WO2021098737A1 - 稠和杂环类衍生物及其应用 - Google Patents

稠和杂环类衍生物及其应用 Download PDF

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WO2021098737A1
WO2021098737A1 PCT/CN2020/129850 CN2020129850W WO2021098737A1 WO 2021098737 A1 WO2021098737 A1 WO 2021098737A1 CN 2020129850 W CN2020129850 W CN 2020129850W WO 2021098737 A1 WO2021098737 A1 WO 2021098737A1
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independently
hydrogen
compound
halogen
general formula
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PCT/CN2020/129850
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English (en)
French (fr)
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靖鹏
郭强
窦飞
万泽红
胡志京
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上海枢境生物科技有限公司
江苏恩华药业股份有限公司
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Priority to CN202080079053.0A priority Critical patent/CN114728956B/zh
Publication of WO2021098737A1 publication Critical patent/WO2021098737A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • 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
    • 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
    • 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 specifically relates to a condensed heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the same, and use in the preparation of drugs for the prevention and/or treatment of neuropsychiatric diseases.
  • Schizophrenia is a disease characterized by a deep division of cognition and emotion, manifested as the most basic human behavior is affected, such as language, thought, perception and self-perception.
  • the symptoms of the disease include a wide range, the most common are mental disorders, such as hallucinations, delusions, and delusions.
  • schizophrenia usually causes comorbidities, such as anxiety disorders, depression, or psychotropic drug abuse.
  • antipsychotic drugs that exert pharmacological effects by blocking dopamine D2 receptors are called first-generation antipsychotic drugs, that is, "typical” antipsychotic drugs (such as haloperidol). They treat schizophrenia with positive symptoms. Breakthrough, but failed to treat negative symptoms and cognitive impairment. Typical antipsychotic drugs generally have severe EPS side effects and are ineffective in one-third of patients with schizophrenia.
  • the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory.
  • PFC prefrontal cortex
  • the pyramidal neurons and GABA interneurons of PFC contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with particularly high density. It has recently been proved that PFC and NMDA receptor channels are the targets of 5-HT1AR. These two receptors regulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various pre-clinical data indicate that 5-HT1AR may be a new target for the development of antipsychotic drugs.
  • atypical antipsychotics such as olanzapine, aripiprazole, etc.
  • 5-HT1AR atypical antipsychotics
  • EPS side effects indicate that the serotonin system plays an important role in regulating the function of the prefrontal cortex (PFC), including mood Control, cognitive behavior, and working memory.
  • PFC prefrontal cortex
  • the pyramidal neurons and GABA interneurons of PFC contain several 5-HT1A and 5-HT2A subtypes with particularly high density of serotonin receptors. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment.
  • 5-HT2A plays a very important role in it, involving various aspects of perception, emotion regulation and movement control. Blocking 5-HT2A receptors can normalize the release of dopamine and play an anti-psychotic effect. In addition, 5-HT2C receptors are closely related to weight gain.
  • the distribution of D3 receptors in the brain is mainly selectively distributed in the limbic system.
  • There are two main DA nerve pathways in the brain one is the substantia nigra striatum that regulates motor function, and the other is the ventral midbrain tegmental area.
  • the DA pathway in the prefrontal cortex of the septal nucleus is closely related to learning, cognition and emotional activities, and its abnormal function will lead to schizophrenia.
  • the DA pathway is also the main pathway of reward effects in the brain.
  • D3R is in the two DA neural pathways. They are distributed and have complex interactions with other DA receptor subtypes. They may be used as a target of antipsychotic treatment.
  • the antagonism of selective D3 receptors can reduce the negative and cognitive symptoms of schizophrenia.
  • WO201771576A1 discloses a fused heterocyclic compound for potential treatment of schizophrenia, and its structure is as follows:
  • Z is -(CH 2 ) m -which is unsubstituted or substituted with one or more hydroxyl groups, carbonyl groups and C 1-5 alkyl substituents.
  • Refractory schizophrenia refers to a type of patients who cannot obtain the desired effect after treatment according to the general method. This type of patient has been treated with three different active ingredients of antipsychotic drugs, and has a sufficient course of treatment but the treatment response is poor or unable Tolerate the adverse effects of antipsychotic drugs, or the condition recurs or worsens even if adequate maintenance or preventive treatment is given. Therefore, anti-refractory schizophrenia treatment drugs have always been a problem in current clinical drug research, and it has always been a direction that needs to be overcome. .
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
  • the hydrocarbon chain is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl groups and hydroxyl groups;
  • A is a group represented by formula A*:
  • R is selected from the group of formula (R-1), (R-2), (R-3), (R-4), (R-5), (R-6) or (R-7):
  • Q is N or CH
  • Y is O or S
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen, halogen and C 1 -C 6 alkyl, wherein the alkyl is optionally selected from halogen, Substitution of amino and hydroxyl substituents;
  • X 1 and X 2 are each independently selected from O and S;
  • n 1 is an integer selected from 1-3;
  • n 2 and n 3 are each independently an integer selected from 0-3.
  • -Z- is a C 2 -C 8 hydrocarbon chain containing oxygen or sulfur atoms or is substituted by one or A plurality of halogen-substituted C 2 -C 8 hydrocarbon chains, wherein the hydrocarbon chain is optionally substituted by one or more substituents selected from C 1 -C 5 alkyl groups and hydroxyl groups, preferably methyl, ethyl, N-propyl, isopropyl or hydroxyl;
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, and C 1 -C 5 alkyl, wherein the alkyl is optionally substituted with a substituent selected from halogen, amino and hydroxy;
  • R 4 and R 7 are each independently selected from hydrogen and halogen
  • R 5 and R 6 are each independently selected from hydrogen, halogen, and C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one or more halogens.
  • the C 1 -C 3 alkyl group is substituted with one or more halogens.
  • the present invention provides a method for preparing the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, which is characterized in that it comprises:
  • Z, A, R, Q, R 1 , R 2 , R 3 , and n 1 are as defined above;
  • R 8 and R 9 are each independently hydrogen or halogen, but are not hydrogen at the same time;
  • n 4 is any integer between 0 and 3, preferably any integer between 0 and 2;
  • n 5 is any integer between 1 and 5, preferably any integer between 1 and 4;
  • n 6 is any integer between 1-5, preferably any integer between 1-4.
  • n 4 is 1.
  • the present invention provides a pharmaceutical composition characterized by comprising a therapeutically effective amount of the compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the preparation of a medicament for treating neuropsychiatric diseases.
  • the neuropsychiatric disease is selected from depression, anxiety, sleep disorder, neurodegenerative disease, bipolar disorder, post-traumatic stress syndrome, addiction disease, withdrawal syndrome or attention deficit One or more of them, preferably one or more of depression, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder, more preferably schizophrenia.
  • one (species) or more (species) can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).
  • mn used herein refers to the range from m to n and the sub-range composed of each point value therein and each point value.
  • C 2 -C 8 "or “C 2-8” covers the range of 2-8 carbon atoms, and should be understood to also cover any sub-range and each point value, such as C 2 -C 5 , C 3 -C 4 , C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 4 -C 7 , C 4 -C 8 , C 2 -C 5, etc., and C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 and so on.
  • C 3 -C 10 or “C 3-10” should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C 3 -C 9 , C 6 -C 9 , C 6 -C 8 , C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , C 8 -C 9, etc. and C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 and so on.
  • C 1 -C 6 or “C 1-6” covers the range of 1-6 carbon atoms, and should be understood to also cover any sub-range and each point value, such as C 2 -C 5.
  • the expression "three yuan to ten yuan” should be understood as covering any sub-range and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan , Four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine Yuan to ten Yuan, etc., and three, four, five, six, seven, eight, nine, ten Yuan, etc.
  • Other similar expressions in this article should also be understood in a similar way.
  • substituted and “substituted” mean that one or more (for example, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that it does not exceed the specified amount.
  • the specified atom has the normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds. When it is described that a certain substituent does not exist, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure can make the compound reach a stable state.
  • each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group under the current situation is not exceeded, and a stable compound is formed.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • a bond of a substituent is shown as a bond connecting two atoms through a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.
  • variable such as R
  • a variable with a label such as R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, etc.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, etc. appear more than once in the composition or structure of the compound. Its definition in each case is independent at each occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted with up to four R substituents, and each The options for the R substituents are all independent of each other.
  • substituted means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is to form a stable valence state or compound.
  • non-substituted can also be understood as “unsubstituted”. It should be understood that when the substituent is hydrogen, this can also mean that the corresponding group is “unsubstituted” or “unsubstituted”.
  • halogen or halogen or “halo” should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine, bromine atoms.
  • hydrocarbon chain refers to a chain-like group composed of C and H.
  • the hydrocarbon chain may be saturated or unsaturated, and in a preferred embodiment, the hydrocarbon chain is saturated.
  • the hydrocarbon chain may be straight or branched, and in a preferred embodiment, the hydrocarbon chain is straight.
  • the hydrocarbon chain may optionally contain one or more heteroatoms such as O and S. In the case of containing heteroatoms, the heteroatoms may be located on the main chain.
  • the hydrocarbon chain may be straight or branched, and the hydrocarbon chain is saturated, the hydrocarbon chain optionally including one or more heteroatoms such as O and S in the main chain.
  • C 2 -C 8 or C 2 -C 6 refers to a hydrocarbon chain containing 2-8 or 2-6 carbon atoms, which may optionally contain additional heteroatoms.
  • the hydrocarbon chain can be represented as the corresponding alkylene group.
  • the hydrocarbon chain may be represented as, for example, an alkyl ether group or an alkoxy group, such as a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group.
  • a C 2 -C 8 hydrocarbon chain containing oxygen atoms may be an alkoxy subunit, such as "-O-alkylene", “alkylene-O-alkylene” or "alkylene-O-” .
  • examples of C 2 -C 8 hydrocarbon chains containing oxygen atoms include but are not limited to -O-ethylene, -O-propylene, -O-butylene, ethylene-O-, propylene -O-, butylene-O-, methylene-O-ethylene, -methylene-O-propylene, -methylene-O-butylene, -methylene-O-pentylene Group, ethylene-O-ethylene, ethylene-O-propylene, ethylene-O-butylene, propylene-O-ethylene, propylene-O-propylene , Propylene-O-Butylene and so on.
  • alkyl refers to a linear or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond.
  • Alkyl can have 1-8 carbon atoms, ie "C 1 -C 8 alkyl", such as C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 3 alkyl , C 4 alkyl, C 1-6 alkyl, C 3-6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or their isomers body.
  • Subunit refers to a group obtained by removing one more hydrogen atom from a carbon atom containing free valence electrons, and having two connection sites to other parts of the molecule.
  • alkylene or “alkylene” refers to a saturated linear or branched divalent hydrocarbon group.
  • alkylene when used alone or in combination with other groups herein, refers to a linear or branched saturated divalent hydrocarbon group.
  • C 1-8 alkylene refers to an alkylene group having 1-8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1- Methyl ethylene, 2-methyl ethylene, methyl propylene or ethyl propylene, etc.
  • alkoxyalkylene refers to "-O-alkylene", “alkylene-O-alkylene” or "alkylene-O-”.
  • C 1-8 alkoxy subunit examples include, but are not limited to, -O-methylene, -O-ethylene, -O-propylene, -O-butylene, methylene-O- , Ethylene-O-, propylene-O-, butylene-O-, -methylene-O-butylene, -methylene-O-pentylene, etc.
  • pharmaceutically acceptable refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the patient's tissue without undue toxicity, irritation, allergic reactions, etc., and has a reasonable ratio of advantages and disadvantages. And can be effectively used for its purpose.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • preferred compounds are those isomeric compounds that exhibit superior biological activity.
  • Purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present invention are also included in the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.
  • pharmaceutically acceptable carrier refers to those substances that have no obvious stimulating effect on organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carriers” include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
  • administration refers to methods that enable the compound or composition to be delivered to the desired biological site of action. These methods include but are not limited to oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like. Especially injection or oral administration.
  • treatment includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, and promoting Relief of disease or symptom, or cessation of symptoms of disease or symptom, and extended to include prevention.
  • Treatment also includes achieving therapeutic benefits and/or preventive benefits.
  • Therapeutic benefit refers to eradicating or improving the condition being treated.
  • the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease.
  • Prophylactic benefit means that the patient uses the composition to prevent the risk of a certain disease, or when the patient has one or more physiological conditions of the disease, even though the disease has not been diagnosed.
  • active ingredient refers to a chemical entity that can effectively treat or prevent the target disorder, disease or condition.
  • neuropsychiatric diseases refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
  • the terms "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refer to a sufficient amount of a drug or medicament that has acceptable side effects but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general conditions of the individual, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • A, Z, Q and R are each independently a different group.
  • part A is a group represented by formula A*:
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen and C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with a substituent selected from halogen, amino and hydroxy;
  • Y is O or S
  • n 1 is an integer selected from 1-3.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl, wherein the alkyl is optionally selected from halogen, amino and hydroxy. Substituents are substituted.
  • R 1 and R 2 are each independently selected from hydrogen or halogen.
  • R 3 is selected from hydrogen or C 1 -C 5 alkyl group.
  • R 3 is selected from hydrogen or an unsubstituted C 1 -C 5 alkyl group.
  • R 3 is selected from hydrogen, methyl, ethyl, propyl, butyl and pentyl groups, such as methyl.
  • n 1 is an integer of 1 or 2.
  • Y is O.
  • R 1 and R 2 are each independently selected from hydrogen and halogen
  • R 3 is selected from hydrogen and unsubstituted C 1 -C 5 alkyl
  • Y is O
  • n 1 is 1 or 2. Integer.
  • the group of formula A* is selected from the group of formula (A-1) or formula (A*-2),
  • R 1 , R 2 , R 3 and n 1 are as defined above.
  • the group of formula A is selected from any one of groups (A-1), (A-2) or (A-3):
  • R 1 , R 2 , R 3 and n 1 are as defined above.
  • Z is part comprising an oxygen or sulfur atom C 2 -C 8 hydrocarbon chain substituted with one or more halogens or substituted C 2 -C 8 hydrocarbon chain, wherein The hydrocarbon chain is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl groups and hydroxyl groups.
  • Z is an oxygen or sulfur atom, comprising of C 2 -C 8 hydrocarbon chain or substituted with one or more halogen substituted C 2 -C 8 hydrocarbon chain, said hydrocarbon chain is saturated, and the oxygen or sulfur atom located at the chain The main chain of hydrocarbons.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen or sulfur atoms, wherein the hydrocarbon chain is optionally substituted by one or more selected from the group consisting of C 1 -C 6 alkyl and hydroxyl groups. Substituents are substituted.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen atoms, wherein the hydrocarbon chain is optionally substituted with one or more selected from the group consisting of C 1 -C 6 alkyl and hydroxyl Substitution.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen atoms, wherein the hydrocarbon chain is optionally substituted by one or more selected from methyl, ethyl, propyl, butyl Substituents of hydroxy, pentyl and hydroxy.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen atoms, wherein the hydrocarbon chain is optionally substituted by one or more selected from methyl, ethyl or propyl Substituents are substituted, such as methyl.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen atoms, wherein the hydrocarbon chain is unsubstituted.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain, wherein the hydrocarbon chain is substituted with one or more halogens.
  • the Z moiety is a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group. In another preferred embodiment, Z moiety is substituted with at least one halogen, a C 2 -C 8 straight chain alkyl group.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen atoms, wherein the hydrocarbon chain is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl and propyl ,
  • substituents selected from the group consisting of methyl, ethyl and propyl ,
  • methyl or the Z moiety is a C 2 -C 6 hydrocarbon chain, wherein the hydrocarbon chain is substituted by one or more halogens.
  • the Z moiety is a C 2 -C 6 hydrocarbon chain containing oxygen atoms, wherein the hydrocarbon chain is unsubstituted; or the Z moiety is a C 2 -C 6 hydrocarbon chain, wherein the hydrocarbon chain Substituted by one or more halogens.
  • the -Z- is a C 2 -C 8 linear alkyl group substituted by 1 to 2 halogens, and the halogens may be the same or different.
  • the -Z- is a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group
  • the C 2 -C 8 linear alkyl group The alkane ether group or the C 2 -C 8 linear alkoxy group is -R 10 -OR 11 -, and the R 10 or R 11 is a C 1 -C 4 hydrocarbylene group or a single bond.
  • the -Z- is a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group
  • -Z- is the substituent (Z-1) as shown below:
  • n 4 is independently any integer between 0 and 3
  • n 5 is any integer between 1 and 5
  • the n 4 end is close to the substituent A end.
  • n 4 is independently any integer between 0 and 2
  • n 5 is any integer between 1 and 4.
  • the C 2 -C 8 linear alkoxy group (substituent Z-1) is selected from -O-(CH 2 ) 2 -, -O-(CH 2 ) 3- , Any one of -O-(CH 2 ) 4 -or -O-(CH 2 ) 5 -.
  • the C 2 -C 8 linear alkyl ether group (substituent Z-1) is selected from -CH 2 -O-CH 2 -, -CH 2 -O-(CH 2 ) 2 -, -CH 2 -O-(CH 2 ) 3 -, -CH 2 -O-(CH 2 ) 4 -or any one of -CH 2 -O-(CH 2 ) 5 -.
  • the -Z- is a C 2 -C 8 linear chain substituted by at least one halogen
  • Z is a substituent (Z-2) as shown below:
  • n 6 is any integer between 1 and 5
  • R 8 and R 9 are each independently hydrogen or halogen, but are not hydrogen at the same time, and the n 6 terminal is close to the N terminal.
  • R 8 and R 9 are each independently hydrogen or halogen, but are not hydrogen at the same time.
  • n 6 is any integer between 1-4.
  • Q is N or CH.
  • R is selected from formula (R-1), (R-2), (R-3), (R-4), (R-5), (R-6) and (R-7 ) Group:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen, halogen, and C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with a substituent selected from halogen, amino and hydroxy ;
  • X 1 and X 2 are each independently selected from O or S;
  • n 2 and n 3 are each independently an integer selected from 0-3.
  • R is selected from the group of formula (R-1), wherein R 4 is selected from hydrogen, halogen and C 1 -C 5 alkyl, wherein said alkyl is optionally selected from halogen , Amino and hydroxyl substituents are substituted.
  • R is selected from the group of formula (R-1), wherein R 4 is selected from hydrogen or halogen.
  • R is selected from the group of formula (R-1), wherein X 1 is O.
  • R is selected from the group of formula (R-2), wherein R 5 and R 6 are each independently selected from hydrogen, halogen and C 1 -C 3 alkyl, wherein the alkyl is any Optionally substituted by one or more halogens.
