in step 6 of Example 1, with a purity of 95.2%.
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.40(d,J＝7.6Hz,1H),7.16(d,J＝8.0Hz,1H),4.38(s,2H),3.50(q,J＝7.2Hz,2H),3.40-3.32(m,1H),3.25(br s,2H),3.04-2.99(m,2H),2.43-2.36(m,2H),1.10(t,J＝7.2Hz,3H)；[M+H] +256.1 1 H NMR (400MHz, CDCl 3 ) δ7.91 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.38 (s, 2H), 3.50 (q,J=7.2Hz,2H), 3.40-3.32 (m, 1H), 3.25 (br s, 2H), 3.04-2.99 (m, 2H), 2.43-2.36 (m, 2H), 1.10 (t, J=7.2Hz,3H); [M+H] + 256.1
实施例14 3-氨基-6′,7′-二氯-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003H)Example 14 3-Amino-6′,7′-dichloro-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200003H)
Figure PCTCN2020129826-appb-000056
Figure PCTCN2020129826-appb-000056
步骤1：6,7-二氯-2-乙基-1,4-二氢异喹啉-3(2H)-酮(NH200003H-int 1)Step 1: 6,7-Dichloro-2-ethyl-1,4-dihydroisoquinolin-3(2H)-one (NH200003H-int 1)
将3-氯苯乙酸换成3,4-二氯苯乙酸，按实施例2步骤1～2的方法制备标题化合物。The 3-chlorophenylacetic acid was replaced with 3,4-dichlorophenylacetic acid, and the title compound was prepared according to the method of step 1 to 2 in Example 2.
步骤2：6′,7′-二氯-2′-乙基-3-羟基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003H-int 2)Step 2: 6′,7′-Dichloro-2′-ethyl-3-hydroxy-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200003H-int 2)
在50ml三口瓶中，加入1.76g异丙基氯化镁(17.26mmol)，0℃下加入1g中间体NH200003H-int 1(4.11mmol)溶于10ml四氢呋喃中，在40℃下搅拌70分钟，然后在0℃加入684.6mg环氧氯丙烷(7.4mmol)，氮气保护下60℃搅拌过夜。反应结束后，加入50mL水和50mL乙酸乙酯萃取，有机相减压浓缩得粗产品，经过柱层析分离得800mg标题化合物。In a 50ml three-necked flask, add 1.76g isopropylmagnesium chloride (17.26mmol), add 1g intermediate NH200003H-int 1 (4.11mmol) at 0°C and dissolve in 10ml tetrahydrofuran, stir at 40°C for 70 minutes, then at 0°C Add 684.6 mg of epichlorohydrin (7.4 mmol) at °C, and stir overnight at 60 °C under nitrogen protection. After the reaction, 50 mL of water and 50 mL of ethyl acetate were added for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain 800 mg of the title compound.
步骤3：6′，7′-二氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基甲磺酸酯(NH200003H-int 3)Step 3: 6′,7′-Dichloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquine Linyl]-3-yl methanesulfonate (NH200003H-int 3)
在50mL单口瓶中，加入800mg NH200003H-int 2(2.67mmol)溶于6mL二氯甲烷，0℃下加入539.34mg三乙胺(5.34mmol)和456mg甲基磺酰氯(4mmol)，室温下搅拌反应2小时。反应结束后，加入30mL水和30mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品1.1g，经过预制备板分离得550mg标题化合物。In a 50mL single-neck flask, add 800mg NH200003H-int 2 (2.67mmol) dissolved in 6mL dichloromethane, add 539.34mg triethylamine (5.34mmol) and 456mg methanesulfonyl chloride (4mmol) at 0℃, and stir the reaction at room temperature. 2 hours. After the reaction, 30 mL of water and 30 mL of dichloromethane were added to extract the organic phase, and the organic phase was concentrated under reduced pressure to obtain 1.1 g of the crude product, which was separated by a pre-preparation plate to obtain 550 mg of the title compound.
步骤4：6′，7′-二氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1,3-二酮(NH200003H-int 4)Step 4: 6′,7′-Dichloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquine (Aline)-3-yl)isoindoline-1,3-dione (NH200003H-int 4)
在50mL单口瓶中，加入550mg NH200003H-int 4(1.46mmol)、321.6mg邻苯二甲酰亚胺(2.19mmol)和503.7mg碳酸钾(3.65mmol)溶于5mL N,N-二甲基甲酰胺中，110℃搅拌反应2.5小时。反应结束后，加入50mL水和50mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离得标题化合物。In a 50mL single-mouth bottle, add 550mg NH200003H-int 4 (1.46mmol), 321.6mg phthalimide (2.19mmol) and 503.7mg potassium carbonate (3.65mmol) dissolved in 5mL N,N-dimethylformaldehyde In the amide, the reaction was stirred at 110°C for 2.5 hours. After the reaction, 50 mL of water and 50 mL of ethyl acetate were added to extract the organic phase, and the organic phase was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography to obtain the title compound.
步骤5：3-氨基-4′，5′-二氯-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003H)Step 5: 3-Amino-4',5'-dichloro-2'-ethyl-1',2'-dihydro-3'H-spiro[cyclobutane-1,4'-isoquinoline] -3′-ketone (NH200003H)
将NH200002-int 5换成NH200003H-int 4，按实施例1的方法6制备目标化合物，纯度97.73％。Replace NH200002-int 5 with NH200003H-int 4, and prepare the target compound according to Method 6 of Example 1, with a purity of 97.73%.
1H NMR(400MHz,CDCl 3)δ6.89(s,1H),6.82(s,1H),3.94(s,2H),3.62–3.54(m,1H),3.22-3.09(m,2H),2.69-2.63(m,2H),1.91-1.86(m,2H),0.80-0.76(m,3H)；[M+H] +299.0 1 H NMR (400MHz, CDCl 3 ) δ 6.89 (s, 1H), 6.82 (s, 1H), 3.94 (s, 2H), 3.62-3.54 (m, 1H), 3.22-3.09 (m, 2H), 2.69-2.63(m,2H),1.91-1.86(m,2H),0.80-0.76(m,3H); [M+H] + 299.0
实施例15-1 3-氨基-6′-氯-2′-甲基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200102)Example 15-1 3-Amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3 ′-Ketone (NH200102)
将乙胺换成甲胺，按实施例2的方法或者将3,4-二氯苯乙酸换成3-氯苯乙酸，乙胺换成甲胺按照实施例14的方法制备目标化合物，纯度为99.40％。Replace ethylamine with methylamine, follow the method in Example 2 or replace 3,4-dichlorophenylacetic acid with 3-chlorophenylacetic acid, and replace ethylamine with methylamine. Prepare the target compound according to the method of Example 14. The purity is 99.40%.
1H NMR(400MHz,CDCl 3)δ7.45(s,1H),7.20(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),4.37(s,2H),3.89-3.81(m,1H),3.11(s,3H),3.08-3.02(m,2H),2.06-2.00(m,2H)；[M+H] +251.0 1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H), 7.20(d,J=8.4Hz,1H), 7.06(d,J=8.4Hz,1H), 4.37(s,2H), 3.89 -3.81(m,1H),3.11(s,3H),3.08-3.02(m,2H),2.06-2.00(m,2H); [M+H] + 251.0
实施例15-2反式-3-氨基-6′-氯-2′-甲基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200102-1)及顺式-3-氨基-6′-氯-2′-甲基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮 (NH200102-2)Example 15-2 Trans-3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200102-1) and cis-3-amino-6′-chloro-2′-methyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1 ,4′-isoquinoline)-3′-one (NH200102-2)
NH200102经制备HPLC(Mobile Phase A:H 2O(0.1％TFA,Mobile Phase B:CAN,Column:C18,5um,4.6x250mm,Flow rate:15mL·min -1)分离可分别得到NH200102-1和NH200102-2。 NH200102 is separated by preparative HPLC (Mobile Phase A: H 2 O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL·min -1 ) to obtain NH200102-1 and NH200102, respectively -2.
NH200102-1: 1H NMR(400MHz,Methanol-d 4)δ7.58(d,J＝4.0Hz,1H),7.26-7.20(m,2H),4.47(s,2H),3.75-3.67(m,1H),3.10(s,3H),2.98-2.92(m,2H),2.20-2.13(m,2H)；[M+H] +251.1 NH200102-1: 1 H NMR(400MHz,Methanol-d 4 )δ7.58(d,J=4.0Hz,1H),7.26-7.20(m,2H),4.47(s,2H),3.75-3.67(m ,1H),3.10(s,3H),2.98-2.92(m,2H),2.20-2.13(m,2H); [M+H] + 251.1
NH200102-2: 1H NMR(400MHz,Methanol-d 4)δ7.67(d,J＝4.0Hz,1H),7.32-7.24(m,2H),4.53(s,2H),4.12-4.03(m,1H),3.12(s,3H),3.05-3.02(m,2H),2.53-2.27(m,2H).；[M+H] +251.1 NH200102-2: 1 H NMR(400MHz,Methanol-d 4 )δ7.67(d,J=4.0Hz,1H),7.32-7.24(m,2H),4.53(s,2H),4.12-4.03(m ,1H),3.12(s,3H),3.05-3.02(m,2H),2.53-2.27(m,2H).; [M+H] + 251.1
实施例16-1 3-氨基-6′-氯-2′-正丙基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003P)Example 16-1 3-Amino-6′-chloro-2′-n-propyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200003P)
Figure PCTCN2020129826-appb-000057
Figure PCTCN2020129826-appb-000057
将乙胺换成正丙胺，按实施例2的方法或者将3,4-二氯苯乙酸换成3-氯苯乙酸，乙胺换成丙胺按照实施例14的方法制备目标化合物，纯度93.45％。Replace ethylamine with n-propylamine, follow the method of Example 2 or replace 3,4-dichlorophenylacetic acid with 3-chlorophenylacetic acid, and replace ethylamine with propylamine. Prepare the target compound according to the method of Example 14, with a purity of 93.45% .
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝4.0Hz,1H),7.15(d,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,1H),4.33(s,2H),4.11-4.01(m,1H),3.49-3.44(m,2H),3.08-3.03(m,2H),2.51-2.46(m,2H),1.62-1.57(m,2H),0.91-0.87(m,3H)；[M+H] +279.0 1 H NMR (400MHz, CDCl 3 ) δ7.62 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.33 (s ,2H),4.11-4.01(m,1H),3.49-3.44(m,2H),3.08-3.03(m,2H),2.51-2.46(m,2H),1.62-1.57(m,2H),0.91 -0.87(m,3H); [M+H] + 279.0
实施例16-2反式-3-氨基-6′-氯-2′-正丙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003P-1)及顺式-3-氨基-6′-氯-2′-正丙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003P-2)Example 16-2 trans-3-amino-6′-chloro-2′-n-propyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquine Morpholine]-3′-one (NH200003P-1) and cis-3-amino-6′-chloro-2′-n-propyl-1′,2′-dihydro-3′H-spiro[cyclobutane -1,4′-isoquinoline]-3′-one (NH200003P-2)
NH200003P经制备HPLC(Mobile Phase A:H 2O(0.1％TFA,Mobile Phase B:CAN,Column:C18,5um,4.6x250mm,Flow rate:15mL·min -1)分离可分别得到NH200003P-1和NH200003P-2。 NH200003P is separated by preparative HPLC (Mobile Phase A: H 2 O (0.1% TFA, Mobile Phase B: CAN, Column: C18, 5um, 4.6x250mm, Flow rate: 15mL·min -1 ) to obtain NH200003P-1 and NH200003P, respectively -2.
