A tetrahydro(iso)quinoline or indoline derivative, composition and application thereof

Abstract

The present invention discloses a tetrahydro(iso)quinoline or indoline derivative, a composition and its application. The derivative is a compound having a general structural formula (I) or a pharmaceutically acceptable salt thereof; the composition comprises a tetrahydro(iso)quinoline derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The present invention also provides the application of a tetrahydro(iso)quinoline derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a drug for preventing or treating a neuropsychiatric disease, wherein the neuropsychiatric disease is schizophrenia. The derivative has small extrapyramidal side effects; its application in the treatment of schizophrenia has the potential to improve the positive symptoms of schizophrenia, and can improve the therapeutic efficacy of negative symptoms and cognitive impairment, so as to meet the needs of clinical medication.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a tetrahydro(iso)quinoline or indoline derivative, a composition and application thereof. Background Art

[0002] Schizophrenia is a disease characterized by a deep split in cognition and emotion, which affects the most basic human behaviors, such as language, thought, perception, and self-perception. The symptoms of the disease can be divided into positive symptoms, negative symptoms, and cognitive impairment. Schizophrenia is one of the most serious mental illnesses. About 1% of people worldwide suffer from schizophrenia, and only 5% of all patients who receive treatment can eventually recover completely. In addition, because schizophrenia often causes comorbidities, such as anxiety disorders, depression, or psychotropic drug abuse, according to surveys and studies, more than 1 / 3 of schizophrenia patients suffer from at least one or more concurrent mental illnesses or cognitive disorders.

[0003] According to the dopamine hypothesis, D2 receptors are considered to be the targets most closely related to schizophrenia. D2 receptors are highly expressed in the striatum and pituitary gland, and the neural signals sent by D2 receptors affect multiple physiological functions such as movement, hormone secretion and drug abuse. The positive symptoms of schizophrenia are believed to be caused by the overactivity of D2 receptors in the mesolimbic dopamine pathway (including projections from the ventral tegmental area to the nucleus accumbens, amygdala and hippocampus) after activation. Therefore, almost all typical and atypical antipsychotic drugs for schizophrenia achieve the purpose of treating positive symptoms by antagonizing D2 receptors. Traditionally, 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 have made breakthroughs in the treatment of positive symptoms of schizophrenia, but have little effect on negative symptoms and cognitive impairment, and often produce extrapyramidal side effects. They are ineffective for one-third of schizophrenia patients.

[0004] After the 1960s, a new generation of antipsychotics with novel mechanisms of action were developed, including Ziprasidone, Risperidone, etc., which are called second-generation antipsychotics, that is, new antipsychotics. Although their pharmacological effects are not completely consistent, they have common pharmacological characteristics, that is, they have good affinity for multiple subtypes of the 5-hydroxytryptamine receptor family. The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes with a particularly high density of 5-HT. 1A and 5-HT 2A5-HT in the primary motor cortex and dorsolateral striatum 1A Activation of the receptors can modulate dopaminergic transmission in the nervous system, thereby alleviating extrapyramidal side effects. 1A Activation of 5-HT receptors can promote the release of dopamine, thereby enhancing the function of the mesocortical dopamine pathway, and can also enhance the inhibitory effect of dopamine D2 receptor antagonists on dopamine release, and also increase choline levels. This may be beneficial for improving the negative symptoms and cognitive impairment of schizophrenia patients; 2A Activation of the receptor can activate serotonergic neurons through a variety of mechanisms, including direct or indirect inhibition of GABAergic interneurons, as well as direct activation of other neurons, especially glutamate neurons. 2A The antagonistic effect of the receptor helps to improve the positive and negative symptoms of schizophrenia, and can also reduce the side effects of EPS (extrapyramidal syndrome) caused by the blockade of D2 receptors in the striatum. 5-HT6 receptors are expressed in the presynapses of the striatum, limbic and specific cortical areas, and are accompanied by other non-5-HT neurons such as acetyl choline (ACh), glutamate (Glutamicacid, Glu), γ-aminobutyric acid (γ-amino-butyric acid GABA), and their distribution almost overlaps with that of DA receptors. Functionally, 5-HT6 receptors are involved in the regulation of a variety of cognitive-related neurotransmitters such as Ach and Glu. In addition, 5-HT 2C Receptors are closely related to weight gain. The second-generation antipsychotic drugs developed based on this have more advantages in clinical effects than the first-generation antipsychotic drugs. They are not only as effective as traditional antipsychotics for positive symptoms, but also effective for negative symptoms and cognitive deficits, and have a wider spectrum of action. However, these drugs have a certain affinity for side effect targets such as norepinephrine receptors (α1, α2) and histamine H1 receptors, which can produce adverse reactions such as QT interval prolongation, hyperprolactinemia and weight gain.

[0005] Aripiprazole, which was approved by the FDA in November 2002, has a unique mechanism of action, interacting with dopamine D2, D3, and 5-HT 1A and 5-HT 2A The receptors have high affinity for D4 and 5-HT 2c Aripiprazole has moderate affinity for D2 and 5-HT7, α1, H1 receptors and 5-HT reabsorption sites. 1A Partial agonism of 5-HT receptors 2AAripiprazole can produce anti-schizophrenia effects by antagonizing the dopamine receptors, and has the effect of stabilizing the activity of the dopamine system. Clinical trials have shown that aripiprazole is effective for both positive and negative symptoms of schizophrenia, and long-term use can also reduce the relapse rate of schizophrenia and improve mood and cognitive dysfunction. Its EPS adverse reactions and the effect of increasing serum prolactin levels are smaller than those of traditional antipsychotics or the aforementioned atypical antipsychotics.

[0006] The distribution of D3 receptors in the brain is mainly selectively distributed in the limbic system. There are two main DA neural pathways in the brain. One is the substantia nigra striatum pathway that regulates motor function, and the other is the ventral tegmental area of ​​the midbrain. The prefrontal cortex DA pathway is closely related to learning, cognition and emotional activities. Its dysfunction will lead to schizophrenia. This DA pathway is also the main pathway for reward effects in the brain. D3R is distributed in both DA neural pathways and has complex interactions with other DA receptor subtypes. It may be a target for antipsychotic drug treatment. The selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia. In addition, it can prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease. Therefore, finding an anti-schizophrenia drug with multi-receptor binding and few side effects is of great significance for clinical treatment. Summary of the invention

[0007] One of the purposes of the present invention is to provide a tetrahydro(iso)quinoline or indoline derivative, which can bind to multiple receptors and has small extrapyramidal side effects; the use of the derivative in the treatment of schizophrenia can potentially improve the positive symptoms of schizophrenia and improve the therapeutic efficacy of negative symptoms and cognitive disorders to meet the needs of clinical medication.

[0008] The second object of the present invention is to provide the above derivatives for use in the preparation of drugs for preventing or treating neuropsychiatric diseases.

