WO2014146553A1

WO2014146553A1 - Flavonoid derivatives and use thereof

Info

Publication number: WO2014146553A1
Application number: PCT/CN2014/073439
Authority: WO
Inventors: 陈寅; 徐祥清; 赵松; 于民权; 邱印利; 张桂森
Original assignee: 江苏恩华药业股份有限公司
Priority date: 2013-03-18
Filing date: 2014-03-14
Publication date: 2014-09-25
Also published as: CN104059046B; CN104059046A

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and, in particular, disclosed therein are a flavonoid derivative and use thereof. Disclosed is a flavonoid derivative having the structure of general formula (I) or a pharmaceutically acceptable salt thereof. This compound can be used in the preparation of drugs for preventing or treating central nervous system diseases.

Description

Flavonoid derivatives and their application

The invention belongs to the field of medicinal chemistry, and particularly relates to flavonoid derivatives and applications thereof. Background technique

Schizophrenia has been an independent disease unit for more than a hundred years. In 1896, Kraepelin summarized the previous clinical phenomena into a disease called early-onset dementia. In the early 20th century, Bleuler stated his new ideas and believed that the disease had associations, emotions, The core of obstacles such as will and autism is schizophrenia and has been in use ever since.

Schizophrenia is the most serious and most harmful of all mental illnesses. The global incidence is about 1-2%. The lifetime prevalence of patients with schizophrenia is 0.7-0.8%, which is not significantly related to gender, ethnicity, or social boundaries, and the mortality rate is 2-3 times higher than that of the general population. The latest research shows that the social burden of mental illness ranks first in Chinese diseases, exceeding the cardiovascular, respiratory and malignant diseases.

There are two main types of existing schizophrenic drugs: typical anti-schizophrenic drugs and atypical anti-schizophrenic drugs. Typical anti-schizophrenic drugs (such as chlorpromazine and haloperidol) block the dopamine D ₂ receptor and have a good effect on positive symptoms of schizophrenia. However, due to the strong blockade of dopamine receptors, adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia, and increased prolactin are also caused, and they are ineffective for negative symptoms of schizophrenia.

Atypical anti-schizophrenic drugs, represented by clozapine and risperidone, not only have a strong effect on dopamine (D ₂ ) receptors, but also have a strong effect on serotonin (5-HT _2A ) receptors. Compared with typical anti-schizophrenic drugs, these drugs have great advantages: good effects on positive symptoms of schizophrenia; side effects such as extrapyramidal reaction and tardive dyskinesia are significantly reduced; some atypical anti-schizophrenic drugs Negative symptoms and cognitive impairment have some improvement. However, the current clinical application of atypical anti-schizophrenic drugs have varying degrees of QT interval prolongation and high prolactin and other adverse reactions]. Therefore, it is very important to find new drugs that can effectively cure schizophrenia and have fewer side effects.

After several decades of research, it was found that five receptors such as D ₂ , 5-HT _1A , 5-HT _2A , 5 ^^ and ^ are very important for schizophrenia. The action with the receptor can effectively treat the positive symptoms of schizophrenia. The serotonin system plays an important role in regulating the function of the prefrontal cortex, including mood control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the prefrontal cortex contain serotonin receptors 5 butyl and 5-HT _2A . The serotonin system plays an important role in regulating the function of the prefrontal cortex, including mood control, cognitive behavior, and working memory. 5-HT _1A and atypical antipsychotic treatment Related, can improve negative symptoms and cognitive impairment. The 5-HT _2A receptor is involved in various aspects of perception, mood regulation, and motor control. Blocking the 5-HT _2A receptor normalizes the release of dopamine and acts as an antipsychotic.

At the same time, in the long-term treatment of schizophrenia, some drugs are prone to cause side effects of weight gain, and studies have shown that these side effects are closely related to histamine receptors.