NH200003P-1: 1H NMR(400MHz,Methanol-d 4)δ7.58(d,J＝2.0Hz,1H),7.31–7.23(m,2H),4.47(s,2H),3.86–3.74(m,1H),3.55–3.47(m,2H),3.03–2.91(m,2H),2.37–2.26(m,2H),1.70–1.58(m,2H),0.92(t,J＝7.6Hz,3H)；[M+H] +279.1 NH200003P-1: 1 H NMR(400MHz,Methanol-d 4 )δ7.58(d,J=2.0Hz,1H), 7.31–7.23(m,2H), 4.47(s,2H), 3.86–3.74(m ,1H),3.55–3.47(m,2H),3.03–2.91(m,2H),2.37–2.26(m,2H),1.70–1.58(m,2H),0.92(t,J=7.6Hz,3H ); [M+H] + 279.1
NH200003P-2: 1H NMR(400MHz,Methanol-d 4)δ7.55(dd,J＝7.6,1.6Hz,1H),7.45–7.35(m,2H),4.59(s,2H),3.95–3.75(m,1H),3.61–3.49(m,2H),3.06–2.95(m,2H),2.41–2.28(m,2H),1.74–1.59(m,2H),0.94(t,J＝7.6Hz,3H)；[M+H] +279.1 NH200003P-2: 1 H NMR(400MHz,Methanol-d 4 )δ7.55(dd,J=7.6,1.6Hz,1H),7.45-7.35(m,2H),4.59(s,2H),3.95-3.75 (m,1H),3.61–3.49(m,2H),3.06–2.95(m,2H),2.41–2.28(m,2H),1.74–1.59(m,2H),0.94(t,J=7.6Hz ,3H); [M+H] + 279.1
实施例17 3-氨基-6′-氯-2′-苯基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200127)Example 17 3-Amino-6′-chloro-2′-phenyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200127)
将乙胺换成苯胺，按实施例2的方法制备目标化合物，纯度为97.52％。The ethylamine was replaced with aniline, and the target compound was prepared according to the method of Example 2 with a purity of 97.52%.
1H NMR(400MHz,CD 3OD)δ7.64(d,J＝4.0Hz,1H),7.48-7.44(m,2H),7.35-7.28(m,5H),4.83(s,2H),3.90-3.82(m,1H),3.16-3.11(m,2H),2.49-2.43(m,2H).[M+H] +313.0 1 H NMR (400MHz, CD 3 OD) δ 7.64 (d, J = 4.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.35-7.28 (m, 5H), 4.83 (s, 2H), 3.90 -3.82(m,1H),3.16-3.11(m,2H),2.49-2.43(m,2H).[M+H] + 313.0
实施例18 3-氨基-2′-乙基-6′-氟-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200089)Example 18 3-Amino-2′-ethyl-6′-fluoro-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′- Ketone (NH200089)
将3-氯苯乙酸换成3-氟苯乙酸，按实施例2的方法制备目标化合物，纯度为97.52％。The 3-chlorophenylacetic acid was replaced with 3-fluorophenylacetic acid, and the target compound was prepared according to the method of Example 2 with a purity of 97.52%.
1H NMR(400MHz,CDCl 3)δ7.27-7.24(m,1H),7.14-7.10(m,1H),6.97-6.92(m,1H),4.40(s,2H),4.13-4.06(m,1H),3.57(q,J＝7.2Hz,2H),3.01-2.95(m,2H),2.81-2.74(m,2H),1.18(t,J＝7.2Hz,3H)；[M+H] +249.1 1 H NMR (400MHz, CDCl 3 ) δ 7.27-7.24 (m, 1H), 7.14-7.10 (m, 1H), 6.97-6.92 (m, 1H), 4.40 (s, 2H), 4.13-4.06 (m ,1H),3.57(q,J=7.2Hz,2H),3.01-2.95(m,2H),2.81-2.74(m,2H),1.18(t,J=7.2Hz,3H); [M+H ] + 249.1
实施例19 3-氨基-2′-异丙基-6′-氯-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003N)Example 19 3-Amino-2′-isopropyl-6′-chloro-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′ -Ketone (NH200003N)
将乙胺换成异丙胺，按实施例2的方法制备目标化合物，纯度为96.7％Replace ethylamine with isopropylamine, prepare the target compound according to the method of Example 2, with a purity of 96.7%
1H NMR(400MHz,CDCl 3)δ7.42(s,1H),7.19(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),4.94–4.91(m,1H),4.17(s,2H),3.82-3.78(m,1H),3.07–3.02(m,2H),2.09-2.04(m,2H),1.15(d,J＝4.0Hz,6H)；[M+H] +279.1 1 H NMR(400MHz,CDCl 3 )δ7.42(s,1H), 7.19(d,J=8.0Hz,1H), 7.10(d,J=8.0Hz,1H), 4.94–4.91(m,1H) ,4.17(s,2H),3.82-3.78(m,1H),3.07–3.02(m,2H),2.09-2.04(m,2H),1.15(d,J=4.0Hz,6H); [M+ H] + 279.1
实施例20 3-氨基-2′-环丁基-6′-氯-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200003Z’)Example 20 3-Amino-2′-cyclobutyl-6′-chloro-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3′ -Ketone (NH200003Z')
将乙胺换成环丁胺，按实施例2的方法制备目标化合物，纯度为91.0％The ethylamine was replaced with cyclobutylamine, and the target compound was prepared according to the method of Example 2. The purity was 91.0%
1H NMR(400MHz,Chloroform-d)δ7.43(s,1H),7.20(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),5.06-5.01(m,1H),4.32(s,2H),3.80(s,1H),3.06–3.01(m,2H),2.20–2.14(m,3H),2.12–2.06(m,3H),1.77–1.71(m,2H)；[M+H] +291.1 1 H NMR(400MHz,Chloroform-d)δ7.43(s,1H), 7.20(d,J=8.0Hz,1H), 7.13(d,J=8.0Hz,1H), 5.06-5.01(m,1H ), 4.32 (s, 2H), 3.80 (s, 1H), 3.06-3.01 (m, 2H), 2.20-2.14 (m, 3H), 2.12-2.06 (m, 3H), 1.77-1.71 (m, 2H) ); [M+H] + 291.1
实施例21 3-氨基-6′-氯-2′-(2-甲氧基乙基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH2000121)Example 21 3-Amino-6′-chloro-2′-(2-methoxyethyl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-iso Quinoline)-3′-one (NH2000121)
将乙胺换成2-甲氧基乙基-1-胺，按实施例2或者实施例14的方法制备目标化合物，纯度为97.68％Replace ethylamine with 2-methoxyethyl-1-amine, and prepare the target compound according to the method of Example 2 or Example 14. The purity is 97.68%
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.12(d,J＝8Hz,1H),6.99(d,J＝8.0Hz,1H),4.47(s,2H),4.28–4.08(m,1H),3.67(t,J＝5.0Hz,2H),3.56(t,J＝5.0Hz,2H),3.30(s,3H),3.10–3.00(m,2H),2.74–2.64(m,2H)；[M+H] +295.4 1 H NMR (400MHz, CDCl 3 ) δ 7.69 (s, 1H), 7.12 (d, J = 8 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 4.28- 4.08(m,1H), 3.67(t,J=5.0Hz,2H),3.56(t,J=5.0Hz,2H), 3.30(s,3H), 3.10–3.00(m,2H), 2.74–2.64 (m,2H); [M+H] + 295.4
实施例22 3-氨基-6′-环丙基-2′-乙基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200105)Example 22 3-Amino-6′-cyclopropyl-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3 ′-Ketone (NH200105)
Figure PCTCN2020129826-appb-000058
Figure PCTCN2020129826-appb-000058
步骤1：2-(6′-环丙基-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1,3-二酮(NH2000105-int1)Step 1: 2-(6′-Cyclopropyl-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-iso Quinoline)-3-yl)isoindoline-1,3-dione (NH2000105-int1)
在50mL单口瓶中，加入100mg NH2000099-int1(0.23mmol)溶于2.4mL二氧六环，加入29.3mg环丙基硼酸(0.34mmol)，96.6mg磷酸钾(0.46mmol)，0.4mL水和16.6mg Pd(dppf)Cl 2(0.023mmol)，氮气保护下升温至95℃，反应6小时。反应结束后，加入20mL水和30mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离得40mg标题化合物，收率44％。 In a 50mL single-mouth flask, add 100mg NH2000099-int1 (0.23mmol) dissolved in 2.4mL dioxane, add 29.3mg cyclopropylboronic acid (0.34mmol), 96.6mg potassium phosphate (0.46mmol), 0.4mL water and 16.6 mg Pd(dppf)Cl 2 (0.023 mmol), heated to 95°C under nitrogen protection, and reacted for 6 hours. After the reaction, 20 mL of water and 30 mL of ethyl acetate were added to extract the organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain 40 mg of the title compound with a yield of 44%.
步骤2：3-氨基-6′-环丙基-2′-乙基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH2000105)Step 2: 3-Amino-6′-cyclopropyl-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]-3 ′-Ketone (NH2000105)
将NH200002-int 5换成NH2000105-int1，按实施例1的步骤6制备目标化合物，纯度为92.38％。Replace NH200002-int 5 with NH2000105-int1, and prepare the target compound according to step 6 of Example 1, with a purity of 92.38%.
1H NMR(400MHz,CDCl 3)δ7.23(s,1H),7.02(d,J＝7.6Hz,1H),6.88(d,J＝7.6Hz,1H),4.32(s,2H),3.88(m,1H),3.55(q,J＝7.2Hz,2H),3.06-2.99(m,2H),3.36(br s,2H),2.21-2.15(m,2H),1.97-1.90(m,1H),1.16(t,J＝7.2,3H),1.00-0.95(m,2H),0.74-0.69(m,2H)；[M+H] +271.1 1 H NMR(400MHz,CDCl 3 )δ7.23(s,1H), 7.02(d,J=7.6Hz,1H), 6.88(d,J=7.6Hz,1H), 4.32(s,2H), 3.88 (m,1H),3.55(q,J=7.2Hz,2H),3.06-2.99(m,2H),3.36(br s,2H),2.21-2.15(m,2H),1.97-1.90(m, 1H), 1.16(t,J=7.2,3H),1.00-0.95(m,2H),0.74-0.69(m,2H); [M+H] + 271.1
实施例23 3-氨基-2′-乙基-6′-(吡咯烷-1-基)-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200141)Example 23 3-Amino-2′-ethyl-6′-(pyrrolidin-1-yl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-iso Quinoline)-3′-one (NH200141)
Figure PCTCN2020129826-appb-000059
Figure PCTCN2020129826-appb-000059
步骤1：2-(2′-乙基-3′-氧代-6′-(吡咯烷-1-基)-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)异吲哚啉-1，3-二酮(NH2000141-int1)Step 1: 2-(2′-Ethyl-3′-oxo-6′-(pyrrolidin-1-yl)-2′,3′-dihydro-1′H-spiro[cyclobutane-1 ,4′-isoquinoline)-3-yl)isoindoline-1,3-dione (NH2000141-int1)
在50mL单口瓶中，加入150mg NH200099-int1(0.342mmol)溶于10mL甲苯，加入48.6mg吡咯烷(0.684mmol)，19mg三(二亚苄基丙酮)二钯(0.0342mmol)，20mg 4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.0342mmol)和223mg碳酸铯(0.684mmol)80℃搅拌反应18小时。反应结束后，加入30mL水和30mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离得54.3mg标题化合物，收率37％。In a 50mL single-mouth bottle, add 150mg NH200099-int1 (0.342mmol) dissolved in 10mL toluene, add 48.6mg pyrrolidine (0.684mmol), 19mg tris(dibenzylideneacetone) dipalladium (0.0342mmol), 20mg 4,5 -Bisdiphenylphosphine-9,9-dimethylxanthene (0.0342mmol) and 223mg cesium carbonate (0.684mmol) were stirred and reacted at 80°C for 18 hours. After the reaction, 30 mL of water and 30 mL of ethyl acetate were added to extract the organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain 54.3 mg of the title compound with a yield of 37%.