  • R is selected from the group of formula (R-2), wherein R 5 and R 6 are each independently selected from hydrogen, halogen and C 1 -C 3 alkyl, wherein the alkyl Substituted by one or more halogens.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, and C 1 -C 3 halomethyl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, and trifluoromethyl, such as hydrogen, halogen, or trifluoromethyl. In a more specific embodiment R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, bromo and trifluoromethyl, for example hydrogen, chloro or trifluoromethyl.
  • R is selected from the group of formula (R-2), wherein n 2 is an integer selected from 0-3. In a more preferred embodiment, the n 2 is any one of 0, 1, 2 or 3. In a particularly preferred embodiment, the n 2 is any one of 0, 1, and 2.
  • R is selected from the group of formula (R-3), wherein X 2 is selected from S.
  • R is selected from the group of formula (R-4), wherein R 7 is selected from hydrogen and halogen. In a more preferred embodiment, R 7 is selected from hydrogen, fluorine, bromine and chlorine, such as fluorine.
  • R is selected from the group of formula (R-5), wherein n 3 is an integer selected from 0-3. In a more preferred embodiment, n 3 is any one of 0, 1, 2 or 3. In a particularly preferred embodiment, n 3 is any one of 0, 1, and 2.
  • R is a group selected from (R-1), (R-2), (R-3), (R-4 and (R-5), wherein R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , n 2 and n 3 are as defined above.
  • the C 1 -C 5 alkyl group is selected from methyl, ethyl, propyl, butyl and pentyl. In a more preferred embodiment, the C 1 -C 5 alkyl group is selected from methyl, ethyl and propyl, such as methyl.
  • the propyl group includes but is not limited to n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) or isopropyl (i-Pr, -CH(CH 3 ) 2 ) ;
  • the butyl group includes but is not limited to 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 ) or tert-butyl (t-Bu, -C(CH 3 ) 3 );
  • the pentyl includes but is not limited to 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 )
  • the C 1 -C 3 alkyl group substituted by one or more halogens is -(CH 2 ) a CX 3 , wherein a is an integer selected from 0-2, and X is halogen .
  • the C 1 -C 3 alkyl group substituted by one or more halogens includes but is not limited to -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CH 2 CF 3 , -CH 2 CCl 3 , -CH 2 CBr 3 , -CH 2 CI 3 , -(CH 2 ) 2 CF 3 , -(CH 2 ) 2 CCl 3 , -(CH 2 ) 2 CBr 3 , -( CH 2 ) 2 CI 3 and so on.
  • the halogen is selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, the halogen is selected from fluorine, chlorine and bromine. For example, fluorine or chlorine.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • A is selected from group (A-1), (A-2) or (A-3)
  • R is selected from (R-1), (R-2), (R-3), (R- 4) or (R-5)
  • A, Z, Q and R are as defined above.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • -Z- is a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group
  • A is selected from the group (A-1), (A-2) or (A- 3)
  • R is a group selected from (R-1), (R-2), (R-3), (R-4) or (R-5),
  • A, Z, Q and R are as defined above .
  • -Z- is independently a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group
  • A is independently any one selected from the following substituents (A-1), (A-2) and (A-3):
  • R is independently any one selected from the following substituents (R-1), (R-2), (R-3), (R-4) or (R-5):
  • Q is independently N or CH
  • X 1 and X 2 are each independently any one of O or S;
  • R 1 and R 2 are each independently any one of hydrogen or halogen
  • R 3 is independently any one of hydrogen or C 1 -C 5 alkyl
  • R 4 is independently any one of hydrogen or halogen
  • R 5 and R 6 are each independently hydrogen, halogen, or any one of C 1 -C 3 alkyl substituted by one or more halogens;
  • R 7 is independently any one of hydrogen or halogen
  • n 1 is any integer of 1 or 2
  • n 2 is any integer between 0 and 3
  • n 3 is any integer between 0-3.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • -Z- is a C 2 -C 8 linear alkyl group substituted by at least one halogen
  • A is a group (A-1)
  • R is selected from (R-1), (R-2), (R -3), (R-4) or (R-5), A, Z, Q and R are as defined above.
  • -Z- is independently a C 2 -C 8 linear alkyl group substituted by at least one halogen
  • A is independently the substituent (A-1) shown below:
  • R is independently any one selected from the following substituents (R-1), (R-2), (R-3), (R-4) or (R-5):
  • Q is independently N or CH
  • X 1 and X 2 are each independently any one of O or S;
  • R 1 and R 2 are each independently any one of hydrogen or halogen
  • R 3 is independently any one of hydrogen or C 1 -C 5 alkyl
  • R 4 is independently any one of hydrogen or halogen
  • R 5 and R 6 are each independently hydrogen, halogen, or any one of C 1 -C 3 alkyl substituted by one or more halogens;
  • R 7 is independently any one of hydrogen or halogen
  • n 1 is any integer of 1 or 2
  • n 2 is any integer between 0 and 3
  • n 3 is any integer between 0-3.
  • Z is a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group, with the formula
  • the compound represented by (I) is represented by the compound represented by formula (II):
  • n 4 is any integer between 0 and 3
  • n 5 is any integer between 1 and 5
  • A, Q and R are as defined above.
  • n 4 is any integer between 0-2. In a more preferred embodiment, the n 4 is any one of 0, 1, 2 or 3. In a particularly preferred embodiment, the n 4 is any one of 0, 1 or 2.
  • n 5 is any integer between 1-4. In a more preferred embodiment, the n 5 is any one of 1, 2, 3, 4 or 5. In a particularly preferred embodiment, the n 5 is any one of 2, 3 or 4.
  • Z is a C 2 -C 8 linear alkyl ether group or a C 2 -C 8 linear alkoxy group
  • the compound represented by I) is represented by the compound represented by formula (II), wherein A is independently any one selected from the substituents (A-1), (A-2) or (A-3), R Independently is any one selected from substituents (R-1), (R-2), (R-3), (R-4) or (R-5), and Q is independently N or CH;
  • X 1 is independently any one of O or S;
  • X 2 is independently S;
  • R 1 is independently any one of hydrogen, chlorine or fluorine;
  • R 2 is independently any of hydrogen, fluorine or chlorine
  • R 3 is independently any one of hydrogen or methyl;
  • R 4 is independently any one of hydrogen or fluorine
  • R 5 and R 6 are each independently hydrogen, fluorine, chlorine or trifluoromethyl
  • R 7 is independently any one of hydrogen or fluorine;
  • n 1 is independently any one
  • Z is a C 2 -C 8 linear alkyl group substituted by at least one halogen, represented by formula (I)
  • the compound is represented as a compound represented by formula (III):
  • n 6 is any integer between 1 and 5
  • R 8 and R 9 are each independently any one of hydrogen or halogen, and R 8 and R 9 are not hydrogen at the same time, and A, Q and R are as described above Defined.
  • n 6 is any integer between 1-4. In a more preferred embodiment, n 6 is any one of 1, 2, 3, 4 or 5. In a particularly preferred embodiment, the n 6 is any one of 2, 3 or 4.
  • Z is a C 2 -C 8 linear alkyl group substituted by at least one halogen
  • the compound represented by formula (I) Represented as a compound represented by formula (III)
  • A is independently a substituent (A-1), and R is independently selected from substituents (R-1), (R-2), (R-3), ( R-4) or (R-5), Q is independently N or CH
  • X 1 is independently O or S
  • X 2 is independently S
  • R 1 is independently Any one of hydrogen, fluorine or chlorine
  • R 2 is independently any one of hydrogen, fluorine or chlorine
  • R 3 is independently any one of hydrogen or methyl
  • R 4 is independently hydrogen or fluorine
  • Each of R 5 and R 6 is independently any one of hydrogen, fluorine, chlorine or trifluoromethyl
  • R 7 is independently any one of hydrogen or fluorine
  • R 8 and R 9 are each independently Independently fluorine or hydrogen, but not hydrogen at the same time
  • n 1 is independently any one of 1 or
  • the compound represented by the general formula (I) is selected from the following general formula (I-1), (I-2), (I-3) or (I-4 )
  • R is independently any one selected from (R-1), (R-2), (R-3), (R-4), or (R-5).
  • Q, R, R 1 , R 2 , R 3 , R 8 , R 9 , n 1 , n 4 , n 5 and n 6 are as defined above;
  • R 8 and R 9 are each independently hydrogen or halogen, but are not hydrogen at the same time.
  • the compound represented by the general formula (I) is selected from compounds represented by the general formula (I-1), (I-2), (I-3) and (I-4) Or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from hydrogen and halogen, more preferably hydrogen, fluorine, bromine or chlorine, particularly preferably hydrogen, fluorine or chlorine, such as hydrogen; R 3 is selected from hydrogen or And a C 1 -C 5 alkyl group, wherein the alkyl group is optionally substituted by a substituent selected from halogen, amino and hydroxy, preferably hydrogen or an unsubstituted C 1 -C 5 alkyl group, more preferably hydrogen , Methyl or ethyl, such as hydrogen or methyl; R 4 and R 7 are each independently selected from hydrogen, fluorine, bromine and chlorine, more preferably hydrogen, fluorine or chlorine, such as hydrogen or fluorine; R 5 and R 6 each Independently selected from hydrogen, fluorine, chlorine, bromine and tri
  • the compound of formula (I) is selected from compounds of general formulas (I-1) and (I-2) or pharmaceutically acceptable salts thereof, wherein R is selected from (R-1 ) And (R-3), X 1 and X 2 are each independently any one of O or S, more preferably, X 1 is any one of O or S, and X 2 is S; R 1 is H; R 2 is selected from hydrogen and halogen, preferably selected from hydrogen, fluorine and chlorine, such as hydrogen; R 3 is selected from hydrogen and C 1 -C 5 alkyl, wherein the alkyl is optionally selected Substitution from halogen, amino and hydroxyl substituents, preferably hydrogen and unsubstituted C 1 -C 5 alkyl, more preferably selected from hydrogen, methyl and ethyl, such as hydrogen or methyl; R 4 is selected from hydrogen and Halogen is preferably selected from hydrogen, fluorine and chlorine, such as fluorine; n 1 is 1; n 4 is 1; n 5
  • formula (I-4) is selected from the following compounds represented by the general formulas (I-4-a) and (I-4-b) or their pharmaceutically acceptable salts:
  • Q, R, n 1 and n 5 are as defined above.
  • the present invention provides the following compound or a pharmaceutically acceptable salt thereof:
  • the present invention provides a method for preparing a compound represented by general formula (I), which comprises:
  • the compound (I) or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:
  • Q, R, R 1 , R 2 , R 3 , R 8 , R 9 , n 1 , n 4 , n 5 and n 6 are as defined above.
  • the general synthetic method of the compound of the present invention includes making the compound of general formula (Ir) and compound of general formula (Ig), compound of general formula (In), compound of general formula (In), compound of general formula (In), compound of general formula (Ir) and compound of general formula (Ig), compound of general formula (In), and Any one of compound (Il) or compound (Iq) of general formula (Iq) is reacted to obtain the compound represented by formula (I) of the present application.
  • This method links two fragments with similar molecular weights and is suitable for diverse synthesis New compound.
  • the present invention further provides a method for preparing compound (I-c) of general formula, including: any one of method (1) and method (2):
  • R 1 , R 2 , R 3 and n 1 are as defined above.
  • the compound of the general formula (Ia-1) and 3-chloropropionyl chloride are prepared by amidation reaction to obtain the compound of the general formula (Ib-1), and the compound of the general formula (Ib- 1)
  • the compound (Ic) is prepared by ring-closing the Friedel-Crafts alkylation reaction in the molecule.
  • the compound of the general formula (Ia-1) and the compound (Iv) are prepared by an amidation reaction to obtain the compound of the general formula (Ib-2), and the compound of the general formula ( Ib-2)
  • the compound (Ic) of general formula is prepared by an acid-catalyzed cyclization reaction.
  • the present invention further provides a preparation method of compound (I-f) of general formula, comprising:
  • R 1 , R 2 , R 3 and n 1 are as defined above.
  • the general synthesis method of the present invention includes the general formula compound (Ic) prepared by Friedel-Crafts acylation reaction to obtain the general formula compound (Id), and the general formula compound (Id) is prepared by the Baeyer-Villiger oxidation reaction to obtain the general formula Compound (Ie), compound (Ie) of general formula (Ie) is prepared by hydrolysis reaction to obtain compound (If) of general formula.
  • the present invention further provides a preparation method of compound (I-g) of general formula, comprising:
  • R 1 , R 2 , R 3 , n 1 and n 5 are as defined above.
  • the general synthesis method of the present invention includes the general formula compound (I-f) by selectively reacting one bromine of the monosubstituted dibromide with the general formula compound (I-s) to prepare the general formula compound (I-g).
  • the present invention further provides a method for preparing compound (I-n) of general formula, including:
  • R 1 , R 2 , R 3 , R 8 , R 9 , n 1 and n 6 are as defined above.
  • the general synthesis method of the present invention includes the general formula compound (Ic) through the Friedel-Crafts reaction and the general formula compound (Iu) to prepare the general formula compound (Im), the general formula compound (Im) through a halogenated reagent (For example, fluorinated reagent) halogenation reaction (for example, fluorination reaction) to prepare compound (In).
  • a halogenated reagent for example, fluorinated reagent
  • fluorination reaction for example, fluorination reaction
  • the present invention further provides a method for preparing compound (I-j) of general formula, including:
  • R 1 , R 2 , R 3 , n 1 and n 4 are as defined above.
  • the general synthesis method of the present invention includes the general formula compound (Ic) prepared by reaction to obtain the general formula compound (Ih), the general formula compound (Ih) is prepared by hydrolysis reaction to obtain the general formula compound (Ii), and the general formula compound (Ii)
  • the compound (Ij) of general formula is prepared by bromination reaction.
  • the present invention further provides a preparation method of compound (I-1) of general formula, comprising:
  • R 1 , R 2 , R 3 , n 1 , n 4 and n 5 are as defined above.
  • the general synthesis method of the present invention includes the compound (Ij) of the general formula (Ij) through a mono-substitution reaction with the compound (It) of the saturated linear aliphatic dihydric alcohol to prepare the compound (Ik) by the reaction,
  • the compound (Ik) of the general formula is prepared by oxidation reaction to obtain the compound (Il).
  • the present invention further provides a preparation method of compound (I-p) of general formula, comprising:
  • n 1 is as defined above.
  • the general synthesis method of the present invention includes the preparation of compound (Ia-2) of general formula (Ia-2) through amidation reaction with 3-chloropropionyl chloride to obtain compound (Io) of general formula (Io) through Friedel-Crafts alkane
  • the compound (Ip) of general formula is prepared by removing the methyl group while the ring is closed by the grouping reaction.
  • the present invention further provides a method for preparing compound (I-q) of general formula, including:
  • n 1 and n 5 are as defined above.
  • the general synthesis method of the present invention includes the general formula compound (I-p) by selectively reacting one bromine of the monosubstituted dibromide with the general formula compound (I-s) to prepare the general formula compound (I-q).
  • compositions and pharmaceutical preparations are provided.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle administered with the therapeutic agent, and it is suitable for contact with humans and/or within the scope of reasonable medical judgment Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids such as water and oil.
  • the composition may also contain small amounts of wetting agents, emulsifiers, lubricants, Stabilizer or pH buffer, etc.
  • Oral formulations may contain standard carriers.
  • Effective amount refers to a dose of a compound or a pharmaceutically acceptable salt thereof that can cause a biological or medical response in tissues, systems, animals, or humans that can be observed by researchers, veterinarians, clinicians or other clinical personnel.
  • the pharmaceutical composition of the present invention can be administered in any manner as long as it achieves the effect of preventing, alleviating, preventing or curing the symptoms of human or animal patients.
  • various suitable dosage forms can be prepared according to the route of administration, especially injections, such as freeze-dried powder for injection, injection or sterile powder for injection.
  • the pharmaceutical composition of the present invention may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, and the like.
  • the composition can be formulated to contain the daily dose or an appropriate portion of the daily dose in a dosage unit, which can be a single tablet or capsule or a liquid of a suitable volume.
  • the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation.
  • the dosage form of the medicine can also be formulated into a sustained-release dosage form.
  • an effective dose of the compound of the present invention or a pharmaceutically acceptable salt thereof can be taken orally together with, for example, an inert diluent or a certain carrier.
  • the compound of the present invention can be encapsulated in a gelatin capsule or compressed into a tablet.
  • the compound of the present invention can be used together with excipients and used in the form of tablets, lozenges, capsules, suspensions, syrups and the like.
  • the above formulation should contain at least 0.5% (w/w) of the active compound of the present invention, but it can vary according to specific dosage forms, and it is convenient to account for 4% to about 70% of the unit weight. The amount of active compound in such a pharmaceutical composition should reach an appropriate dose.
  • the active compound of the present invention can be formulated into tablets or capsules by conventional means and pharmaceutically acceptable excipients, such as binders, fillers, and lubricants. , Disintegrant or wetting agent.
  • the tablets can be coated by methods well known in the art.
  • Liquid preparations for oral administration such as solutions, syrups or suspensions, or volatilized into dry products, can be regenerated with water or other suitable carriers before use.
  • Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifiers, non-aqueous carriers and preservatives.
  • the active compound of the present invention when used for parenteral administration, can be combined with sterile water or an organic medium to form an injectable solution or suspension.
  • the active compounds of the present invention may be formulated into rectal compositions, such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.
  • the present invention provides the use of the compound of the present invention, its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for regulating 5-HT2A and/or D2 receptors, wherein the medicament Optionally, it contains another one or more active agents that regulate the mammalian nervous system or alleviate mental illness.
  • the present invention also provides a method for modulating 5-HT2A and/or D2 receptors, which comprises administering the compound of the present invention to an individual in need thereof (for example, a mammalian individual, such as a human).
  • a mammalian individual such as a human
  • Pharmaceutical salt or pharmaceutical composition of the present invention comprises administering the compound of the present invention to an individual in need thereof (for example, a mammalian individual, such as a human).
  • the regulation includes, but is not limited to, the inhibitory activity or the antagonistic activity of the modulating receptor.
  • the present invention provides the use of the compound of the present invention, its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of neuropsychiatric diseases.
  • the present invention also provides a method for treating neuropsychiatric diseases, which comprises administering the compound of the present invention, a pharmaceutically acceptable salt or the compound thereof to an individual in need thereof (for example, a mammalian individual, such as a human).
  • a mammalian individual such as a human
  • the pharmaceutical composition of the present invention comprises administering the compound of the present invention, a pharmaceutically acceptable salt or the compound thereof to an individual in need thereof (for example, a mammalian individual, such as a human).
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the treatment of neuropsychiatric diseases.
  • the neuropsychiatric disease is selected from the group consisting of schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, abstinence One or more of severe syndrome or attention deficit, preferably any one or more of depression, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder.