[0009] To achieve the above object, the technical solution adopted by the present invention is: a tetrahydro(iso)quinoline derivative, which is a compound having the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Where Z is -(CH2) i - or substituted -(CH2) i -, i is an integer from 1 to 5, the substituted -(CH2) i - is a substituent selected from the group consisting of hydroxyl, carbonyl and methyl; Y is O or S; X and Q are N or CH respectively; n and m are 0, 1 or 2 respectively;

[0012] R1, R2, and R3 are each selected from hydrogen, phenyl, halogenated phenyl, halogen, C 1-5 Alkyl, substituted C 1-5 One of an alkyl group and a ring-opening amino group, wherein the substituted C 1-5 The substituent on the alkyl group is selected from one of halogen, amino and hydroxyl.

[0013] Preferably, i is an integer of 2-5, and the halogen is fluorine, chlorine, bromine or iodine.

[0014] Preferably, R1, R2, and R3 are each selected from one of hydrogen, fluorine, phenyl, methyl, ethyl, propyl, trifluoromethyl, and hydroxymethyl.

[0015] Preferably, the salt is a pharmaceutically acceptable inorganic acid salt selected from one of hydrochloride, hydrobromide, phosphate, sulfate and perchlorate.

[0016] Preferably, the salt is a pharmaceutically acceptable organic acid salt selected from one of acetate, oxalate, maleate, tartrate, citrate, succinate and malonate.

[0017] Preferably, the salt is a pharmaceutically acceptable salt selected from the group consisting of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0018] Preferably, the tetrahydro(iso)quinoline or indoline derivative is:

[0019] 1-(1-acetylindolin-5-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one,

[0020] 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)indolin-1-yl)ethan-1-one,

[0021] 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)indolin-1-yl)ethan-1-one,

[0022] 1-(1-acetylindolin-5-yl)-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butanone,

[0023] 3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-(1-propionylindolin-5-yl)propan-1-one,

[0024] 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)indolin-1-yl)propan-1-one,

[0025] 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)indolin-1-yl)propan-1-one,

[0026] 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propanoyl)-N,N-dimethylindoline-1-carboxamide,

[0027] 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)-N,N-dimethylindoline-1-carboxamide,

[0028] 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)-N,N-dimethylindoline-1-carboxamide,

[0029] 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one,

[0030] 1-(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one

[0031] 1-(1-acetylindolin-5-yl)-3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)propan-1-one,

[0032] 3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-(1-propionylindolin-5-yl)propan-1-one,

[0033] 5-(3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)propionyl)-N,N-dimethylindoline-1-carboxamide,

[0034] 5-(3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-hydroxypropyl)-N,N-dimethylindoline-1-carboxamide,

[0035] 3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-(1-acetylindolin-5-yl)propan-1-one,

[0036] 1-(5-(3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-hydroxypropyl)indolin-1-yl)ethan-1-one,

[0037] 5-(3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)-N,N-dimethylindoline-1-carboxamide.

[0038] On the other hand, the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the tetrahydro(iso)quinoline or indoline derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0039] The present invention further provides the use of the tetrahydro(iso)quinoline or indoline derivatives or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present invention in the preparation of drugs for preventing or treating neuropsychiatric diseases. Preferably, the neuropsychiatric disease is schizophrenia.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The compounds provided by the present invention have an effect on D2, D3, 5HT 1A , 5HT 2A It has a strong affinity for 5-HT6 and σ1 receptors, and has the potential to improve the positive symptoms of schizophrenia, and has a potential improvement effect on negative symptoms and cognitive impairment; 2C The compounds of the present invention have the advantages of low affinity for α1, H1 and α2, and thus will not cause weight gain. Animal experiments show that the compounds of the present invention have little extrapyramidal side effects. DETAILED DESCRIPTION

[0042] The present invention is further described in detail below in conjunction with embodiments.

[0043] In the following examples, the following definitions used herein shall apply unless otherwise stated. For purposes of the present invention, chemical elements are consistent with the periodic table CAS version and Handbook of Chemistry and Physics (75th edition, 1994). In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0044] The term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.

[0045] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-5 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl and C5 alkyl as disclosed independently.

[0046] Unless explicitly described, the term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described in the present invention. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl and the like.

[0047] The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0048] The general synthesis method of the derivatives of the present invention is to first synthesize a tetrahydro(iso)quinoline or indoline, then react it with a straight-chain chloroacyl chloride, and then react with the nitrogen end to obtain the derivatives. For example:

[0049]

[0050] Example 1

[0051] Preparation of 1-(1-acetylindolin-5-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one, the reaction formula is:

[0052]

[0053] The specific preparation process is:

[0054] (1) Take 5.0 g of indoline, add 50 ml of acetone, then slowly add 3.3 g of acetyl chloride, stir until reflux, and the reaction is complete after 4 hours. Cool to room temperature, concentrate the reaction solution, dissolve it with ethyl acetate, wash it with water, dry it with anhydrous magnesium sulfate, filter it with suction, concentrate it, and beat it to obtain 6.3 g of white solid, with a yield of 93.2%.

[0055] (2) Take 5.0g of the product of the first step, add 4.9g of 3-chloropropionyl chloride and 25mL of 1,2-dichloroethane, cool to about 0°C in an ice-water bath, add 11.8g of anhydrous aluminum chloride in batches, control the internal temperature to about 0°C, keep warm for half an hour after the addition, remove the ice-water bath, and react at room temperature for 2 hours. Add ice water to quench the system, filter, extract with ethyl acetate, wash with water, dry with anhydrous magnesium sulfate, filter, concentrate, and column chromatography (PE: EA = 6:1) to obtain 6.8g of solid, with a yield of 87.3%.

[0056] (3) Take 0.5 g of the product of the third step, add 0.58 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, 1 g of anhydrous potassium carbonate, 0.01 g of potassium iodide and 25 ml of DMF, react at 80° C. for 7 hours, cool to room temperature, add 100 ml of tap water, add an appropriate amount of dichloromethane, wash with water, separate the water layer, dry the organic layer with anhydrous magnesium sulfate, evaporate the solvent to obtain a light yellow oil, and obtain 0.65 g of a white solid by column chromatography.

[0057] 1 HNMR(400MHz,Chloroform-d)δ8.24(d,J=8.4Hz,1H),7.88–7.81(m,2H),7.68(dd,J =8.8,5.6Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),7.04(t,J=8.8Hz,1H),4.12(t,J=8.4Hz,2H) ,3.24(t,J=8.4Hz,2H),3.18(dd,J=8.0,6.8Hz,2H),3.12–3.05(m,3H),2.88(dd,J=8.0,6.8 Hz,2H),2.25(s,5H),2.08–2.05(m,4H).MS(ESI)m / z436.1([M+H] + ).

[0058] Example 2

[0059] Preparation of 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)indolin-1-yl)ethane-1-one, the reaction formula is:

[0060]

[0061] The specific preparation process is as follows: 0.5 g of the target compound prepared in Example 1 was dissolved in 20 mL of anhydrous methanol, cooled to zero degrees in an ice-water bath, 0.1 g of sodium borohydride was added, stirring continued for 1 hour, and 10 mL of water was added to quench the reaction. The solvent was evaporated, an appropriate amount of dichloromethane was added, washed with water, the water layer was separated, the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated to obtain a light yellow oil, and 0.40 g of a white solid was obtained by column chromatography.