步骤2：3-氨基-2′-乙基-6′-(吡咯烷-1-基)-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH2000141)Step 2: 3-Amino-2′-ethyl-6′-(pyrrolidin-1-yl)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-iso Quinoline)-3′-one (NH2000141)
将NH200002-int 5换成NH2000141-int 1，按实施例1的步骤6制备目标化合物，纯度为100％Replace NH200002-int 5 with NH2000141-int 1, and prepare the target compound according to step 6 of Example 1, with a purity of 100%
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.44(d,J＝8Hz,1H),7.21(d,J＝8.0Hz,1H),4.47(s,2H),3.95-3.85(m,1H),3.61-3.54(m,2H),3.35-3.30(m,4H),3.01-2.95(m,2H),2.50-2.45(m,2H),2.06-2.02(m,2H),2.06-2.02(m,2H),1.30-1.25(m,2H),1.20-1.15(m,3H)；[M+H] +300.0 1 H NMR (400MHz, CDCl3) δ 7.75 (s, 1H), 7.44 (d, J = 8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 3.95 to 3.85 (m, 1H), 3.61-3.54 (m, 2H), 3.35-3.30 (m, 4H), 3.01-2.95 (m, 2H), 2.50-2.45 (m, 2H), 2.06-2.02 (m, 2H) ,2.06-2.02(m,2H),1.30-1.25(m,2H),1.20-1.15(m,3H); [M+H] + 300.0
实施例24 3-氨基-6′-(二甲基氨基)-2′-乙基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200123)Example 24 3-Amino-6′-(dimethylamino)-2′-ethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline ]-3′-ketone (NH200123)
Figure PCTCN2020129826-appb-000060
Figure PCTCN2020129826-appb-000060
将吡咯烷换成二甲胺，按实施例23的方法制备目标化合物，纯度为98.0％。The pyrrolidine was replaced with dimethylamine, and the target compound was prepared according to the method of Example 23, with a purity of 98.0%.
1H NMR(400MHz,CDCl 3)δ7.26–7.19(m,2H),6.94-6.92(m,1H),4.38(s,2H),4.06-4.01(m,1H),3.55-3.49(m,2H),3.05–3.00(m,2H),2.64(s,6H),2.56-2.51(m,2H),1.15-1.11(m,3H)；[M+H] +274.2 1 H NMR (400MHz, CDCl 3 ) δ 7.26--7.19 (m, 2H), 6.94-6.92 (m, 1H), 4.38 (s, 2H), 4.06-4.01 (m, 1H), 3.55-3.49 (m ,2H),3.05–3.00(m,2H),2.64(s,6H),2.56-2.51(m,2H),1.15-1.11(m,3H); [M+H] + 274.2
实施例25 6′-氯-2′-乙基-3-(甲基氨基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200074)Example 25 6′-chloro-2′-ethyl-3-(methylamino)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200074)
Figure PCTCN2020129826-appb-000061
Figure PCTCN2020129826-appb-000061
步骤1：叔丁基(6′-氯-2′-乙基-3′-氧代2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)氨基甲酸酯(NH200074-int 1)Step 1: Tert-butyl (6'-chloro-2'-ethyl-3'-oxo 2', 3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline )-3-yl)carbamate (NH200074-int 1)
在50mL单口瓶中，加入40mg NH200003(0.15mmol)、36mg二碳酸二叔丁酯(0.165mmol)、23mg三乙胺(0.225mmol)和2mL二氯甲烷，室温搅拌反应0.5小时。反应结束后，加入40mL水和25mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，直接用于下一步。In a 50 mL single-neck flask, add 40 mg NH200003 (0.15 mmol), 36 mg di-tert-butyl dicarbonate (0.165 mmol), 23 mg triethylamine (0.225 mmol) and 2 mL dichloromethane, and stir at room temperature to react for 0.5 hours. After the reaction, 40 mL of water and 25 mL of dichloromethane were added to extract an organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.
步骤2：叔丁基(6′-氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)(甲基)氨基甲酸酯(NH200074-int 2)Step 2: Tert-butyl (6'-chloro-2'-ethyl-3'-oxo-2', 3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquine (Pholino)-3-yl)(methyl)carbamate (NH200074-int 2)
在50mL单口瓶中，加入55mg NH200074-int 1(0.15mmol)溶于3mL四氢呋喃(THF)，加入60mg 60％的NaH(1.5mmol)，半小时后加入213mg碘甲烷(1.5mmol)，室温搅拌反应过夜。反应结束后，加入20mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，直接用于下一步。In a 50mL single-mouth flask, add 55mg NH200074-int 1 (0.15mmol) dissolved in 3mL tetrahydrofuran (THF), add 60mg 60% NaH (1.5mmol), add 213mg methyl iodide (1.5mmol) after half an hour, stir at room temperature for reaction overnight. After the reaction, 20 mL of water and 15 mL of dichloromethane were added to extract an organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.
步骤3：6′-氯-2′-乙基-3-(甲基氨基)-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200074)Step 3: 6′-chloro-2′-ethyl-3-(methylamino)-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline] -3′-ketone (NH200074)
在50mL单口瓶中，加入40mg上一步产物粗产品、1mL三氟乙酸和2mL二氯甲烷，室温搅拌反应2小时。反应结束后，加入20mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(二氯甲烷：甲醇＝10：1)得无色油状物20mg，纯度98.63％。In a 50 mL single-neck flask, add 40 mg of the crude product from the previous step, 1 mL of trifluoroacetic acid and 2 mL of dichloromethane, and stir for reaction at room temperature for 2 hours. After the reaction, add 20mL of water and 15mL of dichloromethane to extract the organic phase. The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by a pre-preparation plate (dichloromethane: methanol = 10:1) to obtain 20 mg of colorless oil with purity 98.63%.
1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.18(d,J＝8.0Hz,1H),7.02(d,J＝8.2Hz,1H),4.37(s,2H),4.09-4.04(m,1H),3.59-3.54(m,2H),3.15-3.10(m,1H),3.04-2.99(m,2H),2.85–2.81(m,2H),2.61(s,3H),1.20-1.17(m,3H)；[M+H] +279.0 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H), 7.18(d,J=8.0Hz,1H), 7.02(d,J=8.2Hz,1H), 4.37(s,2H), 4.09-4.04(m,1H),3.59-3.54(m,2H),3.15-3.10(m,1H),3.04-2.99(m,2H),2.85-2.81(m,2H),2.61(s,3H) ),1.20-1.17(m,3H); [M+H] + 279.0
实施例26 2-氨基-N-(6′-氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)乙酰胺(NH200073)Example 26 2-Amino-N-(6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′ -Isoquinoline)-3-yl)acetamide (NH200073)
Figure PCTCN2020129826-appb-000062
Figure PCTCN2020129826-appb-000062
步骤1：叔丁基(2-(((6′-氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)氨基)-2-氧乙基)氨基甲酸酯(NH200073-int1)Step 1: tert-butyl (2-(((6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1, 4′-Isoquinoline)-3-yl)amino)-2-oxoethyl)carbamate (NH200073-int1)
在50mL单口瓶中，加入40mg NH200003(0.15mmol)、32mg BOC-甘氨酸(0.18mmol)、58mg HATU(0.15mmol)、46mg三乙胺(0.45mmol)和2mL N,N-二甲基甲酰胺，室温搅拌反应4.5小时。反应结束后，加入40mL水和25mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，直接用于下一步。In a 50mL single-mouth bottle, add 40mg NH200003 (0.15mmol), 32mg BOC-glycine (0.18mmol), 58mg HATU (0.15mmol), 46mg triethylamine (0.45mmol) and 2mL N,N-dimethylformamide, The reaction was stirred at room temperature for 4.5 hours. After the reaction, 40 mL of water and 25 mL of dichloromethane were added to extract an organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.
步骤2：2-氨基-N-(6′-氯-2′-乙基-3′-氧代-2′，3′-二氢-1′H-螺[环丁烷-1,4′-异喹啉]-3-基)乙酰胺(NH200073)Step 2: 2-Amino-N-(6′-chloro-2′-ethyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′ -Isoquinoline)-3-yl)acetamide (NH200073)
在50mL单口瓶中，加入50mg上一步产物、1mL三氟乙酸和2mL二氯甲烷，室温搅拌反应4小时。反应结束后，加入20mL水和15mL二氯甲烷萃取得有机相，有机相用饱和NaHCO 3洗涤，有机相减压浓缩得粗产品，经过预制备板分离(二氯甲烷：甲醇＝10：1)得无色油状物6.10mg，纯度98.44％。 In a 50 mL single-neck flask, add 50 mg of the product from the previous step, 1 mL of trifluoroacetic acid and 2 mL of dichloromethane, and stir and react at room temperature for 4 hours. After completion of the reaction, 20mL of water and 15mL was added to give organic phase was extracted with dichloromethane, the organic phase was washed with saturated NaHCO 3, the organic phase concentrated under reduced pressure to give the crude product, isolated pre preparative plate (dichloromethane: methanol = 10: 1) 6.10 mg of colorless oily substance with a purity of 98.44% was obtained.
1H NMR(400MHz,Methanol-d 4)δ7.60(s,1H),7.30–7.25(m,2H),4.66–4.60(m,1H),4.49(s,2H),3.68(s,2H),3.62-3.56(m,2H),3.06–3.00(m,2H),2.46-2.41(m,2H),1.21-1.17(m,3H)；[M+H] +322.1 1 H NMR(400MHz,Methanol-d 4 )δ7.60(s,1H), 7.30-7.25(m,2H), 4.66-4.60(m,1H), 4.49(s,2H), 3.68(s,2H) ),3.62-3.56(m,2H),3.06–3.00(m,2H),2.46-2.41(m,2H),1.21-1.17(m,3H); [M+H] + 322.1
实施例27 3-氨基-6′-氯-2,2′-二甲基-1′,2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200193)Example 27 3-Amino-6′-chloro-2,2′-dimethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200193)
Figure PCTCN2020129826-appb-000063
Figure PCTCN2020129826-appb-000063
步骤1：6-氯-2-甲基-1,4-二氢异喹啉-3(2H)-酮(NH200193-int1)Step 1: 6-Chloro-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (NH200193-int1)
将乙胺换成甲胺，按实施例2的方法1～2制备标题化合物。The ethylamine was replaced with methylamine, and the title compound was prepared according to the method 1-2 of Example 2.
步骤2：3-氨基-6′-氯-2,2′-二甲基-1′，2′-二氢-3′H-螺[环丁烷-1,4′-异喹啉]-3′-酮(NH200193)Step 2: 3-Amino-6′-chloro-2,2′-dimethyl-1′,2′-dihydro-3′H-spiro[cyclobutane-1,4′-isoquinoline]- 3′-ketone (NH200193)
将2-(氯甲基)环氧乙烷换成2-(氯甲基)-3-甲基环氧乙烷，按实施例6的方法4-7制备标题化合物，纯度98.2％。The 2-(chloromethyl)oxirane was replaced with 2-(chloromethyl)-3-methyloxirane, and the title compound was prepared according to the method 4-7 of Example 6, with a purity of 98.2%.