  • the neuropsychiatric disease is schizophrenia.
  • A is independently any one selected from the following substituents (A-1), (A-2) or (A-3):
  • R is independently any one selected from the following substituents (R-1), (R-2), (R-3), (R-4) or (R-5):
  • Q is independently N or CH; X 1 and X 2 are each independently any one of O or S; R 1 and R 2 are each independently any one of hydrogen or halogen; R 3 is independently hydrogen Or any one of C 1 -C 5 alkyl groups; R 4 is independently any one of hydrogen or halogen; R 5 and R 6 are each independently hydrogen, halogen, or substituted by one or more halogens Any one of the C 1 -C 3 alkyl groups; R 7 is independently any one of hydrogen or halogen; n 1 is any integer of 1 or 2, and n 2 is between 0 and 3. Any integer, n 3 is any integer between 0 and 3; or,
  • A is independently the substituent (A-1) shown below:
  • R is independently any one selected from the following substituents (R-1), (R-2), (R-3), (R-4) or (R-5):
  • Q is independently N or CH; X 1 and X 2 are each independently any one of O or S; R 1 and R 2 are each independently any one of hydrogen or halogen; R 3 is independently hydrogen Or any one of C 1 -C 5 alkyl groups; R 4 is independently any one of hydrogen or halogen; R 5 and R 6 are each independently hydrogen, halogen, or substituted by one or more halogens Any one of the C 1 -C 3 alkyl groups; R 7 is independently any one of hydrogen or halogen; n 1 is any one of 1 or 2, and n 2 is any between 0 and 3. An integer, n 3 is any integer between 0-3.
  • n 4 is independently any integer between 0 and 3, preferably any integer between 0 and 2; n 5 is any integer between 1 and 5, preferably any integer between 1 and 4; A, Q and R are as defined in item 1.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
  • n 6 is any integer between 1 and 5, preferably any integer between 1 and 4; R 8 and R 9 are each independently hydrogen or halogen, but are not hydrogen at the same time; A, Q and R are as defined in item 1.
  • the general formula compound (Ir) is introduced into the general formula compound (Ig), general formula compound (In), general formula compound (Il) or general formula compound (Iq) at the nitrogen end of the general formula compound (Ir) Prepared by any one of;
  • Z, A, R, Q, R 1 , R 2 , R 3 , R 8 , R 9 , n 1 , n 5 and n 6 are as defined in any one of items 1 to 3.
  • a pharmaceutical composition characterized by comprising a therapeutically effective amount of the compound represented by the general formula (I) according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, and a medically acceptable Carrier.
  • neuropsychiatric disease is selected from schizophrenia.
  • the compound provided by the present invention is an antagonist that acts on 5-HT2A receptor and/or D2 receptor, and has good affinity for 5-HT2A receptor and/or D2 receptor; and has a suitable D2/5-
  • the ratio of HT2A is not only effective for positive symptoms and traditional antipsychotics, but also has a stronger improvement effect on negative symptoms and cognitive deficit symptoms; in addition, the compound of the present invention has a higher B/P ratio, and the drug distribution has Better brain targeting is beneficial to reduce the dosage and reduce the possibility of adverse reactions.
  • the compound was prepared according to the method of Example 1, but using 1-(benzo[b]thiophen-4-yl)piperazine (commercially available) instead of 6-fluoro-3-(4-piperidinyl)-1,2-benzene And isoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 1-(2,3-dichlorophenyl)piperazine (commercially available) instead of 6-fluoro-3-(4-piperidinyl)-1,2-benziso Oxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but 3-(piperazin-1-yl)benzo[d]isothiazole (commercially available) was used instead of 6-fluoro-3-(4-piperidinyl)-1,2- Benzisoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 1,3-dibromopropane instead of 1,4-dibromobutane.
  • the compound was prepared according to the method of Example 1, but using 1,3-dibromopropane instead of 1,4-dibromobutane, and 1-(2,3-dichlorophenyl)piperazine instead of 6-fluoro-3-( 4-piperidinyl)-1,2-benzisoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 1,3-dibromopropane instead of 1,4-dibromobutane, and 1-(benzo[b]thiophen-4-yl)piperazine instead of 6-fluoro-3 -(4-piperidinyl)-1,2-benzisoxazole hydrochloride
  • the compound was prepared according to the method of Example 1, but using 1,3-dibromopropane instead of 1,4-dibromobutane, and 3-(piperazin-1-yl)benzo[d]isothiazole instead of 6-fluoro- 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, except that 4-fluoroindoline (commercially available) was used instead of indoline.
  • the compound was prepared as in Example 1, but using 6-fluoroindoline instead of indoline.
  • the compound was prepared according to the method of Example 1, but using 6-fluoroindoline (commercially available) instead of indoline, and 3-(piperazin-1-yl)benzo[d]isothiazole instead of 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 6-fluoroindoline instead of indoline, 1,3-dibromopropane instead of 1,4-dibromobutane, and 3-(piperazin-1-yl) Benzo[d]isothiazole replaces 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 6-chloroindoline (commercially available) instead of indoline and 3-(piperazin-1-yl)benzo[d]isothiazole instead of 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 6-chloroindoline (commercially available) instead of indoline, and 1,3-dibromopropane instead of 1,4-dibromobutane.
  • the compound was prepared according to the method of Example 1, but using 6-chloroindoline (commercially available) instead of indoline.
  • the compound was prepared according to the method of Example 1, but using 6-chloroindoline (commercially available) instead of indoline, 1,3-dibromopropane instead of 1,4-dibromobutane, and 3-(piperazine- 1-yl)benzo[d]isothiazole instead of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride
  • the compound was prepared according to the method of Example 1, but using 1-(3-trifluoromethylphenyl)piperazine (commercially available) instead of 6-fluoro-3-(4-piperidinyl)-1,2-benziso Oxazole hydrochloride.
  • the compound was prepared according to the method of Example 1, but using 1-piperonylpiperazine (commercially available) instead of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride
  • the target compound was prepared according to the method of Example 22, but 1,2-ethylene glycol was used instead of 1,3-propanediol.
  • the target compound was prepared according to the method of Example 24, but 1,4-dibromobutane was used instead of 1,3-dibromopropane.
  • the target compound was prepared according to the method of Example 24, but 3-(piperazin-1-yl)benzo[d]isothiazole was used instead of 6-fluoro-3-(4-piperidinyl)-1,2-benzo Isoxazole hydrochloride.
  • the target compound was prepared according to the method of Example 24, but 1,4-dibromobutane was used instead of 1,3-dibromopropane; 3-(piperazin-1-yl)benzo[d]isothiazole was used instead of 6 Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.
  • the target compound was prepared according to the method of Example 28, but 1,3-dibromopropane was used instead of 1,4-dibromobutane.
  • the target compound was prepared according to the method of Example 28, but 4-methoxyindole (commercially available) was used instead of 6-methoxyindole.
  • the target compound was prepared according to the method of Example 28, but 4-methoxyindole (commercially available) was used instead of 6-methoxyindole; 1,3-dibromopropane was used instead of 1,4-dibromobutane.
  • the target compound was prepared according to the method of Example 28, but 5-methoxytetrahydroquinoline (commercially available) was used instead of 6-methoxyindole.
  • the target compound was prepared according to the method of Example 1, but 1,2-dibromoethane was used instead of 1,4-dibromobutane.
  • the following compound ( ⁇ ) of the present invention is as follows, and is prepared by referring to the method described in Example 18 described in patent WO2017071576A1.
  • Test Example 1 Affinity test of each compound to the receptor
  • B (for preparing D 2 receptor membrane): Dopamine Binding Buffer (50 mM NaCl, 50 mM HEPES-HCl, 5 mM MgCl 2 , 0.5 mM EDTA, pH 7.4).
  • Cells such as CHO-D 2 were taken out from the refrigerator at -80°C and thawed naturally, and centrifuged at 1000g for 10 minutes at 4°C. Take the precipitate and discard the supernatant. Precipitate with solution B (50mM NaCl, 50mM HEPES-HCl, 5mM MgCl 2 , 0.5mM EDTA, pH 7.4). The cells were mixed for 20-30 seconds, and then centrifuged at 50,000g for 15min at 4°C. Carefully discard the upper layer, add solution B again, mix well, and centrifuge at 50,000g for 15min at 4°C. repeat three times. Store at -80°C.
  • solution B 50mM NaCl, 50mM HEPES-HCl, 5mM MgCl 2 , 0.5mM EDTA, pH 7.4
  • Step 1 Add 50 ⁇ L of solvent (5% DMSO) to the total binding tube (TB), add 50 ⁇ L of Methysergide to the non-specific binding tube (NB) (final concentration 1.0 ⁇ 10 -5 M), and add 50 ⁇ L to each test compound tube (CB) Test compound.
  • solvent 5% DMSO
  • NB non-specific binding tube
  • CB test compound tube
  • Step 2 Add 100 ⁇ L of buffer (homogeneous solution A) to each reaction tube.
  • the third step first make the prepared membrane homogenate A into a 20 mg/mL membrane suspension for later use.
  • Step 4 Add 50 ⁇ L of the radioligand [3 H] Ketanserin to each reaction tube, with a final concentration of 2.975 nM.
  • Step 5 Incubate each reaction tube at 25°C for 90 minutes. After the reaction is complete, the bound ligands are quickly filtered under reduced pressure.
  • the UniFilter GF/C plate is saturated with 0.5% PEI solution 1 hour in advance, and washed thoroughly with ice-cold Tris buffer. After suction filtration, put it into a constant temperature drying oven to dry for 30 minutes. Remove the filter plate and add MICROSCINTPS scintillation fluid, 40 ⁇ L/well.
  • Step 6 Put the filter plate into the liquid scintillation counter to count.
  • Step 1 Add 50 ⁇ L of solvent (5% DMSO) to the total binding tube (TB), add 50 ⁇ L of Haloperidol to the non-specific binding tube (NB) (final concentration 1.0 ⁇ 10 -5 M), and add 50 ⁇ L to each test compound tube (CB) Test compound.
  • solvent 5% DMSO
  • NB non-specific binding tube
  • CB test compound tube
  • Step 2 Add 100 ⁇ L of buffer (homogenate B) to each reaction tube.
  • the third step first prepare the prepared membrane homogenate B into a 20 mg/mL membrane suspension for later use.
  • Step 4 Add 50 ⁇ L of radioligand [3 H]Spiperone to each reaction tube, with a final concentration of 3nM.
  • Step 5 Incubate each reaction tube at 25°C for 90 minutes. After the reaction is complete, the bound ligands are quickly filtered under reduced pressure.
  • the UniFilter GF/C plate is saturated with 0.5% PEI solution 1 hour in advance, and washed thoroughly with ice-cold Tris buffer. After suction filtration, put it into a constant temperature drying oven to dry for 30 minutes. Take out the filter plate and add MICROSCINT PS scintillation fluid, 40 ⁇ L/well.
  • Step 6 Put the filter plate into the liquid scintillation counter to count.
  • Test Example 2 Spontaneous activity of each compound in mice, MK-801 high activity experiment, and plasma and brain tissue drug concentration test
  • mice After stratified by body weight, the animals were randomly divided into blank group, model group, and each compound dose group. Each group has 8 mice.
  • Administration route and method intragastric administration, 10mL/kg body weight
  • Each compound is generally set in 0.03, 0.1, 0.3, 1 mg/kg groups, and compound ( ⁇ ) is set in 0.03, 0.1, 0.3, 1, and 3 mg/kg groups.
  • mice 30min after the mouse is given the test substance (or positive drug), put the mouse into an autonomous activity box (a black polyethylene box with a size of 29cm ⁇ 29cm ⁇ 30cm) to start video recording.
  • the video recording time is 30min, and the video is finished for video analysis. , To evaluate the spontaneous activity of mice.
  • Inhibition of high activity percentage (administration group activity distance-blank group activity distance) / (model group activity distance-blank group activity distance) * 100%.
  • Percentage of inhibiting spontaneous activity of normal mice (movement distance of blank group—movement distance of administration group)/movement distance of blank group*100%.
  • mice Immediately after the induced mouse hyperactivity test, that is, about 130-150 minutes after administration, take 0.5-0.8 mL of blood from the eyeball and place it in an EDTA-2K anticoagulation tube, separate the plasma, and store it at -20°C for testing; at the same time; The whole brain of the mouse was quickly taken out and stored at -20°C for testing. Take 4 mice, and then carry out plasma and brain tissue drug determination.
  • the ED 50 of high activity induced by MK-801 of compound ( ⁇ ), compound 5, 30, 28, 31, 29, 33, 27, 10, 22 is less than 1 mg/kg, and the dose less than a normal mouse locomotor activity inhibition ED 50, suggesting the compounds of the present invention does not affect normal spontaneous activity while inhibiting MK-801-induced high activities.
  • the plasma and brain tissue drugs were measured 2 hours after the above compounds were administered, and it was found that although the compounds in Table 3 can be brain-permeable, the compounds 30, 28, 31, 29, 33 and 27 of the present invention B/P are better than compound ( ⁇ ), suggesting that the brain targeting of the compound of the present invention is better than compound ( ⁇ ), which is beneficial to reduce the influence of the drug on the peripheral nervous system, and can reduce the drug while maintaining the same efficacy. Adverse reactions.
  • mice healthy Kunming mice, half male and half male, (22 ⁇ 2) g, provided by Nanjing Qinglongshan Animal Breeding Center.
  • mice were stratified by body weight and randomly divided into a blank group, a model group, and each compound dose group.
  • DOI D-2,5-dimethoxy-4-iodoamphetamine
  • the compounds 22, 31, 29 and 5 of the present invention have obvious inhibitory effects on the DOI-induced head shaking behavior of mice, and are superior to compound ( ⁇ ).
  • mice healthy Kunming mice, half male and half male, (22 ⁇ 2) g, provided by Nanjing Qinglongshan Animal Breeding Center.
  • Apparatus Self-made rod-grabbing equipment, a stainless steel rod with a diameter of 0.3 cm and a height of 5 cm above the worktable is placed in the mouse box.
  • mice were randomly divided into blank control group, model group, and each compound dosage group. Animals are given the vehicle or test compound by gavage, and the gavage volume is 0.1mL/10g.
  • intragastric administration is 30min, 60min, and 90min, the two forepaws of the mouse are gently placed on a small stick 20cm long, 0.3cm in diameter, and 5cm higher than the worktable, and then the hind limbs of the animal are gently placed on the bottom of the box and recorded The duration of the mouse's two front paws maintaining the posture on the rod, with 30 seconds of rigidity as a positive reaction. If the front paw of the mouse has not been put down, the observation will be terminated at 60s. Count the number of positive reaction animals in each compound dose group. The results are shown in Table 5.
  • the compounds of the present invention is 5 to induce catalepsy in mice ED 50 of 5.90mg / kg, and the ED mouse catalepsy 50 / MK-801 induced a high activity (pharmacodynamics) ED 50
  • the risk of EPS induced by clinical application is low.

