WO2017071576A1 - 稠和杂环类化合物衍生物及其应用 - Google Patents

稠和杂环类化合物衍生物及其应用 Download PDF

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Publication number
WO2017071576A1
WO2017071576A1 PCT/CN2016/103329 CN2016103329W WO2017071576A1 WO 2017071576 A1 WO2017071576 A1 WO 2017071576A1 CN 2016103329 W CN2016103329 W CN 2016103329W WO 2017071576 A1 WO2017071576 A1 WO 2017071576A1
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WIPO (PCT)
Prior art keywords
quinoline
fluorobenzoisoxazole
piperazin
dihydro
group
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PCT/CN2016/103329
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English (en)
French (fr)
Inventor
张桂森
曹旭东
陈寅
张译芳
于民权
邱印利
徐祥清
张探
刘笔锋
刘欣
Original Assignee
江苏恩华药业股份有限公司
武汉珈瑜科技有限公司
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Application filed by 江苏恩华药业股份有限公司, 武汉珈瑜科技有限公司 filed Critical 江苏恩华药业股份有限公司
Priority to CN201680062480.1A priority Critical patent/CN108368106B/zh
Priority to US15/771,225 priority patent/US10517862B2/en
Priority to JP2018522505A priority patent/JP6786599B2/ja
Priority to EP16859011.5A priority patent/EP3372600B1/en
Publication of WO2017071576A1 publication Critical patent/WO2017071576A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D471/02—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 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to the synthesis and application of a fused heterocyclic compound derivative. More particularly, the present invention relates to a fused heterocyclic compound derivative, a pharmaceutical composition comprising the fused heterocyclic compound derivative, and a pharmaceutical composition and the fused heterocyclic compound derivative in the preparation of prevention Or use in medicines for the treatment of neuropsychiatric disorders.
  • Schizophrenia is a disease characterized by deep division of cognition and emotion, manifested by the most basic human behaviors such as language, thought, perception, and self-perception. Symptoms of the disease include a wide range of symptoms, the most common being mental disorders such as hallucinations, delusions and illusions. Schizophrenia is the most serious mental illness. About 1% of people worldwide suffer from schizophrenia, and only 5% of all treated patients eventually recover completely. In addition, schizophrenia usually causes comorbidities such as anxiety disorders, depression or psychotropic substance abuse. According to a survey conducted by Datamonitor, more than one-third of people with schizophrenia suffer from at least one or more concurrent diseases such as mental illness or cognitive impairment.
  • antipsychotic drugs that exert pharmacological effects by blocking dopamine D 2 receptors are called first-generation antipsychotics, ie, "typical” antipsychotics (such as haloperidol), which treat positive symptoms of schizophrenia. Breakthrough, but failed to treat negative symptoms and cognitive impairment.
  • Typical antipsychotic drugs generally have severe EPS (pyramidal) side effects and are ineffective for one-third of patients with schizophrenia.
  • Aripiprazole is a phenbutyrazine compound that was approved by the FDA in November 2002.
  • the drug has a unique mechanism of action and has high affinity with dopamine D 2 , D 3 , 5-HT 1A and 5-HT 2A receptors, with D 4 , 5-HT 2c , 5-HT 7 , ⁇ 1 ,
  • the H 1 receptor and 5-HT reabsorption sites have moderate affinity.
  • Aripiprazole produces anti-schizophrenia effects by partial agonism of D 2 and 5-HT 1A receptors and antagonism of 5-HT 2A receptors, and has an effect of stabilizing dopamine system activity.
  • the serotonin system plays an important role in the regulation of the function of the prefrontal cortex (PFC), including mood control, cognitive behavior, and working memory.
  • PFC pyramidal neurons and GABA interneurons contain several 5-HT 1A and 5-HT 2A with particularly high-density serotonin receptor subtypes.
  • the PFC and NMDA receptor channels have recently been shown to be targets of 5-HT1AR, which regulate cerebral cortical excitatory neurons and thereby affect cognitive function.
  • 5-HT1AR may be a new target for the development of antipsychotic drugs.
  • atypical antipsychotic drugs such as olanzapine, aripiprazole, etc.
  • 5-HT1AR prefrontal cortex
  • PFC pyramidal neurons and GABA interneurons contain several 5-HT 1A and 5-HT 2A with particularly high density serotonin receptor subtypes.
  • 5-HT1A agonists are associated with atypical antipsychotic treatments that improve negative symptoms and cognitive impairment.
  • 5-HT 2A has been found to play an important role in all aspects of perception, mood regulation and motor control. Blocking the 5-HT 2A receptor normalizes the release of dopamine and acts as an antipsychotic.
  • the 5-HT 2C receptor is closely related to weight gain.
  • the distribution of D 3 receptor in the brain is mainly selectively distributed in the limbic system.
  • the prefrontal cortex DA pathway in the nucleus accumbens is closely related to learning cognitive and emotional activities. Its dysfunction will lead to schizophrenia.
  • the DA pathway is also the main pathway for reward effect in the brain.
  • D3R is in the two DA neural pathways.
  • the selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia. In addition, it can prevent extrapyramidal side effects, including tardive dyskinesia, Parkinson's disease.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof,
  • Z is an unsubstituted or -(CH 2 ) m -, m substituted by one or more substituents selected from the group consisting of a hydroxyl group, a carbonyl group and a C 1-5 alkyl group (such as a methyl group), m is an integer of from 2 to 5;
  • Y is O or S
  • Q is N or CH
  • n 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently hydrogen, halogen, unsubstituted or C 1-5 alkyl substituted by one or more substituents selected from the group consisting of halogen, amino and hydroxy;
  • R is a group of a phenyl group, a formula (II), a formula (III) or a formula (IV), and the above group may be unsubstituted or one or more selected from the group consisting of halogen, cyano and C 1-5 alkyl a C 1-5 alkoxy group (such as a methoxy group) and a substituent in the hydroxy group;
  • X is O or S; and R 5 is H or halogen.
  • Z is a substituted group unsubstituted or substituted with one or more substituents selected from hydroxyl, a carbonyl group and a methyl group - (CH 2) m -, m is 2 to An integer of 5.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • R in formula (I) is a group of formula (II), wherein when X is O, R 5 is selected from the group consisting of fluorine, chlorine, bromine and iodine; when X is S, R 5 is hydrogen.
  • R in formula (I) is substituted by one or more selected from the group consisting of methoxy, methyl, ethyl, ethyl fluoride, fluorine, chlorine, bromine, iodine and cyano.
  • a substituted phenyl group is substituted by one or more selected from the group consisting of methoxy, methyl, ethyl, ethyl fluoride, fluorine, chlorine, bromine, iodine and cyano.
  • R 1 , R 2 , R 3 or R 4 in formula (I) are each independently hydrogen, phenyl, halophenyl, C 1-5 alkyl, halo C 1-5 alkyl or C 1-5 hydroxyalkyl; preferably, R 1 , R 2 , R 3 or R 4 are each independently hydrogen, fluoro, phenyl, methyl, ethyl, propyl, trifluoro Methyl or hydroxymethyl.
  • Z of the formula (I) is -(CH 2 ) m - which is unsubstituted or substituted by one or more substituents selected from the group consisting of a hydroxyl group and a carbonyl group, and m is an integer of from 2 to 5. .
  • Y is O or S
  • Q is N or CH
  • n 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently hydrogen, fluoro, phenyl, methyl, ethyl or propyl;
  • R is a phenyl group, a group of formula (III) or a group of formula (IV);
  • R is a group of the formula (II), wherein when X is O, R 5 is selected from fluorine and chlorine, or when X is S, R 5 is hydrogen;
  • R is a phenyl group substituted by one or more substituents selected from the group consisting of methoxy, methyl, ethyl, ethyl fluoride, fluorine, chlorine, bromine and cyano.
  • the invention relates to at least one of the following compounds or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • the present invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, Agent, vehicle or a combination thereof.
  • the compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof or the pharmaceutical composition of the present invention can be used for the prevention or treatment of a psychiatric disorder.
  • the invention also relates to a method of preventing or treating a psychiatric disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof or a medicament of the invention combination.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prevention or treatment of a psychiatric disorder.
  • the psychotic disorder is schizophrenia.
  • patient or “individual” as used herein refers to a human (including adults and children) or other animals (including mammals). According to some embodiments of the invention, “patient” or “individual” refers to a person.
  • the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • C 1-5 alkyl refers specifically to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, and C 5 alkyl groups.
  • 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 ), 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
  • Ranges (such as ranges of values) recited herein can encompass each of the ranges and the various sub-ranges formed by the various values. Therefore, the expression “m is an integer of 2 to 5” includes, for example, an integer of 2 to 4, an integer of 3 to 5, and the like, for example, 2, 3, 4, and 5.
  • one or more may mean 1, 2, 3, 4, 5, 6 or more.
  • hydrox (H) means a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group may contain from 1 to 12 carbon atoms. According to one embodiment of the invention, the alkoxy group may contain from 1 to 6 carbon atoms. According to another embodiment of the invention, the alkoxy group may contain from 1 to 5 or from 1 to 4 carbon atoms. According to still another embodiment of the present invention, the alkoxy group may have 1 to 3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -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-butyl 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
  • ring includes carbocyclic, heterocyclic, aromatic, heteroaryl, and the like, wherein the carbocyclic, heterocyclic, aromatic, heteroaryl ring group has the meaning as described herein.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic systems can include fused rings, bridged rings, and spiro rings. According to one embodiment of the invention, the cycloalkyl group may contain from 3 to 10 carbon atoms. According to another embodiment of the invention, the cycloalkyl group may contain from 3 to 8 carbon atoms. According to still another embodiment of the present invention, the cycloalkyl group may contain 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described herein.
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic .
  • the aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene.
  • the aryl group is optionally substituted with one or more substituents described herein.
  • prodrug denotes a compound which can be converted in vivo to a compound of the formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • prodrugs can be found in the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.
  • metabolite refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of the compounds can be identified by techniques well known in the art, the activity of which can be characterized by experimental methods as described herein. Such products can be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention encompasses metabolites of the compounds of the invention, such as those produced by the compounds of the invention in sufficient contact with a mammal for a period of time.
  • the present invention also encompasses stereoisomers, tautomers, nitrogen oxides, solvates (e.g., hydrates), metabolites, and the like of the compounds of the present invention or salts thereof. These forms are preferably pharmaceutically acceptable.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, salts formed by reaction with inorganic acids, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates; a salt formed by the reaction of an organic acid, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange as described in the literature.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate , camphorate, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl Sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, pers
  • Salts obtained by appropriate bases include, but are not limited to, alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the invention also encompasses quaternary ammonium salts formed from compounds of any of the groups comprising N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • the compounds provided by the invention have strong affinity for D 2 , D 3 , 5HT 1A and/or 5HT 2A , have the potential to improve the positive symptoms of schizophrenia, and have potential improvement effects on negative symptoms and cognitive disorders. .
  • the compounds provided by the present invention have low affinity for 5HT 2C , H 1 and/or ⁇ 1 and thus have the advantage of a reduced weight gain effect. Animal experiments have shown that the compounds of the invention have less extrapyramidal side effects.
  • a general synthetic method for the compounds of the present invention can include first synthesizing a tricyclic fused precursor, then reacting it with a linear chloroformyl chloride and then reacting with the nitrogen terminus.
  • the title compound was prepared in the same manner as in Example 1, except that 3-chloropropanoyl chloride was used instead of 2-chloroacetyl chloride.
  • Example 2 The title compound (0.5 g) of Example 2 was obtained, and the mixture was dissolved in trifluoroacetic acid (20 mL), and triethylsilane (0.10 g) was slowly added to the mixture and stirred at room temperature overnight. The solvent was evaporated to dryness, adding an appropriate amount of dichloromethane, washed with saturated NaHCO 3 solution, layer of water. The organic layer was dried over anhydrous magnesium sulfate was added, solvent was evaporated to give a pale yellow oil. Column chromatography gave a colorless transparent oil (0.35 g).
  • the title compound was prepared in the same manner as in Example 1, except that 4-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 3 except that the target compound of Example 5 was used instead of the target compound of Example 2.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 5 was used instead of the target compound of Example 2.
  • the title compound was prepared in the same manner as in Example 1 except that 5-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 9 was used instead.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 2-chloropropanoyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 3 except that the target compound of Example 12 was used instead.
  • the target compound was prepared in the same manner as in Example 4 except that the target compound of Example 12 was used instead of Example 2. Target compound.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 4-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 3 except that the target compound of Example 15 was used instead.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 15 was used instead.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 5-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared according to the method of Example 3, and the target compound of Example 2 was replaced with the target compound of Example 17.