1H NMR(400MHz,Methanol-d 4)(2:1mixture)δ7.40–6.93(m,3H),4.76–4.25(m,2H),3.84–2.52(m,2H),3.13(s,2H),3.11(s,1H),2.28–1.87(m,2H),1.19(d,J＝6.6Hz,2H),0.64(d,J＝7.5Hz,1H).；[M+H] +265.0 1 H NMR(400MHz,Methanol-d 4 )(2:1mixture)δ7.40–6.93(m,3H), 4.76–4.25(m,2H), 3.84–2.52(m,2H), 3.13(s,2H) ),3.11(s,1H),2.28–1.87(m,2H),1.19(d,J=6.6Hz,2H),0.64(d,J=7.5Hz,1H).; [M+H] + 265.0
测试例Test case
测试实施例1NMDAR抑制活性Test Example 1 NMDAR inhibitory activity
测试药物：化合物1a1参照CN106957285A的方法进行制备，其结构如下所示：Test drug: Compound 1a1 was prepared according to the method of CN106957285A, and its structure is as follows:
Figure PCTCN2020129826-appb-000064
Figure PCTCN2020129826-appb-000064
NH200003、NH200003P、NH200003H、NH200073、NH200088、NH200098、NH200099、NH200102、NH200105、NH200121、NH200123、NH200141按照上述实施例制备。NH200003, NH200003P, NH200003H, NH200073, NH200088, NH200098, NH200099, NH200102, NH200105, NH200121, NH200123, NH200141 were prepared according to the above-mentioned examples.
阴性对照：称量合适体积的DMSO作为储液。Negative control: Weigh an appropriate volume of DMSO as a stock solution.
测试化合物：称量合适质量的化合物(实际量＝理论浓度×体积×分子量/纯度)，根据公式，计算出所需的DMSO的体积，然后换算出最终所需的DMSO的质量。之后将粉末用称量的DMSO超声溶解。根据最终的DMSO使用量计算出实际的储液浓度，一般地实际储液浓度与理论浓度略有差异。若有溶解度的问题，对储液浓度进行适当调整。Test compound: Weigh a compound of appropriate mass (actual amount = theoretical concentration x volume x molecular weight/purity), calculate the required DMSO volume according to the formula, and then convert the final required DMSO mass. Then the powder was ultrasonically dissolved with weighed DMSO. The actual storage solution concentration is calculated according to the final DMSO usage. Generally, the actual storage solution concentration is slightly different from the theoretical concentration. If there is a problem with solubility, adjust the concentration of the stock solution appropriately.
给药制剂工作液配制方法：通道电流测试之前，将阴性对照和测试化合物储液稀释到适量的细胞外液中作为工作液。稀释到适量的细胞外液中作为工作液。详情见下表：Preparation method of working solution of drug delivery preparation: before channel current test, dilute the negative control and test compound stock solution into an appropriate amount of extracellular fluid as the working solution. Dilute to an appropriate amount of extracellular fluid as a working fluid. See the table below for details:
表1给药方法及测试浓度Table 1 Method of administration and test concentration
Figure PCTCN2020129826-appb-000065
Figure PCTCN2020129826-appb-000065
实验***experiment system
细胞系的选择Choice of cell line
本试验中，采用稳定表达大鼠NR1/NR2B基因的HEK293细胞系，其基因号为NR1：NM_017010,NR2B：NM_012574。In this experiment, the HEK293 cell line stably expressing the rat NR1/NR2B gene was used, and its gene number was NR1: NM_017010, NR2B: NM_012574.
浓度选择依据Concentration selection basis
本实验中，测试化合物的检测浓度为0.3μM，1μM，3μM，10μM以及30μM。阴性对照为0.1％DMSO。In this experiment, the detection concentration of the test compound was 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM. The negative control is 0.1% DMSO.
检测液体的准备Preparation of test liquid
细胞外液:140mM NaCl，4mM KCl，2mM CaCl 2，10mM HEPES，5mM D-Glucose pH＝7.4(NaOH)。 Extracellular solution: 140mM NaCl, 4mM KCl, 2mM CaCl 2, 10mM HEPES, 5mM D-Glucose pH = 7.4 (NaOH).
细胞内液:10mM NaCl，135mM CsMes，2mM MgCl 2，10mM HEPES，10mM EGTA，2mM Na 2-ATP，0.2mM Na 2-GTP pH＝7.2(CsOH)。 Intracellular fluid: 10mM NaCl, 135mM CsMes, 2mM MgCl 2 , 10mM HEPES, 10mM EGTA, 2mM Na 2 -ATP, 0.2mM Na 2 -GTP pH=7.2 (CsOH).
所用电极内液配好后分装为每管1mL，冻存于-20℃冰箱，每天实验使用新融化的电极内液。所有电极内液在一个月内用完。超过一个月，丢弃旧电极内液，并重新配置。The electrode inner liquid used is prepared and divided into 1 mL per tube, and stored in a refrigerator at -20℃. The newly melted electrode inner liquid is used in the experiment every day. All the electrode fluid is used up within one month. For more than one month, discard the inner liquid of the old electrode and reconfigure it.
膜片钳检测试验方法如下：The patch clamp test method is as follows:
用微电极拉制仪(P97，Sutter Instruments)将毛细玻璃管(BF150-86-10，Sutter Instruments)拉制成记录电极。在倒置显微镜(Olympus，IX71)下操纵微电极操纵仪(Sutter instruments，MP285)将记录电极接触到细胞上，给予负压抽吸，形成GΩ封接。形成GΩ封接后进行快速电容补偿，然后继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢速电容的补偿并记录膜电容及串联电阻。不给予漏电补偿。The capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode with a microelectrode drawing instrument (P97, Sutter Instruments). Under an inverted microscope (Olympus, IX71), the microelectrode manipulator (Sutter instruments, MP285) was operated to contact the recording electrode on the cell, and negative pressure suction was applied to form a GΩ seal. After forming the GΩ seal, perform fast capacitance compensation, and then continue to give negative pressure to suck and break the cell membrane to form a whole-cell recording mode. Then perform slow capacitance compensation and record the film capacitance and series resistance. No leakage compensation is given.
将铺有细胞的盖玻片置于倒置显微中的记录浴槽中，形成全细胞封接后，在正常细胞外液灌流下，使用快速喷射给药***，将NMDA和测试化合物喷射到细胞表面，记录NMDA电流。到达细胞表面的测试化合物会被细胞外液迅速带走。独立重复检测多个细胞。所有电生理实验在室温下进行。Place the cell-covered coverslip in the recording bath in the inverted microscope to form a whole cell seal. Under normal extracellular fluid perfusion, use a rapid jet drug delivery system to jet NMDA and test compounds onto the cell surface , Record the NMDA current. The test compound that reaches the cell surface is quickly taken away by the extracellular fluid. Test multiple cells independently and repeatedly. All electrophysiological experiments were performed at room temperature.
全细胞膜片钳记录全细胞NMDA电流的电压刺激方案如下：当形成全细胞封接后细胞膜电压钳制于-70mV或者-60mV。给药顺序如下：The voltage stimulation scheme for whole-cell patch clamp recording of whole-cell NMDA current is as follows: when a whole-cell seal is formed, the cell membrane voltage is clamped at -70mV or -60mV. The order of administration is as follows:
第一步：细胞外液(NMDA 100μM+甘氨酸10μM)；The first step: extracellular fluid (NMDA 100μM + glycine 10μM);
第二步：细胞外液(NMDA 100μM+甘氨酸10μM+测试化合物(0.3μM))；Step 2: Extracellular fluid (NMDA 100μM + Glycine 10μM + test compound (0.3μM));
第三步：细胞外液(NMDA 100μM+甘氨酸10μM)；Step 3: Extracellular fluid (NMDA 100μM + Glycine 10μM);
第四步：细胞外液(NMDA 100μM+甘氨酸10μM+测试化合物(1μM))；Step 4: Extracellular fluid (NMDA 100μM + Glycine 10μM + test compound (1μM));
第五步：细胞外液(NMDA 100μM+甘氨酸10μM)；Step 5: Extracellular fluid (NMDA 100μM + Glycine 10μM);
第六步：细胞外液(NMDA 100μM+甘氨酸10μM+测试化合物(3μM))；Step 6: Extracellular fluid (NMDA 100μM + Glycine 10μM + test compound (3μM));
第七步：细胞外液(NMDA 100μM+甘氨酸10μM)；Step 7: Extracellular fluid (NMDA 100μM + Glycine 10μM);
第八步：细胞外液(NMDA 100μM+甘氨酸10μM+测试化合物(10μM))；The eighth step: extracellular fluid (NMDA 100μM + glycine 10μM + test compound (10μM));
第九步：细胞外液(NMDA 100μM+甘氨酸10μM)；Step 9: Extracellular fluid (NMDA 100μM + Glycine 10μM);
第十步：细胞外液(NMDA 100μM+甘氨酸10μM+测试化合物(30μM))。The tenth step: extracellular fluid (NMDA 100μM + glycine 10μM + test compound (30μM)).
数据分析data analysis
首先将每一个待测化合物不同浓度作用后的电流和空白对照电流标准化，计算对应的抑制率。对每一个浓度计算平均数和标准误，并用以下方程计算每个待测化合物的半抑制浓度：First, normalize the current of each test compound at different concentrations and the blank control current to calculate the corresponding inhibition rate. Calculate the average and standard error for each concentration, and use the following equation to calculate the half-inhibitory concentration of each test compound:
inhibition＝1/[1+(IC 50/C) h] inhibition=1/[1+(IC 50 /C) h ]
用以上方程对剂量依赖效应进行非线性拟合，其中C代表药物浓度，IC 50代表半抑制浓度，h代表希尔系数，曲线拟合以及IC 50的计算利用IGOR软件完成。 The above equation is used to perform non-linear fitting of the dose-dependent effect, where C represents the drug concentration, IC 50 represents the half-inhibitory concentration, and h represents the Hill coefficient. The curve fitting and the calculation of IC 50 are completed by IGOR software.
表2 NMDAR抑制活性测试结果Table 2 NMDAR inhibitory activity test results
测试化合物Test compound IC 50(μM) IC 50 (μM)
化合物1a1Compound 1a1 0.990.99
NH200003NH200003 3.73.7
NH200003PNH200003P 2.22.2
NH200003HNH200003H >10>10
NH200073NH200073 >30>30
NH200088NH200088 4.94.9
NH200098NH200098 >30>30
NH200099NH200099 >30>30
NH200102NH200102 1.11.1
NH200105NH200105 >30>30
NH200121NH200121 8.18.1
NH200123NH200123 >30>30
NH200141NH200141 >30>30
结论in conclusion
上述结果显示，本发明提供的化合物对NMDAR有良好的抑制活性，尤其是NH200003、NH200003P和NH200102与化合物1a1基本相当或近似，提示具有良好的临床治疗效果的潜力。The above results show that the compound provided by the present invention has a good inhibitory activity on NMDAR, especially NH200003, NH200003P and NH200102 are basically equivalent or similar to compound 1a1, suggesting the potential for good clinical therapeutic effects.
测试实施例2解离速度检测Test Example 2 Dissociation rate detection
测试药物：化合物1a1、NH200102、***(Ketamine)、美金刚(Memantine)Test drugs: Compound 1a1, NH200102, Ketamine, Memantine
阳性对照：N-甲基-D-天冬氨酸(NMDA)，购买自默克生命科学(上海)有限公司；甘氨酸(Glycine)，购买自默克生命科学(上海)有限公司。Positive control: N-methyl-D-aspartic acid (NMDA), purchased from Merck Life Sciences (Shanghai) Co., Ltd.; Glycine (Glycine), purchased from Merck Life Sciences (Shanghai) Co., Ltd.
给药制剂储液配制方法Preparation method of drug delivery stock solution
测试药物：称量合适质量的供试品，根据公式DMSO体积＝实际量×纯度/(分子量×理论浓度)，计算出所需的DMSO的体积，吸取相应体积的DMSO，之后将已经称量的 供试品用吸取的DMSO溶解，同时称量出DMSO的质量，根据最终的DMSO使用量，计算出实际的储液浓度，一般地，实际储液浓度与理论浓度略有差异。若有溶解度的问题，对储液浓度进行调整。Test drug: Weigh the test product of suitable quality, calculate the required DMSO volume according to the formula DMSO volume=actual amount×purity/(molecular weight×theoretical concentration), draw the corresponding volume of DMSO, and then the already weighed The test product is dissolved with the absorbed DMSO, and the mass of DMSO is weighed at the same time. According to the final DMSO usage, the actual stock solution concentration is calculated. Generally, the actual stock solution concentration is slightly different from the theoretical concentration. If there is a problem with solubility, adjust the concentration of the stock solution.