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Abstract

本发明属于医疗领域，具体涉及一种稠和杂环类衍生物及其应用，其具有如式(I)所示化合物结构，该类化合物可用于制备治疗神经精神类疾病的药物。

Description

稠和杂环类衍生物及其应用
本申请要求要求2019年11月18日提交的题为“一种稠合杂环类衍生物及其应用”的201911124813.0号中国申请的优先权，以及2020年6月30日提交的题为“稠合杂环类衍生物及其应用”的202010607189.6号中国申请的优先权，其内容整体援引加入本文。
技术领域
本发明属于药物化学领域，具体涉及一种稠和杂环类衍生物、其制备方法、包含其的药物组合物，以及在制备用于预防和/或治疗神经精神类疾病的药物中的用途。
技术背景
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。
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。
传统上习惯把通过阻断多巴胺D2受体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。
5-羟色胺系统在调节前额叶皮层(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的5-羟色胺受体亚型5-HT1A和5-HT2A。最近得到证明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 efects)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，寻找一个多受体结合副作用小的抗精神分裂症药物对临床治疗具有重要意义。
WO201771576A1公开了一种稠和杂环类化合物，用于精神分裂症的潜在治疗，其结构如下所示：
Figure PCTCN2020129850-appb-000001
其中，Z为未取代或被一个或多个羟基，羰基和C 1-5的烷基取代基取代的-(CH 2) m-。
尽管用于抗精神分裂症的治疗药物较多，但目前临床应用的精神分裂症药物依然存在着多种多样的不良反应，如在目前应用非常广泛的非典型抗精神分裂症药物阿立哌唑的用药患者中，有超过10％的患者会发生包括体重增加，头痛，静坐不能，失眠和胃肠道不适等不良反应，导致患者停药使病情反复。此外，虽然目前的抗精神分裂症阴性症状(指存在正常情绪反应和其他思维过程的缺陷)药物已经应用于临床，使部分患者的阴性症状得到改善，但总体而言效果有限，仍然有许多患者因阴性症状而无法痊愈和修复正常的社交功能，导致难以恢复正常的社会劳动。另外，认知障碍治疗也是目前精神分裂症治疗的一个重点，影响大多数精神分裂症患者的言语记忆、语义处理能力和注意力功能，而目前在研或上市的抗精神分裂症药物对认知功能的改善也非常有限。
目前的抗精神分裂药物除了上述问题，难治性精神分裂症的治疗依然处于困境之中。 难治性精神分裂症指按照通用方法进行治疗而不能获得理想疗效的一类患者，该类患者已经经过了三种不同活性成分的抗精神病药物治疗，足量足疗程但治疗反应不佳或者无法耐受抗精神病药物的不良反应，或者即便得到充分的维持或预防治疗依然病情反复或恶化，因此抗难治性精神分裂症治疗药物一直是当下临床药物研究的难题，也是一直亟需攻克的方向。
综上所述，具备良好且持续有效的阴性症状治疗效果，改善患者认知功能，能够有效治疗难治性精神分裂症，此外还需具备较低的药物不良反应(如椎体外系反应，体重增加，恶心呕吐等药物不良反应)，且作用于多靶点的抗精神分裂症药物仍然是中枢神经领域的热点研究方向。
发明内容
在一方面，本发明提供通式(I)所示的化合物或其可药用的盐，
Figure PCTCN2020129850-appb-000002
其中，
-Z-为包含氧或硫原子的C 2-C 8烃链或者被一个或多个卤素取代的C 2-C 8烃链，其中
所述烃链任选地被选自C 1-C 6烷基和羟基的一个或多个取代基取代；
A为式A*所示的基团：
Figure PCTCN2020129850-appb-000003
R选自式(R-1)、(R-2)、(R-3)、(R-4)、(R-5)、(R-6)或(R-7)的基团：
Figure PCTCN2020129850-appb-000004
Q为N或CH；
Y为O或S；
R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地选自氢、卤素和C 1-C 6烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代；
X 1和X 2各自独立地选自O和S；
n 1为选自1-3的整数；
n 2和n 3各自独立地为选自0-3的整数。
在一个优选的实施方案中，在本发明的式(I)所示的化合物或其可药用的盐中，-Z-为包含氧或硫原子的C 2-C 8烃链或者被一个或多个卤素取代的C 2-C 8烃链，其中所述烃链任选地被选自C 1-C 5的烷基和羟基的一个或多个取代基取代，优选甲基、乙基、正丙基、异丙基或羟基；
R 1、R 2和R 3各自独立地选自氢、卤素、C 1-C 5的烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代；
R 4和R 7各自独立地选自氢和卤素；
R 5和R 6各自独立地选自氢、卤素和C 1-C 3烷基，其中所述烷基任选地被一个或多个卤素取代。优选地，C 1-C 3烷基被一个或多个卤素取代。
在另一方面，本发明提供一种制备本发明的通式(I)所示的化合物或其可药用的盐的方法，其特征在于，包括：
Figure PCTCN2020129850-appb-000005
通过亲核取代反应或还原胺化反应，使通式化合物(I-r)与通式化合物(I-g)、通式化合物(I-n)、通式化合物(I-l)或通式化合物(I-q)中的任意一种反应制备得到式(I)所示的化合物；
其中，Z、A、R、Q、R 1、R 2、R 3、和n 1如上述所定义；
R 8和R 9各自独立地为氢或卤素中的任意一种，但不同时为氢；
n 4为0～3之间的任意一个整数，优选0～2之间的任意一个整数；
n 5为1～5之间的任意一个整数，优选1～4之间的任意一个整数；
n 6为1～5之间的任意一个整数，优选1～4之间的任意一个整数。
在一个优选的实施方案中，在制备本发明的通式(I)所示的化合物或其可药用的盐的方法中，n 4为1。
在又一方面，本发明提供一种药物组合物，其特征在于，包含治疗有效量的本发明的通式(I)所示的化合物或其可药用的盐和药学上可接受的载体。
在还一方面，本发明提供本发明的通式(I)所示的化合物或其可药用的盐或药物组合物在制备治疗神经精神类疾病的药物中的用途。
特定地，所述神经精神类疾病选自抑郁症、焦虑症、睡眠障碍、神经退行性疾病、 双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选抑郁症、焦虑症、精神分裂症、睡眠障碍、神经退行性疾病或双相情感障碍中的一种或多种，更优选为精神分裂症。
具体实施方式
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。
一般术语和定义
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C 2-C 8”或“C 2-8”涵盖2-8个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C 2-C 5、C 3-C 4、C 2-C 6、C 3-C 6、C 4-C 6、C 4-C 7、C 4-C 8、C 2-C 5等，以及C 2、C 3、C 4、C 5、C 6、C 7、C 8等。例如，表述“C 3-C 10”或“C 3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C 3-C 9、C 6-C 9、C 6-C 8、C 6-C 7、C 7-C 10、C 7-C 9、C 7-C 8、C 8-C 9等以及C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10等。又例如，表述“C 1-C 6”或“C 1-6”涵盖1-6个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C 2-C 5、C 3-C 4、C 1-C 2、C 1-C 3、C 1-C 4、C 1-C 5、C 1-C 6等，以及C 1、C 2、C 3、C 4、C 5、C 6等。又例如，表述“三元至十元”应理解为涵盖其中的任意亚范围以及每个点值，例如三元至五元、三元至六元、三元至七元、三元至八元、四元至五元、四元至六元、四元至七元、四元至八元、五元至七元、五元至八元、六元至七元、六元至八元、九元至十元，等，以及三、四、五、六、七、八、九、十元，等。本文中其他类似的表述也应当以类似的方式理解。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。
当描述基团中的每个碳原子可以任选地被杂原子代替时，条件是未超过基团中的所有原子在当前情况下的正常原子价，并且形成稳定的化合物。
如果取代基被描述为“任选地…被取代”，则取代基可以是未被取代的，或者可以是被取代的。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被替代。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
当任何变量(例如R)，以及带有标记的变量(例如R 1、R 2、R 3、R 4、R 5、R 6、R 7等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独立的。例如，如果一个基团被0、1、2、3或4个R取代基所取代，则所述基团可以任选地至多被四个R取代基所取代，并且每种情况下的每个R取代基的选项都是相互独立的。
术语“取代”表示化合物或基团上的一个或多个氢原子被其他原子或基团代替。条件是形成稳定的价态或化合物。表述“非取代”又可以理解为“未被取代”的。应当理解，取代基为氢时，这也可以表示对应的基团为“非取代”或者“未被取代”的。
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯、溴原子。
本文所用的术语“烃链”指由C和H构成的链状基团。烃链可以是饱和或者不饱和，并且在优选的实施方案中，烃链为饱和的。烃链可以是直链或支化的，并且在优选的实施方案中，烃链是直链的。烃链可以任选地包含一个或多个诸如O和S的杂原子。在包含杂原子的情况下，杂原子可以位于主链上。在优选的实施方案中，烃链可以是直链或支化的，并且烃链是饱和的，所述烃链在主链上任选地包含一个或多个诸如O和S的杂原子。当描述烃链时，无论是否包含杂原子，可以用C原子数进行描述，而不计入杂原子数目。例如，C 2-C 8或C 2-C 6指的烃链包含2-8或2-6个碳原子的烃链，其可以任选地包含额外的杂原子。在不包含杂原子的情况下，烃链可以表示为相应的亚烷基。在包含杂原子的情况下，烃链可以表示为例如，烷醚基或烷氧基，如C 2-C 8的直链烷醚基或C 2-C 8的直链烷 氧基。例如包含氧原子的C 2-C 8烃链可以是烷氧基亚基，例如“-O-亚烷基”、“亚烷基-O-亚烷基”或“亚烷基-O-”。具体地，含氧原子的C 2-C 8烃链的实例包括但不限于-O-亚乙基、-O-亚丙基、-O-亚丁基、亚乙基-O-、亚丙基-O-、亚丁基-O-、亚甲基-O-亚乙基、-亚甲基-O-亚丙基、-亚甲基-O-亚丁基、-亚甲基-O-亚戊基、亚乙基-O-亚乙基、亚乙基-O-亚丙基、亚乙基-O-亚丁基、亚丙基-O-亚乙基、亚丙基-O-亚丙基、亚丙基-O-亚丁基等。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。“烷基”可以具有1-8个碳原子，即“C 1-C 8烷基”，例如C 1-4烷基、C 1-3烷基、C 1-2烷基、C 3烷基、C 4烷基、C 1-6烷基、C 3-6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基，或者它们的异构体。
“亚基”是指在含有自由价电子的碳原子上再去掉一个氢原子而得到的，具有两个与分子其他部分连接的连接位点的基团。例如“亚烷基”或“烷基亚基”指饱和的直链或支链的二价烃基。
术语“亚烷基”，在本文中单独或与其他基团组合使用时，指直链或支链的饱和的二价烃基。例如，术语“C 1-8亚烷基”指具有1-8个碳原子的亚烷基，例如亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基、1-甲基亚乙基、2-甲基亚乙基、甲基亚丙基或乙基亚丙基等。术语“烷氧基亚基”是指“-O-亚烷基”，“亚烷基-O-亚烷基”或“亚烷基-O-”。“C 1-8烷氧基亚基”的实例包括但不限于-O-亚甲基、-O-亚乙基、-O-亚丙基、-O-亚丁基、亚甲基-O-、亚乙基-O-、亚丙基-O-、亚丁基-O-、-亚甲基-O-亚丁基、-亚甲基-O-亚戊基，等。
术语“药学上可接受”的物质指这样的物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些物质。“药学上可接受的载体”包括但不限于助流剂、增甜 剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服或肠胃外(包括脑室内、静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。特别是注射或口服。
如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标紊乱、疾病或病症。
术语“神经精神类疾病”是指神经类疾病与精神类疾病的总称，包含神经类疾病和/或精神类疾病。
针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量”是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
在本文中，“Z”和“-Z-”均表示为同一特定的基团，其可以互换使用。
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。
式(I)化合物
在一方面，本发明提供式(I)所示的化合物或其可药用的盐，
Figure PCTCN2020129850-appb-000006
其中，A、Z、Q和R各自独立地为不同的基团。
A部分
在式(I)所示的化合物的一实施方案中，A部分为式A*所示的基团：
Figure PCTCN2020129850-appb-000007
其中，R 1、R 2和R 3各自独立地选自氢、卤素和C 1-C 6烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代；
Y为O或S；
n 1为选自1-3的整数。
在一个优选的实施方案中，R 1、R 2和R 3各自独立地选自氢、卤素和C 1-C 5烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代。在一个更优选的实施方案中，R 1和R 2各自独立地选自氢或卤素。在另一个进一步的实施方案中，R 3选自氢或C 1-C 5的烷基。在更优选的实施方案中，R 3选自氢或非取代的C 1-C 5的烷基。在一个特别优选的实施方案中，R 3选自氢、甲基、乙基、丙基、丁基和戊基，例如甲基。
在一个优选的实施方案中，n 1为1或2的整数。
在一个优选的实施方案中，Y为O。
在一具体的实施方案中，R 1和R 2各自独立地选自氢和卤素，R 3选自氢和非取代的C 1-C 5烷基，Y为O，n 1为1或2的整数。
式A*的基团
在一个优选的实施方案中，式A*的基团选自式(A-1)或式(A*-2)的基团，
Figure PCTCN2020129850-appb-000008
其中，R 1、R 2、R 3和n 1如上文所定义。
在一个更优选的实施方案中，式A的基团选自基团(A-1)、(A-2)或(A-3)中的任意一种：
Figure PCTCN2020129850-appb-000009
其中，R 1、R 2、R 3和n 1如上文所定义。
Z部分
在式(I)所示的化合物的一实施方案中，Z部分为包含氧或硫原子的C 2-C 8烃链或者被一个或多个卤素取代的C 2-C 8烃链，其中所述烃链任选地被选自C 1-C 6烷基和羟基的一个或多个取代基取代。Z为包含氧或硫原子的C 2-C 8烃链或者被一个或多个卤素取代的C 2-C 8烃链时，所述链烃为饱和的，并且所述氧或硫原子位于链烃的主链。
在一个优选的实施方案中，Z部分为含氧或硫原子的C 2-C 6烃链，其中所述烃链任选地被一个或多个选自C 1-C 6烷基和羟基的取代基取代。在一个更优选的实施方案中，Z部分为含氧原子的C 2-C 6烃链，其中所述烃链任选地被一个或多个选自C 1-C 6烷基和羟基的取代基取代。在又一个更优选的实施方案中，Z部分为含氧原子的C 2-C 6烃链，其中所述烃链任选地被一个或多个选自甲基、乙基、丙基、丁基、戊基和羟基的取代基取代。在另一个特别优选的实施方案中，Z部分为含氧原子的C 2-C 6烃链，其中所述烃链任选地被一个或多个选自甲基、乙基或和丙基的取代基取代，例如甲基。在另外一个特别优选的实施方案中，Z部分为含氧原子的C 2-C 6烃链，其中所述烃链为非取代的。
在另一个优选的实施方案中，Z部分为C 2-C 6烃链，其中所述烃链被一个或多个卤素取代。
在一个优选的实施方案中，Z部分为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基。在另一个优选的实施方案中，Z部分为至少被一个卤素取代的C 2-C 8的直链烷基。
在一个具体的实施方案中，Z部分为含氧原子的C 2-C 6烃链，其中所述烃链任选地被一个或多个选自甲基、乙基和丙基的取代基取代，例如甲基，或者Z部分为C 2-C 6烃链，其中所述烃链被一个或多个卤素取代。
在一个具体的实施方案中，Z部分为含氧原子的C 2-C 6烃链，其中所述烃链为非取代的；或者Z部分为C 2-C 6烃链，其中所述烃链被一个或多个卤素取代。
在一个优选的实施方案中，所述-Z-为被1～2个卤素取代的C 2-C 8的直链烷基，卤素可以相同，也可以不相同。
在另一个优选的实施方案中，当所述-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基时，所述C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基为-R 10-O-R 11-，所述R 10或R 11为C 1-C 4 的亚烃基或为单键。
在一个更优选的实施方案中，在如通式(I)所示的化合物中，所述-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基时，-Z-为如下所示取代基(Z-1)：
Figure PCTCN2020129850-appb-000010
n 4独立地为0～3之间的任意一个整数，n 5为1～5之间的任意一个整数，n 4端靠近取代基A端。在一个优选的实施方案中，n 4独立地为0～2之间的任意一个整数，n 5为1～4之间的任意一个整数。
在一个具体的实施例方案中，所述C 2-C 8的直链烷氧基(取代基Z-1)选自-O-(CH 2) 2-，-O-(CH 2) 3-，-O-(CH 2) 4-或-O-(CH 2) 5-中的任意一种。在另一个具体的实施方案中，所述C 2-C 8的直链烷醚基(取代基Z-1)为选自-CH 2-O-CH 2-，-CH 2-O-(CH 2) 2-，-CH 2-O-(CH 2) 3-，-CH 2-O-(CH 2) 4-或-CH 2-O-(CH 2) 5-中的任意一种。
在另一个优选的实施例方案中，在如通式(I)所示的化合物或其可药用盐的中，所述-Z-为至少被一个卤素取代的C 2-C 8的直链烷基时，Z为如下所示取代基(Z-2)：
Figure PCTCN2020129850-appb-000011
n 6为1～5之间的任意一个整数，R 8和R 9各自独立地为氢或卤素中的任意一种，但不同时为氢，n 6端靠近N端。在一个优选的实施方案中，R 8和R 9各自独立地为氢或卤素中的任意一种，但不同时为氢。在另一个更优选的实施方案中，n 6为1～4之间的任意一个整数。
Q部分
在一个实施方案中，Q为N或CH。
R部分
在一个实施方案中，R选自式(R-1)、(R-2)、(R-3)、(R-4)、(R-5)、(R-6)和(R-7)的基团：
Figure PCTCN2020129850-appb-000012
Figure PCTCN2020129850-appb-000013
其中，R 4、R 5、R 6和R 7各自独立地选自氢、卤素和C 1-C 6烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代；
X 1和X 2各自独立地选自O或S；
n 2和n 3各自独立地为选自0-3的整数。
在一个优选的实施方案中，R选自式(R-1)的基团，其中R 4选自氢、卤素和C 1-C 5烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代。在一个更优选的实施方案中，R选自式(R-1)的基团，其中R 4选自氢或卤素。
在一个优选的实施方案中，R选自式(R-1)的基团，其中X 1为O。