[0062] 1 H NMR(400MHz,Chloroform-d)δ8.14(d,J=8.4Hz,1H),7.66(dd,J=8.8,5.2Hz,1H), 7.26–7.22(m,2H),7.15(d,J=8.4Hz,1H),7.04(td,J=8.8,2.4Hz,1H),4.91(dd,J=7.6,3. 6Hz,1H),4.05(t,J=8.4Hz,2H),3.19–3.15(m,5H),2.83–2.57(m,3H),2.21(s,3H),2.18– 2.06(m,6H),1.88–1.84(m,2H).MS(ESI)m / z 438.2([M+H] + ).

[0063] Example 3

[0064] Preparation of 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)indolin-1-yl)ethane-1-one, the reaction is:

[0065]

[0066] The specific preparation process is as follows: 0.5 g of the target compound prepared in Example 1 was dissolved in 10 mL of trifluoroacetic acid, and then 0.10 g of triethylsilane was slowly added, and stirred at room temperature overnight. The solvent was evaporated, and an appropriate amount of dichloromethane was added, and the mixture was washed with a saturated NaHCO3 solution. The water layer was separated, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated to obtain a light yellow oily substance, and 0.35 g of a colorless transparent oily substance was obtained by column chromatography.

[0067] 1H NMR(400MHz,Chloroform-d)δ8.07(d,J=8.8Hz,1H),7.67(dd,J=8.8,5.6Hz,1H), 7.20(dd,J=8.6,2.0Hz,1H),7.05–6.95(m,3H),4.01(t,J=8.4Hz,2H),3.14(t,J=8.4Hz, 2H),3.08–2.95(m,3H),2.58(t,J=7.6Hz,2H),2.41–2.35(m,2H),2.18(s,3H),2.15–1.97 (m,6H),1.89–1.71(m,2H).MS(ESI)m / z 422.2([M+H] + ).

[0068] Example 4

[0069] Preparation of 1-(1-acetylindolin-5-yl)-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butanone

[0070] The target compound was prepared by using 4-chlorobutyryl chloride instead of 3-chloropropionyl chloride in Example 1 and following the method of Example 1 for the rest of the process.

[0071] 1 H NMR(400MHz,Chloroform-d)δ8.27(d,J=8.4Hz,1H),7.93–7.80(m,2H),7.66(dd, J=8.8,5.2Hz,1H),7.25(dd,J=8.4,2.0Hz,1H),7.06(td,J=8.8,2.0Hz,1H),4.15(t,J=8.4 Hz,2H),3.27(t,J=8.4Hz,2H),3.13–3.04(m,3H),3.01(t,J=7.2Hz,2H),2.49(t,J=7.2Hz, 2H),2.29(s,3H),2.19–2.13(m,2H),2.05–1.96(m,6H).MS(ESI)m / z 450.2([M+H] + ).

[0072] Example 5

[0073] Preparation of 3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-(1-propionylindolin-5-yl)propan-1-one

[0074] The target compound was prepared by using propionyl chloride instead of acetyl chloride in Example 1 and following the method of Example 1 for the rest of the process.

[0075] 1 H NMR(400MHz,Chloroform-d)δ8.27(d,J=8.4Hz,1H),7.88–7.79(m,2H),7.67(dd, J=8.8,5.2Hz,1H),7.26–7.19(m,1H),7.03(td,J=8.8,2.0Hz,1H),4.10(t,J=8.8Hz,2H), 3.22–3.18(m,4H),3.13–2.99(m,3H),2.87(t,J=7.2Hz,2H),2.47(q,J=7.2Hz,2H),2 .28–2.24(m,2H),2.08–2.04(m,4H),1.22(t,J=7.3Hz,3H).MS(ESI)m / z450.2([M+H] + ).

[0076] Example 6

[0077] Preparation of 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)indolin-1-yl)propan-1-one

[0078] The target compound prepared in Example 1 in Example 2 was replaced by “the target compound prepared in Example 5”, and the target compound was prepared according to the method of Example 2 in other processes.

[0079] 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J=8.4Hz,1H),7.66(dd,J=8.8,5.2Hz,1H), 7.24(d,J=9.2Hz,2H),7.16(d,J=8.4Hz,1H),7.04(td,J=8.8,2.0Hz,1H),4.91(dd,J=8. 0,3.6Hz,1H),4.03(t,J=8.4Hz,2H),3.35–3.02(m,5H),2.83–2.59(m,2H),2.50–2.25(m, 3H),2.11(d,J=6.4Hz,5H),1.86(dq,J=13.2,4.8,4.1Hz,2H),1.22(q,J=7.2Hz,4H).MS(ESI)m / z 452.2([M+H] + ).

[0080] Example 7

[0081] Preparation of 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)indolin-1-yl)propan-1-one

[0082] The target compound prepared in Example 1 in Example 3 was replaced by “the target compound prepared in Example 5”, and the target compound was prepared according to the method of Example 3 in other processes.

[0083] 1 H NMR(400MHz,Chloroform-d)δ8.12(d,J=8.8Hz,1H),7.69(dd,J=8.8,5.2Hz,1H), 7.22(dd,J=8.4,2.4Hz,1H),7.08–6.94(m,3H),4.01(t,J=8.4Hz,2H),3.15(t,J=8.4Hz, 2H),3.06(dd,J=9.2,5.2Hz,3H),2.59(t,J=7.6Hz,2H),2.46–2.36(m,4H),2.14–2.03(m, 4H),1.82(dd,J=8.8,6.0Hz,2H),1.28–1.17(m,5H).MS(ESI)m / z 436.2([M+H] + ).

[0084] Example 8

[0085] Preparation of 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propionyl)-N,N-dimethylindoline-1-carboxamide

[0086] The target compound was prepared by using N,N-dimethylformyl chloride instead of acetyl chloride in Example 1 and following the method of Example 1 for other processes.

[0087] 1 H NMR(400MHz,Chloroform-d)δ7.85–7.76(m,2H),7.67(dd,J=8.8,5.2Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.03(td,J=8.8,2.0H z,1H),6.95–6.88(m,1H),3.95(t,J=8.4Hz,2H),3.16(dd,J=8.0,6.8Hz,2H),3.13–3.03(m,5H),2.94(s,6H),2.92–2.85(m,2H), 2.28–2.25(m,2H),2.06(tt,J=6.4,3.6Hz,4H).MS(ESI)m / z 465.2([M+H] +).

[0088] Example 9

[0089] Preparation of 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)-N,N-dimethylindoline-1-carboxamide

[0090] The target compound prepared in Example 1 in Example 2 was replaced by “the target compound prepared in Example 8”, and the target compound was prepared according to the method of Example 2 in other processes.

[0091] 1 H NMR(400MHz,Chloroform-d)δ7.66(dd,J=8.8,5.2Hz,1H),7.25–7.19(m,2H),7.12(dd,J=8.4,1.6Hz,1H),7.04(td,J=8.8,2.4H z,1H),6.90(d,J=8.0Hz,1H),4.88(d,J=7.6Hz,1H),3.89(t,J=8.0Hz,2H),3.21(d,J=8.0Hz,3H),3.01(t,J=8.4Hz,2H),2.91(s, 7H),2.81–2.59(m,2H),2.33(s,1H),2.15–2.10(m,5H),1.96–1.76(m,2H).MS(ESI)m / z467.2([M+H] + ).