阳性对照品：称量适量的NMDA和Glycine(甘氨酸)用超纯水配制成100mM的储液。分装后-20℃保存。Positive control: Weigh an appropriate amount of NMDA and Glycine (glycine) to prepare a 100mM stock solution with ultrapure water. Store at -20°C after aliquoting.
给药制剂工作液配制方法Preparation method of working liquid for drug administration preparation
NMDA/NR2B电流测试之前，将阳性对照品储液和供试品储液从-20℃取出，稀释到适量的细胞外液中作为工作液。Before the NMDA/NR2B current test, take the stock solution of the positive control substance and the stock solution of the test substance from -20°C, and dilute them into an appropriate amount of extracellular fluid as the working solution.
供试品的检测浓度用DMSO稀释成稀释液，再用细胞外液对稀释液进行稀释至工作液浓度。DMSO在每一个工作液中，浓度为0.1％。The detection concentration of the test substance is diluted with DMSO into a diluent, and then the diluent is diluted with extracellular fluid to the concentration of the working solution. The concentration of DMSO in each working solution is 0.1%.
供试品储液和阳性对照品储液保存在-20℃，供试品工作液与阳性对照品工作液测试当天配制，室温保存。The test product stock solution and the positive control substance stock solution are stored at -20°C, and the test product working solution and the positive control substance working solution are prepared on the day of the test and stored at room temperature.
细胞培养Cell culture
稳定表达rNR2B通道的HEK细胞系，基因信息：rNR1:Grin1,NM_017010；rNR2B:Grin2b,NM_012574HEK cell line stably expressing rNR2B channel, gene information: rNR1: Grin1, NM_017010; rNR2B: Grin2b, NM_012574
细胞在含有10％胎牛血清以及10μg/mL Blasticidin(杀稻瘟菌素)、100μg/mL Zeocin(博来霉素)、200μg/mL Hygromycin B(潮霉素B)的DMEM培养基中培养，培养温度为37℃，二氧化碳浓度为5％。Cells were cultured in DMEM medium containing 10% fetal bovine serum and 10μg/mL Blasticidin (blasticidin), 100μg/mL Zeocin (bleomycin), 200μg/mL Hygromycin B (hygromycin B), The culture temperature is 37°C, and the carbon dioxide concentration is 5%.
细胞传代：除去旧培养基并用PBS洗一次，然后加入1mL 0.25％-Trypsin(胰蛋白酶)-EDTA溶液，37℃孵育1min。当细胞从皿底脱离，加入5mL 37℃预热的完全培养基。将细胞悬液用吸管轻轻吹打使聚集的细胞分离。将细胞悬液转移至无菌的离心管中，1000rpm离心5min收集细胞。扩增或维持培养，将细胞接种于6厘米细胞培养皿，每个细胞培养皿，接种细胞量为2.5×10 5cells(最终体积：5mL)。 Cell passage: Remove the old medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution, and incubate at 37°C for 1 min. When the cells detach from the bottom of the dish, add 5 mL of complete medium pre-warmed at 37°C. The cell suspension was gently pipetted to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 min. To expand or maintain the culture, inoculate the cells in a 6 cm cell culture dish, each cell culture dish, the amount of cells inoculated is 2.5×10 5 cells (final volume: 5 mL).
为维持细胞的电生理活性，细胞密度必须不能超过80％。In order to maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.
膜片钳检测，实验之前细胞用0.25％-Trypsin-EDTA分离，将2×10 4细胞铺到盖玻片上并加入四环素及DAP-5，在24孔板中培养(最终体积：500μL)。18个小时后，进行实验检测。 For patch clamp detection, the cells were separated with 0.25%-Trypsin-EDTA before the experiment, 2×10 4 cells were spread on a cover glass, tetracycline and DAP-5 were added, and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, an experimental test was carried out.
膜片钳检测Patch clamp detection
记录所用液体Record the liquid used
细胞外液：140mM NaCl，4mM KCl，2mM CaCl 2·2H 2O，10mM HEPES(4-羟乙基哌嗪乙磺酸)，5mM D-Glucose(D-葡萄糖)，NaOH调节pH＝7.4。 Extracellular fluid: 140 mM NaCl, 4 mM KCl, 2 mM CaCl 2 ·2H 2 O, 10 mM HEPES (4-hydroxyethylpiperazine ethanesulfonic acid), 5 mM D-Glucose (D-glucose), NaOH adjusted pH=7.4.
细胞内液：110mM甲磺酸铯，10mM NaCl，2mM MgCl 2·6H 2O，10mM EGTA(乙二醇双(2-氨基乙基醚)四乙酸)，2mM Na 2-ATP，0.2mM Na 2-GTP，10mM HEPES，CsOH调节pH＝7.2。 Intracellular fluid: 110mM cesium methanesulfonate, 10mM NaCl, 2mM MgCl 2 ·6H 2 O, 10mM EGTA (ethylene glycol bis(2-aminoethyl ether)tetraacetic acid), 2mM Na 2 -ATP, 0.2mM Na 2 -GTP, 10mM HEPES, CsOH adjust pH=7.2.
细胞内液配好后分装为每管1mL，冻存于-20℃冰箱，每天试验使用新融化的细胞 内液。所有细胞内液在一个月内用完。超过一个月，丢弃旧细胞内液，并重新配制。After the intracellular solution is prepared, aliquot into 1 mL per tube and store it in a refrigerator at -20°C. Use the newly thawed intracellular solution for daily experiments. All intracellular fluids are used up within one month. For more than one month, discard the old intracellular fluid and reconstitute it.
膜片钳检测Patch clamp detection
用微电极拉制仪将毛细玻璃管拉制成记录电极。在倒置显微镜下操纵微电极操纵仪将记录电极接触到细胞上，给予负压抽吸，形成GΩ封接。形成GΩ封接后进行快速电容补偿(pF)，然后继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢速电容的补偿并记录膜电容(pF)及串联电阻。不给予漏电补偿。The capillary glass tube is drawn into a recording electrode with a microelectrode drawing instrument. Operate the microelectrode manipulator under the inverted microscope to touch the recording electrode to the cell, and apply negative pressure suction to form a GΩ seal. After the GΩ seal is formed, fast capacitance compensation (pF) is performed, and then negative pressure is continued to suck and break the cell membrane to form a whole-cell recording mode. Then perform slow capacitance compensation and record the film capacitance (pF) and series resistance. No leakage compensation is given.
将铺有细胞的盖玻片置于倒置显微镜中的记录浴槽中，供试品工作液以及不含化合物的NMDA+Glycine外液利用重力灌流的方法流经记录浴槽从而作用于细胞，在记录中利用真空泵进行液体交换。每个浓度重复检测多例数据。所有电生理试验在室温下进行。Place the cell-covered cover glass in the recording bath of the inverted microscope. The working solution of the test product and the compound-free NMDA+Glycine external fluid flow through the recording bath by gravity perfusion to act on the cells. During recording Use a vacuum pump for liquid exchange. Repeat the test for multiple cases of data for each concentration. All electrophysiological tests are performed at room temperature.
全细胞膜片钳记录NR2B电流的电压刺激方案如下：当形成全细胞封接后细胞膜电压钳制于-70mV。在Gap-free模式下记录600s。具体给药方式如下：首先给予NMDA+Glycine直至电流稳定后给予供试品与NMDA和Glycine的混合液至电流平稳，最后用NMDA+Glycine进行冲洗3-5min。试验数据由EPC-10放大器(HEKA)进行采集并储存于PatchMaster(HEKA)软件中。The voltage stimulation scheme for whole-cell patch clamp recording of NR2B current is as follows: when a whole-cell seal is formed, the cell membrane voltage is clamped to -70mV. Record 600s in Gap-free mode. The specific administration method is as follows: first administer NMDA+Glycine until the current is stable, then give the test product and the mixture of NMDA and Glycine until the current is stable, and finally rinse with NMDA+Glycine for 3-5 min. The test data is collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
数据分析data analysis
将每一个药物作用后用NMDA+Glycine进行冲洗的电流进行非线性拟合，用以下的方程计算电流恢复至平稳时的时间常数(Tau，τ)：After the action of each drug, the current flushed with NMDA+Glycine is nonlinearly fitted, and the time constant (Tau, τ) when the current returns to a plateau is calculated using the following equation:
Figure PCTCN2020129826-appb-000066
Figure PCTCN2020129826-appb-000066
并用Tau值除以1.44269504求得Half-life的数值。曲线拟合利用IGOR软件完成。结果如下表3所示：And divide the Tau value by 1.44269504 to find the value of Half-life. Curve fitting is done using IGOR software. The results are shown in Table 3 below:
表3解离速度抑制活性测试结果Table 3 Dissociation rate inhibition activity test results
化合物Compound Tau(s)Tau(s) Half life(s)Half life(s)
美金刚Memantine 4.13±0.244.13±0.24 2.86±0.162.86±0.16
NH200102NH200102 4.28±0.554.28±0.55 2.97±0.382.97±0.38
化合物1a1Compound 1a1 27.32±5.2727.32±5.27 18.94±3.6518.94±3.65
***Ketamine 16.80±3.9316.80±3.93 11.65±2.7311.65±2.73
结论in conclusion
上述解离速度实验结果显示，本专利化合物NH200102与其他测试药物化合物1a1和***相比，解离速度显著增快，与美金刚相当，提示本发明的化合物能够与NMDAR快速解离，具有良好的临床治疗耐受性的潜力。The above dissociation rate experiment results show that compared with other tested drug compounds 1a1 and ketamine, the dissociation rate of the compound NH200102 is significantly faster, which is comparable to memantine, suggesting that the compound of the present invention can dissociate quickly from NMDAR and has good properties. Potential for clinical treatment tolerance.
测试实施例3大鼠CCI(慢性压迫性损伤)神经痛实验模型Test Example 3 Rat CCI (Chronic Compressive Injury) Neuralgia Experimental Model
实验方法experimental method
测试药物：化合物1a1，NH200003，NH200102按照上述实施例制备。Test drugs: Compound 1a1, NH200003, NH200102 were prepared according to the above examples.
阴性对照：称量合适体积的溶媒作为储液。Negative control: Weigh a suitable volume of solvent as a stock solution.
测试化合物：配制供试品时，按设计浓度和所需体积计算理论称样量。将配制好的药液贴好标签备用。如供试品溶解不好，或混悬不均匀，可进行适当的涡旋或超声。Test compound: When preparing the test product, calculate the theoretical weighing amount according to the design concentration and the required volume. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
计算公式：理论浓度(mg/mL)＝剂量(mg/kg)/给药容积(mL/kg)Calculation formula: theoretical concentration (mg/mL) = dose (mg/kg)/dose volume (mL/kg)
理论称样量(mg)＝供试品理论浓度(mg/mL)×配制体积(mL)Theoretical weighing amount (mg) = theoretical concentration of test product (mg/mL) × preparation volume (mL)
给药方法：采用20％PEG+80％水作为溶媒，分别进行IP给药。各组给药体积均为10mL/kg，受试药的给药时间为测试前30min。Administration method: use 20% PEG+80% water as the vehicle, and perform IP administration respectively. The administration volume of each group was 10 mL/kg, and the administration time of the test drug was 30 minutes before the test.