  • Example 20 8-(5-(4-(3-(6-fluorobenzoisoxazole)-1-piperidyl)pentyl)-5,6-dihydro-1H-pyrrole [3,2 , 1-ij]-quinoline-4(2H)-one.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 17 was used instead.
  • the title compound was prepared in the same manner as in Example 1 except that 4-fluoroporphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 2-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 1 except that 6-fluoroporphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 4-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(2-methoxyphenyl)piperazine was used instead of 1-phenylpiperazine.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(2,3-dimethylphenyl)piperazine hydrochloride was used instead of 1-phenylpiperazine.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(2,3-dichlorophenyl)piperazine hydrochloride was used instead of 1-phenylpiperazine.
  • the title compound (0.5 g) from m.
  • the solvent was evaporated to dryness, adding an appropriate amount of dichloromethane, washed with saturated NaHCO 3 solution, to the water layer.
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(4-(benzo[d]isothiazol-3-yl)piperazine was used instead of 1-phenylpiperazine.
  • the title compound was prepared according to the procedure of Example 23 except that 4-chloropropanoyl chloride was used instead of 3-chloropropanoyl chloride, and 1-(2,3-dimethylphenyl)piperazine hydrochloride was used instead of 1-phenylpiperazine. .
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead.
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead of the target compound of Example 29.
  • the target compound was prepared as in Example 23 except that porphyrin was used instead of 1,2,3,4-tetrahydroquinoline.
  • 1-(2,3-Dimethylphenyl)piperazine was substituted for 1-phenylpiperazine.
  • the title compound was prepared in the same manner as in Example 38 except that 1-(2,3-chlorophenyl)piperazine was used instead of 1-(2,3-dimethylphenyl)piperazine.
  • the title compound was prepared according to the method of Example 31 except that the target compound of Example 40 was used instead of the target compound of Example 8.
  • the title compound was prepared according to the procedure of Example 23 except that 4-chloropropanoyl chloride was used instead of 3-chloropropanoyl chloride, and 1-(2,3-dichlorophenyl)piperazine was used instead of 1-phenylpiperazine.
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead of the target compound of Example 29.
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead of the target compound of Example.
  • the homogenate used includes A homogenate, B homogenate, C homogenate, E homogenate and F homogenate, and the configuration methods are as follows:
  • the A homogenate contained a final concentration of 0.01 M Tris-HCl buffer and a final concentration of 0.32 M sucrose solution at a pH of 7.4.
  • the B homogenate was a 0.01 M Tris-HCl buffer with a pH of 7.4.
  • the C homogenate was 50 mM Tris buffer and had a pH of 7.4.
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10um excellent descending Ning and 4mM CaCl 2 ), homogenized in 4th gear for 3-4s, homogenized 4 times. Then, 5 ml of buffer (0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10 um eugenin and 4 mM CaCl 2 ) was added, and the mixture was incubated at 37 ° C for 10 min. After the incubation, the test tube was adjusted in weight with a balance.
  • buffer 0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10um excellent descending Ning and 4mM CaCl 2
  • Isotope ligand 3 H-8-OH-DPAT (67.0 Ci/mmol) was purchased from PerkinElmer; 5-HT was purchased from RBI; GF/C glass fiber filter paper was purchased from Whatman; Tris imported package; PPO, POPOP purchased Since Shanghai Reagent No. 1; fat-soluble scintillation fluid was purchased from Shanghai Reagent Factory. Beckman LS-6500 multi-function liquid scintillation counter.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in 1000 ml) was added. In double distilled water, adjust the pH to 7.5 with concentrated HCl) and homogenize for 3-4 s in 4 steps, and homogenize 4 times. Then 5 ml of buffer was added and incubated at 37 ° C for 10 min. After the incubation, the test tube was adjusted to a weight with a balance, centrifuged, and the supernatant was discarded. 3 ml of the A homogenate was added, mixed with a vortex mixer, and 5 ml of a buffer was added. After centrifugation, the supernatant was discarded and the pellet was stored at -80 ° C until use.
  • buffer 0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in
  • the isotope ligand [ 3 H]-Ketanserin (67.0 Ci/mmol) was purchased from PerkinElmer; Methysergide was purchased from RBI; GF/C glass fiber filter was purchased from Whatman; Tris was dispensed; PPO and POPOP were purchased from Shanghai Reagent Factory; fat-soluble scintillation fluid purchased from Shanghai Reagent Factory; Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of A homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • reaction tube was separately added with 100 ⁇ L of the membrane preparation and 100 ⁇ L of the buffer.
  • Total binding tube (TB) was added to 100 ⁇ L homogenate, non-specific binding tube (NB) was added to Methysergide 100 ⁇ L (final concentration 10 -5 M), and each test compound specific binding tube (SB) was added with 100 ⁇ L of test compound (final Concentration 10 -5 M);
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer containing NaCl 120 mM, KCl 5 mM) was added. , MgCl 2 1 mM, CaCl 2 1 mM), homogenate in 4 steps for 3-4 s, homogenate 4 times, then add 5 ml of buffer.
  • buffer 0.05 M Tris-HCl buffer containing NaCl 120 mM, KCl 5 mM
  • the isotopic ligand 3 H-Spiperone (67.0 Ci/mmol) was purchased from PerkinElmer; Butaclamol was purchased from RBI; GF/C glass fiber filter paper was purchased from Whatman; Tris was imported; PPO and POPOP were purchased from Shanghai Reagent 1; The fat-soluble scintillation fluid was purchased from Shanghai Reagent Factory; Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of B homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • the receptor protein was expressed on the membrane after 48-72 hours.
  • the cells were centrifuged at 1000 rpm for 5 min, and the supernatant was discarded.
  • the cells were harvested and stored in a refrigerator at -20 °C. Resuspend with Tris-Cl (pH 7.4) during the experiment.
  • D 3 receptor isotope [ 3 H]-Spiperone was purchased from Amersham; (+) Butaclamol was purchased from RBI; GF/C glass fiber filter was purchased from Whatman; fat soluble scintillation was purchased from Shanghai Reagent; Beckman LS -6500 multi-function liquid scintillation counter; Tris is packaged by Jitai Technology Co., Ltd.
  • Receptor competition binding assay 20 ⁇ l of each test compound and radioactive ligand and 160 ⁇ l of receptor protein were added to the reaction tube, so that the final concentration of the test compound and the positive drug was 10 ⁇ mol/L. After incubation for 50 min in a 30 ° C water bath, the reaction was immediately stopped by moving to an ice bath. On a Millipore cell sample collector, rapidly filtered through GF/C glass fiber filter paper, and eluted 3 times with 3 ml of eluent (50 mM Tris-HCl, pH 7.4), dried in a microwave oven for 4-5 min, and the filter paper was transferred.
  • eluent 50 mM Tris-HCl, pH 7.4
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in 1000 ml) was added. In double distilled water, adjust the pH to 7.5 with concentrated HCl. Homogenize in 4 steps for 3-4 s and homogenize 4 times. Then add 5 ml of buffer and incubate at 37 ° C for 10 min.
  • buffer 0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in 1000 ml
  • the isotope ligand [ 3 H]-mesulergine (67.0 Ci/mmol) was purchased from PerkinElmer; the mianserin was purchased from RBI; the GF/C glass fiber filter was purchased from Whatman; the Tris was dispensed; the PPO and POPOP were purchased from Shanghai Reagent Factory; fat-soluble scintillation fluid purchased from Shanghai Reagent Factory; Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of A homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • the rats were decapitated and operated on ice.
  • the rat cerebellum was quickly taken, and the homogenate of F was added, mixed with a vortex mixer, centrifuged at 4 ° C, and the supernatant was discarded to take a precipitate.
  • the F homogenate was further added thereto for washing, and the centrifugation was repeated three times. After centrifugation, the supernatant was discarded, and the precipitate was stored at -80 ° C until use.
  • the prepared membrane was uniformly dispersed by a homogenizer with a proper amount of the F homogenate, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of the F homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Each reaction tube was separately added to 10 L of a radioligand 3 H-pyrilamine (purchased from PerkinElmer Co., Ltd.) (two parallel tubes were provided for each reaction tube, and each tube was placed on ice when the sample was applied).
  • a radioligand 3 H-pyrilamine purchased from PerkinElmer Co., Ltd.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • the rats were decapitated, operated on ice, and the brain cortex was quickly taken. E homogenate was added, mixed with a vortex mixer, centrifuged at 48000 g and 4 ° C for 15 min, the supernatant was discarded, and the precipitate was taken, and 0.05 M was added thereto.
  • the Tris-HCl buffer pH 7.7 was washed and centrifuged three times. After centrifugation, the supernatant was discarded and the pellet was stored at -80 ° C until use.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of E homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • Example 54 MK-801 induced high activity: anti-schizophrenia activity of compounds in vivo
  • mice Male and female, weighing (20 ⁇ 2) g, were provided by the Nanjing Qinglongshan Animal Breeding Center.
  • Ascorbic acid was purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • MK-801 is produced by Sigma, USA, and is prepared by formulating 0.1% vitamin C into a 1 mg/ml solution;
  • Positive drugs tested haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;
  • mice with acceptable body weight were randomly divided into blank group, model group, positive control group (risperidone group) and drug group.
  • the blank group and the model group were intragastrically administered with 10% Tween (0.1 ml/10 g), and the positive control group was administered with risperidone (0.1 mg/kg).
  • the drug group was given the corresponding dose of the drug.
  • the blank group was intraperitoneally injected with 0.1% ascorbic acid (0.1 ml/10 g), and the model group, the positive control group (30 min) and the drug group were intraperitoneally injected with MK-801 solution (0.1 mg/kg). Thereafter, spontaneous activity of each group of mice was measured within 90 minutes. The results are shown in Table 3.
  • Positive drugs tested haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;
  • Apomorphine is supplied by Sigma and dissolved in 0.9% NaCl (containing 0.1% vitamin C) before use.
  • Vitamin C F20061113, purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • Sodium chloride injection H32026305, was purchased from Xuzhou Fifth Pharmaceutical Factory Co., Ltd.
  • Instrument Homemade climbing cage, stopwatch.
  • mice male, weighing 18-22 g, were randomly divided into negative control group, model group, and positive drug groups (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, fluoride). Piperidinol, clozapine) and combination Each dose group (see the table below for specific doses), 10 in each group.
  • the negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (first adding a small amount of acetic acid and then adding double distilled water), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound.
  • the volume of the gavage was 0.1 ml/10 g.
  • apomorphine (1 mg/kg) was subcutaneously injected in a volume of 0.1 ml/10 g.
  • the rats were placed in a climbing cage for 5 minutes, and the behaviors of 10-11, 20-21, and 30-31 minutes after the injection of apomorphine were observed and scored. Scoring criteria: Four feet scored 0 on the floor; two forefoot scored 1 on the cage; four feet scored 2 on the cage. The results are shown in Table 3.
  • Example 56 a method of catalepsy
  • Test drug haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone
  • Self-made grab bar equipment A stainless steel rod with a diameter of 0.3 cm and a height of 5 cm above the table is placed in the mouse box.
  • mice male and female, weighing 20-24 g, were randomly divided into negative control group, model group and positive drug group (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine). , haloperidol, clozapine) and compound dose groups, 10 per group.
  • the negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (first adding a small amount of acetic acid and then adding double distilled water), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound.
  • the volume of the gavage was 0.1 ml/10 g.
  • Sequential method limit experiment KM mice, male and female, were randomly divided into several groups, each group of 2-5, each group 2000mg/kg group and solvent group, administered by 0.2ml/10g . Animals were observed for death within 3 days. If the animal survives in 3 or more days within three days and there is no obvious abnormality in the state of life, continue to observe until the end of the experiment after 7 days. If the animal dies 3 or more in three days, the LD 50 is determined by the median lethal dose method.
  • Half-lethal dose method pre-test KM mice, male and female, were randomly divided into several groups, 4 in each group, respectively, each group of 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, according to 0.2ml/ 10 g was administered by intragastric administration, and the animals were observed for death within 1-3 days.
  • LD 50 of a single administration of the compound of the present invention was greater than 2000 mg/kg, which was comparable to ziprasidone (>2000 mg/kg), much higher than risperidone (82.1 mg/kg) and Ali. Piperazole (93 mg/kg) has less acute toxicity.
  • compositions of the present invention were prepared according to the following formulations, using the compounds prepared in Examples 1-46 as the active ingredients, respectively, in the form of a tablet dosage form:
  • Excipients are passed through a 80 mesh sieve for use, and the prescribed amount of active ingredient, microcrystalline cellulose, lactose, povidone is weighed. K30, added to the high-speed mixing machine, mix well at low speed, add appropriate amount of purified water, stir at low speed, cut granulation at high speed, then dry the wet granules at 60 ° C for 3 h, sift through 24 mesh, and add the prescribed amount of carboxymethyl Sodium starch, silica and magnesium stearate, total mixing, tableting by rotary tableting machine, that is, a pharmaceutical composition of a tablet dosage form.