[0092] Example 10

[0093] Preparation of 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)-N,N-dimethylindoline-1-carboxamide

[0094] The target compound prepared in Example 1 was replaced by “the target compound prepared in Example 8” in Example 3, and the target compound was prepared according to the method of Example 3 in other processes.

[0095] 1H NMR(400MHz,Chloroform-d)δ7.65(dd,J=8.8,5.2Hz,1H),7.24–7.18(m,2H),7.11(dd,J=8.0,1.6Hz,1H),7.05(td,J=8.8,2.4Hz,1H),6.91(d,J=8.0Hz,1 H),3.90(t,J=8.0Hz,2H),3.24–3.18(m,5H),3.02(t,J=8.0Hz,2H),2.92(s, 6H),2.81–2.59(m,2H),2.11(d,J=6.0Hz,6H),1.96–1.76(m,2H).MS(ESI)m / z 451.2([M+H] + ).

[0096] Embodiment 11

[0097] Preparation of 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one

[0098] The target compound was prepared by using "1,2,3,4-tetrahydroisoquinoline" instead of "indoline" in Example 1 and following the method of Example 1 for the rest of the process.

[0099] 1 HNMR (400MHz, DMSO-d6) δ8.23–8.13(m,1H),7.88(d,J=15.5Hz,1H),7.86–7.80(m,1H),7.72(dd,J=9.1,2.1Hz,1H),7.41–7.29(m ,2H),4.71(d,J=21.9Hz,2H),3.70(q,J=8.8,5.8Hz,7H),3.23(t,J=11.3Hz,3H),2.90(dt,J=44.3,6.0Hz,2H),2.31(d,J=24.0Hz, 5H),2.10(d,J=3.8Hz,3H).MS(ESI)m / z 450.2([M+H] + ).

[0100] Example 12

[0101] Preparation of 1-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one

[0102] The target compound was prepared by substituting "1,2,3,4-tetrahydroquinoline" for "indoline" in Example 1 and following the method of Example 1 for other steps.

[0103] 1 HNMR(400MHz,Chloroform-d)δ7.82–7.75(m,1H),7.70–7.65(m,2H),7.25–7.17(m,2H),7.07–7.00(m,1H),3.78(t,J=6.4Hz,2H),3.18(t,J=7. 3Hz,2H),3.10–3.02(m,3H),2.87(t,J=7.3Hz,2H),2.80–2.76(m,2H),2.30–2.18(m,5H),2.08–2.02(m,4H),1.97(p,J=6.5Hz,2H).MS(ESI)m / z 450.2([M+H] + ).

[0104] Embodiment 13

[0105] Preparation of 1-(1-acetylindolin-5-yl)-3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)propan-1-one

[0106] The target compound was prepared by substituting "3-(1-piperazinyl)-1,2-benzisothiazole" for "6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole hydrochloride" in Example 1, and the other processes were carried out according to the method of Example 1.

[0107] 1 HNMR(400MHz,Chloroform-d)δ8.27(d,J=8.4Hz,1H),7.93(d,J=8.2Hz,1H),7.91 –7.87(m,1H),7.86(s,1H),7.83(d,J=8.1Hz,1H),7.53–7.45(m,1H),7.41–7.34(m,1H),4 .15(t,J=8.5Hz,2H),3.71–3.50(m,4H),3.34–3.17(m,4H),2.96(t,J=7.3Hz,2H),2.78(t, J=4.8Hz,4H),2.29(s,3H).MS(ESI)m / z 435.1([M+H] + ).

[0108] Embodiment 14

[0109] Preparation of 3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-(1-propionylindolyl-5-yl)propan-1-one

[0110] Substitute "3-(1-piperazinyl)-1,2-benzisothiazole" for "6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole hydrochloride" in Example 5, and prepare the target compound according to the method of Example 5 in other processes.

[0111] 1 H NMR(400MHz,Chloroform-d)δ8.27(t,J=6.3Hz,1H),7.88(q,J=7.5,6.7Hz,2H), 7.84–7.76(m,2H),7.45(q,J=6.8Hz,1H),7.34(q,J=6.9Hz,1H),4.10(q,J=7.3Hz,2H),3 .55(d,J=6.6Hz,4H),3.21(dq,J=13.2,6.3Hz,4H),2.92(q,J=6.5Hz,2H),2.74(d,J=6.0 Hz,4H),2.46(t,J=6.9Hz,2H),1.23(q,J=6.6Hz,3H).MS(ESI)m / z 471.1([M+Na] + ).

[0112] Embodiment 15

[0113] Preparation of 5-(3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)propionyl)-N,N-dimethylindoline-1-carboxamide

[0114] Substitute "3-(1-piperazinyl)-1,2-benzisothiazole" for "6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole hydrochloride" in Example 8, and prepare the target compound according to the method of Example 8 in other processes.

[0115] 1 H NMR(400MHz,Chloroform-d)δ7.92–7.86(m,1H),7.85–7.76(m,3H),7.45(ddd,J =8.2,7.0,1.1Hz,1H),7.34(ddd,J=8.2,7.0,1.1Hz,1H),6.92(d,J=8.2Hz,1H),3.96(t,J=8.3Hz,2H),3.56(t ,J=4.9Hz,4H),3.22–3.14(m,2H),3.07(t,J=8.3Hz,2H),2.96–2.88(m,8H),2.75(t,J=4.9Hz,4H).MS(ESI)m / z 464.2([M+Na] + ).

[0116] Example 16

[0117] Preparation of 5-(3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-hydroxypropyl)-N,N-dimethylindoline-1-carboxamide

[0118] The target compound prepared in Example 1 was replaced by “the target compound prepared in Example 15” in Example 2, and the target compound was prepared according to the method of Example 2 in other processes.

[0119] 1 HNMR(400MHz,Chloroform-d)δ7.66(dd,J=8.8,5.1Hz,1H),7.25–7.19(m,2H),7.12(dd,J=8.2,1.8Hz,1H),7.04(td,J=8.8,2.2H z,1H),6.90(d,J=8.2Hz,1H),4.88(d,J=7.5Hz,1H),3.89(t,J=8.2Hz,2H),3.21(d,J=56.7Hz,3H),3.01(t,J=8.2Hz,2H),2.91(s, 6H),2.81–2.59(m,2H),2.33(s,1H),2.11(d,J=6.1Hz,5H),1.96–1.76(m,2H).MS(ESI)m / z 466.2([M+H] + ).

[0120] Embodiment 17

[0121] Preparation of 3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-(1-acetylindolin-5-yl)propan-1-one

[0122] The target compound was prepared by using "3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole" instead of "6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride" in Example 1, and the other processes were carried out according to the method of Example 1.

[0123] 1HNMR(400MHz,Chloroform-d)δ8.28(d,J=8.5Hz,1H),8.14(s,1H),7.96–7.83(m, 3H),7.39(d,J=8.0Hz,1H),7.27–7.10(m,3H),6.23(s,1H),4.15(t,J=8.6Hz,2H),3.38–3. 21(m,6H),3.00(t,J=7.4Hz,2H),2.85(t,J=5.7Hz,2H),2.67(s,2H),2.29(s,3H).MS(ESI) m / z 414.2([M+H] + ).