Therefore, it is now looking for a multi-receptor binding approach that increases the range of anti-schizophrenic drugs and reduces side effects such as EPS and weight gain.

Abaperidone(7-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]propoxy]-3-(hydroxymethyl)c hromen-4-one, US5736558) as D ₂ (IC ₅₀ = 17.0 nM ) and 5-HT _2A ( IC ₅₀ = 6.2 nM ) Receptor antagonism [J, can significantly inhibit the symptoms of schizophrenia in animal models without causing catalepsy. In an in vitro assay, the compounds of the present invention are superior to Abaperidone to three receptors (D ₂ , 5-HT _1A , and 5-HT _2A ), and the affinity of the compounds involved is low, compared to Abaperidone. The side effects of producing weight gain are less likely; in animal models, the compounds of the present invention are capable of significantly improving MK-801-induced high activity and effectively apomorphine-induced climbing symptoms. Moreover, the compounds of the invention have a stronger effect and a greater therapeutic index than Abaperidone. In the acute toxicity study, the mice of the present invention have an LD _5Q greater than 2000 mg/kg, which is higher than Abaperidone (160 mg/kg) and has less acute toxicity. Summary of the invention

It is an object of the present invention to provide a novel active flavonoid derivative based on the prior art.

Another object of the present invention is to provide an application of the above flavonoid derivative for the preparation of a medicament for treating neuropsychiatric diseases.

The object of the invention can be achieved by the following measures:

A flavonoid derivative having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

Z is a substituted or unsubstituted C ₂ ～C ₆ alkylene group, the C ₂ ～C ₆ alkylene group is —(CH ₂ ) _n —, n is an integer of 2 to 6; or substituted or unsubstituted a C ₂ -C ₆ alkenylene group, wherein the C ₂ ～C ₆ alkenylene group means that -(CH ₂ ) _n - contains a carbon-carbon double bond, wherein n is an integer of 2 to 6;

Or a (CH ₂ ) _X — A—(CH ₂ ) _y —, wherein A is 0 or a C ₃ —C ₆ cycloalkyl group, and X and y are each independently selected from an integer of 0 to 5, and x+y An integer of =2~7;

_{_{Ri R 2, R 3, R}} 4 R 5 or R ₆ are independently hydrogen, halogen, a C _r C ₅ Huan, substituted C _r to C ₅ alkyl;

Or R1 and R2 together may also form together with its attached carbon atoms (: cycloalkyl or heterocycloalkyl, heterocycloalkyl hetero atom is ₄₆ N; substituent group is preferably a C _r C ₅ alkyl on the ring base;

X is CH or

Ar is of formula II or formula II I;

Its towel:

Q is 0 or S;

R _7, R ₈ or R ₉ are each independently hydrogen, halogen, C _r C ₅ Huan group, substituted C _r C alkyl or C _r C ₅ alkoxy group _5. In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, the substituted _5- alkyl substituent is one or more of a halogen, an amino group or a hydroxyl group; the substituted ₅ -alkane The group is further preferably a trifluoromethyl group or a hydroxymethyl group.

In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, the alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a n-pentyl group, an isopentyl group or a neopentyl group.

Pharmaceutically said flavonoid derivatives of the present invention or a pharmaceutically acceptable salt thereof, said C _r C ₅ alkoxy group are methoxy, ethoxy, propoxy, butoxy.

In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, the halogen is fluorine, chlorine, bromine or iodine. In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, more specifically, R ₂ , R ₃ , R ₄ R ₅ or R _{6 are} independently hydrogen, chlorine, methyl, or B. Base, propyl, trifluoromethyl or hydroxymethyl.

In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, more specifically, R ₇ or independently hydrogen, chlorine, fluorine, methyl, ethyl, trifluoromethyl, A Oxy or ethoxy.