CCI造模：大鼠腹腔注射7％水合氯醛(350mg/kg)麻醉，然后右下肢剃毛器剃毛、常规碘伏消毒，用手术刀片在股骨外侧切开长约0.5-1cm的纵行切口，切开皮肤及皮下组织，钝性分离肌肉，于股骨后找到坐骨神经主干，暴露坐骨神经，游离周围组织，在接近其分叉之前游离出约7mm的神经，分别用4根4.0的手术线间隔1mm进行松结扎，结扎线以第一根或某一根丝线引起大鼠腿部或脚趾轻微抽搐、收缩为准，且以不能影响神经外膜的血运、使神经外膜轻度凹陷为度，然后逐层缝合。手术时间5-8min，术后每只大鼠肌注青霉素3次，每次4万单位。CCI model: Rats were anesthetized by intraperitoneal injection of 7% chloral hydrate (350 mg/kg), then the right lower limb was shaved with a shaver, and routinely iodophor disinfected, and a vertical line of about 0.5-1 cm in length was cut on the outer femur with a surgical blade. Make an incision, cut the skin and subcutaneous tissues, bluntly separate the muscles, find the main sciatic nerve behind the femur, expose the sciatic nerve, free the surrounding tissues, and free the nerve about 7mm before approaching its bifurcation, separated by four 4.0 surgical lines. 1mm for loose ligation. The ligation thread should be based on the slight twitching and contraction of the rat's leg or toe caused by the first or a certain silk thread, and should not affect the blood supply of the epineurium and make the epineurium slightly sunken. , And then stitched layer by layer. The operation time was 5-8 minutes, and each rat was intramuscularly injected with penicillin 3 times, 40,000 units each time.
行为学测定：行为学检测采用组间对照，分别检测术前、术后14天进行机械痛阈值测定，根据第14天痛阈值以确定是否造模成功(一般痛阈值下降25％以上)，并进行实验分组，检测单次给药后30min的机械痛阈值。Behavioral testing: The behavioral testing uses an inter-group control. The mechanical pain threshold is measured before and 14 days after the operation. The pain threshold on the 14th day is used to determine whether the model is successful (generally, the pain threshold is reduced by more than 25%), and The experimental grouping was carried out to detect the mechanical pain threshold 30min after a single administration.
机械缩足反射阈值(Paw withdrawal threshold，PWT)的测定：置大鼠于透明的有机玻璃箱中，每个箱内放置1只大鼠，底为0.5cm×0.5cm孔径的铁丝网。实验前使之适应10min。用动态触觉测痛仪配置直径为0.5mm的不锈钢丝垂直刺激术侧右后肢足底中部，缓慢施加力度，直到大鼠抬足或舔足，此力度为PWT，每次刺激在10s完成，最大值为40g，测定2-3次，为避免或减少前一次刺激对随后刺激效应造成的影响，同一部位刺激的间隔时间为10min，取其平均值。分别检测第1d给药后30min、60min的PWT，计算药后的最大镇痛效应。Paw withdrawal threshold (PWT) measurement: Place rats in a transparent plexiglass box, and place one rat in each box, with a 0.5cm×0.5cm pore size barbed wire at the bottom. Allow them to adapt for 10 minutes before the experiment. Use a dynamic tactile pain meter with a stainless steel wire with a diameter of 0.5 mm to vertically stimulate the middle of the right hind limb on the surgical side. Slowly apply force until the rat lifts or licks the foot. This force is PWT. Each stimulation is completed in 10 seconds, the maximum The value is 40g, measured 2-3 times, in order to avoid or reduce the influence of the previous stimulation on the subsequent stimulation effect, the interval of stimulation of the same part is 10min, and the average value is taken. The PWT at 30min and 60min after the first day of administration were detected respectively, and the maximum analgesic effect after the drug was calculated.
数据分析及结果Data analysis and results
数据分析：检测第1天给药后30min、60min的PWT。Data analysis: PWT was detected 30min and 60min after the first day of administration.
最大镇痛效应％＝(给药后PWT-给药前PWT)*100％/(50-给药前PWT)。数据处理和统计分析：结果以平均值±SD表示，模型组与假手术组比较采用T检验， ##P＜0.01为差异有显著性；各给药组与模型组比较采用T检验，以*P＜0.05，**P＜0.01为显著性差异。。 The maximum analgesic effect% = (PWT after administration-PWT before administration) * 100% / (50-PWT before administration). Data processing and statistical analysis: The results are expressed as mean±SD. The model group is compared with the sham operation group by T test, ## P＜0.01 is the difference is significant; each drug group is compared with the model group by T test, with * P<0.05, **P<0.01 is a significant difference. .
测试结果如下表4所示：The test results are shown in Table 4 below:
表4各测试化合物镇痛测试结果Table 4 Analgesic test results of each test compound
Figure PCTCN2020129826-appb-000067
Figure PCTCN2020129826-appb-000067
Figure PCTCN2020129826-appb-000068
Figure PCTCN2020129826-appb-000068
结论in conclusion
通过上述测试结果可知，模型组与假手术组或空白组相比，第30min和第60min的机械缩足反射阈值显著降低( ##P<0.01vs假手术组或空白组)，提示CCI造模成功。分别给予大鼠测试药物普瑞巴林、化合物1a1，NH200102和NH200003，结果显示在给予20mg/kg的NH200102和NH200003时，二者与模型组相比明显提高机械缩足反射阈值，显示出显著的镇痛效果，与高剂量下(40mg/kg)的普瑞巴林和化合物1a1镇痛效果基本相当，提示本发明化合物在具有更好的镇痛药效。 It can be seen from the above test results that compared with the sham operation group or the blank group, the mechanical foot reflex threshold at the 30th and 60th min in the model group was significantly lower (## P<0.01vs sham operation group or blank group), suggesting CCI modeling success. Rats were given the test drugs pregabalin, compound 1a1, NH200102 and NH200003, and the results showed that when NH200102 and NH200003 were administered at 20 mg/kg, the two significantly increased the mechanical withdrawal threshold compared with the model group, showing significant suppression. The pain effect is basically equivalent to the analgesic effect of pregabalin and compound 1a1 at a high dose (40 mg/kg), suggesting that the compound of the present invention has a better analgesic effect.
测试实施例4大鼠强迫游泳试验和大鼠前脉冲抑制损害测试Test Example 4 Rat Forced Swimming Test and Rat Prepulse Inhibition Damage Test
测试药物：丙咪嗪(市售)；化合物1a1，NH200003，NH200102按照上述实施例制备。Test drug: Imipramine (commercially available); Compound 1a1, NH200003, NH200102 were prepared according to the above examples.
阴性对照：称量合适体积的溶媒作为储液。Negative control: Weigh a suitable volume of solvent as a stock solution.
测试化合物：配制供试品时，按设计浓度和所需体积计算理论称样量。将配制好的药液贴好标签备用。如供试品溶解不好，或混悬不均匀，可进行适当的涡旋或超声。Test compound: When preparing the test product, calculate the theoretical sample weight according to the design concentration and the required volume. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
计算公式：Calculation formula:
理论浓度(mg/mL)＝剂量(mg/kg)/给药容积(mL/kg)Theoretical concentration (mg/mL) = dose (mg/kg) / administration volume (mL/kg)
理论称样量(mg)＝供试品理论浓度(mg/mL)×配制体积(mL)Theoretical weighing amount (mg) = theoretical concentration of test product (mg/mL) × preparation volume (mL)
4-1大鼠强迫游泳试验4-1 Rat forced swimming test
实验方法experimental method
实验方法及步骤：全部大鼠经15分钟预游泳(水温23-25℃，水深17cm)。次日(24小时后)进行正式游泳5分钟(水温和水深同预游泳)。NH200102组和溶媒组在正式游泳前30 分钟IP方式给药1次(30或60mg/kg)溶媒。阳性对照药丙咪嗪有两种给药方式，一种为正式游泳前23.5、17和0.5小时前给药(每次30mg/kg，共3次)；另外一种为在正式游泳前30分钟前给药1次(30mg/kg)。各组大鼠分别在给药后30分钟，1小时，3小时和24小时测试不动时间。Experimental methods and procedures: All rats were pre-swimmed for 15 minutes (water temperature 23-25°C, water depth 17cm). On the next day (24 hours later), perform a formal swim for 5 minutes (water temperature and water depth are the same as the pre-swim). The NH200102 group and the vehicle group were given the vehicle (30 or 60 mg/kg) by IP once 30 minutes before the formal swimming. The positive control drug imipramine has two ways of administration, one is administered 23.5, 17 and 0.5 hours before the formal swimming (30mg/kg each time, 3 times in total); the other is 30 minutes before the formal swimming Before administration 1 time (30mg/kg). Rats in each group were tested for immobility time 30 minutes, 1 hour, 3 hours and 24 hours after administration.
数据分析及结果Data analysis and results
数据处理和统计分析：结果以平均值±SD表示，各组与溶媒组比较采用T检验，以*P＜0.05，**P＜0.01为差异有显著性。Data processing and statistical analysis: The results are expressed as the mean ± SD, and the comparison between each group and the vehicle group adopts the T test, and *P<0.05, **P<0.01 as the difference is significant.
测试结果如下表5所示：The test results are shown in Table 5 below:
表5各测试化合物对大鼠强迫游泳测试的抑制作用Table 5 The inhibitory effect of each test compound on the forced swimming test in rats
Figure PCTCN2020129826-appb-000069
Figure PCTCN2020129826-appb-000069
结论in conclusion
通过上述表5测试结果可知，在大鼠强迫游泳实验中，本发明所述化合物可显著降低大鼠的不动时间，通过对比相同剂量下的丙咪嗪和NH200102(30mg/kg)，可见本发明化合物具有更好的长时间改善不动时间的效果；在高剂量下，本发明化合物(60mg/kg)与丙咪嗪(3*30mg/kg)相比，药效持续时间明显优于丙咪嗪(3h，24h)，提示本发明化合物具有良好的抗抑郁效果。From the test results in Table 5 above, it can be seen that in the forced swimming experiment of rats, the compound of the present invention can significantly reduce the immobility time of rats. By comparing imipramine and NH200102 (30mg/kg) at the same dose, it can be seen that this The compound of the present invention has a better effect of improving immobility time for a long time; at high doses, the compound of the present invention (60mg/kg) is significantly better than imipramine (3*30mg/kg) in duration of efficacy. Imidazine (3h, 24h), suggesting that the compound of the present invention has a good antidepressant effect.
4-2大鼠前脉冲抑制损害测试4-2 Rat prepulse inhibition damage test
实验方法experimental method
将大鼠按体重分层后随机分为空白组(溶媒)，MK-801给药组，化合物1a1给药组，NH200003给药组。动物在腹腔注射给药(或给予溶媒)后30min后，将大鼠放入震惊反射测试箱进行测试。首先是5min的适应时间(62dB的背景声音)，在适应期之后给予5次单独的震惊反射刺激(block1，结果不纳入分析，用以将动物的初始反应降低到一个平台水平)，随后呈现4种不同类型试验(block2)，并以假随机的方式出现，分别是：1)单独的震惊反射刺激(pulse-alone，120dB，持续20ms)；2)高于背景音13dB的单独的前脉冲刺激(prepulse-alone，75dB，持续20ms)；3)前脉冲刺激与震惊反射刺激的联合试验(prepulse+pulse，各持续20ms，二者间隔100ms)；4)只给予背景声音的无刺激试验(no stimulus)，每种试验(trial)呈现5次，每个试验间的平均间隔为20s(10-30s)。After stratified by body weight, rats were randomly divided into blank group (vehicle), MK-801 administration group, compound 1a1 administration group, and NH200003 administration group. After 30 minutes of intraperitoneal injection of the drug (or vehicle), the rat was put into the shock reflex test box for testing. The first is an adaptation time of 5 minutes (62dB of background sound). After the adaptation period, 5 separate shock reflex stimuli are given (block1, the results are not included in the analysis to reduce the animal’s initial response to a plateau level), and then 4 Two different types of tests (block2) appear in a pseudo-random manner. They are: 1) a single shock reflex stimulus (pulse-alone, 120dB, duration 20ms); 2) a single prepulse stimulus 13dB higher than the background sound (prepulse-alone, 75dB, duration 20ms); 3) Combined test of prepulse stimulation and shock reflex stimulation (prepulse+pulse, each duration 20ms, 100ms interval between the two); 4) No stimulation test with background sound only (no stimulus), each trial is presented 5 times, and the average interval between each trial is 20s (10-30s).