在一个优选的实施方案中，R选自式(R-2)的基团，其中R 5和R 6各自独立地选自氢、卤素和C 1-C 3烷基，其中所述烷基任选地被一个或多个卤素取代。在一个更优选的实施方案中，R选自式(R-2)的基团，其中R 5和R 6各自独立地选自氢、卤素和C 1-C 3烷基，其中所述烷基被一个或多个卤素取代。在一个特别选的实施方案中，R 5和R 6各自独立地选自氢、卤素和C 1-C 3卤代甲基。在一个具体的实施方案中，R 5和R 6各自独立地选自氢、卤素和三氟甲基，例如氢、卤素或三氟甲基。在一个更具体的实施方案中R 5和R 6各自独立地选自氢、氟、氯、溴和三氟甲基，例如氢、氯或三氟甲基。
在一个优选的实施方案中，R选自式(R-2)的基团，其中n 2为选自0-3的整数。在一个更优选的实施方案中，所述n 2为0，1，2或3中的任意一个。在一个特别优选的实施方案中，所述n 2为0，1，2中的任意一个。
在一个优选的实施方案中，R选自式(R-3)的基团，其中X 2选自S。
在一个优选的实施方案中，R选自式(R-4)的基团，其中R 7选自氢和卤素。在一个更优选的实施方案中，R 7选自氢、氟、溴和氯，例如氟。
在一个优选的实施方案中，R选自式(R-5)的基团，其中n 3为选自0-3的整数。在一个更优选的实施方案中，n 3为0，1，2或3中的任意一个。在一个特别优选的实施方案中，n 3为0，1，2中的任意一个。
在一个优选的实施方案中，R为选自(R-1)、(R-2)、(R-3)、(R-4和(R-5)的基团，其中R 4、R 5、R 6、R 7、X 1、X 2、n 2和n 3如上文所定义。
在一个优选的实施方案中，所述C 1-C 5的烷基选自甲基、乙基、丙基、丁基和戊基。在一个更优选的实施方案中，所述C 1-C 5的烷基选自甲基、乙基和丙基，例如甲基。
在一个具体的实施例方案中，所述丙基包括但不限于正丙基(n-Pr、-CH 2CH 2CH 3)或异丙基(i-Pr、-CH(CH 3) 2)；所述丁基包括但不限于正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)或叔丁基(t-Bu、-C(CH 3) 3)；所述戊基包括但不限于正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)， 3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)或2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)。
在一个优选的实施方案中，所述被一个或多个卤素取代的C 1-C 3的烷基为-(CH 2) aCX 3，其中a为选自0～2的整数，X为卤素。
在一个具体的实施例方案中，所述被一个或多个卤素取代的C 1-C 3的烷基包括但不限于-CF 3，-CCl 3，-CBr 3，-CI 3，-CH 2CF 3，-CH 2CCl 3，-CH 2CBr 3，-CH 2CI 3，-(CH 2) 2CF 3，-(CH 2) 2CCl 3，-(CH 2) 2CBr 3，-(CH 2) 2CI 3等。
在一个优选的实施方案中，所述卤素选自氟、氯、溴和碘。在一个更优选的实施方案，所述卤素选自氟、氯和溴。例如氟或氯。
在一个优选的实施方案中，在一具体的实施方案中，本发明提供式(I)所示的化合物或其可药用的盐，
Figure PCTCN2020129850-appb-000014
其中，-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，或至少被一个卤素取代的C 2-C 8的直链烷基中的任意一种，A选自基团(A-1)、(A-2)或(A-3)，R选自(R-1)、(R-2)、(R-3)、(R-4)或(R-5)的基团，A、Z、Q和R如上文所定义。
在一具体的实施方案中，本发明提供式(I)所示的化合物或其可药用的盐，
Figure PCTCN2020129850-appb-000015
其中，-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，A选自基团(A-1)、(A-2)或(A-3)，R选自(R-1)、(R-2)、(R-3)、(R-4)或(R-5)的基团，A、Z、Q和R如上文所定义。
具体地，-Z-独立地为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，
A独立地为选自如下所示取代基(A-1)、(A-2)和(A-3)中的任意一种：
Figure PCTCN2020129850-appb-000016
R独立地为选自如下所示取代基(R-1)，(R-2)，(R-3)，(R-4)或(R-5)中的任意一种：
Figure PCTCN2020129850-appb-000017
Q独立地为N或CH；
X 1和X 2各自独立地为O或S中的任意一种；
R 1和R 2各自独立地为氢或卤素中的任意一种；
R 3独立地为氢或C 1-C 5的烷基中的任意一种；
R 4独立地为氢或卤素中的任意一种；
R 5和R 6各自独立地为氢，卤素，或被一个或多个卤素取代的C 1-C 3的烷基中的任意一种；
R 7独立地为氢或卤素中的任意一种；
n 1为1或2中的任意一个整数，
n 2为0～3之间的任意一个整数，
n 3为0～3之间的任意一个整数。
在另一具体的实施方案中，本发明提供式(I)所示的化合物或其可药用的盐，
Figure PCTCN2020129850-appb-000018
其中，-Z-为至少被一个卤素取代的C 2-C 8的直链烷基，A为基团(A-1)，R选自(R-1)、(R-2)、(R-3)、(R-4)或(R-5)的基团，A、Z、Q和R如上文所定义。
具体地，-Z-独立地为至少被一个卤素取代的C 2-C 8的直链烷基，
A独立地为如下所示取代基(A-1)：
Figure PCTCN2020129850-appb-000019
R独立地为选自如下所示取代基(R-1)，(R-2)，(R-3)，(R-4)或(R-5)中的任意一种：
Figure PCTCN2020129850-appb-000020
Q独立地为N或CH；
X 1和X 2各自独立地为O或S中的任意一种；
R 1和R 2各自独立地为氢或卤素中的任意一种；
R 3独立地为氢或C 1-C 5的烷基中的任意一种；
R 4独立地为氢或卤素中的任意一种；
R 5和R 6各自独立地为氢，卤素，或被一个或多个卤素取代的C 1-C 3的烷基中的任意一种；
R 7独立地为氢或卤素中的任意一种；
n 1为1或2中的任意一个整数，
n 2为0～3之间的任意一个整数，
n 3为0～3之间的任意一个整数。
在一个更优选的实施方案中，在本发明的式(I)所示的化合物中，Z为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，式(I)所示的化合物表示为式(II)所示的化合物：
Figure PCTCN2020129850-appb-000021
其中n 4为0～3之间的任意一个整数，n 5为1～5之间的任意一个整数，A、Q和R如上述所定义。
在一个优选的实施方案中，在式(II)所示的化合物中，n 4为0～2之间的任意一个整数。在一个更优选的实施方案中，所述n 4为0，1，2或3中的任意一个。在一个特别优选的实施方案中，所述n 4为0，1或2中的任意一个。
在另一个优选的实施方案中，在式(II)所示的化合物中，n 5为1～4之间的任意一个整数。在一个更优选的实施方案中，所述n 5为1，2，3，4或5中的任意一个。在一个特别优选的实施方案中，所述n 5为2，3或4中的任意一个。
在一个具体的实施方案中，在本发明的式(I)所示的化合物中，Z为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，式(I)所示的化合物表示为式(II)所示的化合物，其中A独立地为选自取代基(A-1)，(A-2)或(A-3)中的任意一种，R独立地为选自取代基(R-1)，(R-2)，(R-3)，(R-4)或(R-5)中的任意一种，Q独立地为N或CH；X 1独立地为O或S中的任意一种；X 2独立地为S；R 1独立地为氢，氯或氟中的任意一种；R 2独立地为氢，氟或氯中的任意一种；R 3独立地为氢或甲基中的任意一种；R 4独立地为氢或氟中的任意一种R 5和R 6各自独立地为氢，氟，氯或三氟甲基中的任意一种；R 7独立地为氢或氟中的任意一种；n 1独立地为1或2中的任意一个；n 2独立地为0或1中的任意一个；n 3独立地为0或1中的任意一个；n 4独立地为0或1中的任意一个；n 5独立地为2，3或4中的任意一个。
在另一个更优选的实施方案中，在本发明的式(I)所示的化合物中，Z为至少被一个卤素取代的C 2-C 8的直链烷基，式(I)所示的化合物表示为式(III)所示的化合物：
Figure PCTCN2020129850-appb-000022
其中n 6为1～5之间的任意一个整数，R 8和R 9各自独立地为氢或卤素中的任意一种，且R 8和R 9不同时为氢，A、Q和R如上述所定义。
在一个优选的实施方案中，在式(III)所示的化合物中，n 6为1～4之间的任意一个整数。在一个更优选的实施方案中，述n 6为1，2，3，4或5中的任意一个。在一个特别优选的实施方案中，所述n 6为2，3或4中的任意一个。
在另一个具体的实施方案中，在本发明的式(I)所示的化合物中，Z为至少被一个卤素取代的C 2-C 8的直链烷基，式(I)所示的化合物表示为式(III)所示的化合物，A独立地为取代基(A-1)，R独立地为选自取代基(R-1)，(R-2)，(R-3)，(R-4)或(R-5)中的任意一种，Q独立地为N或CH；X 1独立地为O或S中的任意一种；X 2独立地为S；R 1独立地为氢，氟或氯中的任意一种；R 2独立地为氢，氟或氯中的任意一种；R 3独立地为氢或甲基中的任意一种；R 4独立地为氢或氟中的任意一种R 5和R 6各自独立地为氢，氟，氯或三氟甲基中的任意一种；R 7独立地为氢或氟中的任意一种；R 8和R 9各自独立地为氟或氢，但不同时为氢；n 1独立地为1或2中的任意一个；n 2独立地为0或1中的任意一个；n 3独立地为0或1中的任意一个；n 6独立地为2，3或4中的任意一个。
在一个更具体的实施例方案中，所述通式(I)所示的化合物选自如下所示通式(I-1)、(I-2)、(I-3)或(I-4)所示的化合物或其可药用盐：
Figure PCTCN2020129850-appb-000023
其中：
R独立地为选自(R-1)、(R-2)、(R-3)、(R-4)或(R-5)中的任意一种。其中Q、R、R 1、R 2、R 3、R 8、R 9、n 1、n 4、n 5和n 6如上述所定义；
R 8和R 9各自独立地为氢或卤素中的任意一种，但不同时为氢。
在一个优选的实施方案中，所述通式(I)所示的化合物选自通式(I-1)、(I-2)、(I-3)和 (I-4)所示的化合物或其可药用盐，其中，R 1和R 2各自独立地选自氢和卤素，更优选氢、氟、溴或氯，特别优选氢、氟或氯，例如氢；R 3选自氢或和C 1-C 5的烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代，优选氢或和非取代的C 1-C 5的烷基，更优选氢、甲基或乙基，例如氢或甲基；R 4和R 7各自独立地选自氢、氟、溴和氯，更优选氢、氟或氯，例如氢或氟；R 5和R 6各自独立地选自氢、氟、氯、溴和三氟甲基，更优选氢、氟、氯和三氟甲基，例如氢、氯或三氟甲基；R 8和R 9各自独立地选自氢、氟、溴和氯，更优选氢、氟或氯，例如氟，其中R 8和R 9不同时为氢。n 1为1或2的整数；n 4为1或2的整数；n 5和n 6各自独立地为1～4之间的任意一个整数。
在一个更优选的实施方案中，所述式(I)化合物选自通式(I-1)和(I-2)的化合物或其可药用的盐，其中，R选自(R-1)和(R-3)的基团，X 1和X 2各自独立地为O或S中的任意一种，更优选地，X 1为O或S中的任意一种，X 2为S；R 1为H；R 2选自氢和卤素，优选选自氢、氟和氯，例如氢；R 3选自氢和C 1-C 5的烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代，优选氢和非取代的C 1-C 5的烷基，更优选选自氢、甲基和乙基，例如氢或甲基；R 4选自氢和卤素，优选选自氢、氟和氯，例如氟；n 1为1；n 4为1；n 5为1～4之间的任意一个整数。
在另一个优选的实施方案中，所述式(I-4)选自如下所示通式(I-4-a)和(I-4-b)所示的化合物或其可药用盐：
Figure PCTCN2020129850-appb-000024
其中，Q、R、n 1和n 5如上述所定义。
在一具体的实施方案中，本发明提供如下所示的化合物或其可药用的盐：
Figure PCTCN2020129850-appb-000025
Figure PCTCN2020129850-appb-000026
Figure PCTCN2020129850-appb-000027
Figure PCTCN2020129850-appb-000028
Figure PCTCN2020129850-appb-000029
Figure PCTCN2020129850-appb-000030
Figure PCTCN2020129850-appb-000031
Figure PCTCN2020129850-appb-000032
制备式(I)化合物的方法
在另一方面，本发明提供制备通式(I)所示的化合物的方法，其包括：
Figure PCTCN2020129850-appb-000033
其中：
具体地，化合物(I)或其可药用的盐选自如下所示化合物或其可药用盐的任意一种：
Figure PCTCN2020129850-appb-000034
其中，Q、R、R 1、R 2、R 3、R 8、R 9、n 1、n 4、n 5和n 6如上述所定义。
在一个实施方案中，本发明的化合物的通用合成方法包括通过亲核取代反应或还原 胺化反应，使通式化合物(I-r)与通式化合物(I-g)、通式化合物(I-n)、通式化合物(I-l)或通式化合物(I-q)中的任意一种反应，以获得本申请的式(I)所示的化合物，该方法把两个分子量相近的片段链接起来，适用于多样性的合成新的化合物。
式(I-g)化合物的制备
式(I-c)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-c)的制备方法，包括：方法(1)和方法(2)中的任意一种：
Figure PCTCN2020129850-appb-000035
其中：R 1、R 2、R 3和n 1如上述所定义。
在一个实施例方案中，在方法(1)中，包括通式化合物(I-a-1)与3-氯丙酰氯通过酰胺化反应制备得到通式化合物(I-b-1)，通式化合物(I-b-1)通过分子内的Friedel-Crafts烷基化反应关环制备得到通式化合物(I-c)。
在另一个实施例方案中，在方法(2)中，包括通式化合物(I-a-1)与通式化合物(I-v)通过酰胺化反应制备得到通式化合物(I-b-2)，通式化合物(I-b-2)通过酸催化的环化反应制备得到通式化合物(I-c)。
式(I-f)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-f)的制备方法，包括：
Figure PCTCN2020129850-appb-000036
其中，R 1、R 2、R 3和n 1如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-c)通过Friedel-Crafts酰基化反应制备得到通式化合物(I-d)，通式化合物(I-d)通过Baeyer-Villiger氧化反应制备得到 通式化合物(I-e)，通式化合物(I-e)通过水解反应制备得到通式化合物(I-f)。
式(I-g)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-g)的制备方法，包括：
Figure PCTCN2020129850-appb-000037
R 1、R 2、R 3、n 1和n 5如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-f)通过选择性的单取代二溴代物的一个溴与通式化合物(I-s)反应制备得到通式化合物(I-g)。
式(I-n)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-n)的制备方法，包括：
Figure PCTCN2020129850-appb-000038
其中，R 1、R 2、R 3、R 8、R 9、n 1和n 6如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-c)通过Friedel-Crafts反应与通式化合物(I-u)反应制备得到通式化合物(I-m)，通式化合物(I-m)通过卤代试剂(如氟代试剂)的卤化反应(例如氟化反应)制备得到化合物(I-n)。
式(I-l)化合物的制备
式(I-j)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-j)的制备方法，包括：
Figure PCTCN2020129850-appb-000039
其中，R 1、R 2、R 3、n 1和n 4如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-c)通过反应制备得到通式化合物(I-h)，通式化合物(I-h)通过水解反应制备得到通式化合物(I-i)，通式化合物(I-i)通 过溴代反应制备得到通式化合物(I-j)。
式(I-l)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-l)的制备方法，包括：
Figure PCTCN2020129850-appb-000040
其中，R 1、R 2、R 3、n 1、n 4和n 5如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-j)通过与通式化合物(I-t)发生对饱和直链脂肪二原醇的单取代反应，反应制备得到通式化合物(I-k)，通式化合物(I-k)通过氧化反应制备得到化合物(I-l)。
式(I-q)化合物的制备
式(I-p)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-p)的制备方法，包括：
Figure PCTCN2020129850-appb-000041
其中，n 1如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-a-2)通过酰胺化反应与3-氯丙酰氯制备得到通式化合物(I-o)，通式化合物(I-o)通过Friedel-Crafts烷基化反应关环的同时，脱去甲基制备得到通式化合物(I-p)。
式(I-q)化合物的制备
在一个实施方案中，本发明进一步提供通式化合物(I-q)的制备方法，包括：
Figure PCTCN2020129850-appb-000042
其中，n 1和n 5如上述所定义。
在上述方法中，本发明的通用合成方法包括通式化合物(I-p)通过选择性的单取代二溴代物的一个溴与通式化合物(I-s)反应制备得到通式化合物(I-q)。
药物组合物和药物制剂
本发明的另一目的在于提供一种药物组合物，其包含治疗有效量的本发明的化合物、其可药用的盐，以及一种或多种药学上可接受的载体。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，所述组合物还可以视需要包含少量的湿润剂、乳化剂、润滑剂、稳定剂或pH缓冲剂等。口服制剂可以包含标准载体。
“有效量”是指化合物或其药学上可接受的盐能够引起组织、系统、动物或人类出现可被研究人员、兽医、临床医生或其他临床人员观察到的生物学或医学反应的剂量。
本发明的药物组合物可以以任意方式施用，只要其实现预防、减轻、防止或者治愈人类或动物患者症状的效果。例如，可根据给药途径制成各种适宜的剂型，尤其是注射剂，例如冻干粉针剂、注射液或注射用无菌粉末。
本发明的药物组合物可以是片剂、咀嚼片、胶囊、溶液、肠胃外溶液、锭剂、栓剂和混悬剂等的形式。组合物可以经配制成在剂量单位中含有每日剂量或每日剂量的适宜部分，所述剂量单位可以是单一片剂或胶囊或适宜体积的液体。
在一个实施方案中，药物组合物可以利用一种或多种可药用的载体按照常规的方式加以配制。因此，本发明的活性化合物可以被配制成口服、口腔含化给药、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠给药的剂型，或者适用于通过吸入或吹入给药的剂型。本发明的化合物或其可药用的盐也可以被配制成持续释放的剂型。
在一个实施方案中，有效剂量的本发明的化合物或其可药用的盐可与如惰性稀释剂或某种载体一起口服。根据本发明的一些实施例，可将本发明的化合物包裹于明胶胶囊中或压制成片。为口服治疗的目的，本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。根据本发明的实施例，上述制剂应含有至少0.5％(w/w)的本发明的活性化合物，但可根据特定的剂型变化，其中占单位重量的4％至约70％是便利的。在这样的药物组合物中活性化合物的量应达到适当的剂量。
在一个实施方案中，对于口服给药，本发明的活性化合物例如可通过常规手段与可药用的赋形剂加以配制成片剂或胶囊，赋形剂例如粘合剂，填充剂，润滑剂，崩解剂或润湿剂。片剂可以通过本领域熟知的方法加以包衣。用于口服给药的液体制剂，如可以采用溶液、糖浆或悬液，或挥发为干燥产物，使用前用水或其他合适的载体再生。这类液体制剂可利用药用的添加剂通过常规手段加以制备，添加剂例如悬浮剂，乳化剂，非水性载体和防腐剂。
在一个实施方案中，当本发明的活性化合物用于胃肠外施用时，可将本发明提供的化合物与无菌水或有机介质组合形成可注射的溶液或悬液。
在一个实施方案中，本发明的活性化合物可以被配制成直肠组合物，例如栓剂或保留灌肠剂，例如含有常规的栓剂基质，例如可可脂或其他甘油酯。