In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, more specifically, the R1 and R2 are common thereto The linked carbon atoms together form a substituted or unsubstituted cyclopentane, cyclohexane or piperidine wherein the substituent is selected from one or more of methyl, ethyl, propyl or butyl. Most preferably, said R1 and R2 together with the carbon atom to which they are attached form an unsubstituted cyclopentane, cyclohexane or piperidine.

In the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof, the Z is methyl, ethyl, propyl, butyl, propenyl, vinyl, ethoxy, propoxy, 1,4-2methylcyclohexane group; or Z is a (CH ₂ ) _X — A—(CH ₂ ) _y — wherein A is a cyclohexane group or a cyclopentyl group, and X and y are each independently An integer selected from 0 to 5, and an integer of x _{+ y} = 2 to 7, preferably an integer of x + y = 2 to 5.

The flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof is most preferably selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:

(1) 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-helix [chroman-2-y-cyclopentane]-4-one;

(2) 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-helix [color-2-1'-ring Pentamidine]-4-one;

(3) 7-(3-(4-(2-methoxyphenyl)piperazine)-propoxy)-helix [chroman-2-y-cyclopentane]-4-one;

(4) 7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy) Helical [color-2-1'-ring Pentamidine]-4-one;

(5) 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-helix [color-2-1'-ring -4- 浣 -4- ketone;

(6) 7-(4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)butoxy) Helical [color-2-1'-cyclohexan]-4 -ketone;

(7) 7-(4-(4-(2,3-Dimethylphenyl)piperazin-1-yl)butoxy) Helical [color-2-1'-cyclohexan]-4- ketone;

(8) 7-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy) Helical [chroman-2-1'-cyclohexan]-4-one ;

(9) 7-(4-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy) Helical [color-2-1'-cyclohexanium]- 4-ketone;

(10) 7-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propoxy) spirulin [chromo-2-1'-cyclohexan]-4-one;

(11) 7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)helix [chroman-2-cyclohexane ]■

(12) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2,2 dimethylchroman-4- ketone;

(13) 7-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butoxy) 2,2-dimethylchroman-4-one;

(14) 7-(3-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy) 2,2 dimethylchroman-4- ketone;

(15) 7-(3-(4-(2-Methoxyphenyl)piperazine-1-yl)propoxy) 2,2-dimethylchroman-4-one;

(16) 7-((4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)cyclohexyl)methoxy) 2,2 - Methylchroman-4-one;

(17) 7-(2-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethoxy)ethoxy) 2,2- Dimethylchroman-4-one;

(18) (E)7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-buten-1-yl) Oxygen) Spiral [color full-2-1'-cyclopentan-4-one;

(19) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-helix [color-2-4'-piperidite Pyridine]-4-one hydrochloride;

(20) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-2-methylchroman-4-one;

(21) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-2-methyl-8-chlorochroman- 4-ketone;

(22) 7-(4-(4-(6-Fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl)butoxy)chroman-4-one;

(23) 7-(4-(4-(6-Fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl)butoxy)-5-methylchroman-4-one;

(24) 7-(4-(4-(6-Fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl)butoxy) 6-methylchroman-4-one;

(25) 7-(4-(4-(6-Fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl)butoxy) 8-methylchroman-4-one;

(26) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2,3-dimethylchroman-4 Ketones and their pharmaceutically acceptable salts.

The present invention also includes a structural compound of the formula (I) and a salt of each of the above specific compounds, the salt being a pharmaceutically acceptable anionic salt: such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, Sulfate or hydrogen sulphate, phosphate or acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, mesylate, gluconate, A saccharide, a benzoate, an ethanesulfonate, a besylate, a p-toluenesulfonate, and the like.

The general synthesis method for this class of compounds is to first synthesize the parent of the flavonoid and then connect it with a piperazinyl or piperidinyl group through a carbon chain.

The present invention provides a pharmaceutical composition comprising a compound of the formula (I), and a pharmaceutically acceptable adjuvant (such as a carrier and/or an excipient, etc.), the pharmaceutical composition comprising the present invention sufficient to produce an antipsychotic effect An antipsychotic composition of the compound.