[0124] Embodiment 18

[0125] Preparation of 1-(5-(3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-hydroxypropyl)indolin-1-yl)ethan-1-one

[0126] The target compound prepared in Example 1 was replaced by “the target compound prepared in Example 17” in Example 2, and the target compound was prepared according to the method of Example 2 in other processes.

[0127] 1 HNMR(400MHz,Chloroform-d)δ8.19(d,J=10.0Hz,1H),7.91(d,J=7.9Hz,1H),7.40(d,J=8.0Hz,1H),7.30(d,J=9.5Hz,3H),7.26 –7.15(m,4H),6.22(s,2H),4.98(t,J=5.8Hz,1H),4.08(t,J=8.4Hz,2H),3.41(d,J=16.3Hz,1H),3.31(s,1H),3.24(q,J=8.6Hz, 2H),3.00–2.92(m,1H),2.88–2.73(m,3H),2.69(s,2H),2.46(s,1H),2.25(s,3H),1.94(q,J= 5.2Hz,3H).MS(ESI)m / z 416.2([M+H] + ).

[0128] Embodiment 19

[0129] Preparation of 5-(3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)propionyl)-N,N-dimethylindoline-1-carboxamide

[0130] Substitute "3-(1-piperazinyl)-1,2-benzisothiazole" for "6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole hydrochloride" in Example 8, and prepare the target compound according to the method of Example 8 in other processes.

[0131] 1 HNMR(400MHz,Chloroform-d)δ8.27(s,1H),7.93–7.83(m,3H),7.39(d,J=8.0Hz, 1H),7.26–7.13(m,3H),6.95(d,J=8.2Hz,1H),6.22(s,1H),3.99(t,J=8.3Hz,2H),3.41– 3.32(m,2H),3.29(t,J=7.5Hz,2H),3.11(t,J=8.3Hz,2H),3.04(t,J=7.5Hz,2H),2.99( d,J=1.2Hz,6H),2.89(t,J=5.8Hz,2H),2.68(d,J=6.3Hz,2H).MS(ESI)m / z443.2([M+H] + ).

[0132] The structural formula of the compound prepared in the above examples is shown in Table 1 below:

[0133] Table 1 Structural formula of the compounds prepared in Examples 1-19

[0134]

[0135]

[0136] Embodiment 20

[0137] Preparation of receptor membranes and determination of ligand affinity (inhibition rate)

[0138] Receptor binding assay materials:

[0139] Isotope ligand 3 H]-Ketanserin (67.0 Ci / mmol), 3 H-8-OH-DPAT (67.0 Ci / mmol), 3 H-Spiperone (67.0Ci / mmol), [3H]-Spiperone, [ 3 H]-mesulergine(67.0Ci / mmol), 3 H-pyrilamine, 3 H-prazosin, [ 3H]-(+)-pentazocine (250 μCi), purchased from PerkinElmer; Methysergide, purchased from RBI; GF / C glass fiber filter paper, purchased from Whatman; Tris imported and packaged; PPO and POPOP purchased from Shanghai Reagent Factory No. 1; lipid-soluble scintillation fluid. Wallace 1450 MicroBeta TriLux scintillation counter, a product of Perkin Elmer. CHO-5-HT 1A Cells, Thermo Fisher.

[0140] (1) 5HT 1A Preparation of receptor membranes and determination of ligand affinity (inhibition rate)

[0141] CHO-5-HT 1A The cells were taken out of the -80°C freezer and thawed naturally. They were centrifuged at 1000 g and 4°C for 10 min. The supernatant was discarded, the precipitate was taken, and a homogenate solution (50 mM Tris-HCl buffer, containing 1 mM EDTA, 0.1% ascorbic acid, 20 μM pargyline and 10 mM MgSO4, pH = 7.4) was added to the precipitate and mixed for 20-30 s. The cells were then centrifuged at 50,000 g and 4°C for 15 min. The supernatant was carefully discarded, and the homogenate solution (50 mM Tris-HCl buffer, containing 1 mM EDTA, 0.1% ascorbic acid, 20 μM pargyline and 10 mM MgSO4, pH = 7.4) was added again and mixed. The cells were centrifuged at 50,000 g and 4°C for 15 min. The centrifugation was repeated three times. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80°C for later use.

[0142] Experimental methods:

[0143] (1-1) Prepared 5HT 1A Add an appropriate amount of homogenate (0.05M Tris-HCl buffer, containing 0.1% ascorbic acid, 10 μM pargyline and 4 mM CaCl2) to the receptor membrane and disperse it evenly with a homogenizer to prepare a suspension of 8 mg / mL membrane for later use;

[0144] (1-2) Add 100 μL of membrane suspension and 100 μL of homogenate (0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10 μM pargyline and 4 mM CaCl2) to each reaction tube;

[0145] (1-3) Add 100 μL of homogenate (0.05 M Tris-HCl buffer, containing 0.1% ascorbic acid, 10 μM pargyline and 4 mM CaCl2) to the total binding tube (TB), and add 100 μL of 5-HT (final concentration 10 -5 M), 100 μL of the test compound (final concentration 10 -5 M);

[0146] (1-4) Add radioligand to each reaction tube 3 H-8-OH-DPAT 10 μL (each reaction tube has 2 parallel tubes, and each tube is placed on ice during sample addition);

[0147] (1-5) Incubate each reaction tube at 37°C for 10 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure and washed thoroughly with ice-cold assay buffer (0.05 M Tris-HCl). The filter is removed and placed in a 3 ml scintillation cup, and 2 ml of toluene scintillation fluid is added and mixed.

[0148] (1-6) Place the scintillation vial into a liquid scintillation counter for counting.

[0149] Each compound was tested in duplicate and two separate experiments were performed.

[0150] (2) 5HT 2A Preparation of receptor membranes and determination of ligand affinity (inhibition rate)

[0151] 5HT 2A Preparation of receptor membrane: The rat was decapitated and the operation was carried out on ice. The brain striatum was quickly taken out, and two striatums were combined in a centrifuge tube. 3 ml of buffer (0.05 M Tris-HCl buffer) was added and homogenized at gear 4 for 3-4 seconds. Homogenization was performed 4 times, and then 5 ml of buffer (0.05 M Tris-HCl buffer) was added. The tubes were incubated at 37°C for 10 min. After incubation, the weight of the tubes was adjusted with a balance, and the tubes were centrifuged at 12000 r and 4°C for 20 min. The supernatant was discarded, 3 ml of homogenate (0.05 M Tris-HCl buffer) was added, and the mixture was mixed with a vortex mixer. Then 5 ml of buffer (0.05 M Tris-HCl buffer) was added, and the mixture was centrifuged. The supernatant was discarded, and the precipitate was stored at -80°C for later use.