治疗用途和方法
在另一方面，本发明提供本发明的化合物、其可药用的盐或本发明的药物组合物在制备用于调控5-HT2A和/或D2受体的药物中的用途，其中所述药物任选包含另外一种或多种调节哺乳动物神经系统或缓解精神疾病的活性剂。
在又一方面，本发明还提供一种调控5-HT2A和/或D2受体的方法，其包括向有此需要的个体(例如哺乳动物个体，如人)给药本发明的化合物、其可药用的盐或本发明的药物组合物。
在一个优选的实施方案中，所述调控包括但不限于调节作用的受体的抑制活性或拮抗活性。
在还一方面，本发明提供本发明的化合物、其可药用的盐或本发明的药物组合物在制备用于治疗神经精神类疾病的药物中的用途。
在另一方面，本发明还提供一种治疗神经精神类疾病的方法，其包括向有此需要的个体(例如哺乳动物个体，如人)给药本发明的化合物、其可药用的盐或本发明的药物组合物。
在又一方面，本发明提供一种通式(I)所示的化合物或其可药用的盐或其药物组合物，用于治疗神经精神类疾病。
在一个实施方案中，所述神经精神类疾病选自精神分裂症、抑郁症、焦虑症、睡眠障碍、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选抑郁症、焦虑症、精神分裂症、睡眠障碍、神经退行性疾病或双相情感障碍中的任意一种或多种。在一个优选的实施方案中，所述神经精神类疾病为精神分裂症。
实施方案
1.一种如通式(I)所示的化合物或其可药用的盐，
Figure PCTCN2020129850-appb-000043
其中，-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，或至少被一个卤素取代的C 2-C 8的直链烷基中的任意一种；
(1)当-Z-独立地为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基时，
A独立地为选自如下所示取代基(A-1)，(A-2)或(A-3)中的任意一种：
Figure PCTCN2020129850-appb-000044
R独立地为选自如下所示取代基(R-1)，(R-2)，(R-3)，(R-4)或(R-5)中的任意一种：
Figure PCTCN2020129850-appb-000045
Q独立地为N或CH；X 1和X 2各自独立地为O或S中的任意一种；R 1和R 2各自独立地为氢或卤素中的任意一种；R 3独立地为氢或C 1-C 5的烷基中的任意一种；R 4独立地为氢或卤素中的任意一种；R 5和R 6各自独立地为氢，卤素，或被一个或多个卤素取代的C 1-C 3的烷基中的任意一种；R 7独立地为氢或卤素中的任意一种；n 1为1或2中的任意一个整数，n 2为0～3之间的任意一个整数，n 3为0～3之间的任意一个整数；或者，
(2)当-Z-独立地为至少被一个卤素取代的C 2-C 8的直链烷基时，
A独立地为如下所示取代基(A-1)：
Figure PCTCN2020129850-appb-000046
R独立地为选自如下所示取代基(R-1)，(R-2)，(R-3)，(R-4)或(R-5)中的任意一种：
Figure PCTCN2020129850-appb-000047
Q独立地为N或CH；X 1和X 2各自独立地为O或S中的任意一种；R 1和R 2各自独立地为氢或卤素中的任意一种；R 3独立地为氢或C 1-C 5的烷基中的任意一种；R 4独立地为氢或卤素中的任意一种；R 5和R 6各自独立地为氢，卤素，或被一个或多个卤素取代的C 1-C 3的烷基中的任意一种；R 7独立地为氢或卤素中的任意一种；n 1为1或2中的任意一个，n 2为0～3之间的任意一个整数，n 3为0～3之间的任意一个整数。
2.如第1项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，所述-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基时，通式(I)所示的化合物或其可药用的盐选自如下所示通式(II)所示的化合物或其可药用的盐：
Figure PCTCN2020129850-appb-000048
n 4独立地为0～3之间的任意一个整数，优选0～2之间的任意一个整数；n 5为1～5之间的任意一个整数，优选1～4之间的任意一个整数；A，Q和R如第1项中所定义。
3.如第1项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，所述-Z-为至少被一个卤素取代的C 2-C 8的直链烷基时，通式(I)所示的化合物或其可药用的盐选自如下所示通式(III)所示的化合物或其可药用的盐：
Figure PCTCN2020129850-appb-000049
n 6为1～5之间的任意一个整数，优选1～4之间的任意一个整数；R 8和R 9各自独立地为氢或卤素中的任意一种，但不同时为氢；A，Q和R如第1项中所定义。
4.如1-3项中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，所述C 1-C 5的烷基选自甲基、乙基、丙基、丁基或戊基中的任意一种，优选甲基、乙基或丙基中的任意一种；所述被一个或多个卤素取代的C 1-C 3的烷基为-(CH 2) aCX 3，所述a为0～2之间的任意整数，X为卤素。
5.如1-4项中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，所述卤素选自氟、氯、溴或碘中的任意一种。
6.如1-5项中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，所述通式(I)所示化合物选自如下所示任意一个化合物：
Figure PCTCN2020129850-appb-000050
Figure PCTCN2020129850-appb-000051
Figure PCTCN2020129850-appb-000052
Figure PCTCN2020129850-appb-000053
7. 1-6项中任一项所述的式(I)所示的化合物或其可药用的盐的制备方法，其特征在于，包括：
Figure PCTCN2020129850-appb-000054
通过亲核取代反应或还原胺化反应，在通式化合物(I-r)的氮端引入通式化合物(I-g)，通式化合物(I-n)，通式化合物(I-l)或通式化合物(I-q)中的任意一种制备得到；
其中，Z，A，R，Q，R 1，R 2，R 3，R 8，R 9，n 1，n 5和n 6如1～3项中任一项所定义。
8.一种药物组合物，其特征在于，包含治疗有效量的1～6项中任一项所述的通式(I)所示的化合物或其可药用的盐和医学上可接受的载体。
9. 1～6相中任一项所述的通式(I)所示的化合物或其可药用的盐或上述药物组合物在制备治疗神经精神类疾病的药物中的用途。
10.第10项所述的用途，其特征在于，所述神经精神类疾病选自精神分裂症。
有益效果
本发明提供的化合物为一种作用于5-HT2A受体和/或D2受体的拮抗剂，对5-HT2A受体和/或D2受体具有良好的亲和力；且具有合适的D2/5-HT2A的比值，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、认知缺陷症状具有更强的改善作用；另外本发明的化合物具有更高的B/P的比值，药物分布具有更好的脑靶向作用，有利于减少给药剂量，减少不良反应发生可能性。
实施例
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。如无特别指明，本文所用的比例或百分比按重量计。
合成实施例
实施例1 8-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-IJ]喹啉4(2H)-酮
Figure PCTCN2020129850-appb-000055
1)取吲哚啉(10g)加入丙酮(50mL)，搅拌混匀，降温至-10℃，缓慢滴加3-氯丙酰氯(10.9g)，搅拌回流，8小时反应完毕。使反应液冷却至室温，浓缩反应液，用二氯甲烷溶解，水洗，无水硫酸钠干燥，抽滤，浓缩，乙酸乙酯重结晶，得白色固体13.6g，收率77.1％。
2)取第一步产物(13.6g)，加入无水三氯化铝(16.4g))，在搅拌下加热反应6小时。使反应混合物冷却至室温后，加入冰水淬灭体系，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝4:1)，得白色固体6.9g，收率61.7％。
3)取第二步产物(5g)，加入乙酰氯(2.1g)和1,2-二氯乙烷(25mL)，将体系以冰盐浴降至0℃左右，加入三氯化铝(7.7g)，内温控制在0℃左右，保温半小时，撤去冰浴，40℃反应4小时。加入冰水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝4:1)，得白色固体4.2g，收率66.3％。
4)取第三步产物(4.2g)，加入二氯甲烷(50mL)、间氯过氧苯甲酸(4.2g)、三氟乙酸(14.4g)，室温反应48小时。加入饱和碳酸氢钠溶液至中性，二氯甲烷萃取，无水硫酸 钠干燥，抽滤，浓缩，得油状物4.4g，收率100％。
5)取第四步产物(4.4g)，加入甲醇(40mL)，加热至40℃，滴加氢氧化锂饱和溶液至pH为13，反应1小时，以稀盐酸调至近中性，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，得浅黄色固体3.7g，收率100％。
6)取第五步产物(3.7g)，加入碳酸钾(5.4g)、1,4-二溴丁烷(8.4g)和乙腈(100mL)。加热回流反应12小时，使反应物冷却至室温，抽滤，浓缩，柱层析纯化(PE:EA＝1:1)，得类白色固体4.1g，收率65.2％。
7)取第六步化合物(4g)，加入碳酸钾(1.7g)，6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(2.7g，市售)和乙腈(100mL)。加热回流反应12小时，使反应物冷却至室温，抽滤，浓缩，柱层析纯化(DCM:MetOH＝20:1)，得类白色固体1.2g。
1H NMR(400MHz,CDCl 3)δ7.74(dd,J＝8.6,5.1Hz,1H),7.30–7.24(m,1H),7.09(t,J＝8.8Hz,1H),6.70(s,1H),6.61(s,1H),4.10(t,J＝8.4Hz,2H),3.99(t,J＝6.2Hz,2H),3.23–3.06(m,5H),2.96(t,J＝7.7Hz,2H),2.69(t,J＝7.7Hz,2H),2.51(t,J＝7.3Hz,2H),2.29–2.05(m,6H),1.80(ddt,J＝43.0,14.7,6.7Hz,4H).MS(ESI)m/z464.2([M+H] +)
实施例2 8-(4-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1-(苯并[b]噻吩-4-基)哌嗪(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.68(d,J＝8.1Hz,1H),7.49(d,J＝5.5Hz,1H),7.38–7.32(m,2H),7.03(d,J＝7.5Hz,1H),6.69(s,1H),6.60(s,1H),4.16–4.08(m,2H),4.03(t,J＝5.8Hz,2H),3.65(m,6H),3.20(t,J＝8.3Hz,4H),2.98(t,J＝7.7Hz,2H),2.70(t,J＝7.8Hz,2H),2.31–2.17(m,2H),1.95(dt,J＝13.3,6.0Hz,2H),1.81(m,2H).MS(ESI)m/z462.2([M+H] +)
实施例3 8-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1-(2,3-二氯苯基)哌嗪(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.28(dd,J＝8.1,1.6Hz,1H),7.22(t,J＝8.0Hz,1H),7.06(dd,J＝8.1,1.6Hz,1H),6.67(s,1H),6.58(s,1H),4.15–4.06(m,2H),4.00(t,J＝5.8Hz,2H),3.55(m,6H),3.23–3.02(m,6H),2.96(t,J＝7.7Hz,2H),2.68(t,J＝7.8Hz,2H),2.26–2.17(m,2H),1.98–1.86(m,2H).MS(ESI)m/z474.2([M+H] +)
实施例4 8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用3-(哌嗪-1-基)苯并[d]异噻唑(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.88(d,J＝8.6Hz,2H),7.54(ddd,J＝8.2,7.0,1.0Hz,1H),7.43(ddd,J＝8.2,7.0,1.0Hz,1H),6.67(d,J＝2.1Hz,1H),6.58(d,J＝2.1Hz,1H),4.14–3.93(m,8H),3.35–3.13(m,6H),2.99(dt,J＝25.4,7.5Hz,4H),2.68(t,J＝7.8Hz,2H),2.12(dt,J＝14.2,6.9Hz,2H),1.96–1.84(m,2H).MS(ESI)m/z463.2([M+H] +)
实施例5 8-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1,3-二溴丙烷替代1,4-二溴丁烷。
1H NMR(400MHz,CDCl 3)δ7.73(dd,J＝8.7,5.1Hz,1H),7.26(dd,J＝8.5,2.1Hz,1H),7.08(td,J＝8.8,2.1Hz,1H),6.71(d,J＝2.1Hz,1H),6.61(d,J＝2.1Hz,1H),4.13–3.97(m,4H),3.22–3.08(m,5H),2.95(t,J＝7.7Hz,2H),2.65(dt,J＝18.3,7.6Hz,4H),2.31–2.18(m,2H),2.12(td,J＝8.6,7.5,3.6Hz,4H),2.08–1.98(m,2H).MS(ESI)m/z450.2([M+H] +)
实施例6 8-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1,3-二溴丙烷替代1,4-二溴丁烷,用1-(2,3-二氯苯基)哌嗪替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.23–7.17(m,2H),7.00(ddd,J＝6.6,3.1,1.4Hz,1H),6.72(d,J＝2.0Hz,1H),6.62(d,J＝2.1Hz,1H),4.11(t,J＝8.3Hz,2H),4.04(t,J＝6.3Hz,2H),3.27–3.06(m,6H),2.97(t,J＝7.8Hz,2H),2.69(td,J＝14.2,13.4,7.5Hz,8H),2.10–1.99(m,2H).MS(ESI)m/z460.2([M+H] +)
实施例7 8-(3-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1,3-二溴丙烷替代1,4-二溴丁烷，用1-(苯并[b]噻吩-4-基)哌嗪替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐
1H NMR(400MHz,CDCl 3)δ7.61(d,J＝8.1Hz,1H),7.49–7.42(m,2H),7.37–7.31(m,1H),6.95(dd,J＝7.7,0.8Hz,1H),6.74(d,J＝2.1Hz,1H),6.66–6.62(m,1H),4.18–4.09(m,2H),4.06(t,J＝6.3Hz,2H),3.35–3.17(m,6H),2.98(t,J＝7.7Hz,2H),2.81(m,4H),2.76–2.68(m,4H),2.16–2.01(m,2H).MS(ESI)m/z448.2([M+H] +)
实施例8 8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1,3-二溴丙烷替代1,4-二溴丁烷，用3-(哌嗪-1-基)苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.95(dd,J＝8.2,1.0Hz,1H),7.89–7.82(m,1H),7.51(ddd,J＝8.0,6.9,1.0Hz,1H),7.40(ddd,J＝8.0,6.9,1.0Hz,1H),6.76–6.70(m,1H),6.66–6.61(m,1H),4.11(t,J＝8.4Hz,2H),4.06(t,J＝6.3Hz,2H),3.63(t,J＝4.9Hz,4H),3.19 (t,J＝8.4Hz,2H),2.97(t,J＝7.7Hz,2H),2.77(t,J＝4.9Hz,4H),2.69(q,J＝7.6Hz,4H),2.12–2.00(m,2H).MS(ESI)m/z449.2([M+H] +)
实施例9 9-氟-8-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用4-氟吲哚啉(市售)替代吲哚啉。
1H NMR(400MHz,CDCl 3)δ7.81(m,1H),δ7.29(d,J＝2.1Hz,1H),7.12(td,J＝9.0,2.0Hz,1H),6.71(d,J＝7.2Hz,1H),4.15(t,J＝8.4Hz,2H),4.06(t,J＝5.7Hz,2H),3.25(m,6H),2.95(t,J＝7.8Hz,2H),2.70(m,3H),1.78(m,8H),1.31(s,2H).MS(ESI)m/z482.2([M+H] +)
实施例10 7-氟-8-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氟吲哚啉替代吲哚啉。
1H NMR(400MHz,CDCl 3δ7.29(d,J＝2.1Hz,2H),7.15(t,J＝8.9Hz,1H),6.80(d,J＝7.2Hz,1H),4.13(t,J＝8.4Hz,2H),4.07(t,J＝5.8Hz,2H),3.18(t,J＝8.4Hz,2H),3.04(t,J＝7.8Hz,4H),2.71(t,J＝7.8Hz,4H),2.32–1.99(m,5H),1.93(m,2H),1.63(m,2H),1.31(m,2H).MS(ESI)m/z482.2([M+H] +)
实施例11 8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁氧基)-7-氟-1,2,5,6-四氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氟吲哚啉(市售)替代吲哚啉，用3-(哌嗪-1-基)苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,DMSO)δ8.22(s,1H),7.75(d,J＝8.3Hz,1H),7.36(t,J＝8.6Hz,1H),6.94(s,1H),6.88(s,1H),4.07(t,J＝5.9Hz,2H),3.69(d,J＝11.3Hz,2H),3.50(m,2H),3.29(d,J＝6.9Hz,2H),3.24–3.10(m,6H),2.88–2.76(m,2H),2.31–2.15(m,8H).MS(ESI)m/z481.2([M+H] +)
实施例12 8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙氧基)-7-氟-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氟吲哚啉替代吲哚啉，用1,3-二溴丙烷替代1,4-二溴丁烷，用3-(哌嗪-1-基)苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,DMSO)δ8.06(d,J＝8.0Hz,2H),7.56(t,J＝7.5Hz,1H),7.44(t,J＝7.6Hz,1H),6.99(d,J＝7.5Hz,1H),4.05(t,J＝6.2Hz,2H),3.93(t,J＝8.4Hz,2H),3.45(s,4H),3.09(t,J＝8.2Hz,2H),2.92(t,J＝7.7Hz,2H),2.62(s,4H),2.56–2.50(m,4H),1.95–1.86(m,2H).MS(ESI)m/z467.2([M+H] +)
实施例13 8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁氧基)-7-氯-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氯吲哚啉(市售)替代吲哚啉，用3-(哌嗪-1-基) 苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.96(d,J＝8.2Hz,1H),7.87(d,J＝8.2Hz,1H),7.52(t,J＝7.5Hz,1H),7.41(t,J＝7.5Hz,1H),6.79(s,1H),4.20–4.10(m,2H),4.08(t,J＝6.1Hz,2H),3.66(m,2H),3.20(t,J＝8.4Hz,2H),3.09(t,J＝7.8Hz,2H),2.93–2.68(m,6H),2.62(m,2H),2.01–1.79(m,4H),1.67(m,2H).MS(ESI)m/z497.2([M+H] +).