An effective amount of a compound of the invention can be administered orally, such as with an inert diluent or a carrier. It can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention can be used together with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like. These preparations should contain at least 0.5% by weight of the active compound of the invention, but may vary from 4% to about 70% by weight of the unit, depending on the particular dosage form. The amount of active compound in such compositions should be such that a suitable dosage will be employed. Oral unit doses of the compositions and formulations of the present invention contain from 1.0 to 300 mg of the active compound of the invention. The compounds provided by the present invention, and pharmaceutically acceptable salts, solvates and hydrates thereof, can be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.

The amount of the compound of the present invention depends on the type and severity of the disease or condition, and also on the characteristics of the subject, such as general health, age, sex, body weight, and drug tolerance. The skilled person is able to determine the appropriate dosage based on these or other factors. Effective dosages of the central nervous system drugs commonly used are well known to the skilled artisan. The total daily dose is usually between about 0.05 mg and 2000 mg.

The present invention relates to a pharmaceutical composition which provides from about 0.01 to 1000 mg of active ingredient per unit dose. The composition may be administered by any suitable route, for example, orally in the form of a capsule, parenterally in the form of an injection, topically in the form of a cream or lotion, rectal administration in the form of a suppository, in the form of a patch delivery system. Transdermal administration.

The compounds provided herein can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, and the like. Tablets, pills, capsules and the like comprise from about 0.01 to about 99 weight percent of active ingredient and binder such as gelatin, corn starch, gum arabic; excipients such as calcium hydrogen phosphate; disintegrants such as corn starch, potato starch or algae An acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose or lactose. When the preparation form is a capsule, a liquid carrier such as a fat or oil may be contained in addition to the above-mentioned types of raw materials.

For parenteral administration, the compounds provided herein can be combined with sterile aqueous or organic vehicles to form injectable solutions or suspensions.

The compounds of formula I may contain a chiral center and thus may exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and all stereoisomers of the compounds of formula I, as racemic mixtures of such compounds and in the form of the respective enantiomers and diastereomers, and the invention relates to All pharmaceutical compositions and methods of treatment containing or using them are defined.

Further, the derivative provided by the present invention and a pharmaceutical composition composed of the derivative can be applied to the preparation of a medicament for treating or preventing a neuropsychiatric disease which is schizophrenia. The present invention relates to the use of said derivatives for the preparation of other diseases of the central nervous system diseases, such as drugs for the treatment of depression, memory disorders and dysfunctional diseases associated with intelligence and learning.

In vitro receptor binding assays have shown that the derivatives of the present invention have a higher affinity for the dopamine D ₂ , 5-HUB5-HT _2A receptors, and a lower affinity for the receptors.

Animal studies have shown that these compounds can significantly improve the high activity induced by MK-801, and can effectively improve apomorphine-induced climbing symptoms, and do not cause EPS at an effective dose. Due to these in vitro targets and in vivo pharmacology The type is closely related to neurological diseases caused by dopamine dysfunction, particularly schizophrenia, and therefore the compounds of the present invention have a therapeutic effect on neuropsychiatric diseases, particularly for schizophrenia.

detailed description

The following examples are for illustrative purposes only and are not to be considered as limiting.

A. Examples of synthesis

Example 1, 7-(4-(4-(2-methoxyphenyl) piperazine small)butyloxy) helix [color-2-1,-cyclopentamidine]-4-one (1 Reaction formula 1

1) 2,4-dihydroxyacetophenone 7.6 g, cyclopentanone 8.4 g, tetrahydropyrrole 7.1 g, anhydrous acetonitrile 50 ml, and reacted at 50 ° C for 12 h. After TLC, the reaction was completed, and the mixture was cooled to room temperature. The solution was poured into a 2M hydrochloric acid ice-water mixture. The solid was precipitated, stirred for 30 minutes, and filtered to give a yellow solid which crystallised from 95% ethanol to give a white solid. 8.4 g, melting point 186-188 ° C, yield 77.1%.