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Abstract

本发明属于药物化学领域，具体涉及一种稠和杂环化合物类衍生物及其应用。所述稠和杂环类化合物衍生物具有通式(I)的结构，可用于治疗神经精神类疾病。

Description

稠和杂环类化合物衍生物及其应用 技术领域
本发明属于药物化学领域，并且具体涉及一种稠和杂环类化合物衍生物的合成及其应用。更具体地，本发明涉及一种稠和杂环类化合物衍生物、包含该稠和杂环类化合物衍生物的药物组合物以及该药物组合物和该稠和杂环类化合物衍生物在制备预防或治疗神经精神类疾病的药物中的用途。
背景技术
精神分裂症是以认知力和情感深度分裂为特征的一种疾病，表现为最基本的人类行为受到影响，例如语言、思想、知觉和自我感知等。该疾病的症状所包含的范围较广，最常见的为精神方面的障碍，比如产生幻觉、妄想症和错觉等。精神分裂症是最严重的心理疾病，全球范围内约有1％的人患精神分裂症，而在所有接受治疗的患者中只有5％最终能够得以完全康复。此外，由于精神分裂症通常会引发合并症，例如焦虑障碍、抑郁或精神性药物滥用等。据Datamonitor的一项调查研究显示，超过1/3的精神分裂症患者要遭受至少一项或多项并发的精神病或认知障碍等疾病的困扰。
传统上把通过阻断多巴胺D2受体来发挥药理作用的抗精神病药物称为第一代抗精神病药物，即“典型”抗精神病药物(如氟哌啶醇)，它们治疗精神分裂症阳性症状有突破性，但未能治疗阴性症状和认知障碍。典型抗精神病药物一般有严重的EPS(锥体外系)副作用，并且对三分之一的精神分裂症病人无效。
20世纪60年代以后，又陆续开发了一系列新一代抗精神病药，包括齐拉西酮(Ziprasidone)、利培酮(Risperidone)等，被称为第二代抗精神病药物，即新型抗精神病药。虽然它们各自的药理作用不完全一致，但却具有共同的药理特征，即对5-羟色胺(5-HT)受体(5-HT1A、2A、2c)和去甲肾上腺素(NA)受体(α1、α2)的亲和力远比对D2受体的要高，导致D2/5-HT2A的比值较低。其临床效果与第一代抗精神病药物相比有更多优势，不但对阳性症状与传统抗精神病药同样有效，而且对阴性症状、认知缺陷症状有效，作用谱更广。但是这些药物有QT间隙延长，高泌乳素血症和体重增加等不良反应。因此寻找能对精神分裂症阳性、阴性症状和认知障碍有效，而 且副作用小的药物是现在研究的热点。
阿立哌唑是一种苯丁哌唑嗪类化合物，2002年11月已获FDA批准上市。该药具有独特的作用机制，与多巴胺D2、D3、5-HT1A和5-HT2A受体有很高的亲和力，与D4、5-HT2c、5-HT7、α1、H1受体及5-HT重吸收位点具有中度亲和力。阿立哌唑是通过对D2和5-HT1A受体的部分激动作用及对5-HT2A受体的拮抗作用来产生抗精神分裂症效果，具有稳定多巴胺系统活性的作用。临床试验研究表明，阿立哌唑对精神分裂症阳性和阴性症状都有效，长期应用还能降低精神分裂症的复发率，改善情绪和认知功能障碍。其EPS不良反应及升高血清催乳素水平的作用比传统的抗精神病药物或前述的非典型抗精神病药都小。
5-羟色胺系统在调节的前额叶皮层(PFC)的功能中起着重要作用，包括情绪控制，认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度羟色胺受体亚型5-HT1A和5-HT2A。最近证明PFC和NMDA受体通道是5-HT1AR的目标，这两个受体调节大脑皮层兴奋性神经元，从而影响认知功能。实际上，各种临床前数据表明5-HT1AR可能是抗精神病药发展药物的新目标。非典型抗精神药物(如olanzapine，aripiprazole等)对5-HT1AR的高亲和力及其低的EPS副作用均说明5-羟色胺系统在调节的前额叶皮层(PFC)的功能中起着重要作用，包括情绪控制、认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度5-羟色胺受体亚型5-HT1A和5-HT2A。最近研究表明5-HT1A激动剂与非典型抗精神病药物治疗相关，能改善阴性症状和认知障碍。在应用非典型抗精神病药物氯氮平治疗精神分裂症中，人们发现5-HT2A在其中起着很重要的作用，涉及到感知、情绪调节以及运动控制的各个方面。阻断5-HT2A受体可使多巴胺的释放正常化，而起到抗精神病作用。另外，5-HT2C受体与体重增加密切相关。
D3受体在脑内的分布情况主要选择性分布于边缘系统，脑内有两条主要DA神经通路，一条是黑质纹状体通路调控运动功能，另一条是中脑腹侧被盖区伏隔核前额叶皮层DA通路与学习认知和情感活动密切相关，其功能异常将导致精神分裂症，该DA通路也是脑内奖赏效应(reward efect)的主要通路，D3R在两条DA神经通路中都有分布，并和其他DA受体亚型间存在着复杂相互作用，可能作为抗精神病药物治疗的一个目标，选择性D3受体的拮抗作用能减少精神分裂症的消极和认知症状，此外能阻止锥体外系副作用，包括迟发性运动障碍，帕金森病。
因此，寻找多受体结合且副作用小的抗精神分裂症药物对临床治疗具有重要意义。
发明内容
在第一方面，本发明提供式(I)所示的化合物或者其药学上可接受的盐或前药，
Figure PCTCN2016103329-appb-000001
其中，
Z为未取代的或被一个或多个选自羟基、羰基和C1-5烷基(如甲基)中的取代基取代的-(CH2)m-，m为2～5的整数；
Y为O或S；
Q为N或CH；
n＝1、2或3；
R1、R2、R3或R4分别独立地为氢、卤素、未取代的或被一个或多个选自卤素、氨基和羟基中的取代基取代的C1-5烷基；
R为苯基、式(II)、式(III)或式(IV)的基团，上述基团可以是未取代的或被一个或多个选自卤素、氰基、C1-5烷基、C1-5烷氧基(如甲氧基)和羟基中的取代基取代；
Figure PCTCN2016103329-appb-000002
其中，在式(II)中，X为O或S；R5为H或卤素。
在一优选实施方案中，式(I)中的Z为未取代的或被一个或多个选自羟基、羰基 和甲基中的取代基取代的-(CH2)m-，m为2～5的整数。
在另一优选实施方案中，卤素为氟、氯、溴或碘。
在另一优选实施方案中，式(I)中的R为式(II)的基团，其中当X为O时，R5选自氟、氯、溴和碘；当X为S时，R5为氢。
在另一优选实施方案中，式(I)中的R为被一个或多个选自甲氧基、甲基、乙基、乙基氟、氟、氯、溴、碘和氰基中的取代基取代的苯基。
在另一优选实施方案中，式(I)中的R1、R2、R3或R4分别独立地为氢、苯基、卤代苯基、C1-5烷基、卤代的C1-5烷基或C1-5羟烷基；优选地，R1、R2、R3或R4分别独立地为氢、氟、苯基、甲基、乙基、丙基、三氟甲基或羟甲基。
在另一优选实施方案中，式(I)的Z为未取代或被一个或多个选自羟基和羰基中的取代基取代的的-(CH2)m-，m为2～5的整数。
在进一步优选的实施方案中，在式(I)中，
Y为O或S；
Q为N或CH；
n＝1、2或3；
R1、R2、R3或R4分别独立地为氢、氟、苯基、甲基、乙基或丙基；
R为苯基、式(III)的基团或式(IV)的基团；或者
R为式(II)的基团，其中当X为O时，R5选自氟和氯，或者当X为S时，R5为氢；或者
R为被一个或多个选自甲氧基、甲基、乙基、乙基氟、氟、氯、溴和氰基中的取代基取代的苯基。
具体地，本发明涉及以下的化合物中的至少一种或者其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药：
9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)乙酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丙基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)- 酮；
9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基戊基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
8-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)乙酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丙基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉 -4(2H)-酮；
8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-6-甲基-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-6-甲基-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-6-甲基-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基戊基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
9-氟-8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
7-氟-8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
9-(3-(4-苯基哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(吡啶-2-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(嘧啶-2-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(4-氯苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-1-羟基丙基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)- 酮；
9-(4-(4-(2,3-二甲基苯基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
9-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
8-(3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
3-氟-4-(4-(3-氧代-3-(4-氧代-2,4,5,6-四氢-1H-吡咯并[3,2,1-ij]喹啉-8-基)丙基)哌嗪-1-基)苯甲腈；
8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(3-三氟甲基苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(4-氯苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(2,3-二甲基苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮。
在第二方面，本发明还涉及一种药物组合物，其含有本发明的化合物或者其药学上可接受的盐或前药，任选地进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
在第三方面，本发明的化合物或者其药学上可接受的盐或前药或者本发明的药物组合物可用于预防或治疗精神类疾病。
本发明还涉及一种预防或治疗精神类疾病的方法，所述方法包括向有此需要的个体给药有效量的本发明的化合物或者其药学上可接受的盐或前药或者本发明的药物组合物。
本发明进一步涉及本发明的化合物或者其药学上可接受的盐或前药或者本发明的药物组合物在制备用于预防或治疗精神类疾病的药物中的用途。
优选地，所述精神类疾病为精神分裂症。
具体实施方式
定义和一般术语
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版和《化学和物理手册》(第75版，1994)一致。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999和“March's Advanced Organic Chemistry”,Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
本发明所使用的术语“患者”或“个体”是指人(包括成人和儿童)或者其他动物(包括哺乳动物)。根据本发明的一些实施例，“患者”或“个体”是指人。
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。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。应当理解，术语“包含”可以涵盖封闭式的含义，即“由…组成”。
术语“不饱和”或“不饱和的”表示部分地含有一个或多个不饱和度。
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。
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“分别独立地为”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。
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“C1-5烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基和C5烷基。烷基基团的实例包括但不限于甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)、异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)、异丁基(i-Bu、-CH2CH(CH3)2)、仲丁基(s-Bu、-CH(CH3)CH2CH3)、叔丁基(t-Bu、-C(CH3)3)、正戊基(-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、正己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)、正庚基、正辛基，等等。
术语“羰基”，无论是单独使用还是和其他术语连用，如“氨基羰基”或“酰氧基”，表示-(C＝O)-。本领域技术人员应当理解，被羰基取代还可以表示碳原子上的氢原子(例如碳原子上的两个氢原子)被氧代(＝O)基团代替从而形成羰基。
本文列举的范围(如数值范围)可以涵盖其范围中的每一个值以及由各个值形成的各个亚范围。因此，表述“m为2～5的整数”包括例如2～4的整数、3～5的整数等，例如2、3、4、5。
表述“一个或多个”可以表示1、2、3、4、5、6个或更多个。
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。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
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1-3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。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)、乙氧基(EtO、-OCH2CH3)、1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)、2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)、1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)、2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)、2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)、2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)、1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)、2-戊氧基(-OCH(CH3)CH2CH2CH3)、3-戊氧基(-OCH(CH2CH3)2)、2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)、3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)、3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)、2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。