单独震惊反射刺激或前脉冲联合震惊反射刺激反应幅度以AVG(仪器的专用单位)值表示，AVG值间接反映了大鼠身体的畏缩反应大小。The shock reflex stimulation alone or the pre-pulse combined shock reflex stimulation response amplitude is expressed in AVG (special unit of the instrument) value. The AVG value indirectly reflects the shrinking response of the rat body.
数据分析及结果Data analysis and results
评价指标：PPI％＝(1-前脉冲联合震惊反射刺激的反应幅度/单独震惊反射刺激的反应幅度)×100。数值越大代表抑制程度越深。Evaluation index: PPI%=(1-prepulse combined shock reflex stimulus response amplitude/single shock reflex stimulus response amplitude)×100. The larger the value, the deeper the degree of inhibition.
数据处理和统计分析：结果以平均值±SD表示，各组与溶媒组比较采用T检验，以*P＜0.05，**P＜0.01为差异有显著性。Data processing and statistical analysis: The results are expressed as the mean ± SD, and the comparison between each group and the vehicle group adopts the T test, and *P<0.05, **P<0.01 as the difference is significant.
测试结果如下表6所示：The test results are shown in Table 6 below:
表6各测试化合物对大鼠震惊反射幅度的影响
Figure PCTCN2020129826-appb-000070
Table 6 Effects of each test compound on the amplitude of shock reflex in rats
Figure PCTCN2020129826-appb-000070
Figure PCTCN2020129826-appb-000071
Figure PCTCN2020129826-appb-000071
结论in conclusion
通过上述表6所示结果可知，本发明化合物几乎对大鼠PPI无抑制作用，明显好于化合物1a1，提示本发明化合物在拟精神副作用方面要明显优于化合物1a1。From the results shown in Table 6 above, it can be seen that the compound of the present invention has almost no inhibitory effect on PPI in rats, which is significantly better than compound 1a1, suggesting that the compound of the present invention is significantly better than compound 1a1 in terms of psychiatric side effects.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and their purpose is to enable those familiar with the technology to understand the content of the present invention and implement them accordingly, and should not limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered by the protection scope of the present invention.

Claims (14)

  1. 化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，其中化合物如通式(A)所示：The compound or its pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoisomer, racemate or mixture thereof, It is characterized in that the compound is represented by general formula (A):
    Figure PCTCN2020129826-appb-100001
    Figure PCTCN2020129826-appb-100001
    其中：among them:
    R 1独立地选自氢、烷基、烯基、炔基、羟基、被一个或多个烷基取代的或非取代的氨基、烷氧基、硫代烷基、氰基、卤代烷基、环烷基、杂环基、取代或非取代的杂芳基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxy, amino substituted or unsubstituted by one or more alkyl groups, alkoxy, thioalkyl, cyano, haloalkyl, ring Alkyl, heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
    R 2和每个R 3相同或不同，且各自独立地选自氢、卤素、烷基、烯基、炔基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及杂环基； R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, haloalkyl, cyano, and one or more Alkyl substituted or unsubstituted amino, cycloalkyl and heterocyclic groups;
    R 4、R 5和每个R 6相同或不同，且各自独立地选自氢、烷基、卤代烷基、羟基、烷氧基、硫代烷基、卤素和氰基； R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, thioalkyl, halogen and cyano;
    R 7独立地选自氢、烷基、卤代烷基和
    Figure PCTCN2020129826-appb-100002
    R 7 is independently selected from hydrogen, alkyl, haloalkyl and
    Figure PCTCN2020129826-appb-100002
    n 1独立地为0～1之间的任意一个整数；n 2独立地为0～3之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1～3之间的任意一个整数；n 5独立地为1～3之间的任意一个整数； n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 3; n 3 is independently any integer between 1 and 2; n 4 is independently Any integer between 1 and 3; n 5 is independently any integer between 1 and 3;
    所述烷基、烷氧基和硫代烷基各自独立地任选地被一个或多个选自卤素和Rx的取代基取代，所述卤代烷基中的烷基任选地被一个或多个Rx取代基取代，所述环烷基和杂环基各自独立地任选地被一个或多个选自卤素、Rx、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6硫代烷基的取代基取代；The alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more Rx substituents are substituted, the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more selected from halogen, Rx, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and Substituent substitution of C1-C6 thioalkyl;
    所述芳基选自苯基或萘基，其中苯基或萘基任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6硫代烷基和Rx的取代基取代；The aryl group is selected from phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted with one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1 -C6 thioalkyl and Rx substituent substitution;
    所述杂芳基为五元至十元杂芳基，其环原子中包含1、2或3个选自氧、氮和硫的杂原子，优选其环原子中包含1或2个选自氧、氮和硫的杂原子，并且杂芳基任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6硫代烷基和Rx的取代基取代；The heteroaryl group is a five-membered to ten-membered heteroaryl group, and its ring atoms contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, and preferably its ring atoms contain 1 or 2 selected from oxygen. , Nitrogen and sulfur heteroatoms, and the heteroaryl group is optionally substituted by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl And the substituent of Rx;
    其中，Rx每次出现时各自独立地选自-OH、-NH 2、-NO 2和-CN。 Wherein, each occurrence of Rx is independently selected from -OH, -NH 2 , -NO 2 and -CN.
  2. 如权利要求1的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，The compound of claim 1 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, racemate or Its mixture form is characterized by:
    其中：among them:
    R 1独立地选自氢、烷基、羟基、烷氧基、氰基、卤代烷基、环烷基以及取代或非取代的芳基； R 1 is independently selected from hydrogen, alkyl, hydroxy, alkoxy, cyano, haloalkyl, cycloalkyl, and substituted or unsubstituted aryl;
    R 2和R 3相同或不同，且各自独立地选自氢、卤素、烷基、烷氧基、硫代烷基、卤代烷基、氰基、被一个或多个烷基取代的或非取代的氨基、环烷基以及含N杂环基； R 2 and R 3 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkyl, haloalkyl, cyano, substituted or unsubstituted by one or more alkyl groups Amino, cycloalkyl and N-containing heterocyclic groups;
    R 4、R 5和每个R 6相同或不同，且各自独立地选自氢和烷基； R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and alkyl;
    R 7独立地选自氢、烷基和
    Figure PCTCN2020129826-appb-100003
    R 7 is independently selected from hydrogen, alkyl and
    Figure PCTCN2020129826-appb-100003
    n 1独立地为0～1之间的任意一个整数；n 2独立地为0～3之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1～3之间的任意一个整数；n 5为1。 n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 3; n 3 is independently any integer between 1 and 2; n 4 is independently Any integer between 1 and 3; n 5 is 1.
  3. 如权利要求1或2所述的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，所述烷基选自C1-C6的烷基；The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, mesoisomer, or exoisomer thereof. A racemate or a mixture thereof, characterized in that the alkyl group is selected from C1-C6 alkyl groups;
    所述环烷基选自C3-C6的环烷基；The cycloalkyl group is selected from C3-C6 cycloalkyl groups;
    所述卤代烷基选自C1-C6的卤代烷基；The haloalkyl group is selected from C1-C6 haloalkyl groups;
    所述烷氧基选自C1-C6的烷氧基；The alkoxy group is selected from C1-C6 alkoxy groups;
    所述硫代烷基选自C1-C6的硫代烷基；The thioalkyl group is selected from C1-C6 thioalkyl groups;
    所述杂环基优选为含N杂环基，更优选为仅含有一个N原子的杂环基；The heterocyclic group is preferably an N-containing heterocyclic group, more preferably a heterocyclic group containing only one N atom;
    所述被一个或多个烷基取代的氨基选自被一个或多个C1-C6的烷基取代的氨基；The amino group substituted by one or more alkyl groups is selected from amino groups substituted by one or more C1-C6 alkyl groups;
    所述芳基选自苯基或萘基；The aryl group is selected from phenyl or naphthyl;
    所述卤素选自氟、氯、溴或碘；The halogen is selected from fluorine, chlorine, bromine or iodine;
    优选地，所述烷基、烷氧基、硫代烷基、环烷基、杂环基、芳基和杂芳基均为非取代的；并且所述卤代烷基中的烷基未被卤素之外的基团取代。Preferably, the alkyl group, alkoxy group, thioalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are all unsubstituted; and the alkyl group in the halogenated alkyl group is not among the halogenated groups. Substitution outside the group.
  4. 如权利要求1～3中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, or mesoisomer thereof , Racemate or its mixture form, characterized in that:
    R 1选自氢、C1-C3的烷基、羟基、C1-C3的烷氧基、氰基、C1-C3的卤代烷基和C3-C6的环烷基和苯基，优选地，R 1独立地选自氢、C1-C3的烷基、羟基、C1-C3的烷氧基、氰基和C1-C3的卤代烷基，苯基和C3-C4的环烷基，特别是C1-C3的烷基、羟基、C1-C2的烷氧基、氰基和C1-C3的卤代烷基、苯基和C3-C4的环烷基；和/或 R 1 is selected from hydrogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, cyano, C1-C3 haloalkyl and C3-C6 cycloalkyl and phenyl. Preferably, R 1 is independent Is selected from hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, cyano and C1-C3 haloalkyl, phenyl and C3-C4 cycloalkyl, especially C1-C3 alkane Group, hydroxyl, C1-C2 alkoxy, cyano and C1-C3 haloalkyl, phenyl and C3-C4 cycloalkyl; and/or
    R 2和每个R 3各自独立地选自氢、卤素、C1-C3的烷基、C1-C3的烷氧基、C1-C3的硫代烷基、C1-C3的卤代烷基、氰基、被一个或多个C1-C3的烷基取代的或非取代的氨基、C3-C6的环烷基以及C3-C6的仅含一个N原子的杂环基；优选地，R 2和每个R 3各自独立地选自氢、卤素和氰基；更优选地，R 2为卤素，R 3每次出现时各自独立地选自卤素和氢； R 2 and each R 3 are independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 haloalkyl, cyano, Amino groups substituted or unsubstituted by one or more C1-C3 alkyl groups, C3-C6 cycloalkyl groups, and C3-C6 heterocyclic groups containing only one N atom; preferably, R 2 and each R 3 are each independently selected from hydrogen, halogen and cyano; more preferably, R 2 is halogen, and each occurrence of R 3 is independently selected from halogen and hydrogen;
    其中所述烷基、烷氧基和硫代烷基各自独立地任选地被一个或多个选自卤素和Rx的取代基取代，所述卤代烷基中的烷基任选地被一个或多个Rx取代，所述环烷基和杂环基各自独立地任选地被一个或多个选自卤素、C1-C3烷基和Rx的取代基取代；Wherein the alkyl group, alkoxy group and thioalkyl group are each independently optionally substituted by one or more substituents selected from halogen and Rx, and the alkyl group in the haloalkyl group is optionally substituted by one or more substituents. One Rx substitution, the cycloalkyl and heterocyclic groups are each independently optionally substituted with one or more substituents selected from halogen, C1-C3 alkyl and Rx;
    优选地，所述烷基、烷氧基、硫代烷基、环烷基、仅含一个N原子的杂环基和苯基均为非取代的；并且所述卤代烷基中的烷基未被卤素之外的基团取代。Preferably, the alkyl group, alkoxy group, thioalkyl group, cycloalkyl group, heterocyclic group containing only one N atom and phenyl group are all unsubstituted; and the alkyl group in the haloalkyl group is not Substitution of groups other than halogen.