[0152] Experimental methods:

[0153] (2-1) Prepared 5HT 2A Add an appropriate amount of homogenate (0.05 M Tris-HCl buffer) to the membrane and disperse it evenly using a homogenizer to make a 210 mg / mL membrane suspension for later use;

[0154] (2-2) Add 100 μL of membrane suspension and 100 μL of homogenate (0.05 M Tris-HCl buffer) to each reaction tube;

[0155] (2-3) Add 100 μL of homogenate (0.05 M Tris-HCl buffer) to the total binding tube (TB) and 100 μL of Methysergide (final concentration 10 -5 M), add 100 μL of the test compound (final concentration 10 -5 M);

[0156] (2-4) Add radioligand to each reaction tube 3 H-Ketanserin 10 μL (each reaction tube has 2 parallel tubes, and each tube is placed on ice during sample addition);

[0157] (2-5) Incubate each reaction tube at 37°C for 15 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure and washed thoroughly with ice-cold 0.05 M Tris-HCl buffer. The filter is removed and placed in a 3 ml scintillation cup. 2 ml of toluene scintillation fluid is added and mixed.

[0158] (2-6) Place the scintillation vial into a liquid scintillation counter for counting.

[0159] Each compound was tested in duplicate and two separate experiments were performed.

[0160] (3) Preparation of D2 receptor membrane and determination of ligand affinity (inhibition rate)

[0161] Preparation of D2 receptor membrane: The rats were decapitated and the operation was performed on ice. The striatum of the brain was quickly taken out, and the two striata were combined in a centrifuge tube. 3 ml of buffer solution (containing HEPES 20 mM, MgCl2 2 mM) was added, and homogenization was performed at gear 4 for 3-4 seconds, and homogenization was performed 4 times. Then 5 ml of buffer solution (containing HEPES 20 mM, MgCl2 2 mM) was added, and the weight of the homogenized tube was adjusted with a balance, and the tube was centrifuged at 12000r and 4°C for 20 min. The supernatant was discarded, 3 ml of buffer solution (containing HEPES 20 mM, MgCl2 2 mM) was added, and the mixture was mixed with a vortex mixer. Then 5 ml of buffer solution (containing HEPES 20 mM, MgCl2 2 mM) was added, and the mixture was centrifuged. The supernatant was discarded, and the precipitate was stored at -80°C for later use.

[0162] Experimental methods:

[0163] (3-1) Add an appropriate amount of buffer (containing 20 mM HEPES and 2 mM MgCl2) to the prepared D2 receptor membrane and disperse it evenly using a homogenizer. Mix 15 test tubes into a 100 ml container and add an appropriate amount of buffer (containing 20 mM HEPES and 2 mM MgCl2) to prepare a suspension of 8 mg / mL membrane for later use.

[0164] (3-2) Add 100 μL of membrane suspension and 100 μL of buffer (containing 20 mM HEPES and 2 mM MgCl2) to each reaction tube;

[0165] (3-3) Add 100 μL of buffer (containing 20 mM HEPES and 2 mM MgCl2) to the total binding tube (TB) and 100 μL of Butaclamol (final concentration 10 -5 M), add 100 μL of the test compound (final concentration 10 -5 M);

[0166] (3-4) Add radioligand to each reaction tube 3 H-Spiperone 10 μL (each reaction tube has 2 parallel tubes, and each tube is placed on ice during sample addition);

[0167] (3-5) Incubate each reaction tube at 37°C for 20 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure and washed thoroughly with ice-cold buffer (containing 20 mM HEPES and 2 mM MgCl2). The filter is removed and placed in a 3 ml scintillation cup, and 2 ml of toluene scintillation fluid is added and mixed.

[0168] (3-6) Place the scintillation vial into a liquid scintillation counter for counting.

[0169] Each compound was tested in duplicate and two separate experiments were performed.

[0170] (4) Preparation of D3 receptor cells and determination of ligand affinity (inhibition rate)

[0171] Preparation of D3 receptor cells: HEK-293 cells, after 48-72 hours, the receptor protein is expressed in large quantities on the membrane, the cells are centrifuged at 1000 rpm for 5 minutes, the supernatant is discarded, the cell bodies are collected and stored in a -200°C refrigerator. Resuspend with Tris-Cl (pH 7.4) during the experiment.

[0172] Experimental methods:

[0173] Receptor competition binding assay: The test compound is combined with a radioactive ligand [ 320ul of H]7-OH-DPAT and 160ul of D3 receptor cells were added to the reaction tube, so that the final concentration of the test compound and the positive drug (risperidone) were 10μmol / L. After incubation in a 30℃ water bath for 50min, the reaction was immediately terminated by moving to an ice bath. On a Millipore cell sample collector, the sample was quickly filtered through GF / C glass fiber filter paper, and 3ml of eluent (50mM Tris-HCl, PH 7.4) was used for 3 times. The sample was dried in a microwave oven for 4-5min, and the filter paper was moved to a 0.5ml centrifuge tube, and 500ul of fat-soluble scintillation fluid was added. The sample was kept away from light for more than 30min, and the radioactivity was measured by counting.

[0174] (5)5HT 2C Preparation of receptor membranes and determination of ligand affinity (inhibition rate)

[0175] 5HT 2C Preparation of receptor membrane: The rat was decapitated and the operation was carried out on ice. The brain striatum was quickly taken out, and two striatums were combined in a centrifuge tube. 3 ml of buffer (0.05 M Tris-HCl buffer) was added and homogenized at gear 4 for 3-4 seconds. Homogenization was performed 4 times, and then 5 ml of homogenate (0.05 M Tris-HCl buffer) was added. The tubes were incubated at 37°C for 10 min. After incubation, the weight of the tubes was adjusted with a balance, and the tubes were centrifuged at 12000 r and 4°C for 20 min. The supernatant was discarded, 3 ml of homogenate (0.05 M Tris-HCl buffer) was added, and the mixture was mixed with a vortex mixer. Then 5 ml of homogenate (0.05 M Tris-HCl buffer) was added and centrifuged. After centrifugation, the supernatant was discarded and the precipitate was stored at -80°C for later use.

[0176] Experimental methods:

[0177] (5-1) Prepared 5HT 2C Add an appropriate amount of 0.05 M Tris-HCl buffer to the receptor membrane and disperse it evenly with a homogenizer to prepare a 210 mg / mL membrane suspension for later use;

[0178] (5-2) Add 100 μL of membrane suspension and 100 μL of homogenate (0.05 M Tris-HCl buffer) to each reaction tube;

[0179] (5-3) Add 100 μL of homogenate (0.05 M Tris-HCl buffer) to the total binding tube (TB) and 100 μL of mianserin (final concentration 10 -5 M), 100 μL of the test compound (final concentration 10 -5 M);

[0180] (5-4) Add radioligand [ 3 H]-mesulergine 10 μL (each reaction tube has 2 parallel tubes, and each tube is placed on ice during sample addition);

[0181] (5-5) Incubate each reaction tube at 37°C for 15 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure and washed thoroughly with ice-cold 0.05 M Tris-HCl buffer. The filter is removed and placed in a 3 ml scintillation cup, and 2 ml of toluene scintillation fluid is added and mixed.

[0182] (5-6) Place the scintillation vial into a liquid scintillation counter for counting;

[0183] Each compound was tested in duplicate and two separate experiments were performed.

[0184] (6) Preparation of histamine H1 receptor membrane and determination of ligand affinity (inhibition rate)

[0185] Preparation of histamine H1 receptor membrane: rats were decapitated and the operation was carried out on ice. The guinea pig cerebellum was quickly taken out, 50 mM Tris-HCl buffer was added, and the mixture was mixed with a vortex mixer. The mixture was centrifuged at 48,000 g and 4°C for 10 min, the supernatant was discarded, the precipitate was taken out, and 50 mM Tris-HCl buffer was added to wash the mixture. The centrifugation was repeated three times. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80°C for later use.