2) Take the first step product 4.2g, anhydrous potassium carbonate 6g, acetone 50ml, 1,4-dibromobutane 8.2g, heated to reflux for 6 hours, cooled to room temperature, filtered, evaporated to dryness, eluent Petroleum ether: ethyl acetate 4:1 was passed through a column to yield 5.6 g of colorless oil, yield 75.7%.

3) Take the second step product 0.72g, add 2-methoxyphenylpiperazine hydrochloride 0.58g, anhydrous potassium carbonate 2g, potassium iodide 0.2g and acetonitrile 30ml, heated to reflux for 12 hours, cooled to room temperature, steamed Dry solvent, add appropriate amount of dichloromethane, wash with water, remove the water layer, dry the organic layer with anhydrous magnesium sulfate, and evaporated to dryness to give a pale yellow oil.

(2-methoxyphenyl)piperazin-1-yl)butoxy) Helical [chroman-2-1'-cyclopentanyl]-4-one 0.61 g, melting point: 96-98 ° C, The rate is 66.3%. NMR (CDCI ₃ ) δ 1.69-1.75 (m, 6H), 1.84-1.87 (m, 4H), 2.05-2.10 (m, 2H), 2.49 (t, 2H, = 8 Hz), 2.68 (s, br, 4H), 2.78 (s, 2H), 3.12 (s, br, 4H), 3.88 (s, 3H), 4.03 (t, 2H, 7=8 Hz), 6.37 (d, 1H, J = 4Hz), 6.53 -6.56 (m, 1H), 6.86-7.03 (m, 4H), 7.80 (d, 1H, 7=8 Hz). MS ( ESI ) m/z 465.2 ([M+H] ⁺ ) Example 2, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)helix [color full-2-1'- Cyclopentamidine]-4-one (2)

2-methoxyphenylpiperazine hydrochloride was changed to 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride salt, prepared according to the method of Example 1. The target compound 2: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)helix [color full-2-1' - cyclopentamidine]-4-one.

Melting point: 103-105°. . NMR (CDCI ₃ ) δ 1.63-1.90 (m, 10H), 2.07-2.19 (m, 8H), 2.48 (t, 2H, = 8 Hz), 2.78 (s, 2H), 3.08-3.12 (m, 4H) , 4.04 (t, 2H, 7=8 Hz), 6.38 (d, IH, J = 4Hz), 6.54-6.56 (m, 1Η), 7.04-7.09 (m, IH), 7.24-7.26 (m, IH) , 7.69-7.73 (m, IH), 7.80 (d, IH, 7=8 Hz). MS ( ESI ) m/z 493.3 ([M+H]+) Example 3, 7- ( 3- (4- (2-methoxyphenyl) piperazine small group) propoxy) helix [color full-2-1,-cyclopentan-4-one (3) replaced by 1,3-dibromopropane 1,4 -Dibromobutane, the title compound 3 was prepared as in Example 1 : 7-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy) helix -2-1'-cyclopentan-4-one.

Melting point: 128-130°. . NMR (CDCI ₃ ) δ 1.65-1.74 (m, 4H), 1.87-1.91 (m, 2H), 2.03-2.12 (m, 4H), 2.61 (t, 2H, = 8 Hz), 2.71 (s, br, 4H), 2.79 (s, 2H), 3.13 (s, br, 4H), 3.89 (s, 3H), 4.09 (t, 2H, =8 Hz), 6.41 (d, IH, J = 4Hz), 6.55- 6.58 (m, IH), 6.88-7.04 (m, 4H), 7.81 (d, IH, 7=8 Hz). MS (ESI) m/z 451.2 ([M+H]+) Example 4, 7- (3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)helix [color-2-1'-cyclopentanyl]-4 - Ketone (4)