  5. 权利要求1～4中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，R 4、R 5和每个R 6相同或不同，且各自独立地选自氢和C1-C3的烷基；优选地 The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, The racemate or its mixture form, characterized in that R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and C1-C3 alkyl; preferably
    R 4为氢；和/或 R 4 is hydrogen; and/or
    R 5为氢；和/或 R 5 is hydrogen; and/or
    每个R 6各自独立地选自氢和C1-C3的烷基；和/或 Each R 6 is independently selected from hydrogen and C1-C3 alkyl; and/or
    R 7选自氢、C1-C3的烷基和
    Figure PCTCN2020129826-appb-100004
    所述n 4选自1、2、3，优选为1；     R 7 is selected from hydrogen, C1-C3 alkyl and
    Figure PCTCN2020129826-appb-100004
    The n 4 is selected from 1, 2, 3, preferably 1;
    更优选地，其中所述C1-C3的烷基为非取代的。More preferably, wherein the C1-C3 alkyl group is unsubstituted.
  6. 权利要求3～5中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，所述C1-C6的烷基选自甲基、乙基、丙基、丁基和戊基，优选为甲基、乙基或丙基；所 述C1-C6的卤代烷基选自-(CH 2) aCX 3和-(CH 2) aCH(CX 3) 2；所述C1-C6的烷氧基选自-O-(CH 2) aCH 3和-O-(CH 2) aCH(CH 3) 2；所述C1-C6的硫代烷基选自-S-(CH 2) aCH 3和-S-(CH 2) aCH(CH 3) 2；所述被一个或多个C1-C6的烷基取代的氨基选自-NH-(CH 2) aCH 3和-N[(CH 2) a-CH 3] 2；所述仅含有一个N原子的杂环基选自
    Figure PCTCN2020129826-appb-100005
    The compound of any one of claims 3 to 5 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, The racemate or its mixture form is characterized in that the C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl and pentyl, preferably methyl, ethyl or propyl; The C1-C6 haloalkyl group is selected from -(CH 2 ) a CX 3 and -(CH 2 ) a CH(CX 3 ) 2 ; the C1-C6 alkoxy group is selected from -O-(CH 2 ) a CH 3 and -O-(CH 2 ) a CH(CH 3 ) 2 ; the C1-C6 thioalkyl group is selected from -S-(CH 2 ) a CH 3 and -S-(CH 2 ) a CH (CH 3 ) 2 ; The amino group substituted by one or more C1-C6 alkyl groups is selected from -NH-(CH 2 ) a CH 3 and -N[(CH 2 ) a -CH 3 ] 2 ; The heterocyclic group containing only one N atom is selected from
    Figure PCTCN2020129826-appb-100005
    其中：X代表卤素，所述卤素选自氟、氯、溴和碘；a独立地选自0～3之间的任意一个整数，优选为0、1或2。Wherein: X represents halogen, and the halogen is selected from fluorine, chlorine, bromine and iodine; a is independently selected from any integer between 0 and 3, preferably 0, 1, or 2.
  7. 权利要求1～6中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，R 1独立地选自氢、甲基、乙基、氰基、羟基、苯基、三氟甲基、三氯甲基、环丙基、环丁基、乙氧基、甲氧基、苯基、三氟乙基、三氯乙基、异丙基、正丙基、羟基乙基、氰基甲基和甲氧基乙基； The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, The racemate or its mixture form, characterized in that R 1 is independently selected from hydrogen, methyl, ethyl, cyano, hydroxyl, phenyl, trifluoromethyl, trichloromethyl, cyclopropyl, ring Butyl, ethoxy, methoxy, phenyl, trifluoroethyl, trichloroethyl, isopropyl, n-propyl, hydroxyethyl, cyanomethyl and methoxyethyl;
    R 2和每个R 3相同或不同，且各自独立地选自氢、氟、氯、溴、甲基、氰基、硫代甲基、甲氧基、
    Figure PCTCN2020129826-appb-100006
    三氟甲基、三氯甲基、环丙基和-N(CH 3) 2；     R 2 and each R 3 are the same or different, and are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, cyano, thiomethyl, methoxy,
    Figure PCTCN2020129826-appb-100006
    Trifluoromethyl, trichloromethyl, cyclopropyl and -N(CH 3 ) 2 ;
    R 4、R 5和每个R 6相同或不同，且各自独立地选自氢和甲基； R 4 , R 5 and each R 6 are the same or different, and are each independently selected from hydrogen and methyl;
    R 7独立地选自氢、甲基和
    Figure PCTCN2020129826-appb-100007
    R 7 is independently selected from hydrogen, methyl and
    Figure PCTCN2020129826-appb-100007
    n 1独立地为0～1之间的任意一个整数；n 2独立地为0～1之间的任意一个整数；n 3独立地为1～2之间的任意一个整数；n 4独立地为1；n 5独立地为1～2之间的任意一个整数。 n 1 is independently any integer between 0 and 1; n 2 is independently any integer between 0 and 1; n 3 is independently any integer between 1 and 2; n 4 is independently 1; n 5 is independently any integer between 1 and 2.
  8. 权利要求1～7中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，化合物选自：The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, The racemate or its mixture form, characterized in that the compound is selected from:
    Figure PCTCN2020129826-appb-100008
    Figure PCTCN2020129826-appb-100008
    Figure PCTCN2020129826-appb-100009
    Figure PCTCN2020129826-appb-100010
    Figure PCTCN2020129826-appb-100009
    Figure PCTCN2020129826-appb-100010
  9. 权利要求1～8中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式，其特征在于，化合物选自：The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso, The racemate or its mixture form, characterized in that the compound is selected from:
    Figure PCTCN2020129826-appb-100011
    Figure PCTCN2020129826-appb-100011
  10. 一种制备权利要求1-9中任一项的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式的方法，A preparation of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, internal elimination The method in the form of a rotator, a racemate or a mixture thereof,
    所述方法包括以下步骤(B-1)和步骤(B-2)，或包括步骤(B-i)和步骤(B-ii)：The method includes the following steps (B-1) and (B-2), or includes steps (B-i) and (B-ii):
    Figure PCTCN2020129826-appb-100012
    Figure PCTCN2020129826-appb-100012
    步骤(B-1)：通式(IV)的化合物与邻苯二甲酰亚胺反应制备得到通式(V)的化合物；Step (B-1): The compound of general formula (IV) is reacted with phthalimide to prepare the compound of general formula (V);
    步骤(B-2)：通式(V)的化合物通过脱保护反应制备得到通式(A)的化合物；Step (B-2): The compound of general formula (V) is prepared by deprotection reaction to obtain the compound of general formula (A);
    步骤(B-i)：通式(IV)的化合物通过取代反应制备得到通式(VI)的化合物；Step (B-i): The compound of general formula (IV) is prepared by substitution reaction to obtain the compound of general formula (VI);
    步骤(B-ii)：通式(VI)的化合物通过加氢反应制备得到通式(A)的化合物；Step (B-ii): The compound of general formula (VI) is prepared by hydrogenation reaction to obtain the compound of general formula (A);
    其中R 5和R 7为氢；R 1、R 2、R 3、R 4、R 6、n 1、n 2、n 3和n 5如权利要求1～7中任一项所定义； Wherein R 5 and R 7 are hydrogen; R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 and n 5 are as defined in any one of claims 1-7;
    或者or
    所述方法包括步骤(C-1)、步骤(C-2)和步骤(C-3)，或包括步骤(C-i)和步骤(C-ii)：The method includes step (C-1), step (C-2) and step (C-3), or includes step (C-i) and step (C-ii):
    Figure PCTCN2020129826-appb-100013
    Figure PCTCN2020129826-appb-100013
    步骤(C-1)：通式(VII)的化合物与氨基保护基试剂反应制备得到通式(VIII)的化合物；Step (C-1): The compound of general formula (VII) is reacted with an amino protecting group reagent to prepare a compound of general formula (VIII);
    步骤(C-2)：通式(VIII)的化合物通过烷基化反应得到通式(IX)的化合物；Step (C-2): The compound of general formula (VIII) is alkylated to obtain the compound of general formula (IX);
    步骤(C-3)：通式(IX)的化合物通过脱保护反应制备得到通式(A)的化合物；Step (C-3): The compound of general formula (IX) is prepared by deprotection reaction to obtain the compound of general formula (A);
    步骤(C-i)：通式(VII)的化合物与通式SM-5的化合物反应制备得到通式(X)的化合物；Step (C-i): a compound of general formula (VII) is reacted with a compound of general formula SM-5 to prepare a compound of general formula (X);
    步骤(C-ii)：通式(X)的化合物通过脱保护反应制备得到通式(A)的化合物；Step (C-ii): The compound of general formula (X) is prepared by deprotection reaction to obtain the compound of general formula (A);
    其中R 5为氢；R 7独立地选自烷基和
    Figure PCTCN2020129826-appb-100014
    R 8为氨基保护基；R 1、R 2、R 3、R 4、R 6、n 1、n 2、n 3、n 4和n 5如权利要求1～7中任一项所定义；     Where R 5 is hydrogen; R 7 is independently selected from alkyl and
    Figure PCTCN2020129826-appb-100014
    R 8 is an amino protecting group; R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 2 , n 3 , n 4 and n 5 are as defined in any one of claims 1-7;
    优选地，R 8选自苯甲氧羰基(Cbz)、叔丁基氧羰基(Boc)、三苯基甲基(Trt)、4-甲氧基苄基(PMB)和氯甲酸-9-芴基甲基羰基(Fmoc)。 Preferably, R 8 is selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), triphenylmethyl (Trt), 4-methoxybenzyl (PMB) and 9-fluorene chloroformate Group methyl carbonyl (Fmoc).
  11. 用于制备权利要求1-9中任一项的化合物的中间体，所述中间体选自式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(XI)和式(X)的化合物：An intermediate for preparing the compound of any one of claims 1-9, the intermediate selected from the group consisting of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula Compounds of (VII), formula (VIII), formula (XI) and formula (X):
    Figure PCTCN2020129826-appb-100015
    Figure PCTCN2020129826-appb-100016
    Figure PCTCN2020129826-appb-100017
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、n 1、n 2、n 3、n 4和n 5如权利要求10所定义。
    Figure PCTCN2020129826-appb-100015
    Figure PCTCN2020129826-appb-100016
    Figure PCTCN2020129826-appb-100017
    Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n 1 , n 2 , n 3 , n 4 and n 5 are as defined in claim 10.
  12. 一种药物组合物，其特征在于，包含治疗有效量的权利要求1～9中任一项所述的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式和医学上可接受的载体。A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, and Enantiomers, diastereomers, mesoisomers, racemates, or mixtures thereof, and a medically acceptable carrier.
  13. 权利要求1～9中任一项所述的化合物或其药学上可接受的盐、顺反异构体、互变异构体、对映异构体、非对映异构体、内消旋体、外消旋体或其混合物形式或权利要求12所述的药物组合物在制备治疗神经精神类疾病的药物中的用途。The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, enantiomer, diastereomer, meso The use of the form of the compound, the racemate or the mixture thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for the treatment of neuropsychiatric diseases.
  14. 权利要求13的用途，其特征在于，所述神经精神类疾病为疼痛、精神***症、抑郁症、焦虑症、睡眠障碍、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选疼痛、抑郁症、焦虑症、精神***症、睡眠障碍、神经退行性疾病或双相情感障碍中的任意一种或多种，更优选为抑郁、神经退行性疾病或疼痛。The use according to claim 13, characterized in that the neuropsychiatric diseases are pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, adult One or more of addiction disease, withdrawal syndrome or attention deficit, preferably any one of pain, depression, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder Or more, more preferably depression, neurodegenerative disease or pain.
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