[0186] H1 receptor affinity assay:

[0187] (6-1) First, the prepared membrane is dispersed evenly with an appropriate amount of 50 mM Tris-HCl buffer using a homogenizer to prepare an 8 mg / mL membrane suspension for later use;

[0188] (6-2) Add 100 μL of membrane suspension to each reaction tube;

[0189] (6-3) Add 100 μL 50 mM Tris-HCl buffer to the total binding tube (TB) and 100 μL promethazine (final concentration 10 -5 M), 100 μL of the test compound (final concentration 10 -5 M);

[0190] (6-4) Add radioligand to each reaction tube 3 H-pyrilamine 10 μL (each reaction tube has 2 parallel tubes, and each tube is placed on ice when adding samples);

[0191] (6-5) Incubate each reaction tube at 30°C for 60 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure and washed thoroughly with ice-cold assay buffer (50 mM Tris-HCl buffer). The filter is removed and placed in a 3 ml scintillation cup, and 2 ml of toluene scintillation fluid is added and mixed.

[0192] (6-6) Place the scintillation vial into a liquid scintillation counter for counting.

[0193] Each compound was tested in duplicate and two separate experiments were performed.

[0194] (7) Preparation of norepinephrine receptor membrane and determination of ligand affinity (inhibition rate)

[0195] Preparation of norepinephrine receptor membrane: The rats were decapitated and the operation was carried out on ice. The cerebral cortex was quickly taken out, 50mM Tris-HCl (containing 0.5mM EDTA) was added, and the mixture was mixed with a vortex mixer. The mixture was centrifuged at 48000r and 4℃ for 15min, the supernatant was discarded, the precipitate was taken out, and 0.05M Tris-HCl buffer (PH7.4) was added to wash the mixture. The centrifugation was repeated three times. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80℃ for later use.

[0196] α1 Norepinephrine Receptor Affinity Assay:

[0197] (7-1) Add an appropriate amount of 50 mM Tris-HCl (containing 0.5 mM EDTA) to the prepared membrane and disperse it evenly using a homogenizer to prepare a 200 mg / mL membrane suspension for later use;

[0198] (7-2) Add 100 μL of membrane suspension and 100 μL of 50 mM Tris-HCl (containing 0.5 mM EDTA) to each reaction tube;

[0199] (7-3) Add 100 μL of 50 mM Tris-HCl (containing 0.5 mM EDTA) to the total binding tube (TB) and 100 μL of prazosin (final concentration 10 -5 M), 100 μL of the test compound (final concentration 10 -5 M);

[0200] (7-4) Add radioligand to each reaction tube 3 H-prazosin 10 μL (each reaction tube has 2 parallel tubes, and each tube is placed on ice during sample addition);

[0201] (7-5) Incubate each reaction tube at 25°C for 60 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure and washed thoroughly with ice-cold 50 mM Tris-HCl. The filter is removed and placed in a 3 ml scintillation cup, and 2 ml of toluene scintillation fluid is added and mixed.

[0202] (7-6) Place the scintillation vial into a liquid scintillation counter for counting;

[0203] Each compound was tested in duplicate and two separate experiments were performed.

[0204] (8) Preparation of σ1 receptor membrane and determination of ligand affinity (inhibition rate)

[0205] Preparation of σ1 receptor membrane: decapitate the guinea pig, operate on ice, quickly remove the brain, put the tissue into a centrifuge tube, add 50mM Tris-HCl buffer and homogenize at level 4 for 3-4s, homogenize 4 times, then add 50mM Tris-HCl buffer and adjust to 10ml / g, adjust the weight of the homogenized test tube with a balance, centrifuge at 1000r for 10min; take the upper layer liquid and add 50mM Tris-HCl buffer to adjust to 2ml / g, centrifuge at 1000r and 4℃ for 10min; take the supernatant and centrifuge at 11500r and 4℃ for 25min; take the precipitate and add 50mM Tris-HCl buffer to adjust to 3ml / g, incubate at 25℃ for 15min, centrifuge at 11500r and 4℃ for 25min, store the precipitate at -80℃ for later use.

[0206] Combination test:

[0207] (8-1) The prepared σ1 receptor membrane is prepared into a 220 mg / ml membrane suspension using 50 mM Tris-HCl buffer for later use;

[0208] (8-2) Add 100 μL of membrane suspension to each reaction tube;

[0209] (8-3) Total binding tube: Add 100 μL of 50 mM Tris-HCl buffer to the total binding tube (TB) and 100 μL of haloperidol (final concentration 1.0 × 10 -5 M), add 100 μL of test compound to each test compound tube (CB);

[0210] (8-4) Add 4 nM radioligand to each reaction tube. 3 H]-Pentazocine 10 μL;

[0211] (8-5) Each reaction tube was incubated at 25°C for 135 min. After the reaction was completed, the bound ligand was quickly filtered under reduced pressure. Whatman GF / C test paper was soaked in 0.5% PEI for more than 1 h in advance and washed thoroughly with ice-cold 50 mM Tris-HCl buffer. The filter was taken out and placed in a 4 mL scintillation cup. 2 mL of toluene scintillation fluid was added and mixed. Finally, the scintillation bottle was placed in a liquid scintillation counter for counting.

[0212] Data Statistical Processing

[0213] TB: summary sum constant; NB: nonspecific binding constant; SB: binding constant of the compound.

[0214] Inhibition rate (I%) = (TB-SB) / (TB-NB) x 100%

[0215] The experimental results are shown in Table 2 below.

[0216] The results of in vitro experiments showed that compared with risperidone, the compounds prepared in Examples 1, 6, 7, 8 and 12 had a stronger effect on four receptors (D2, D3, 5HT 1A , 5HT 2A ) has a strong affinity; the compounds prepared in Examples 1-3, Example 6, Example 8, Examples 12-14 and Example 17 have a strong affinity for σ1 receptors; all of them basically have a strong affinity for 5HT 2C The compounds provided by the present invention have low affinity for D2, D3, 5HT 1A and 5HT 2A Strong affinity, with the potential to improve the positive symptoms of schizophrenia, and has a potential improvement effect on negative symptoms and cognitive impairment; 2C , H1 and α1 have low affinity, which may not lead to the advantage of weight gain.

[0217] Table 2 Affinity results of compounds for each receptor (inhibition rate (%))

[0218]

[0219]

[0220] Embodiment 21

[0221] Antipsychotic activity of MK-801-induced hyperactive compounds in vivo

[0222] Experimental animals

[0223] Healthy Kunming mice, half male and half female, weighing (20±2) g, were provided by Nanjing Qinglongshan Animal Breeding Center.

[0224] Main reagents

[0225] Ascorbic acid, provided by Sinopharm Chemical Reagent Co., Ltd.;

[0226] MK-801, produced by Sigma, USA, preparation method: use 0.1% vitamin C to make a 1 mg / ml solution;

[0227] Positive drugs tested: haloperidol, risperidone;

[0228] Tween 80, concentration 10%.