术语“环”包括碳环、杂环、芳环、杂芳环，等等，其中所述碳环、杂环、芳环、杂芳环基团具有如本发明所述的含义。
术语“环烷基”表示含有3-12个碳原子的、单价或多价的饱和单环、双环或三环体系。双环或三环体系可以包括稠环、桥环和螺环。根据本发明的一个实施方案，环烷基可以包含3-10个碳原子。根据本发明的另一个实施例，环烷基可以包含3-8个碳原子。根据本发明的又一个实施方案，环烷基可以包含3-6个碳原子。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、环己基，等等。所述环烷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。
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。
本发明所使用的术语“前药”代表可以在体内转化为式(I)所示的化合物的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。关于前体药物的详细讨论可以参考以下文献：Higuchi et al.,Pro-drugs as Novel  Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345,每篇文献通过引用包含于此。
本发明所使用的术语“代谢产物”是指特定化合物或其盐在体内通过代谢作用所得到的产物。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，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以通过给药的化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、酶裂解等等方法得到。相应地，本发明涵盖本发明的化合物的代谢产物，例如将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。应当理解，本发明还涵盖本发明的化合物或其盐的立体异构体、互变异构体、氮氧化物、溶剂化物(如水合物)、代谢产物等。这些形式优选为药学上可接受的。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为本领域人员所熟知的，如文献：S.M.Berge et al.,J.Pharmaceutical Sciences,66：1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与无机酸反应形成的盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐；和与有机酸反应形成的盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到的盐。其他药学上可接受的盐包括但不限于己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐，等等。通过适当的碱得到的盐包括但不限于碱金属、碱土金属、铵和N+(C1-4烷基)4的盐。本发明也涵盖任何包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。 药学上可接受的盐进一步包括适当的、无毒的铵、季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-8磺酸化物和芳香磺酸化物。
本发明的有益技术效果
本发明提供的化合物对D2、D3、5HT1A和/或5HT2A具有较强的亲和力，具有潜在的改善精神分裂症阳性症状的效果，并对阴性症状和认知障碍也有潜在的改善作用。同时，本发明提供的化合物对5HT2C、H1和/或α1的亲和力低，从而具有减少的体重增加效果的优点。动物实验显示，本发明的化合物具有较小的锥体外系副作用。
一般合成方案
本发明的化合物的通用合成方法可以包括先合成三环稠和母体，然后使之与直链的氯代酰氯反应，再与氮端反应。例如：
Figure PCTCN2016103329-appb-000003
实施例
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。
合成实施例
实施例1、9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)乙酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000004
1)取1,2,3,4-四氢喹啉(5.0g)，加入丙酮(50ml)，然后慢慢加入3-氯丙酰氯(5.1g)，搅拌至回流，4小时后反应完毕。使反应混合物冷却至室温，浓缩反应液，用乙酸乙酯溶解后，水洗，无水硫酸镁干燥，抽滤，浓缩，得油状物8.0g。收率96.4％。
2)取第一步的产物(8g)，加入无水三氯化铝(7.2g)，在搅拌下加热反应3小时。使反应混合物冷却至室温后，加入冰水淬灭体系。将反应混合物过滤，用乙酸乙酯萃取，水洗，无水硫酸镁干燥，抽滤，浓缩，得固体6.05g。收率90.3％。
3)取第二步的产物(5.0g)，加入2-氯乙酰氯(2.30mL)和1,2-二氯乙烷(25mL)。将体系用冰水浴降温至0℃左右，分批次加入无水三氯化铝(7.2g)，内温控制0℃左右。加完后保温半小时，撤去冰水浴，室温反应2小时。加入冰水淬灭体系。将反应混合物过滤，用乙酸乙酯萃取，水洗，无水硫酸镁干燥，抽滤，浓缩，柱层析(PE：EA＝6:1)得固体6.75g。收率80.0％。
4)取第三步的产物(0.66g)，加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(0.52g)，无水碳酸钾(1g)、碘化钾(0.2g)和乙腈(25ml)。加热回流反应12小时，使反应混合物冷至室温，蒸干溶剂。向体系中加入适量二氯甲烷，水洗，分去水层。有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物，柱层析得白色固体0.65g。
1H NMR(600MHz,CDCl3)δ7.81(s,1H),7.77(s,1H),7.72(dd,J＝8.7,5.1Hz,1H),7.25–7.22(m,1H),7.05(ddd,J＝9.0,7.9,2.0Hz,1H),5.31(s,2H),4.14(t,J＝8.5Hz,3H),3.84(s,2H),3.24(t,J＝8.5Hz,2H),3.16(d,J＝11.5Hz,2H),3.04(t,J＝7.8Hz,2H),2.73(t,J＝7.8Hz,2H),2.45–2.38(m,2H),2.24–2.15(m,2H),2.09(d,J＝12.6Hz,2H).MS(ESI)m/z448.6([M+H]+
实施例2、9-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
按实施例1的方法制备目标化合物，但用3-氯丙酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.76(s,1H),7.72(s,1H),7.21–7.11(m,2H),7.03–6.86(m,1H),3.93(dt,J＝12.9,6.4Hz,4H),3.42(t,J＝6.8Hz,2H),3.20(t,J＝7.3Hz,2H),3.11(s,4H),3.05–2.89(m,2H),2.87(d,J＝6.2Hz,2H),2.79–2.65(m,2H),2.05–1.92(m,3H).
MS(ESI)m/z462.5([M+H]+)
实施例3、9-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丙基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000005
取实施例2的目标化合物(0.5g)，用无水甲醇(20mL)溶解后，将反应混合物用冰水浴降温至零度，向其中加入硼氢化钠(0.08g)，继续搅拌1h。加入10mL水淬灭反应。蒸干溶剂，加入适量二氯甲烷，水洗，分去水层。有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物。柱层析得白色固体0.40g。
1H NMR(600MHz,CDCl3)δ7.71(dt,J＝11.6,5.8Hz,1H),7.68(s,1H),7.66(s,1H),7.26(dd,J＝8.5,2.0Hz,1H),7.12–7.02(m,1H),3.94–3.88(m,2H),3.20(t,J＝7.3Hz,2H),3.10(dd,J＝15.3,7.3Hz,3H),3.00–2.95(m,2H),2.92(t,J＝7.3Hz,2H),2.87(t,J＝6.2Hz,2H),2.73–2.69(m,2H),2.30(t,J＝12.5Hz,2H),2.14–2.05(m,4H),1.99(dt,J＝12.1,6.1Hz,2H),1.86-1.80(m,2H).MS(ESI)m/z464.7([M+H]+)
实施例4、9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000006
取实施例2的目标化合物(0.5g)，用三氟乙酸(20mL)溶解后，向混合物中缓慢加入三乙基硅烷(0.10g)，室温搅拌过夜。蒸干溶剂，加入适量二氯甲烷，饱和NaHCO3溶液洗涤，分去水层.有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物。柱层析得无色透明油状物0.35g。
1H NMR(600MHz,CDCl3)δ7.71(dt,J＝11.6,5.8Hz,1H),7.68(s,1H),7.66(s,1H),7.26(dd,J＝8.5,2.0Hz,1H),7.12–7.02(m,1H),3.94–3.88(m,2H),3.20(t,J＝7.3Hz,2H),3.10(dd,J＝15.3,7.3Hz,3H),3.00–2.95(m,2H),2.92(t,J＝7.3Hz,2H),2.87(t,J＝6.2Hz,2H),2.73–2.69(m,2H),2.30(t,J＝12.5Hz,2H),2.14–2.05(m,4H),1.99(dt,J＝12.1,6.1Hz,2H),1.86-1.80(m,2H).MS(ESI)m/z448.5([M+H]+)
实施例5、9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
按实施例1的方法制备目标化合物，但用4-氯丁酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.66(s,1H),7.65(s,1H),7.29(s,1H),7.27(d,J＝7.9Hz,1H),7.14(tt,J＝12.4,6.2Hz,1H),3.95–3.87(m,2H),3.21(t,J＝6.2Hz,2H),3.49-3.40(m,3H),3.07-3.00(m,3H),3.00–2.92(m,3H),2.86(t,J＝6.1Hz,3H),2.72–2.65(m,3H),2.33-2.30(m,3H),1.98-195(m,3H).MS(ESI)m/z476.9([M+H]+)
实施例6、9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
按实施例3的方法制备目标化合物，但用实施例5的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.75(dd,J＝8.7,5.1Hz,1H),7.26(dd,J＝8.4,2.0Hz,1H),7.10–7.03(m,3H),4.67–4.55(m,1H),3.95–3.82(m,2H),3.16(dd,J＝87.8,29.3Hz,2H),2.95–2.85(m,2H),2.83–2.78(m,2H),2.66(dd,J＝8.4,6.5Hz,2H),2.55(t,J＝5.1Hz,2H),2.36(s,1H),2.29–2.18(m,2H),2.18–2.09(m,2H),2.07–1.99(m,1H),1.98–1.91(m,2H),1.91–1.55(m,6H).MS(ESI)m/z478.8([M+H]+)
实施例7、9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
按实施例4的方法制备目标化合物，但用实施例5的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.72(dd,J＝8.5,5.1Hz,1H),7.26(dd,J＝8.4,1.6Hz,1H),7.07(td,J＝8.8,1.7Hz,1H),6.84(d,J＝1.9Hz,2H),3.91–3.85(m,2H),3.09(d,J＝9.2Hz,3H),2.90–2.84(m,2H),2.78(t,J＝6.2Hz,2H),2.68–2.64(m,2H),2.58(t,J＝7.4Hz,2H),2.46–2.41(m,2H),2.19–2.03(m,5H),1.95(dt,J＝12.1,6.2Hz,2H),1.66-1.60(m,19.0Hz,5H).MS(ESI)m/z462.7([M+H]+)
实施例8、9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
按实施例1的方法制备目标化合物，但用5-氯戊酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.71(dd,J＝8.7,5.1Hz,1H),7.64(s,1H),7.63(s,1H),7.24(dd,J＝8.5,2.1Hz,1H),7.10–7.02(m,1H),3.99–3.84(m,2H),3.08(d,J＝10.0Hz,3H),3.01–2.93(m,4H),2.85(t,J＝6.2Hz,2H),2.72–2.66(m,2H),2.49–2.43(m,2H),2.14(dt,J＝21.2,8.7Hz,2H),2.10–2.03(m,4H),1.97(dt,J＝12.1,6.1Hz,2H),1.83–1.75(m,2H),1.71–1.59(m,2H).MS(ESI)m/z 490.9([M+H]+)
实施例9、9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000007
1)取1,2,3,4-四氢喹啉(10.0g)，加入乙酰乙酸乙酯(9.76g)，加入甲苯(100mL)回流过夜，冷却后浓缩溶剂。用乙酸乙酯溶解后，用1M盐酸水洗，无水硫酸镁干燥，抽滤，浓缩，得油状物10.0g，收率61.2％。
2)取第一步的产物(10g)，加入浓硫酸(20mL)，搅拌加热100℃反应6小时，冷至室温后，加入冰水淬灭体系，析出固体。抽滤，干燥，得固体6.45g，收率69.3％。
3)取第二步的产物(6.0g)，加入10％Pd/C(0.12g)和甲醇(50mL)，室温常压下通入氢气6小时反应完全。过滤，浓缩溶剂，用乙酸乙酯萃取，水洗，无水硫酸镁干燥，抽滤，浓缩，柱层析(PE：EA＝6:1)得固体5.45g,收率90.0％。
4)取第三步的产物(5.0g)，加入4-氯丁酰氯(2.80mL)和1,2-二氯乙烷(25mL)，将反应混合物用冰水浴降温至0℃左右，分批次加入无水三氯化铝(7.2g)，内温控制在0℃左右，加完后保温半小时，撤去冰水浴，室温反应2小时。加入冰水淬灭体系，过滤，用乙酸乙酯萃取，水洗，无水硫酸镁干燥，抽滤，浓缩，柱层析(PE：EA＝6:1)得固体6.07g,收率80.0％。