实施例14 7-氯-8-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氯吲哚啉(市售)替代吲哚啉，用1,3-二溴丙烷替代1,4-二溴丁烷。
1H NMR(400MHz,CDCl 3)δ7.75(dd,J＝8.6,5.1Hz,1H),7.29(d,J＝8.5Hz,1H),7.14–7.07(m,1H),6.82(s,1H),4.12(dd,J＝13.6,7.2Hz,4H),3.14(ddd,J＝30.3,16.4,8.1Hz,7H),2.77–2.65(m,4H),2.25(d,J＝12.9Hz,2H),2.15–2.01(m,6H).MS(ESI)m/z484.2([M+H] +)
实施例15 7-氯-8-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氯吲哚啉(市售)替代吲哚啉。
1H NMR(400MHz,CDCl 3)δ7.76(dt,J＝21.9,11.0Hz,1H),7.25(dd,J＝8.5,1.6Hz,1H),7.08(td,J＝8.8,1.7Hz,1H),6.76(s,1H),4.16–3.99(m,4H),3.21–3.10(m,5H),3.05(dd,J＝15.5,7.6Hz,2H),2.69(t,J＝7.8Hz,2H),2.60(dd,J＝16.0,9.0Hz,2H),2.30(dd,J＝24.6,14.2Hz,2H),2.23–2.08(m,4H),1.95–1.78(m,4H).MS(ESI)m/z498.2([M+H] +)
实施例16 8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙氧基)-7-氯-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用6-氯吲哚啉(市售)替代吲哚啉，用1,3-二溴丙烷替代1,4-二溴丁烷，用3-(哌嗪-1-基)苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐
1H NMR(400MHz,CDCl 3)δ7.96(d,J＝8.2Hz,1H),7.87(d,J＝8.2Hz,1H),7.52(t,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),6.82(s,1H),4.13(dd,J＝10.5,4.2Hz,4H),3.70–3.61(m,4H),3.20(t,J＝8.4Hz,2H),3.08(t,J＝7.8Hz,2H),2.85–2.68(m,8H),2.20–2.09(m,2H).MS(ESI)m/z483.2([M+H] +)
实施例17 8-(4-(4-苄基哌嗪-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用苄基哌嗪(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐
1H NMR(400MHz,CDCl 3)δ7.33(m,5H),6.65(s,1H),6.56(s,1H),4.08(t,J＝8.2Hz,2H),3.96(d,J＝5.5Hz,2H),3.64(m,2H),3.16(t,J＝8.1Hz,2H),2.92(m,6H),2.81(m,6H),2.66(t,J＝7.5Hz,2H),1.93(m,2H),1.84(d,J＝6.1Hz,2H).MS(ESI)m/z420.3([M+H] +)
实施例18 8-(4-(4-(4-氟苯甲酰基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用4-(4-氟苯甲酰基)哌啶盐酸盐(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐
1H NMR(400MHz,CDCl 3)δ8.00(s,2H),7.20(s,2H),6.68(s,1H),6.59(s,1H),4.04(m,4H),3.18(m,4H),2.96(m,2H),2.74(m,5H),2.26(m,2H),2.03(m,4H),1.98–1.78(m,4H).MS(ESI)m/z451.2([M+H] +)
实施例19 8-(4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1-(3-三氟甲基苯基)哌嗪(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.40(t,J＝7.8Hz,1H),7.13(dd,J＝16.4,8.2Hz,3H),6.71(s,1H),6.62(s,1H),4.12(t,J＝8.2Hz,2H),4.00(t,J＝5.5Hz,2H),3.33(s,4H),3.20(t,J＝8.1Hz,2H),2.98(t,J＝7.5Hz,2H),2.77–2.63(m,6H),2.56(m,2H),1.93–1.71(m,4H).MS(ESI)m/z474.2([M+H] +)
实施例20 8-(4-(4-(苯并[d][1,3]二氧杂-5-基甲基(哌嗪-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1方法制备化合物，但用1-胡椒基哌嗪(市售)替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐
1H NMR(400MHz,CDCl 3)δ6.88(s,1H),6.78(s,2H),6.66(s,1H),6.57(s,1H),5.97(s,2H),4.08(t,J＝8.3Hz,2H),3.96(t,J＝5.6Hz,2H),3.56(m,2H),3.17(t,J＝8.2Hz,2H),3.03–2.84(m,6H),2.79(s,6H),2.67(t,J＝7.6Hz,2H),1.97–1.78(m,4H).MS(ESI)m/z464.2([M+H] +)
实施例21 8-(1,1-二氟-5-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)戊基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
Figure PCTCN2020129850-appb-000056
1)取吲哚啉(10g)加入丙酮(50mL)，搅拌混匀，降温至-10℃，缓慢滴加3-氯丙酰氯(10.9g)，搅拌回流，8小时反应完毕。使反应液冷却至室温，浓缩反应液，用二氯甲烷溶解，水洗，无水硫酸钠干燥，抽滤，浓缩，乙酸乙酯重结晶，得白色固体13.6g，收率77.1％。
2)取第一步产物(13.6g)，加入无水三氯化铝(16.4g)，在搅拌下加热反应6小时。使反应混合物冷却至室温后，加入冰水淬灭体系，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝4:1)，得白色固体6.9g，收率61.7％。
3)取第二步产物(5g)，加入5-氯戊酰氯(6.7g)和1,2-二氯乙烷(50mL)，将体系以冰盐浴降至0℃左右，加入三氯化铝(11.55g)，内温控制在0℃左右，保温半小时，撤去冰浴，室温反应4小时。加入冰水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝2:1)，得白色固体5.7g，收率67.8％。
4)取第三步产物(3g)，冰浴加入二乙胺基三氟化硫(13.3g)，室温搅拌12小时，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝1:1)，得浅黄色固体1.2g，收率36.5％。
5)取第四步产物(1.2g)，加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(1.5g)，碳酸钾(1.3g)，乙腈(20mL)，60℃反应12小时，抽滤，浓缩，柱层析纯化(DCM:MetOH＝20:1)，得类白色固体1.4g。
1H NMR(400MHz,CDCl 3)δ7.75(dd,J＝8.5,5.1Hz,1H),7.28(d,J＝8.3Hz,1H),7.23(s,1H),7.16(s,1H),7.10(t,J＝8.7Hz,1H),4.15(t,J＝8.4Hz,2H),3.26(t,J＝8.4Hz,2H),3.11(d,J＝10.5Hz,3H),3.04(t,J＝7.7Hz,2H),2.74(t,J＝7.7Hz,2H),2.54–2.42(m,2H),2.32–2.07(m,8H),1.64(m,2H),1.52(m,2H).MS(ESI)m/z498.2([M+H] +)
实施例22 8-((3-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丙氧基)甲基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
Figure PCTCN2020129850-appb-000057
1)取吲哚啉(10g)加入丙酮(50mL)，搅拌混匀，降温至-10℃，缓慢滴加3-氯丙酰氯(10.9g)，搅拌回流，8小时反应完毕。使反应液冷却至室温，浓缩反应液，用二氯甲烷溶解，水洗，无水硫酸钠干燥，抽滤，浓缩，乙酸乙酯重结晶，得白色固体13.6g，收率77.1％。
2)取第一步产物(13.6g)，加入无水三氯化铝(16.4g)，在搅拌下加热反应6小时。使反应混合物冷却至室温后，加入冰水淬灭体系，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝4:1)，得白色固体6.9g，收率61.7％。
3)取第二步产物(3g)，加入醋酸(20mL)，加入多聚甲醛(3.1g)，浓硫酸(1.7g)，90℃反应1小时，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝2:1)，得类白色固体1.1g，收率25.3％。
4)取第三步产物(1.1g)，加入甲醇(10mL)，升温至40℃，滴加氢氧化锂饱和水溶液至pH为13，40℃搅拌1小时，以1M盐酸调至近中性，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，得类白色固体1g，收率100％。
5)取第四步产物(1g)，加入二氯甲烷(20mL)，冰浴冷却至0℃，滴加三溴化磷(1.3g)，冰浴搅拌1小时，缓慢加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，得浅黄色油状物1.5g，收率100％。
6)取四氢呋喃(20mL)，加入氢化钠(0.3g)，滴加1,3-丙二醇(0.6g)，室温搅拌半小时，加入第五步产物(1.5g)，室温反应17小时，缓慢加水淬灭，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(EA)，得浅黄色固体0.8g，收率79.8％。
7)取二氯甲烷(20mL)，加入戴斯马丁氧化剂(1.6g)，冰浴搅拌下加入第六步产物(0.8g)，室温反应1h，加入饱和碳酸氢钠溶液，饱和硫代硫酸钠溶液淬灭，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，得浅黄色固体0.8g，收率100％。
8)取第七步化合物(0.4g)，加入二氯甲烷(20mL)，加入6-氟-3-(4-哌啶基)-1,2-苯并异噁唑(0.4g)，三乙酰氧基硼氢化钠(0.4g)，室温搅拌2小时，二氯甲烷萃取，无水硫酸 钠干燥，抽滤，浓缩，柱层析纯化(DCM:MetOH＝20:1)，得白色固体0.1g。
1H NMR(400MHz,CDCl 3)δ8.01(m,1H),7.37–7.25(m,1H),7.19(tdd,J＝8.8,5.6,2.1Hz,1H),7.09(d,J＝8.5Hz,1H),7.01(d,J＝7.8Hz,1H),4.46(d,J＝11.1Hz,2H),4.22–4.08(m,2H),3.89–3.74(m,2H),3.66(dt,J＝20.0,5.5Hz,2H),3.60–3.40(m,2H),3.24(m,5H),3.09–2.88(m,4H),2.72(t,J＝7.8Hz,2H),2.40–2.12(m,4H).MS(ESI)m/z464.2([M+H] +)
实施例23 8-((2-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)乙氧基)甲基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例22的方法制备目标化合物，但用1,2-乙二醇代替1,3-丙二醇。
1H NMR(400MHz,CDCl 3)δ8.04(m,1H),7.39–7.26(m,1H),7.20(qd,J＝8.9,2.2Hz,1H),6.69(dd,J＝7.3,2.0Hz,1H),6.63(dt,J＝6.9,1.4Hz,1H),4.21–4.07(m,2H),4.03(dt,J＝12.6,5.8Hz,2H),3.87–3.75(m,2H),3.61–3.43(m,2H),3.20(qd,J＝11.7,10.0,4.4Hz,6H),2.97(m,2H),2.76(ddd,J＝16.5,6.4,2.9Hz,1H),2.35–2.15(m,4H),1.94(dt,J＝18.4,6.8Hz,2H).MS(ESI)m/z450.2([M+H] +)
实施例24 8-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丙氧基)-6-甲基-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
Figure PCTCN2020129850-appb-000058
1)取吲哚啉(20g)，加入乙酰乙酸乙酯(21.8g)，110℃反应过夜，二氯甲烷稀释，1M盐酸洗涤一次，无水硫酸酸钠干燥，抽滤，浓缩，得油状物30g，收率88.1％。
2)取第一步产物(30g)，加入浓硫酸(40mL)，搅拌加热100℃反应4小时，倾入冰水，二氯甲烷萃取，无水硫酸酸钠干燥，抽滤，浓缩，得固体20.8g，收率76.0％。
3)取第二步产物(20.8g)，加入甲醇(250mL)，10％钯碳(0.21g)，常压50℃通入氢气反应过夜，抽滤，浓缩，柱层析纯化(PE:EA＝2:1)，得固体15.0g，收率61.7％。
4)取第三步产物(15g)，加入乙酰氯(7.5g)和1,2-二氯乙烷(150mL)，将体系以冰盐浴降至0℃左右，加入三氯化铝(32.1g)，内温控制在0℃左右，保温半小时，撤去冰浴，40℃反应4小时。加入冰水淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化(PE:EA＝4:1)，得白色固体15.0g，收率81.6％。
5)取第四步产物(15g)，加入二氯甲烷(150ml)、间氯过氧苯甲酸(30.0g)、三氟乙酸(51.4g)，室温反应48小时。加入饱和碳酸氢钠溶液至中性，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，得油状物13.4g，收率78.9％。
6)取第五步产物(13.4g)，加入甲醇(40ml)，加热至40℃，滴加氢氧化锂饱和溶液至pH为13，反应2小时，以1M盐酸调至近中性，二氯甲烷萃取，无水硫酸钠干燥，抽滤，浓缩，得浅黄色固体6.8g，收率56.8％。
7)取第六步产物(4.0g)，加入碳酸钾(5.4g)、1,3-二溴丙烷(7.9g)和乙腈(100mL)。加热回流反应12小时，使反应物冷却至室温，抽滤，浓缩，柱层析纯化(PE:EA＝1:1)，得类白色固体3.2g，收率52.4％。
8)取第七步化合物(1.7g)，加入碳酸钾(2.2g)，6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(2.0g)和乙腈(100mL)。加热回流反应12小时，使反应物冷却至室温，抽滤，浓缩，柱层析纯化(DCM:MetOH＝20:1)，得类白色固体1.2g。
1H NMR(400MHz,CDCl 3)δ7.74(dd,J＝8.7,5.1Hz,1H),7.28(dd,J＝8.5,2.1Hz,1H),7.09(td,J＝8.8,2.1Hz,1H),6.73(d,J＝2.1Hz,1H),6.68–6.63(m,1H),4.19–4.01(m,4H),3.25–3.04(m,6H),2.75(dd,J＝16.5,6.3Hz,1H),2.63(t,J＝7.3Hz,2H),2.41(dd,J＝16.5,9.0Hz,1H),2.31–2.17(m,2H),2.12(m,4H),2.08–2.01(m,2H),1.34(d,J＝7.0Hz,3H).MS(ESI)m/z464.2([M+H] +)
实施例25 8-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-6-甲基-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例24的方法制备目标化合物，但用1,4-二溴丁烷替代1,3-二溴丙烷。
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.29(s,1H),7.09(dd,J＝20.3,11.5Hz,1H),6.72(s,1H),6.67(s,1H),4.13(tt,J＝19.7,9.8Hz,2H),4.01(t,J＝6.1Hz,2H),3.21(dt,J＝15.6,8.3Hz,6H),2.76(dd,J＝16.5,6.3Hz,1H),2.54(m,2H),2.43(dd,J＝16.5,9.0Hz,1H),2.14(m,4H),1.83(dt,J＝61.2,22.6Hz,6H),1.35(d,J＝6.9Hz,3H).MS(ESI)m/z478.4([M+H] +)
实施例26 8-(3-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丙氧基)-6-甲基-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例24的方法制备目标化合物，但用3-(哌嗪-1-基)苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.90(dd,J＝11.2,8.2Hz,2H),7.58(t,J＝7.5Hz,1H),7.47(t,J＝7.5Hz,1H),6.68(s,1H),6.63(s,1H),4.33–4.03(m,8H),3.62(d,J＝11.8Hz,2H),3.36–3.12(m,7H),2.76(dd,J＝16.5,6.4Hz,1H),2.58–2.49(m,2H),2.42(m,1H),1.34(d,J＝6.9Hz,3H).MS(ESI)m/z463.2([M+H] +)
实施例27 8-(4-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)丁氧基)-6-甲基-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例24的方法制备目标化合物，但用1，4-二溴丁烷替代1,3-二溴丙烷；用3-(哌嗪-1-基)苯并[d]异噻唑替代6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐。
1H NMR(400MHz,CDCl 3)δ7.95–7.82(m,2H),7.57(t,J＝7.5Hz,1H),7.46(t,J＝7.5Hz,1H),6.68(s,1H),6.63(s,1H),4.29–4.04(m,6H),4.02(t,J＝5.6Hz,2H),3.61(d,J＝11.5Hz,2H),3.19(m,6H),2.76(dd,J＝16.5,6.3Hz,1H),2.48–2.37(m,2H),2.25(m,2H),1.99–1.89(m,2H),1.34(d,J＝6.9Hz,3H).MS(ESI)m/z477.2([M+H] +)
实施例28 7-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
Figure PCTCN2020129850-appb-000059
1)取6-甲氧基吲哚(10g，市售)，加入醋酸(100mL)，冰浴缓慢加入氰基硼氢化钠(5.1g)，缓慢升至室温，搅拌2小时，饱和碳酸钠溶液调节pH至弱碱性，二氯甲烷萃取，无水硫酸酸钠干燥，抽滤，浓缩，得固体10.1g，收率100％。
2)取第一步产物(10.1g)，加入丙酮(100mL)，室温滴加3-氯丙酰氯(8.6g)，升温回流反应4小时，浓缩，二氯甲烷稀释，水洗，无水硫酸酸钠干燥，抽滤，浓缩，得固体8.7g，收率55.2％。
3)取三乙胺盐酸盐(10g)，加入三氯化铝(22g)，室温下机械搅拌至粘稠状液体，加入三氯化铝(30.1g)，加入第二步产物(8.7g)，110℃搅拌6小时，冷却，缓慢加入冰水淬灭，二氯甲烷萃取，无水硫酸钠干燥，抽滤，柱层析纯化(EA)，得固体4.2g，收率58.8％。
4)取第三步产物(2g)，加入碳酸钾(2.9g)、1,4-二溴丁烷(4.5g)和乙腈(100mL)。加热回流反应12小时，使反应物冷却至室温，抽滤，浓缩，柱层析纯化(PE:EA＝1:1)，得固体2.6g，收率75.7％。
5)取第四步化合物(2.6g)，加入碳酸钾(2.9g)，6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(4.8g)和乙腈(100mL)。加热回流反应12小时，使反应物冷却至室温，抽滤，浓缩，柱层析纯化(DCM:MetOH＝20:1)，得类白色固体1.3g。
1H NMR(400MHz,CDCl 3)δ7.77(m,1H),7.29(d,J＝2.1Hz,1H),7.11(td,J＝8.9,2.1Hz,1H),7.03(d,J＝8.2Hz,1H),6.51(d,J＝8.2Hz,1H),4.12(t,J＝8.3Hz,2H),4.05(t,J＝6.0Hz,2H),3.16(t,J＝8.3Hz,5H),3.00(d,J＝7.9Hz,2H),2.71(t,J＝7.9Hz,2H),2.55(m,2H),2.21(d,J＝46.2Hz,6H),1.95–1.74(m,4H).MS(ESI)m/z464.2([M+H] +)
实施例29 7-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例28的方法制备目标化合物，但用1,3-二溴丙烷代替1,4-二溴丁烷。
1H NMR(400MHz,CDCl 3)δ7.77(m,1H),7.29(d,J＝2.1Hz,1H),7.11(td,J＝8.9,2.2Hz,1H),7.04(d,J＝8.1Hz,1H),6.53(d,J＝8.2Hz,1H),4.19–4.07(m,4H),3.26–3.12(m,5H),2.98(t,J＝7.9Hz,2H),2.71(t,J＝7.9Hz,4H),2.21(d,J＝46.0Hz,8H).MS(ESI)m/z450.2([M+H] +)
实施例30 9-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例28的方法制备目标化合物，但用4-甲氧基吲哚(市售)替代6-甲氧基吲哚。
1H NMR(400MHz,CDCl 3)δ7.78(m,1H),7.29(d,J＝2.1Hz,1H),7.11(td,J＝8.9,2.2Hz,1H),6.98(d,J＝8.2Hz,1H),6.49(d,J＝8.2Hz,1H),4.13(t,J＝8.4Hz,2H),4.08(t,J＝6.1Hz,2H),3.18(dd,J＝11.4,5.5Hz,5H),2.95(t,J＝7.7Hz,2H),2.70(t,J＝7.7Hz,2H),2.58(s,2H),2.40–2.07(m,6H),1.94–1.75(m,4H).MS(ESI)m/z464.2([M+H] +)
实施例31 9-(3-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例28的方法制备目标化合物，但用4-甲氧基吲哚(市售)替代6-甲氧基吲哚；用1,3-二溴丙烷替代1,4-二溴丁烷。