[0229] Experimental methods

[0230] Mice with appropriate weight were selected and randomly divided into blank group, model group, positive control group (haloperidol group, risperidone group), and drug group. The blank group and model group were gavaged with 10% Tween 0.1ml / 10g, the positive control group was gavaged with risperidone 0.1mg / kg, and the drug group was gavaged with the corresponding dose of the compound prepared in Example 1 or Example 5 (0.1, 0.3, 1 and 3mg / kg). 1h after administration, the blank group was intraperitoneally injected with 0.1% ascorbic acid 0.1ml / 10g, and the model group, positive control group (30min), and drug group were intraperitoneally injected with MK-801 solution 0.1mg / kg. Thereafter, the spontaneous activity of mice in each group was measured within 90min. The results are shown in Table 3.

[0231] Embodiment 22

[0232] Apomorphine-induced climbing experiment in mice

[0233] Experimental animals

[0234] Healthy Kunming mice, male, weighing 18-22 g, were provided by Nanjing Qinglongshan Animal Breeding Center.

[0235] Main reagents

[0236] Positive drugs tested: haloperidol, risperidone;

[0237] Apomorphine, provided by Sigma, was dissolved in 0.9% NaCl (containing 0.1% vitamin C) before use and was prepared for immediate use;

[0238] Vitamin C, Sinopharm Chemical Reagent Co., Ltd.;

[0239] Sodium chloride injection, Xuzhou Fifth Pharmaceutical Factory Co., Ltd.

[0240] Apparatus: Homemade climbing cage, stopwatch.

[0241] Experimental methods

[0242] Mice with qualified weight were selected and randomly divided into negative control group, model group, positive drug dose groups (haloperidol group, risperidone group) and corresponding doses of compounds prepared in Example 1 or Example 5 (0.3, 1, 3 and 10 mg / kg), 10 mice in each group. Negative control group and model group were gavaged with corresponding solvent double distilled water, positive drug group was gavaged with corresponding positive drug (add a trace amount of acetic acid first and then double distilled water when dissolving), and compound dose groups were gavaged with corresponding dose compounds, and the gavage volume was 0.1 ml / 10 g. Apomorphine (1 mg / kg) was subcutaneously injected 1 hour after gavage, and the volume was 0.1 ml / 10 g. After apomorphine injection, the animals were immediately placed in a climbing cage and allowed to adapt for 5 minutes. Their behaviors were observed and scored at 10-11 minutes, 20-21 minutes, and 30-31 minutes after apomorphine injection. The scoring criteria were as follows: 0 for all four feet on the floor; 1 for both front feet on the mesh cage; and 2 for all four feet on the mesh cage.

[0243] Embodiment 23

[0244] Catalepsy Experiment Method

[0245] Experimental animals

[0246] Healthy Kunming mice, half male and half female, (22±2) g, were provided by Nanjing Qinglongshan Animal Breeding Center.

[0247] Main reagents: Positive drugs tested: haloperidol, risperidone;

[0248] Instrument: Homemade scratching rod Equipment: A stainless steel rod with a diameter of 0.3 cm and 5 cm above the workbench is placed in the mouse box.

[0249] Experimental methods:

[0250] Mice with qualified weight were selected and randomly divided into negative control group, model group, positive drug dose groups (haloperidol group, risperidone group) and compounds prepared in Example 1 or Example 5 (1, 5, 15, 45 and 100 mg / kg) at corresponding doses, with 10 mice in each group. Negative control group and model group were gavaged with corresponding solvent double distilled water, positive drug group was gavaged with corresponding positive drug (add trace acetic acid first and then double distilled water when dissolving), and compound dose groups were gavaged with corresponding dose compounds, with gavage volume of 0.1 ml / 10 g. At 30min, 60min and 90min of gavage administration, the two front paws of the mouse were gently placed on a small stick with a length of 20cm, a diameter of 0.3cm and 5.5cm above the workbench, and then the animal's hind limbs were gently placed on the bottom of the box, and the duration of the two front paws of the mouse maintaining the posture on the stick was recorded, and 30s of stiffness was considered a positive reaction. If the mouse's front paws have not been put down, the observation was terminated at 60s. The number of animals with positive reactions in each compound dose group was counted.

[0251] The data were calculated using SPSS. 50 The values ​​and their 95% confidence intervals are as follows:

[0252] Table 3 Results of in vivo animal model tests on some preferred compounds

[0253]

[0254] The experimental results show that compared with risperidone, the compounds prepared in Example 1 and Example 5 can not only significantly improve the hyperactivity induced by MK-801, but also effectively improve the climbing symptoms induced by apomorphine, and do not cause EPS at an effective dose, indicating that they have a significant anti-schizophrenia effect.

[0255] Embodiment 24

[0256] The compounds prepared in Examples 1-19 were used as active ingredients, respectively, and the pharmaceutical composition of the present invention was prepared in the form of tablets according to the following formula:

[0257]

[0258] The raw and auxiliary materials are sieved through an 80-mesh sieve for later use. The prescribed amount of active ingredients, microcrystalline cellulose, lactose, and povidone K30 are weighed, added into a high-speed mixer, and mixed evenly at a low speed. An appropriate amount of purified water is added, stirred at a low speed, and granulated by high-speed cutting. The wet granules are then dried at 60° C. for 3 h, sieved through a 24-mesh sieve, and the prescribed amount of sodium carboxymethyl starch, silicon dioxide, and magnesium stearate are added, mixed, and tableted on a rotary tablet press to obtain a pharmaceutical composition in tablet form.

Claims

1. A tetrahydro(iso)quinoline derivative, characterized in that: The derivatives are: 1-(1-acetylindolin-5-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one, 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)indolin-1-yl)ethan-1-one, 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)indolin-1-yl)ethan-1-one, 1-(1-acetylindolin-5-yl)-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butanone, 3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-(1-propionylindolin-5-yl)propan-1-one, 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)indolin-1-yl)propan-1-one, 1-(5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)indolin-1-yl)propan-1-one, 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propanoyl)-N,N-dimethylindoline-1-carboxamide, 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-hydroxypropyl)-N,N-dimethylindoline-1-carboxamide, 5-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)-N,N-dimethylindoline-1-carboxamide, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one, 1-(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propan-1-one 1-(1-acetylindolin-5-yl)-3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)propan-1-one, 3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-(1-propionylindolin-5-yl)propan-1-one, 5-(3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)propionyl)-N,N-dimethylindoline-1-carboxamide, 5-(3-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)-1-hydroxypropyl)-N,N-dimethylindoline-1-carboxamide, 3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-(1-acetylindolin-5-yl)propan-1-one, 1-(5-(3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-hydroxypropyl)indolin-1-yl)ethan-1-one, 5-(3-(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)-N,N-dimethylindoline-1-carboxamide.

2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a therapeutically effective amount of the tetrahydro(iso)quinoline derivatives described in claim 1 and one or more pharmaceutically acceptable carriers.

3. Use of the tetrahydro(iso)quinoline derivatives according to claim 1 in the preparation of drugs for preventing or treating neuropsychiatric diseases.

4. The use according to claim 3, wherein the neuropsychiatric disease is schizophrenia.

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