The target compound 4 was prepared by the method of Example 3 by substituting 1,3-dibromopropane for 1,4-dibromobutane. 7-(3-(4-(6-fluorobenzo[d]isoxazole) 3-yl)piperidin-1-yl)propoxy) Helical [chroman-2-1'-cyclopentanyl]-4-one. Melting point: 91-93 °C. NMR (CDCI ₃ ) δ 1.64-1.74 (m, 4H), 1.86-2.23 (m, 12H), 2.58 (t, 2H, = 8 Hz), 2.78 (s, 2H), 3.08-3.11 (m, 3H) , 4.09 (t, 2H, 7=8 Hz), 6.41 (d, IH, J = 4Hz), 6.54-6.57 (m, IH), 7.04-7.09 (m, IH), 7.24-7.26 (m, IH) , 7.69-7.72 (m, IH), 7.80 (d, IH, 7=8 Hz). MS ( ESI ) m/z 479.3 ([M+H]+) Example 5, 7- (4- (4- (6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)helix [chroman-2-1'-cyclohexane]-4-one (5)

2-methoxyphenylpiperazine hydrochloride was changed to 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, and prepared according to the method of Example 5. Target compound 5: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)helix [color full-2-1'- Cyclohexyl]-4-one. Melting point: 126-128 °C o ^X H NMR (CDCI ₃ ) δ 1.31-1.37 (m, IH), 1.50-1.53 (m, 4H), 1.69-1.75 (m, 5H), 1.84-1.86 (m, 2H ), 1.98-2.18 (m, 8H), 2.49 (t, 2H, = 8 Hz), 2.65 (s, 2H), 3.06-3.13 (m, 3H), 4.05 (t, 2H, 7=8 Hz), 6.42 (d, IH, J = 4Hz), 6.52-6.55 (m, IH), 7.04-7.09 (m, IH), 7.24-7.26 (m, IH), 7.70-7.73 (m, IH), 7.78 (d , 1H, =8 Hz). MS ( ESI ) m/z 507.3 ([M+H] ⁺ ) Example 6, 7-( 4- (4-( 3-(trifluoromethyl)phenyl)piperazine -1-yl)butoxy)helix [color full-2-1'-cyclohexanyl]-4-one (6)

2-Methoxyphenylpiperazine hydrochloride was changed to 3-trifluoromethylphenylpiperazine hydrochloride, and the target compound 6 was prepared as in Example 5: 7-(4- (4- 3-(Trifluoromethyl)phenyl)piperazin-1-yl)butoxy)helix [chroman-2-1'-cyclohexane]-4-one.

Melting point: 138-140°. . NMR (CDCI ₃ ) δ 1.32-1.36 (m, IH), 1.48-1.99 (m, 13H), 2.05-2.30 (m, 3H), 2.52-2.70 (m, 6H), 3.28-3.31 (m, 3H) , 4.05 (t, 2H, 7=8 Hz), 6.41 (d, IH, = 4 Hz), 6.52-6.55 (m, IH), 7.06-7.19 (m, 3H), 7.34-7.42 (m, IH) , 7.73-7.80 (m, IH). MS ( ESI ) m/z 517.2 ([M+H] ⁺ ) Example 7, 7- (4- (4- ( 2, 3- dimethylphenyl) Pyridazin-1-yl)butoxy)helix [chroman-2-1'-cyclohexanyl]-4-one (7) 2-methoxyphenylpiperazine hydrochloride was changed to 2, 3- Dimethylphenylpiperazine hydrochloride, the title compound 7 was obtained as in Example 5: 7-(4-(4-(2,3-dimethylphenyl)piperazin-1-yl) Oxy) Helical [chroman-2-1'-cyclohexane]-4-one.