5)取第四步的产物(0.66g)，加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(0.52g)、无水碳酸钾(1g)、碘化钾(0.2g)和乙腈(25ml)，加热回流反应12小时。将反应混合物冷至室温，蒸干溶剂，加入适量二氯甲烷，水洗，分去水层。有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物，柱层析得白色固体0.65g。
1H NMR(600MHz,CDCl3)δ7.72(dd,J＝8.7,5.1Hz,1H),7.68(s,2H),7.66(s,2H),7.26(dd,J＝8.5,2.0Hz,1H),7.07(td,J＝8.8,2.1Hz,1H),3.98–3.81(m,2H),3.24(t,J＝7.3Hz,2H),3.15(dd,J＝13.6,9.9Hz,3H),2.96(q,J＝7.5Hz,4H),2.87(t,J＝6.2Hz,2H),2.70(dd,J＝8.4,6.6Hz,2H),2.35(s,2H),2.20–2.11(m,4H),1.99(dt,J＝12.2,6.1Hz,2H).MS(ESI)m/z 490.7([M+H]+)
实施例10、9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮
按实施例4的方法制备目标化合物，但用实施例9的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.74(dd,J＝8.6,5.1Hz,1H),7.26(dd,J＝8.4,2.0Hz,1H),7.08(td,J＝8.8,2.1Hz,1H),6.84(d,J＝2.4Hz,2H),3.89–3.87(m,2H),3.16(d,J＝10.8Hz,3H),2.89–2.84(m,2H),2.78(t,J＝6.2Hz,2H),2.67–2.63(m,2H),2.57(dd,J＝19.0,12.1Hz,5H),2.24–2.07(m,5H),1.94(dt,J＝12.1,6.1Hz,3H),1.65(s,5H).MS(ESI)m/z 476.6([M+H]+)
实施例11、8-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)乙酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用吲哚啉代替1,2,3,4-四氢喹啉。
1H NMR(600MHz,CDCl3)δ7.74(dd,J＝8.8,5.3Hz,2H),7.70(s,1H),7.26(dd,J＝8.5,2.0Hz,1H),7.07(td,J＝8.8,2.0Hz,1H),5.32(s,2H),3.92–3.89(m,3H),3.17(dd,J＝21.6,7.7Hz,2H),2.98–2.95(m,2H),2.86(t,J＝6.1Hz,2H),2.73–2.68(m,2H),2.46(t,J＝11.0Hz,2H),2.25–2.19(m,2H),2.11(d,J＝12.0Hz,2H).MS(ESI)m/z434.6([M+H]+)
实施例12、8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用吲哚啉代替1,2,3,4-四氢喹啉，并用3-氯丙酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.77(s,1H),7.74–7.69(m,2H),7.26(dd,J＝8.5,2.0Hz,1H),7.07(td,J＝8.8,2.1Hz,1H),4.16(t,J＝8.5Hz,2H),3.26(t,J＝8.5Hz,2H),3.20(t,J＝7.4Hz,2H),3.13(d,J＝11.4Hz,3H),3.05(t,J＝7.8Hz,2H),2.92(t,J＝7.4Hz,2H),2.74(t,J＝7.8Hz,2H),2.29(dd,J＝14.0,11.4Hz,2H),2.18–2.04(m,4H).MS(ESI)m/z448.6([M+H]+)
实施例13、8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丙基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例3的方法制备目标化合物，但用实施例12的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.69(dd,J＝8.7,5.1Hz,1H),7.26(dd,J＝8.4,2.0Hz,1H),7.14(s,1H),7.07(dt,J＝8.7,3.0Hz,2H),4.96–4.81(m,1H),4.10(t,J＝8.4Hz,2H),3.34(s,1H),3.19(dd,J＝16.4,8.0Hz,4H),2.98(t,J＝7.8Hz,2H),2.85–2.73(m,1H),2.69(t,J＝7.7Hz,3H),2.39(s,1H),2.22–2.06(m,6H),1.97-1.93(m,1H),1.88-1.84(m,1H).MS(ESI)m/z450.9([M+H]+)
实施例14、8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例4的方法制备目标化合物，但用实施例12的目标化合物代替实施例2的 目标化合物。
1H NMR(600MHz,CDCl3)δ7.76(s,1H),7.72(s,1H),7.71–7.68(m,1H),7.26-(dt,J＝8.5,2.0Hz,1H),7.06(td,J＝8.8,1.9Hz,2H),4.15(t,J＝8.5Hz,2H),3.25(t,J＝8.5Hz,2H),3.18(dt,J＝13.1,7.8Hz,3H),3.09(dt,J＝22.0,9.4Hz,4H),3.04(t,J＝7.8Hz,2H),2.91(t,J＝7.4Hz,2H),2.74(t,J＝7.8Hz,2H),2.30-2.26(m,2H),2.15–2.06(m,4H).MS(ESI)m/z434.7([M+H]+)
实施例15、8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用吲哚啉代替1,2,3,4-四氢喹啉，并用4-氯丁酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.70(d,J＝17.1Hz,1H),7.67(s,1H),7.62(dt,J＝9.3,4.7Hz,1H),7.17(dt,J＝8.3,4.1Hz,1H),7.00(ddd,J＝8.6,6.4,1.8Hz,1H),4.08(t,J＝8.2Hz,2H),3.19(t,J＝8.0Hz,2H),3.05–2.90(m,7H),2.67(t,J＝7.5Hz,2H),2.44(t,J＝6.5Hz,2H),2.12(t,J＝10.3Hz,2H),2.04–1.89(m,6H).MS(ESI)m/z462.8([M+H]+)
实施例16、8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例3的方法制备目标化合物，但用实施例15的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.76-7.74(m,1H),7.2-7.24(m,1H),7.14(s,1H),7.08-7.04(m,,2H),4.66–4.63(m,1H),4.08(t,J＝8.4Hz,2H),3.18(t,J＝8.4Hz,4H),2.97(t,J＝7.7Hz,4H),2.68(t,J＝7.8Hz,2H),2.59(d,J＝5.0Hz,2H),2.29–2.18(m,2H),2.21–2.09(m,4H),2.03–1.91(m,2H),1.87–1.72(m,2H).MS(ESI)m/z464.7([M+H]+)
实施例17、8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例4的方法制备目标化合物，但用实施例15的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.83(d,J＝7.2Hz,1H),7.26(dd,J＝8.4,1.9Hz, 1H),7.10(td,J＝8.8,2.0Hz,1H),6.92(s,1H),6.83(s,1H),4.08(t,J＝8.4Hz,2H),3.42–3.23(m,3H),3.18(t,J＝8.4Hz,2H),2.96(t,J＝7.7Hz,2H),2.68(t,J＝7.7Hz,4H),2.62(t,J＝7.5Hz,4H),2.33(s,4H),1.76(s,2H),1.71–1.57(m,2H).MS(ESI)m/z448.5([M+H]+)
实施例18、8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用吲哚啉代替1,2,3,4-四氢喹啉，并用5-氯戊酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.68(dd,J＝8.7,5.1Hz,1H),7.66(s,1H),7.64(s,1H),7.16(dd,J＝8.5,2.0Hz,1H),7.02–6.96(m,1H),3.87–3.80(m,5H),3.16–3.07(m,3H),2.88(dd,J＝17.1,9.1Hz,3H),2.79(t,J＝5.2Hz,2H),2.62(dd,J＝13.5,6.3Hz,3H),2.44–2.37(m,2H),2.20–2.10(m,2H),2.04(d,J＝11.5Hz,2H),1.91(dd,J＝11.9,5.9Hz,3H).MS(ESI)m/z 476.9([M+H]+)
实施例19、8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基戊基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例3的方法制备目标化合物，用实施例17的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.79–7.74(m,1H),7.26(dd,J＝8.5,2.0Hz,1H),7.12(s,1H),7.06(td,J＝8.8,2.1Hz,1H),7.03(s,1H),4.66(dd,J＝7.9,5.4Hz,1H),4.11(t,J＝8.4Hz,3H),3.26–3.18(m,2H),3.16-3.06(m,2H),3.04–2.94(m,2H),2.70(t,J＝7.8Hz,2H),2.47-2.39(m,2H),2.28–1.97(m,6H),1.90–1.72(m,3H),1.57–1.49(m,3H),1.46-1.38(m,2H).MS(ESI)m/z478.6([M+H]+)
实施例20、8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮。
按实施例4的方法制备目标化合物，但用实施例17的目标化合物代替实施例2的目标化合物。
1H NMR(600MHz,CDCl3)δ7.74(dd,J＝8.6,5.1Hz,1H),7.26(dd,J＝8.4,2.0Hz,1H),7.15–7.00(m,1H),6.92(s,1H),6.83(s,1H),4.09(t,J＝8.4Hz,2H),3.29–3.09(m,5H),2.96(t,J＝7.8Hz,2H),2.69(t,J＝7.7Hz,2H),2.64–2.54(m,2H),2.49 (s,2H),2.19(dd,J＝43.3,32.1Hz,6H),1.64(dt,J＝15.2,7.7Hz,4H),1.39(dt,J＝15.3,7.7Hz,2H).MS(ESI)m/z462.9([M+H]+)
实施例21、9-氟-8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用4-氟吲哚啉代替1,2,3,4-四氢喹啉，并用4-氯丁酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.72(s,1H),7.62(dt,J＝9.3,4.7Hz,1H),7.17(dt,J＝8.3,4.1Hz,1H),7.00(ddd,J＝8.6,6.4,1.8Hz,1H),4.08(t,J＝8.2Hz,2H),3.19(t,J＝8.0Hz,2H),3.05–2.90(m,7H),2.67(t,J＝7.5Hz,2H),2.44(t,J＝6.5Hz,2H),2.12(t,J＝10.3Hz,2H),2.04–1.89(m,6H).MS(ESI)m/z 480.2([M+H]+)
实施例22、7-氟-8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用6-氟吲哚啉代替1,2,3,4-四氢喹啉，并用4-氯丁酰氯代替2-氯乙酰氯。
1H NMR(600MHz,CDCl3)δ7.65(s,1H),7.62(dt,J＝9.3,4.7Hz,1H),7.17(dt,J＝8.3,4.1Hz,1H),7.00(ddd,J＝8.6,6.4,1.8Hz,1H),4.08(t,J＝8.2Hz,2H),3.19(t,J＝8.0Hz,2H),3.05–2.90(m,7H),2.67(t,J＝7.5Hz,2H),2.44(t,J＝6.5Hz,2H),2.12(t,J＝10.3Hz,2H),2.04–1.89(m,6H).MS(ESI)m/z 480.2([M+H]+)
实施例23、9-(3-(4-苯基哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000008
1)取1,2,3,4-四氢喹啉(5.0g)，加入丙酮(50ml)，然后慢慢加入3-氯丙酰氯(5.1g)，搅拌至回流，4小时后反应完毕。使反应混合物冷却至室温，浓缩反应液，用乙酸乙 酯溶解后，水洗，无水硫酸镁干燥，抽滤，浓缩，得油状物8.0g，收率96.4％。
2)取第一步的产物(8g)，加入无水三氯化铝(7.2g)，搅拌加热反应3小时，冷至室温后，加入冰水淬灭体系，过滤，用乙酸乙酯萃取，水洗，无水硫酸镁干燥，抽滤，浓缩，得固体6.05g，收率90.3％。
3)取第二步的产物(5.0g)，加入3-氯丙酰氯(2.50mL)和1,2-二氯乙烷(25mL)。将反应混合物用冰水浴降温至0℃左右，分批次加入无水三氯化铝(7.2g)，内温控制在0℃左右。加完后保温半小时，撤去冰水浴，室温反应2小时。在无水加入冰水淬灭体系，过滤，用乙酸乙酯萃取，水洗，无水硫酸镁干燥，抽滤，浓缩，柱层析(PE：EA＝6:1)得固体5.95g，收率80.0％。
4)取第三步的产物(0.83g)，加入1-苯基哌嗪(0..48g)、无水碳酸钾(1g)、碘化钾(0.2g)和乙腈(25ml)，将反应混合物加热回流反应12小时，冷至室温，蒸干溶剂，加入适量二氯甲烷，水洗，分去水层，有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物，柱层析得无色油状物0.96g。
1H NMR(600MHz,CDCl3)δ7.67(s,1H),7.66(s,1H),7.33–7.26(m,2H),6.96(d,J＝7.9Hz,2H),6.88(t,J＝7.3Hz,1H),3.95–3.88(m,2H),3.26–3.22(m,4H),3.20(dd,J＝9.4,5.4Hz,2H),2.99–2.95(m,2H),2.92(t,J＝7.4Hz,2H),2.87(t,J＝6.2Hz,2H),2.76–2.64(m,6H),1.99(dt,J＝12.2,6.1Hz,2H).MS(ESI)m/z404.7([M+H]+)