1H NMR(400MHz,CDCl 3)δ7.30(d,J＝2.2Hz,2H),7.17(td,J＝8.8,2.2Hz,1H),6.99(d,J＝8.2Hz,1H),6.48(d,J＝8.2Hz,1H),4.24–4.09(m,4H),3.41(m,5H),3.16(t,J＝8.4Hz,2H),2.96(t,J＝7.7Hz,2H),2.70(t,J＝7.7Hz,2H),2.33(m,6H),1.71(m,2H).MS(ESI)m/z450.2([M+H] +)。
实施例32 8-(4-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)丁氧基)-1,2,6,7-四氢吡啶并[3,2,1-ij]喹啉-3(5H)-酮
按实施例28的方法制备目标化合物，但用5-甲氧基四氢喹啉(市售)替代6-甲氧基吲哚。
1H NMR(400MHz,CDCl 3)δ7.77(dd,J＝8.8,5.1Hz,1H),7.29(dd,J＝8.5,2.2Hz,1H),7.11(td,J＝8.9,2.2Hz,1H),6.65–6.58(m,2H),4.00(t,J＝6.1Hz,2H),3.96–3.86(m,2H),3.16(d,J＝10.0Hz,3H),2.89(dd,J＝8.7,6.1Hz,2H),2.81(t,J＝6.3Hz,2H),2.67(dd,J＝8.7,6.1Hz,2H),2.55(m,2H),2.18(m,6H),1.97(m,2H),1.92–1.73(m,4H).MS(ESI)m/z478.2([M+H] +)
实施例33 8-(2-(4-(6-氟苯并[d]异恶唑-3-基)哌啶-1-基)乙氧基)-5,6-二氢-1H-吡咯并[3,2,1-ij]喹啉-4(2H)-酮
按实施例1的方法制备目标化合物，但用1,2-二溴乙烷替代1,4-二溴丁烷。
1H NMR(400MHz,CDCl 3)δ8.12(m,1H),7.76-7.72(dd,J＝8.7,5.1Hz,1H),7.36-7.31(td,J＝8.8,2.1Hz,1H),6.82-6.81(d,J＝4.0Hz,1H),6.74-6.73(d,J＝4.0Hz, 1H),3.96-3.90(m,4H),3.18–3.09(m,5H),2.91-2.87(m,2H),2.53-2.49(m,4H),2.30–2.16(m,6H),.MS(ESI)m/z436.2([M+H] +)
测试例
本发明下述的化合物(α)如下所示，参照专利WO2017071576A1所述实施例18所述方法进行制备，
Figure PCTCN2020129850-appb-000060
测试例1各化合物对受体的亲和力测试
匀浆液配制
A：(用于制备5-HT 2A受体膜)：称取11.7mgEDTA，380.84mg MgCl 2，加入50mM Tris-HCl缓冲液总体积为400mL，调整pH＝7.4。使其终浓度分别为EDTA 0.1mM、MgCl 2 10mM。B：(用于制备D 2受体膜)：Dopamine Binding Buffer(50mM NaCl,50mM HEPES-HCl,5mM MgCl 2,0.5mM EDTA,pH 7.4)。
受体膜的制备
1)CHO-5-HT 2A受体膜的制备
CHO-5-HT 2A等细胞由-80℃冰箱取出后自然解冻，在1000g，4℃下离心10分钟。取沉淀，弃上清液。沉淀加A液(50mM Tris-HCl缓冲液，含EDTA 0.1mM、MgCl 2 10mM，pH＝7.4)。细胞混匀20-30秒，然后50000g，4℃离心15min。小心的弃去上层液，再次加入A液(50mM Tris-HCl缓冲液，含EDTA 0.1mM、MgCl 2 10mM，pH＝7.4)，混匀，50000g，4℃离心15min离心。重复三次。-80℃储存。
2)CHO-D 2受体膜的制备
CHO-D 2等细胞由-80℃冰箱取出后自然解冻,在1000g，4℃下离心10分钟。取沉淀，弃上清液。沉淀加B液(50mM NaCl,50mM HEPES-HCl,5mM MgCl 2,0.5mM EDTA,pH 7.4)。细胞混匀20-30秒，然后50000g，4℃离心15min。小心的弃去上层液，再次加入B液，混匀，50000g，4℃离心15min离心。重复三次。-80℃储存。
受体竞争结合试验
1)5-HT 2A受体竞争结合试验
第一步：总结合管(TB)加入50μL溶媒(5％DMSO)，非特异性结合管(NB)加入Methysergide 50μL(终浓度1.0×10 -5M)，各受试化合物管(CB)加入50μL受试化合物。
第二步：各反应管分别加入缓冲液(匀浆液A)100μL。
第三步：先将制备好的膜用匀浆液A制成20mg/mL膜的混悬液备用。
第四步：各反应管分别加入放射性配体[ 3H]Ketanserin 50μL，终浓度为2.975nM。
第五步：将各反应管25℃温孵90min，反应完毕，结合的配基通过减压快速过滤，UniFilter GF/C板提前1h使用0.5％PEI溶液饱和，用冰冷的Tris缓冲液充分洗涤，抽滤后放入恒温干燥箱内干燥30min。将滤板取出加入MICROSCINTPS闪烁液，40μL/孔。
第六步：将滤板放入液闪计数仪计数。
2)CHO-D 2受体竞争结合试验
第一步：总结合管(TB)加入50μL溶媒(5％DMSO)，非特异性结合管(NB)加入Haloperidol 50μL(终浓度1.0×10 -5M)，各受试化合物管(CB)加入50μL受试化合物。
第二步：各反应管分别加入缓冲液(匀浆液B)100μL。
第三步：先将制备好的膜用匀浆液B制成20mg/mL膜的混悬液备用。
第四步：各反应管分别加入放射性配体[ 3H]Spiperone 50μL，终浓度为3nM。
第五步：将各反应管25℃温孵90min，反应完毕，结合的配基通过减压快速过滤，UniFilter GF/C板提前1h使用0.5％PEI溶液饱和，用冰冷的Tris缓冲液充分洗涤，抽滤后放入恒温干燥箱内干燥30min。将滤板取出加入MICROSCINT PS闪烁液，40μL/孔。
第六步：将滤板放入液闪计数仪计数。
数据处理和统计分析
Figure PCTCN2020129850-appb-000061
Logit法计算各化合物IC 50；
通过Scatchard作图得出各放射性配基Kd值及Bmax；
Figure PCTCN2020129850-appb-000062
具体结果见表1。
表1各化合物体外亲和力测试结果
化合物 5-HT2A K i(nM) D2Ki(nM) D2/5-HT2A Ki(nM)
化合物2 14.09 135.99 9.66
化合物3 126.27 264.75 2.10
化合物4 9.68 68.40 7.06
化合物5 1.16 43.88 37.94
化合物6 153.50 297.97 1.94
化合物7 7.76 99.97 12.88
化合物8 2.22 46.44 20.90
化合物22 10.31 247.50 24.01
化合物23 18.46 248.25 13.45
化合物25 4.25 38.92 9.15
化合物10 1.75 31.87 18.23
化合物19 387.20 440.50 1.14
化合物18 22.07 436.58 19.78
化合物17 ＞1000 ＞1000 /
化合物20 ＞1000 ＞1000 /
化合物33 6.04 167.67 27.8
化合物α 3.86 39.59 10.26
利培酮 0.99 10.40 10.52
结果
目前研究发现，对5-HT2A受体的典型和典型抗精神病药的高亲和力可提高非临床疗效；另外，对D2/5-HT2A具有高选择性(D2/5-HT2A比值越大越具有高选择性)可降低诱发EPS反应的可能性，也是抗精神分裂症药的一个重要设计目标。
根据上述表1结果可知，体外实验结果表明本发明的化合物(特别是化合物5、7、8、13、25和10)对5HT2A以及D2具有较强的亲和力；另外表1记载的D2/5-HT2A的值中，化合物5、7、8、22、25、10、18的比值均优于化合物(α)和利培酮，提示本发明的化合物具有更好的精神分裂症治疗效果，并减少诱导产生EPS的可能性。
测试例2各化合物小鼠自发活动、MK-801高活动实验，以及血浆及脑组织药物浓度测试
MK-801：SIGMA(M107-250MG)
将动物按体重分层后随机分为空白组，模型组，及各化合物剂量组。每组8只小鼠。
给药途径及方法：灌胃给药，10mL/kg体重
给药频率及期限：单次给药
各化合物一般设置0.03、0.1、0.3、1mg/kg组，化合物(α)设置0.03、0.1、0.3、1、3mg/kg组。
自发活动测试
小鼠在给供试品(或阳性药)后30min，将小鼠放入自主活动箱(规格为29cm×29cm×30cm的黑色聚乙烯箱)开始录像，录像时间为30min，录像结束进行视频分析，评价小鼠自发活动情况。
MK-801诱发小鼠高活动测试
紧接自发活动测试后，即小鼠在灌胃给药后60min，再将小鼠腹腔注射0.3mg/kg的MK-801，继续进行录像，录像时间为60min，录像结束进行视频分析，评价小鼠高活动情况。
抑制高活动百分比＝(给药组活动距离—空白组活动距离)/(模型组活动距离—空白组活动距离)*100％。
抑制正常小鼠自发活动百分比＝(空白组活动距离—给药组活动距离)/空白组活动距离*100％。
紧接诱发小鼠高活动测试后，即约在给药后130-150min后，采用摘眼球取血0.5-0.8mL于EDTA-2K抗凝管中，分离血浆，-20℃保存待测；同时迅速将小鼠全脑取出，-20℃保存待测。取4只小鼠，然后进行血浆及脑组织药物测定。
表2各化合物自主活动测试结果
Figure PCTCN2020129850-appb-000063
表3各化合物给药2h后血浆及脑组织药物浓度结果
Figure PCTCN2020129850-appb-000064
结果
如表2所示内容，化合物(α)、化合物5、30、28、31、29、33、27、10、22的MK-801诱导的高活动的ED 50均小于1mg/kg，且该剂量均小于抑制正常小鼠的自发活动ED 50，提示本发明化合物在抑制MK-801诱导的高活动的同时不影响小鼠的正常的自发活动。相比于化合物(α)，化合物5效应最强，其ED 50为0.03mg/kg，其他化合物如30、31、29、10、22等的ED 50均优于或等同于化合物(α)，且对正常小鼠的自发活动影响小。
如表3所示内容，对以上化合物给药后2h进行血浆及脑组织药物进行测定发现，虽然表3中的化合物均可以透脑，但本发明化合物30，28，31，29，33和27的B/P均优于化合物(α)，提示本发明化合物的脑靶向性优于化合物(α)，有利于减少药物对外周神经系 统的影响，在维持相同药效的情况下能够减少药物不良反应。
测试例3各化合物抑制DOI诱导小鼠甩头行为测试
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、化合物(α)。
将小鼠按体重分层后随机分为空白组，模型组，及各化合物各剂量组，动物灌胃给予溶媒或待测化合物后1h，将动物放入铺有新鲜垫料的烧杯内(直径为13cm，高19cm)，按照1mg/kg的剂量腹腔注射造模药DOI(D-2,5-二甲氧基-4-碘安非他命)，记录小鼠腹腔注射DOI后第0-20分钟内甩头的次数。
表4各化合物抑制DOI诱导小鼠甩头行为测试结果
Figure PCTCN2020129850-appb-000065
结果
如表4内容所示，本发明化合物22、31、29和5对DOI诱导的小鼠甩头行为均有明显的抑制作用，且均优于化合物(α)。
测试例4各化合物的小鼠僵住症试验测试
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、化合物(α)。
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：将小鼠按体重分层后随机分为空白对照组、模型组、各化合物各剂量组。动物灌胃给予溶媒或待测化合物，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，则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5。
表5各化合物诱发小鼠僵住症行为测试结果
Figure PCTCN2020129850-appb-000066
结果
如表5内容所示，本发明化合物5诱发小鼠僵住症的ED 50为5.90mg/kg，且小鼠僵住症的ED 50/MK-801诱导的高活动(药效学)ED 50比值为(5.90/0.03＝196.7)，远大于化合物(α)僵住症的ED 50/MK-801诱导的高活动(药效学)ED 50比值(15.32/0.36＝42.6)，提示本发明化合物具有更好的治疗窗，具有良好的安全性和有效性。临床应用诱发EPS的风险低。
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 (15)

  1. 通式(I)所示的化合物或其可药用的盐，
    Figure PCTCN2020129850-appb-100001
    其中，
    -Z-为包含氧或硫原子的C 2-C 8烃链或者被一个或多个卤素取代的C 2-C 8烃链，其中
    所述烃链任选地被选自C 1-C 6烷基和羟基的一个或多个取代基取代；
    A为式A*所示的基团：
    Figure PCTCN2020129850-appb-100002
    R选自式(R-1)、(R-2)、(R-3)、(R-4)、(R-5)、(R-6)和(R-7)的基团：
    Figure PCTCN2020129850-appb-100003
    Q为N或CH；
    Y为O或S；
    R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地选自氢、卤素和C 1-C 6烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代；
    X 1和X 2各自独立地选自O和S；
    n 1为选自1-3的整数；
    n 2和n 3各自独立地为选自0-3的整数；
    优选地，
    -Z-为包含氧或硫原子的C 2-C 8烃链或者被一个或多个卤素取代的C 2-C 8烃链，其中所述烃链任选地被选自C 1-C 5的烷基和羟基的一个或多个取代基取代，优选甲基、乙基、 正丙基、异丙基或羟基；
    R 1、R 2和R 3各自独立地选自氢、卤素和C 1-C 5的烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代；
    R 4和R 7各自独立地选自氢和卤素；
    R 5和R 6各自独立地选自氢、卤素和C 1-C 3烷基，其中所述烷基任选地被一个或多个卤素取代。
  2. 权利要求1所述的化合物或其可药用的盐，其中
    式A*的基团选自式(A-1)和式(A*-2)的基团，
    Figure PCTCN2020129850-appb-100004
    其中，R 1、R 2、R 3和n 1如权利要求1所定义。
  3. 权利要求1或2所述的化合物或其可药用的盐，其中，
    -Z-为含氧或硫原子的C 2-C 6烃链，其中
    所述烃链任选地被一个或多个选自C 1-C 6烷基和羟基的取代基取代；
    或者
    -Z-为C 2-C 6烃链，其中所述烃链被一个或多个卤素取代；
    优选地，
    -Z-为含氧原子的C 2-C 6烃链，其中
    所述烃链任选地被一个或多个选自C 1-C 5的烷基和羟基的取代基取代；
    或者
    -Z-为C 2-C 6烃链，其中所述烃链被一个或多个卤素取代。
  4. 权利要求1-3中任一项所述的化合物或其可药用的盐，其中
    -Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基，或至少被一个卤素取代的C 2-C 8的直链烷基中的任意一种；
    (1)当-Z-独立地为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基时，
    A独立地为选自如下所示基团(A-1)、(A-2)或(A-3)中的任意一种：
    Figure PCTCN2020129850-appb-100005
    R独立地为选自如下所示的基团(R-1)、(R-2)、(R-3)、(R-4)或(R-5)中的任意一种：
    Figure PCTCN2020129850-appb-100006
    Q独立地为N或CH；
    X 1和X 2各自独立地为O或S中的任意一种；
    R 1和R 2各自独立地为氢或卤素中的任意一种；
    R 3独立地为氢或C 1-C 5的烷基中的任意一种；
    R 4独立地为氢或卤素中的任意一种；
    R 5和R 6各自独立地为氢，卤素，或被一个或多个卤素取代的C 1-C 3的烷基中的任意一种；
    R 7独立地为氢或卤素中的任意一种；
    n 1为1或2中的任意一个整数，
    n 2为0～3之间的任意一个整数，
    n 3为0～3之间的任意一个整数；或者
    (2)当-Z-独立地为至少被一个卤素取代的C 2-C 8的直链烷基时，
    A独立地为如下所示的基团(A-1)：
    Figure PCTCN2020129850-appb-100007
    R独立地为选自如下所示的基团(R-1)、(R-2)、(R-3)、(R-4)或(R-5)中的任意一种：
    Figure PCTCN2020129850-appb-100008
    Q独立地为N或CH；
    X 1和X 2各自独立地为O或S中的任意一种；
    R 1和R 2各自独立地为氢或卤素中的任意一种；
    R 3独立地为氢或C 1-C 5的烷基中的任意一种；
    R 4独立地为氢或卤素中的任意一种；
    R 5和R 6各自独立地为氢、卤素，或被一个或多个卤素取代的C 1-C 3的烷基中的任意一种；
    R 7独立地为氢或卤素中的任意一种；
    n 1为1或2中的任意一个，
    n 2为0～3之间的任意一个整数，
    n 3为0～3之间的任意一个整数。
  5. 如权利要求1-4中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述-Z-为C 2-C 8的直链烷醚基或C 2-C 8的直链烷氧基时，通式(I)所示的化合物或其可药用的盐选自如下所示通式(II)所示的化合物或其可药用的盐：
    Figure PCTCN2020129850-appb-100009
    n 4独立地为0～3之间的任意一个整数，优选0～2之间的任意一个整数；
    n 5为1～5之间的任意一个整数，优选1～4之间的任意一个整数；
    A、Q和R如权利要求1-4中任一项所定义。
  6. 如权利要求1-4中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述-Z-为至少被一个卤素取代的C 2-C 8的直链烷基时，通式(I)所示的化合物选自如下所示通式(III)所示的化合物：
    Figure PCTCN2020129850-appb-100010
    n 6为1～5之间的任意一个整数，优选1～4之间的任意一个整数；
    R 8和R 9各自独立地为氢或卤素中的任意一种，但不同时为氢；
    A、Q和R如权利要求1-4中任一项所定义。
  7. 权利要求1-6中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述C 1-C 5的烷基选自甲基、乙基、丙基、丁基或戊基中的任意一种，优选甲基、 乙基或丙基中的任意一种；
    所述被一个或多个卤素取代的C 1-C 3的烷基为-(CH 2) aCX 3，其中a为选自0～2的整数，X为卤素。
  8. 如权利要求1-7中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述卤素选自氟、氯、溴或碘中的任意一种。
  9. 权利要求1-8中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述式(I)化合物选自如下所示通式(I-1)、(I-2)、(I-3)、或(I-4)的化合物或其可药用的盐：
    Figure PCTCN2020129850-appb-100011
    其中，Q、R、R 1、R 2、R 3、R 8、R 9、n 1、n 4、n 5和n 6如权利要求1-6中任一项所定义,；
    优选地，
    R 1和R 2各自独立地选自氢和卤素，优选氢、氟、溴或氯；
    R 3选自氢和C 1-C 5的烷基，其中所述烷基任选地被选自卤素、氨基和羟基的取代基取代，优选氢、甲基或乙基；
    R 4和R 7各自独立地选自氢、氟、溴和氯；
    R 5和R 6各自独立地选自氢、氟、氯、溴和三氟甲基；
    R 8和R 9各自独立地选自氢、氟、溴和氯，其中R 8和R 9不同时为氢。
    n 1为1或2的整数；
    n 4为1或2的整数；
    n 5和n 6各自独立地为1～4之间的任意一个整数。
  10. 权利要求9所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述式(I)化合物选自通式(I-1)和(I-2)的化合物或其可药用的盐：
    其中，Q、R、R 1、R 2、R 3、n 1、n 4和n 5如权利要求1-6中任一项所定义；
    优选地，
    R选自(R-1)和(R-3)的基团，其中X 1和X 2各自独立地为O或S中的任意一种，更优选地，X 1为O或S中的任意一种，X 2为S；
    R 1为H；
    R 2选自氢和卤素，更优选氢、氟或氯；
    R 3选自氢和非取代的C 1-C 5的烷基，更优选氢、甲基或乙基；
    R 4选自氢和卤素，更优选氢、氟或氯；
    n 1为1；
    n 4为1；
    n 5为1～4之间的任意一个整数。
  11. 如权利要求1-10中任一项所述的通式(I)所示的化合物或其可药用的盐，其特征在于，
    所述通式(I)所示化合物选自如下所示任意一个化合物：
    Figure PCTCN2020129850-appb-100012
    Figure PCTCN2020129850-appb-100013
    Figure PCTCN2020129850-appb-100014
    Figure PCTCN2020129850-appb-100015
    Figure PCTCN2020129850-appb-100016
    Figure PCTCN2020129850-appb-100017
  12. 制备权利要求1-11中任一项所述的通式(I)所示的化合物或其可药用的盐的方法，其特征在于，包括：
    Figure PCTCN2020129850-appb-100018
    通过亲核取代反应或还原胺化反应，使通式化合物(I-r)与通式化合物(I-g)、通式化合物(I-n)、通式化合物(I-l)或通式化合物(I-q)中的任意一种反应制备得到式(I)所示的化合物；
    其中，Z，A，R，Q，R 1，R 2，R 3，R 8，R 9，n 1，n 4，n 5和n 6如权利要求4～6中任一项所定义；
    优选地，n 4为1。
  13. 一种药物组合物，其特征在于，
    包含治疗有效量的如权利要求1-11中任一项所述的通式(I)所示的化合物或其可药用的盐和药学上可接受的载体。
  14. 权利要求1-11中任一项所述的通式(I)所示的化合物或其可药用的盐或如权利要求13所述的药物组合物在制备治疗神经精神类疾病的药物中的用途。
  15. 权利要求14所述的用途，其特征在于，
    所述神经精神类疾病选自精神分裂症、抑郁症、焦虑症、睡眠障碍、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选抑郁症、焦虑症、精神分裂症、睡眠障碍、神经退行性疾病或双相情感障碍中的任意一种或多种，更优选为精神分裂症。
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