Melting point: 113-115 ° C. NMR (CDCI ₃ ) δ 1.32-1.36 (m, IH), 1.48-2.07 (m, 17H), 2.23 (s, 3H), 2.29 (s, 3H), 2.60 (t, 2H, = 8 Hz), 2.66 (s, 2H), 3.00 (s, br, 4H), 4.06 (t, 2H, 7=8 Hz), 6.42 (d, IH, = 4 Hz), 6.52-6.56 (m, IH), 6.92-7.10 (m, 3H), 7.76-7.81 (m, IH). MS (ESI) m/z 477.2 ([M+H] ⁺ ) Example 8, 7- (4- (4- ( 2, 3- Phenyl)piperazin-1-yl)butoxy)helix [color-2-1'-cyclohexanyl]-4-one (8) Replace 2-methoxyphenylpiperazine hydrochloride 2,3-Dichlorophenylpiperazine hydrochloride, the title compound 8 was obtained as in Example 5: 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl ) Butoxy) Spiral [chroman-2-1'-cyclohexan]-4-one.

Melting point: 119-121 ° C. ^ NMR (CDCI ₃ ) δ 1.33-1.37 (m, IH), 1.48-2.01 (m, 13H), 2.54 (t, 2H, = 8 Hz),

2.66(s, 2H), 3.00 (s, br, 4H), 4.06 (t, 2H, 7=8 Hz), 6.42 (d, IH, = 4 Hz), 6.52-6.56 (m, IH), 6.92- 7.10

(m, 3H), 7.76-7.81 (m, IH). MS ( ESI ) m/z 517.2 ([M+H] ⁺ ) Example 9, 7-(4-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy) Helical [color-2-1'-cyclohexan] -4-ketone (9)

The 2-methoxyphenylpiperazine hydrochloride was replaced with 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, and the target compound 9 was prepared as in Example 5: 7- ( 4-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy)helix [chroman-2-1'-cyclohexane H-ketone. Melting point: 129-130 ° C. NMR (CDCI ₃ ) δ 1.31-1.34 (m, IH), 1.48-2.00 (m, 13H), 2.52 (t, 2H, = 8 Hz), 2.66 (s, 2H), 2.70 (s, br, 4H) , 3.11 (s, br, 4H), 4.05 (t, 2H, 7=8 Hz), 6.42 (d, IH, = 4 Hz), 6.53-6.56 (m, IH), 6.96-6.99 (m, IH) , 7.45-7.49 (m, IH), 7.16-7.19 (m, 2H), 7.79 (d, IH, J = 8 Hz). MS (ESI) m/z 506.2 ([M+H] ⁺ ) Example 10 , 7-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)helix [chroman-2-1'-cyclohexane]-4-one (10) The title compound 10 was prepared by the method of Example 5 using 1,3-dibromopropane in place of 1,4-dibromobutane. 7-(3-(4-(2-methoxyphenyl)piperazine- 1-Base) Propoxy) Spiral [chroman-2-1'-cyclohexanyl]-4-one.

Melting point: 105-107 ° C, ^X H NMR (CDCI ₃ ) δ 1.30-1.34 (m, IH), 1.45-1.52 (m, 4H), 1.66-1.72 (m, 3H), 1.97-2.07 (m, 4H ), 2.60 (t, 2H, = 8 Hz), 2.64 (s, 2H), 2.70 (s, br, 4H), 3.12 (m, 4H), 3.87 (s, 3H), 4.09 (t, 2H, 7 =8 Hz), 6.44 (d, IH, = 4 Hz), 6.53-6.56 (m, IH), 6.85-7.00 (m, 4H), 7.79 (d, IH, J = 8 Hz). MS ( ESI ) m/z 465.3 ([M+H] ⁺ ) Example 11. 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy Spiral [color full-2-1'-cyclohexane]-4-one (11)

The target compound was prepared by the method of Example 5 by substituting 1,3-dibromopropane for 1,4-dibromobutane, and the title compound 10 was obtained by the method of Example 6: 7-( 3- (4- (6) -Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)helix [chroman-2-1'-cyclohexan]-4-one.