实施例24、9-(3-(4-(吡啶-2-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(吡啶-2-基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ8.23(d,J＝4.0Hz,1H),7.73(s,1H),7.71(s,1H),7.58(t,J＝7.8Hz,1H),6.79(dd,J＝6.8,5.2Hz,1H),6.71(d,J＝8.5Hz,1H),4.26–3.99(m,4H),3.95–3.84(m,4H),3.57(t,J＝6.4Hz,2H),3.46-3.26(m,4H),3.05–2.94(m,2H),2.87(t,J＝6.0Hz,2H),2.75–2.65(m,2H),2.03–1.93(m,2H).MS(ESI)m/z405.6([M+H]+)
实施例25、9-(3-(4-(嘧啶-2-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(嘧啶-2-基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ8.32(d,J＝4.7Hz,2H),7.66(s,1H),7.65(s,1H),6.51(t,J＝4.7Hz,1H),4.08–3.78(m,6H),3.23(t,J＝7.3Hz,2H),2.97-2.92(m,4H),2.86(t,J＝6.2Hz,2H),2.73–2.67(m,2H),2.66–2.62(m,4H),2.00-1.96(m,2H).MS(ESI)m/z406.4([M+H]+)
实施例26、9-(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(2-甲氧基苯基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.67(s,1H),7.66(s,1H),7.33–7.26(m,2H),6.96(d,J＝7.9Hz,2H),6.88(t,J＝7.3Hz,1H),3.95–3.88(m,2H),3.26–3.22(m,4H),3.20(dd,J＝9.4,5.4Hz,2H),2.99–2.95(m,2H),2.92(t,J＝7.4Hz,2H),2.87(t,J＝6.2Hz,2H),2.76–2.64(m,6H),1.99(dt,J＝12.2,6.1Hz,2H).MS(ESI)m/z434.5([M+H]+)
实施例27、9-(3-(4-(4-氯苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(4-氯苯基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.66(s,1H),7.65(s,1H),7.21(d,J＝9.0Hz,2H),6.91–6.81(d,J＝9.0Hz,2H),3.95–3.85(m,2H),3.19(dd,J＝8.9,4.2Hz,6H),2.98–2.94(m,2H),2.92(t,J＝7.4Hz,2H),2.86(t,J＝6.2Hz,2H),2.75–2.66(m,6H),1.98(m,2H).MS(ESI)m/z438.9[M+H]+)
实施例28、9-(3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(2,3-二甲基苯基)哌嗪盐酸盐代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.68(s,1H),7.67(s,1H),7.10(t,J＝7.7Hz,1H),6.97–6.91(m,2H),3.95–3.89(m,2H),3.23(t,J＝7.4Hz,2H),3.02–2.91(m,8H),2.87(t,J＝6.2Hz,2H),2.80–2.67(m,5H),2.29(s,3H),2.24(s,3H),1.99(dt,J＝12.1,6.1Hz,3H).MS(ESI)m/z432.4([M+H]+)
实施例29、9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(2,3-二氯苯基)哌嗪盐酸盐代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.67(s,1H),7.65(s,1H),7.21–7.10(m,2H),6.98(dd,J＝7.3,2.3Hz,1H),4.01–3.83(m,2H),3.20(t,J＝7.4Hz,2H),3.11(s,4H),2.96(dt,J＝10.5,7.2Hz,4H),2.87(t,J＝6.2Hz,2H),2.79–2.66(m,6H),1.99(dt,J＝12.2,6.1Hz,2H).MS(ESI)m/z472.6([M+H]+)
实施例30、9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-1-羟基丙基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000009
取实施例2中的目标化合物(0.5g)，用无水甲醇(20mL)溶解后，将反应混合物用冰水浴降温至零度，加入硼氢化钠(0.08g)，继续搅拌1h，加入10mL水淬灭反应。蒸干溶剂，加入适量二氯甲烷，水洗，分去水层。有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物，柱层析得白色固体0.40g。
1H NMR(600MHz,CDCl3)δ7.29(s,1H),7.21–7.15(m,1H),7.04(s,2H),6.97(dd,J＝7.4,2.1Hz,1H),4.89(dd,J＝9.0,2.5Hz,1H),3.88(td,J＝5.0,2.0Hz,3H),3.14(s,4H),2.96–2.55(m,12H),1.98–1.79(m,4H).MS(ESI)m/z474.6([M+H]+)
实施例31、9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
Figure PCTCN2016103329-appb-000010
取实施例24中的目标化合物(0.5g)，用三氟乙酸(20mL)溶解后，缓慢加入三乙基硅烷(0.10g)，室温搅拌过夜。蒸干溶剂，加入适量二氯甲烷，用饱和NaHCO3溶液洗涤，分去水层。有机层加无水硫酸镁干燥，蒸干溶剂，得浅黄色油状物，柱层析得无色透明油状物0.35g。
1H NMR(600MHz,CDCl3)δ7.65(s,1H),7.63(s,1H),7.18–7.11(m,2H),6.98–6.93(m,1H),3.93–3.87(m,2H),3.26–3.17(m,2H),3.10(s,2H),2.99–2.91(m,4H),2.83(dd,J＝16.6,10.0Hz,4H),2.76(dd,J＝13.5,7.0Hz,4H),2.67(dd,J＝15.4,8.1Hz,2H),1.99–1.86(m,4H).MS(ESI)m/z458.8([M+H]+)
实施例32、9-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用1-(4-(苯并[d]异噻唑-3-基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.91(d,J＝8.2Hz,1H),7.81(d,J＝8.1Hz,1H),7.66(d,J＝9.5Hz,2H),7.49–7.45(m,1H),7.38–7.32(m,1H),3.93–3.87(m,2H),3.63–3.53(m,4H),3.21(t,J＝7.4Hz,2H),2.95(q,J＝7.1Hz,4H),2.85(t,J＝6.2Hz,2H),2.79–2.75(m,4H),2.72–2.65(m,2H),1.97(dt,J＝12.2,6.1Hz,2H).MS(ESI)m/z461.5([M+H]+)
实施例33、9-(4-(4-(2,3-二甲基苯基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例23的方法制备目标化合物，但用4-氯丁酰氯代替3-氯丙酰氯，并用1-(2,3-二甲基苯基)哌嗪盐酸盐代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.68(s,1H),7.67(s,1H),7.09(t,J＝7.7Hz,1H),6.92(d,J＝7.7Hz,2H),3.95–3.88(m,2H),3.01(t,J＝7.2Hz,2H),2.98–2.95(m,2H),2.91(s,2H),2.87(t,J＝6.2Hz,2H),2.69(dd,J＝17.7,10.5Hz,4H),2.53(t,J＝7.2Hz,2H),2.28(s,3H),2.23(s,3H),2.06–1.95(m,6H).MS(ESI)m/z446.7([M+H]+)
实施例34、9-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例32的方法制备目标化合物，但用1-(2,3-二氯苯基)哌嗪盐酸盐代替1-(2,3-二甲基苯基)哌嗪盐酸盐。
1H NMR(600MHz,CDCl3)δ7.67(s,1H),7.65(s,1H),7.20–7.13(m,2H),6.95(dd,J＝7.1,2.4Hz,1H),3.95–3.88(m,2H),3.03(d,J＝27.0Hz,4H),3.00(t,J＝7.2Hz,2H),2.98–2.94(m,2H),2.86(t,J＝6.2Hz,2H),2.69(dd,J＝15.4,8.2Hz,6H),2.52(t,J＝7.2Hz,2H),2.07–1.89(m,4H).MS(ESI)m/z486.5([M+H]+)
实施例35、9-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例30的方法制备目标化合物，但用实施例34的目标化合物代替实施例29的目标化合物。
1H NMR(600MHz,CDCl3)δ7.21–7.12(m,2H),7.02–6.95(m,1H),6.84(d,J＝2.3Hz,2H),3.93–3.83(m,2H),3.18-3.07(m,4H),2.92–2.85(m,2H),2.78(t,J＝6.2Hz,2H),2.66(dd,J＝8.4,6.5Hz,6H),2.58(t,J＝7.4Hz,2H),2.50–2.45(m,2H),1.97-1.93(m,2H),1.69–1.56(m,4H).MS(ESI)m/z472.4([M+H]+)
实施例36、9-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例32的方法制备目标化合物，但用1-(4-(苯并[d]异噻唑-3-基)哌嗪盐酸盐代替1-(2,3-二甲基苯基)哌嗪盐酸盐。
1H NMR(600MHz,CDCl3)δ7.92(d,J＝8.2Hz,1H),7.83(d,J＝8.1Hz,1H),7.67(s,1H),7.66(s,1H),7.51–7.46(m,1H),7.41–7.34(m,1H),3.95–3.87(m,2H),3.56(d,J＝4.0Hz,4H),3.02(t,J＝7.1Hz,2H),2.98–2.94(m,2H),2.86(t,J＝6.2Hz,2H),2.75–2.68(m,6H),2.55(t,J＝7.1Hz,2H),2.08–1.95(m,4H).MS(ESI)m/z475.4([M+H]+)
实施例37、9-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例30的方法制备目标化合物，但用实施例35的目标化合物代替实施例29的目标化合物。
1H NMR(600MHz,CDCl3)δ7.93(d,J＝8.2Hz,1H),7.83(d,J＝8.1Hz,1H),7.53–7.45(m,1H),7.41–7.34(m,1H),6.85(d,J＝2.6Hz,2H),3.94–3.82(m,2H),3.69–3.54(m,4H),2.91–2.83(m,2H),2.79(t,J＝6.2Hz,2H),2.73–2.68(m,4H),2.66(dd,J＝8.4,6.5Hz,2H),2.59(t,J＝7.5Hz,2H),2.51–2.46(m,2H),1.95(dt,J＝12.2,6.1Hz,2H),1.71–1.57(m,4H).MS(ESI)m/z461.5([M+H]+)
实施例38、8-(3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例23的方法制备目标化合物，但用吲哚啉代替1,2,3,4-四氢喹啉，并用 1-(2,3-二甲基苯基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.09(t,J＝7.7Hz,1H),6.93(dd,J＝10.1,8.1Hz,2H),4.15(t,J＝8.5Hz,2H),3.25(t,J＝8.5Hz,2H),3.21(t,J＝7.4Hz,2H),3.05(t,J＝7.8Hz,2H),3.00–2.90(m,6H),2.74(t,J＝7.8Hz,4H),2.28(s,3H),2.24(s,3H).MS(ESI)m/z 418.8([M+H]+)
实施例39、3-氟-4-(4-(3-氧代-3-(4-氧代-2,4,5,6-四氢-1H-吡咯并[3,2,1-ij]喹啉-8-基)丙基)哌嗪-1-基)苯甲腈
按实施例38的方法制备目标化合物，但用3-氟-4-(哌嗪-1-基)苯甲腈代替1-(2,3-二甲基苯基)哌嗪。
1H NMR(600MHz,CDCl3)δ7.75(s,1H),7.71(s,1H),7.39-7.35(m,J＝8.4,1.4Hz,1H),7.32–7.25(m,1H),6.93(t,J＝8.5Hz,1H),4.15(t,J＝8.4Hz,2H),3.25(dd,J＝9.3,5.5Hz,6H),3.17(t,J＝7.3Hz,2H),3.04(t,J＝7.8Hz,2H),2.92(t,J＝7.3Hz,2H),2.74(t,J＝7.8Hz,2H),2.72–2.70(m,4H).MS(ESI)m/z433.6([M+H]+)
实施例40、8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例38的方法制备目标化合物，但用1-(2,3-氯苯基)哌嗪代替1-(2,3-二甲基苯基)哌嗪。
1H NMR(600MHz,CDCl3)δ7.76(s,1H),7.71(s,1H),7.21–7.14(m,2H),7.02–6.95(m,1H),4.15(t,J＝8.5Hz,2H),3.27–3.20(m,4H),3.12(s,2H),3.04(t,J＝7.8Hz,2H),2.99(t,J＝7.3Hz,2H),2.77(d,J＝21.4Hz,4H),2.74(t,J＝7.8Hz,4H).MS(ESI)m/z458.4([M+H]+)
实施例41、8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例31的方法制备目标化合物，但用实施例40的目标化合物代替实施例8的目标化合物。
1H NMR(600MHz,CDCl3)δ7.76(s,1H),7.71(s,1H),7.21–7.14(m,2H),7.02–6.95(m,1H),4.15(t,J＝8.5Hz,2H),3.27–3.20(m,4H),3.12(s,4H),3.04(t,J＝7.8Hz,2H),2.99(t,J＝7.3Hz,2H),2.77(d,J＝21.4Hz,4H),2.74(t,J＝7.8Hz,4H).MS(ESI)m/z444.6([M+H]+)
实施例42、8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例38的方法制备目标化合物，但用1-(苯并[d]异噻唑-3-基)哌嗪代替1-(2,3-二甲基苯基)哌嗪。
1H NMR(600MHz,CDCl3)δ7.92(d,J＝8.2Hz,1H),7.82(d,J＝8.1Hz,1H),7.77(s,1H),7.72(s,1H),7.48(t,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,1H),4.15(t,J＝8.5Hz,2H),3.63–3.55(m,4H),3.25(t,J＝8.5Hz,2H),3.21(t,J＝7.4Hz,2H),3.04(t,J＝7.8Hz,2H),2.95(t,J＝7.4Hz,2H),2.79–2.76(m,4H),2.74(t,J＝7.8Hz,2H).MS(ESI)m/z447.5([M+H]+)
实施例43、8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例23的方法制备目标化合物，但用4-氯丁酰氯代替3-氯丙酰氯，并用1-(2,3-二氯苯基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.77(s,1H),7.71(d,J＝12.1Hz,1H),7.22–7.12(m,2H),7.01–6.91(m,1H),4.51(t,J＝8.5Hz,2H),4.15(t,J＝8.5Hz,2H),3.78(t,J＝8.5Hz,2H),3.25(t,J＝8.5Hz,2H),3.13–3.06(m,4H),3.03(m,4H),2.75(t,J＝8.5Hz,4H),2.10–1.95(m,2H).MS(ESI)m/z472.8([M+H]+)
实施例44、8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例30的方法制备目标化合物，但用实施例43的目标化合物代替实施例29的目标化合物。
1H NMR(600MHz,CDCl3)δ7.26(dd,J＝8.0,1.3Hz,1H),7.21(t,J＝8.0Hz,1H),7.03(dd,J＝8.0,1.3Hz,1H),6.92(s,1H),6.83(s,1H),4.09(t,J＝8.4Hz,2H),3.48(d,J＝36.7Hz,4H),3.27(s,2H),3.18(t,J＝8.4Hz,4H),2.97(dd,J＝15.4,7.7Hz,4H),2.69(t,J＝7.8Hz,2H),2.64(t,J＝7.5Hz,2H),2.00–1.93(m,2H),1.74–1.65(m,2H).MS(ESI)m/z458.8([M+H]+)
实施例45、8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例23的方法制备目标化合物，但用4-氯丁酰氯代替3-氯丙酰氯，并用1-(苯 并[d]异噻唑-3-基)哌嗪代替1-苯基哌嗪。
1H NMR(600MHz,CDCl3)δ7.87(d,J＝8.2Hz,1H),7.84(d,J＝8.1Hz,1H),7.75(s,1H),7.71(s,1H),7.51(t,J＝7.4Hz,1H),7.39(t,J＝7.5Hz,1H),4.14(td,J＝8.5,3.8Hz,2H),3.89(d,J＝12.5Hz,2H),3.75(dd,J＝10.8,4.8Hz,2H),3.47(t,J＝6.1Hz,2H),3.23(dt,J＝23.0,11.6Hz,2H),3.13(t,J＝7.0Hz,2H),3.03(dd,J＝14.7,7.5Hz,4H),2.73(td,J＝7.8,3.5Hz,2H),2.23(dt,J＝13.2,6.7Hz,2H),2.06–1.98(m,2H).MS(ESI)m/z461.9([M+H]+)
实施例46、8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例30的方法制备目标化合物，但用实施例45的目标化合物代替实施例29的目标化合物。
1H NMR(600MHz,CDCl3)δ7.94(t,J＝14.2Hz,1H),7.83(d,J＝8.1Hz,1H),7.53–7.45(m,1H),7.38(t,J＝7.6Hz,1H),6.93(s,1H),6.84(s,1H),4.09(t,J＝8.4Hz,2H),3.61(s,4H),3.18(t,J＝8.4Hz,2H),2.96(t,J＝7.7Hz,2H),2.70(dd,J＝14.1,6.3Hz,6H),2.62(t,J＝7.3Hz,2H),2.54–2.43(m,2H),1.65(ddd,J＝20.7,10.8,6.3Hz,4H).MS(ESI)m/z447.6([M+H]+)
表1实施例制备的优选化合物编号及其结构式
Figure PCTCN2016103329-appb-000011
Figure PCTCN2016103329-appb-000012
Figure PCTCN2016103329-appb-000013
Figure PCTCN2016103329-appb-000014
Figure PCTCN2016103329-appb-000015
Figure PCTCN2016103329-appb-000016
Figure PCTCN2016103329-appb-000017
Figure PCTCN2016103329-appb-000018
药理实施例
在后面的实施例中，采用的匀浆液包括A匀浆液、B匀浆液、C匀浆液、E匀浆液和F匀浆液，其配置方法分别如下：
A匀浆液含有终浓度为0.01M的Tris-HCl缓冲液和终浓度为0.32M的蔗糖溶液，pH值为7.4。
B匀浆液为0.01M的Tris-HCl缓冲液，pH值为7.4。
C匀浆液为50mM Tris缓冲液，pH值为7.4。
E匀浆液：0.05M的Tris-HCl缓冲液，含5mM EDTA，PH＝7.4。
F匀浆液：磷酸二氢钾1.36g，0.1mol/L的氢氧化钠79ml，用双蒸水定容至200ml，PH＝7.4。
实施例47
5HT1A膜的制备
大鼠断头，冰上操作，迅速取脑纹状体，将2个纹状体合到一根离心试管中，加入3ml缓冲液(0.05M的Tris-HCl缓冲液，含0.1％的抗坏血酸、10um优降宁和4mM CaCl2)，于4档下匀浆3-4s，匀浆4次。然后加入5ml缓冲液(0.05M的Tris-HCl缓冲液，含0.1％的抗坏血酸、10um优降宁和4mM CaCl2)，于37℃温育10min，温育完后，将试管用天平调整重量，在12000rpm和4℃下离心20min。弃上清液，加入3ml B匀浆液，用旋涡混合器混匀，再加入5ml C匀浆液。离心，重复三次离心。离心完毕，弃 上清液，将沉淀于-80℃储存备用。
受体结合实验材料：
同位素配基3H-8-OH-DPAT(67.0Ci/mmol)购自PerkinElmer公司；5-HT购自RBI公司；GF/C玻璃纤维滤纸购自Whatman公司；Tris进口分装；PPO、POPOP购自上海试剂一厂；脂溶性闪烁液购自上海试剂厂。Beckman LS-6500型多功能液体闪烁计数仪。
实验方法：
(1)先将制备好的膜用适量的A匀浆液通过匀浆机分散均匀，将15只试管混入100ml的容器中，向其中加入适量的A匀浆液，获得50ml膜的混悬液，备用。
(2)各反应管分别加入膜制备物100μL和A匀浆液100μL。
(3)总结合管(TB)加入100μL A匀浆液，非特异性结合管(NB)加入5-HT 100μL(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
(4)各反应管分别加入放射性配体3H-8-OH-DPAT 10μL(各反应管均设2个平行管，加样时各管置于冰上)。
(5)将各反应管在37℃下温育10min，反应完毕后，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到3ml闪烁杯中，加入2ml的甲苯闪烁液并混匀；
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
化合物每次实验做两复管，进行两次单独实验。
实验结果见表2。
实施例48
5HT2A膜的制备
大鼠断头，冰上操作，迅速取脑纹状体，将2个纹状体合到一根离心试管中，加入3ml缓冲液(0.05M的Tris-HCl缓冲液：取6.05gTris溶于1000ml双蒸水中，用浓HCl调PH为7.5)于4档下匀浆3-4s，匀浆4次。然后加入5ml缓冲液，于37℃下温育10min。温育完后将试管用天平调整重量，离心，弃上清液，加入3ml A匀浆液，用旋涡混合器混匀，再加入5ml缓冲液。离心，弃上清液，将沉淀于-80℃储存备用。
受体结合实验材料：
同位素配基[3H]-Ketanserin(67.0Ci/mmol)购自PerkinElmer公司；Methysergide购自RBI公司；GF/C玻璃纤维滤纸购自Whatman公司；Tris进口分装；PPO和POPOP购自上海试剂一厂；脂溶性闪烁液购自上海试剂厂；Beckman LS-6500型多功能液体闪烁计数仪。
实验方法：
(1)先将制备好的膜用适量的A匀浆液通过匀浆机分散均匀，将15只试管混入到100ml的容器中，加入适量的A匀浆液获得50ml膜的混悬液，备用。
(2)反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μLA匀浆液，非特异性结合管(NB)加入Methysergide100μL(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
(4)各反应管分别加入放射性配体3H-Ketanserin 10μL(各反应管均设2个平行管，加样时各管置于冰上)。
(5)将各反应管在37℃下温育15min，反应完毕后，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到3ml闪烁杯中，加入2ml的甲苯闪烁液并混匀；
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
化合物每次实验做两复管，进行两次单独实验。
实验结果见表2
实施例49
D2膜的制备
大鼠断头，冰上操作，迅速取脑纹状体，将2个纹状体合到一根离心试管中，加入3ml缓冲液(0.05M的Tris-HCl缓冲液,含NaCl 120mM、KCl 5mM、MgCl2 1mM、CaCl2 1mM)，于4档匀浆3-4s，匀浆4次，然后加入5ml缓冲液。将匀浆完的试管用天平调整重量，离心，弃上清液，加入3ml B匀浆液，用旋涡混合器混匀，再加入5ml B匀浆液，离心，弃上清液，将沉淀于-80℃储存备用。
受体结合实验材料：
同位素配基3H-Spiperone(67.0Ci/mmol)购自PerkinElmer公司；Butaclamol购自RBI公司；GF/C玻璃纤维滤纸购自Whatman公司；Tris进口分装；PPO和POPOP购自上海试剂一厂；脂溶性闪烁液购自上海试剂厂；Beckman LS-6500型多功能液体闪烁计数仪。
实验方法：
(1)先将制备好的膜用适量的A匀浆液通过匀浆机分散均匀，将15只试管混入到100ml的容器中，加入适量的B匀浆液获得50ml膜的混悬液，备用。
(2)各反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μLA匀浆液，非特异性结合管(NB)加入100μL Butaclamol(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
(4)各反应管分别加入放射性配体3H-Spiperone 10μL(各反应管均设2个平行管，加样时各管置于冰上)。
(5)将各反应管在37℃下温育20min，反应完毕后，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到3ml闪烁杯中，加入2ml的甲苯闪烁液并混匀；
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
化合物每次实验做两复管，进行两次单独实验。
实验结果见表2。
实施例50 D3受体实验
细胞
HEK-293细胞，经48-72小时后受体蛋白在膜上大量表达，将细胞以1000rpm离心5min后弃上清，收胞体，存放于-20℃冰箱保存。实验时用Tris-Cl(pH 7.4)重悬。
实验材料：
D3受体同位素配基[3H]-Spiperone购自Amersham公司；(+)Butaclamol购自RBI公司；GF/C玻璃纤维滤纸购自Whatman公司；脂溶性闪烁液购自上海试剂厂；Beckman  LS-6500型多功能液体闪烁计数仪；Tris由吉泰科技有限公司分装。
实验方法：
受体竞争结合实验：将待测化合物与放射性配基各20μl及160μl受体蛋白加入反应试管中，使受试化合物及阳性药物终浓度均为10μmol/L。在30℃水浴中温育50min后，即刻移至冰浴终止其反应。在Millipore细胞样品收集器上，经过GF/C玻璃纤维滤纸快速抽滤，并用洗脱液(50mM Tris-HCl,PH 7.4)3ml洗脱3次，用微波炉处理4～5min烘干，将滤纸移入0.5ml离心管中，向其中加入500μl脂溶性闪烁液。避光静置30min以上，计数测定放射性强度。按以下公式计算各化合物对同位素配基结合的抑制率百分率：
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
实验结果见表2
实施例51
5HT2C膜的制备
大鼠断头，冰上操作，迅速取脑纹状体，将2个纹状体合到一根离心试管中，加入3ml缓冲液(0.05M的Tris-HCl缓冲液：取6.05gTris溶于1000ml双蒸水中，用浓HCl调PH为7.5)于4档匀浆3-4s，匀浆4次。然后加入5ml缓冲液，于37℃温育10min，温育完后，将试管用天平调整重量，在12000rpm和4℃下离心20min，弃上清液，加入3ml A匀浆液，用旋涡混合器混匀，再加入5ml缓冲液，离心，离心完毕，弃上清液，将沉淀于-80℃储存备用。
受体结合实验材料：
同位素配基[3H]-mesulergine(67.0Ci/mmol)购自PerkinElmer公司；mianserin购自RBI公司；GF/C玻璃纤维滤纸购自Whatman公司；Tris进口分装；PPO和POPOP购自上海试剂一厂；脂溶性闪烁液购自上海试剂厂；Beckman LS-6500型多功能液体闪烁计数仪。
实验方法：
(1)先将制备好的膜用适量的A匀浆液通过匀浆机分散均匀，将15只试管混入到100ml的容器中，加入适量的A匀浆液获得50ml膜的混悬液，备用。
(2)各反应管分别加入膜制备物100μL和缓冲液100μL。
(3)总结合管(TB)加入100μL A匀浆液，非特异性结合管(NB)加入mianserin 100μL(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
(4)各反应管分别加入放射性配体[3H]-mesulergine 10μL(各反应管均设2个平行管，加样时各管置于冰上)。
(5)将各反应管在37℃下温育15min，反应完毕，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到3ml闪烁杯中，加入2ml的甲苯闪烁液并混匀；
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
化合物每次实验做两复管，进行两次单独实验。
实施例52
组胺H1受体膜的制备
大鼠断头，冰上操作，迅速取大鼠小脑，加入F匀浆液，用旋涡混合器混匀，4℃离心，弃上清液，取沉淀。向其中再加入F匀浆液洗涤，重复三次离心，离心完毕，弃上清液，将沉淀于-80℃储存备用。
H1受体亲和实验
(1)先将制备好的膜用适量的F匀浆液通过匀浆机分散均匀，将15只试管混入到100ml的容器中，加入适量的F匀浆液获得50ml膜的混悬液，备用。
(2)将各反应管分别加入膜制备物100μL。
(3)总结合管(TB)加入100μL F匀浆液，非特异性结合管(NB)加入100μL promethazine(购自RBI公司)(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
(4)将各反应管分别加入放射性配体3H-pyrilamine(购自PerkinElmer公司)10μL(各反应管均设2个平行管，加样时各管置于冰上)。
(5)将各反应管在30℃下温育60min，反应完毕，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到3ml闪烁杯中，加入2ml的甲苯闪烁液并混匀；
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
化合物每次实验做两复管，进行两次单独实验。
实施例53、去甲肾上腺素受体膜的制备
大鼠断头，冰上操作，迅速取脑皮层，加入E匀浆液，用旋涡混合器混匀，在48000g和4℃下离心15min，弃上清液，取沉淀，向其中再加入0.05M的Tris-HCl缓冲液(PH7.7)洗涤，重复三次离心。离心完毕，弃上清液，将沉淀于-80℃储存备用。
α1去甲肾上腺素受体亲和实验
(1)先将制备好的膜用适量的E匀浆液通过匀浆机分散均匀，将15只试管混入到100ml的容器中，加入适量的E匀浆液获得50ml膜的混悬液，备用。
(2)将各反应管分别加入膜制备物100μL和E匀浆液100μL。
(3)总结合管(TB)加入100μL E匀浆液，非特异性结合管(NB)加入prazosin(购自PerkinElmer公司)100μL(终浓度10-5M)，各受试化合物特异性结合管(SB)加入100μL受试化合物(终浓度10-5M)；
(4)各反应管分别加入放射性配体3H-prazosin(购自PerkinElmer公司)10μL(各反应管均设2个平行管，加样时各管置于冰上)。
(5)将各反应管在25℃下温育60min，反应完毕，结合的配基通过减压快速过滤，用冰冷的试验缓冲液充分洗涤，将滤片取出放到3ml闪烁杯中，加入2ml的甲苯闪烁液并混匀。
(6)将闪烁瓶放入液闪计数仪计数
抑制率(I％)＝(总结合管cpm—化合物cpm)/(总结合管cpm—非特异结合管cpm)×100％
化合物每次实验做两复管，进行两次单独实验。
实验结果见表2
体外实验结果表明本发明的化合物(特别是化合物5、6、12、13、14、16和17)对四种受体(D2、D3、5HT1A、5HT2A)具有较强的亲和力，而对5HT2C、H1、α1的亲和力较低。
实施例54、MK-801诱导的高活动性：化合物体内抗精神分裂活性
实验动物及试剂
健康昆明种小鼠，雌雄各半，体重(20±2)g，由南京青龙山动物养殖中心提供。
抗坏血酸购自国药集团化学试剂有限公司；
MK-801由美国Sigma公司生产，配制方法：用0.1％的维生素C配成1mg/ml的溶液；
受试阳性药物：氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平；
吐温80，浓度10％。
实验方法
选择体重合格的小鼠，随机分为空白组、模型组、阳性对照组(利培酮组)和药物组。空白组和模型组灌胃10％吐温(0.1ml/10g)，阳性对照组灌胃利培酮(0.1mg/kg)，药物组分别灌胃相应剂量的药物。给药后1h，空白组腹腔注射0.1％抗坏血酸(0.1ml/10g)，模型组、阳性对照组(30min)和药物组腹腔注射MK-801溶液(0.1mg/kg)。其后测定各组小鼠90分钟内自发活动。结果见表3。
实施例55、阿扑吗啡诱导小鼠攀爬实验
实验动物
健康昆明种(KM)小鼠，雄性，体重18～22g，由南京青龙山动物养殖中心提供。
主要试剂
受试阳性药物：氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮、奎硫平；
阿扑吗啡由Sigma公司提供，临用前0.9％NaCl(含0.1％维生素C)溶解，现配现用；
维生素C，F20061113，购自国药集团化学试剂有限公司；
氯化钠注射液，H32026305，购自徐州市第五制药厂有限公司。
仪器:自制攀爬笼，秒表。
实验方法：阿扑吗啡诱导小鼠攀爬实验
KM小鼠，雄性，体重18～22g，随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合 物各剂量组(具体给药剂量见下表)，每组10只。阴性对照组和模型组灌胃给予相应溶剂双蒸水，阳性药物组灌胃给予相应阳性药物(溶解时先加微量乙酸，再加双蒸水)，化合物各剂量组灌胃给予相应剂量化合物，灌胃体积为0.1ml/10g。灌胃给药1小时后皮下注射阿扑吗啡(1mg/kg)，体积为0.1ml/10g。注射阿扑吗啡后，立即放入攀爬笼中，适应5分钟，观察注射阿扑吗啡后第10-11、20-21、30-31分钟的行为并进行评分。评分标准：四足在地板上得分为0；两前足在网笼上得分为1；四只足在网笼上得分为2。结果见表3。
实施例56、僵住症实验方法
实验动物
健康昆明种小鼠，雌雄各半，(22±2)g，由南京青龙山动物养殖中心提供。
主要试剂：
受试药、氟哌啶醇、氯氮平、利培酮、奥氮平、阿立哌唑、齐拉西酮
仪器：
自制抓棒器材：小鼠盒内放置直径0.3cm,高于工作台5cm的不锈钢棒。
实验方法：
KM小鼠，雌雄各半，体重20～24g，随机分为阴性对照组、模型组、阳性药物各剂量组(利培酮、阿立哌唑、齐拉西酮、奎硫平、奥氮平、氟哌啶醇、氯氮平)以及化合物各剂量组，每组10只。阴性对照组和模型组灌胃给予相应溶剂双蒸水，阳性药物组灌胃给予相应阳性药物(溶解时先加微量乙酸，再加双蒸水)，化合物各剂量组灌胃给予相应剂量化合物，灌胃体积为0.1ml/10g。灌胃给药30min、60min、90min时，将小鼠两只前爪轻柔地放在长20cm，直径0.3cm，高于工作台5.5cm的小棒上,再将动物后肢轻放于盒底面，记录小鼠两只前爪在棒上保持姿势的持续时间，以30s僵直不动为阳性反应。如果小鼠前爪一直没有放下，60s时终止观察。统计每个化合物剂量组阳性反应动物数。结果见表3。
实验结果表明：与模型组相比，利培酮、本发明的化合既能明显改善MK-801诱导的高活动性，又能有效的改善阿扑吗啡诱导的攀爬症状，并且在有效剂量下不引起EPS，表明其有明显的抗精神分裂作用。
实施例57、急性毒性研究
序贯法之限度实验：取KM小鼠，雌雄各半，随机分为若干组，每组2-5只，分别为各化合物2000mg/kg组和溶剂组，按0.2ml/10g灌胃给药。观察动物3日内的死亡情况。如果动物在三日内有3只或3只以上存活，生命状态无明显异常时，继续观察，直至7日后实验结束。如果动物在三日内死亡3只或3只以上时，采用半数致死量法测定其LD50。
半数致死量法预试验：取KM小鼠，雌雄各半，随机分若干组，每组4只，分别为各化合物1500mg/kg、1000mg/kg、500mg/kg组和溶剂组，按0.2ml/10g灌胃给药，观察动物1-3日内的死亡情况。
结果：本发明的化合物的小鼠单次灌服的LD50大于2000mg/kg，与齐拉西酮(﹥2000mg/kg)相当，远远高于利培酮(82.1mg/kg)和阿立哌唑(93mg/kg)，具有较小的急性毒性。
表2化合物对各受体的抑制率
Figure PCTCN2016103329-appb-000019
表3.优选化合物体内动物模型试验结果
Figure PCTCN2016103329-appb-000020
制剂实施例
实施例58
分别以实施例1-46制备的化合物作为活性成分，以片剂剂型为例，按照以下配方制备本发明的药物组合物：
Figure PCTCN2016103329-appb-000021
将原辅料过80目筛备用，称取处方量活性成分、微晶纤维素、乳糖、聚维酮 K30，加入到高速混合制剂机中，低速搅拌混合均匀，加入适量纯化水，低速搅拌，高速切割制粒，然后将湿颗粒于60℃干燥3h，24目筛整粒，并加入处方量羧甲淀粉钠、二氧化硅和硬脂酸镁，总混，旋转压片机压片，即得片剂剂型的药物组合物。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 式(I)所示化合物或者其药学上可接受的盐或前药，
    Figure PCTCN2016103329-appb-100001
    其中：
    Z为未取代的或被一个或多个选自羟基、羰基和C1-5烷基中的取代基取代的-(CH2)m-，m为2～5的整数；
    Y为O或S；
    Q为N或CH；
    n＝1、2或3；
    R1、R2、R3或R4分别独立地为氢、卤素、未取代的或被一个或多个选自卤素、氨基和羟基中的取代基取代的C1-5烷基；
    R为苯基、式(II)、式(III)或式(IV)的基团，上述基团可以是未取代的或被一个或多个选自卤素、氰基、C1-5烷基、C1-5烷氧基和羟基中的取代基取代；
    Figure PCTCN2016103329-appb-100002
    其中，在式(II)中，X为O或S，R5为H或卤素。
  2. 根据权利要求1所述的化合物或者其药学上可接受的盐或前药，其特征在于，
    Z为未取代的或被一个或多个选自羟基、羰基和甲基中的取代基取代的-(CH2)m-，m为2～5的整数。
  3. 根据权利要求1所述的化合物或者其药学上可接受的盐或前药，其特征在于：
    所述卤素为氟、氯、溴、碘。
  4. 根据权利要求1所述的化合物或者其药学上可接受的盐或前药，其特征在于，
    R为式(II)的基团，其中当X为O时，R5选自氟、氯、溴和碘，或者当X为S时，R5为氢；或者
    R为被一个或多个选自甲氧基、甲基、乙基、氟、氯、溴、碘和氰基中的取代基取代的苯基。
  5. 根据权利要求1所述的化合物或者其药学上可接受的盐或前药，其特征在于，
    R1、R2、R3或R4分别独立地为氢、苯基、卤代苯基、C1-5烷基、卤代的C1-5烷基或C1-5羟烷基；
    优选地R1、R2、R3或R4分别独立地为氢、氟、苯基、甲基、乙基、丙基、三氟甲基或羟甲基。
  6. 根据权利要求1所述的所述的化合物或者其药学上可接受的盐或前药，其特征在于，
    Z为未取代或被一个或多个选自羟基和羰基中的取代基取代的的-(CH2)m-，m为2～5的整数；
    Y为O或S；
    Q为N或CH；
    n＝1、2或3；
    R1、R2、R3或R4分别独立地为氢、氟、苯基、甲基、乙基或丙基；
    R为苯基、式(III)的基团或式(IV)的基团；或者
    R为式(II)的基团，其中当X为O时，R5选自氟和氯，或者当X为S时，R5为氢；或者
    R为被一个或多个选自甲氧基、甲基、乙基、氟、氯、溴和氰基中的取代基取代 的苯基。
  7. 根据权利要求1～6任一所述的化合物或者其药学上可接受的盐或前药，其特征在于，所述化合物选自：
    9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)乙酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丙基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-1-甲基-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊酰基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基戊基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    9-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊基)-1,2,6,7-四氢吡啶[3,2,1-ij]并喹啉-3(5H)-酮；
    8-(2-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)乙酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丙基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(3-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丙基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-6-甲基-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基丁基)-6-甲基-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁基)-6-甲基-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)-1-羟基戊基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    8-(5-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)戊基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    9-氟-8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    7-氟-8-(4-(4-(3-(6-氟苯并异噁唑)-1-哌啶基)丁酰基)-5,6-二氢-1H-吡咯[3,2,1-ij]并喹啉-4(2H)-酮；
    9-(3-(4-苯基哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(吡啶-2-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(嘧啶-2-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(4-氯苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-1-羟基丙基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(4-(4-(2,3-二甲基苯基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁酰基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    9-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮；
    8-(3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    3-氟-4-(4-(3-氧代-3-(4-氧代-2,4,5,6-四氢-1H-吡咯并[3,2,1-ij]喹啉-8-基)丙基)哌嗪-1-基)苯甲腈；
    8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉 -4(2H)-酮；
    8-(4-(4-(3-三氟甲基苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(4-(4-(4-氯苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(4-(4-(2,3-二甲基苯基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁酰基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮；
    8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮。
  8. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1～7任一项所述的化合物或者其药学上可接受的盐或前药，任选地进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
  9. 权利要求1～7任一项所述的化合物或者其药学上可接受的盐或前药或者权利要求8所述的药物组合物在制备用于治疗或预防神经精神类疾病药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述神经精神类疾病是精神分裂症。
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EP3372600B1 (en) 2021-09-08
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CN108368106A (zh) 2018-08-03
EP3372600A1 (en) 2018-09-12
US10517862B2 (en) 2019-12-31
CN106608875A (zh) 2017-05-03
US20180318286A1 (en) 2018-11-08
JP6786599B2 (ja) 2020-11-18
CN108368106B (zh) 2021-06-01

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