Melting point: 96-98 °C. NMR (CDCI ₃ ) δ 1.33-1.36 (m, IH), 1.48-1.74 (m, 5H), 1.98-2.22 (m, 10H), , 2.61 (t, 2H, = 8 Hz), 2.66 (s, 2H) ), 3.10-3.12 (m, 3H), 4.11 (t, 2H, 7=8 Hz), 6.45 (d, IH, = 4 Hz), 6.55-6.58 (m, IH), 7.05-7.10 (m, IH) ), 7.24-7.26 (m, IH), 7.70-7.74 (m, IH), 7.79 (d, IH, J = 8 Hz). MS ( ESI ) m/z 493.2 ([M+H] ⁺ ). Example 12, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2,2-dimethylchroman- 4-ketone (12) Using acetone instead of cyclopentanone, the title compound 12 was prepared as in Example 2: 7-(4-(4-(6-fluorobenzo[d]isoxazole-3-yl) Piperidin-1-yl)butoxy) 2,2-dimethylchroman-4-one.

Melting point: 97-99 °C. NMR (CDCI ₃ ) δ 1.47 (s, 6H), 1.67-1.87 (m, 4H), 2.08-2.13 (m, 6H), 2.49 (t, 2H,

7 = 8 Hz), 2.68 (s, 2H), 3.09-3.11 (m, 3H), 4.04 (t, 2H, =8 Hz), 6.39 (d, 1H, = 4 Hz), 6.54-6.57 (m, IH),

7.05-7.10 (m, IH), 7.25-7.27 (m, IH), 7.70-7.74 (m, IH), 7.80 (d, IH, J = 8 Hz). MS ( ESI ) m/z 467.3

([M+H]+) Example 13, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy) 2,2-dimethylchroman- 4-ketone (13)

6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride was replaced with 2-methoxyphenylpiperazine hydrochloride, and prepared according to the method of Example 12. The title compound 13 was obtained: 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy) 2,2-dimethylchroman-4-one.

Melting point: 116-118 ° C. ^X H NMR (CDCI ₃ ) S 1.47 (s, 6H), 1.70-1.88 (m, 4H), 2.50 (t, 2H, = 8 Hz), 2.68 (s, br, 6H), 3.12 (s, br, 4H), 3.88 (s, 3H), 4.04 (t, 2H, 7=8 Hz), 6.38 (d, IH, = 4 Hz), 6.53-6.56 (m, IH), 6.87-7.02 (m, 4H) , 7.80 (d, IH, J = 8 Hz). MS (ESI) m/z 439.3 ([M+H] ⁺ ) Example 14, 7- ( 3- (4- (6-fluorobenzo[d] Isoxazol-3-yl)piperidin-1-yl)propoxy) 2,2-dimethylchroman-4-one (14) Substituting 1,3-dibromopropane for 1,4-dibromo Butane, the title compound 14 was obtained as in Example 12: 7-(3-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperidin-1-yl)propoxy 2,2-dimethylchroman-4-one.

Melting 146-148 °C ^X H NMR (CDCI ₃ ) δ 1.47 (s, 6H), 2.00-2.21 (m, 8H), 2.59 (t, 2H, = 8 Hz), 2.68 (s,

2H), 3.09-3.13 (m, 3H), 4.10 (t, 2H, 7=8 Hz), 6.40 (d, IH, = 4 Hz), 6.54-6.57 (m, IH), 7.05-7.09 (m,

IH), 7.25-7.27 (m, IH), 7.70-7.74 (m, IH), 7.80 (d, IH, J = 8 Hz). MS ( ESI ) m/z 453.3 ([M+H]+)

Example 15, 7-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy) 2,2-dimethylchroman-4-one (15)

The title compound 15 was prepared as in Example 13 by substituting 1,3-dibromopropane for 1,4-dibromobutane. 7-(3-(4-(2-methoxyphenyl)piperazine- 1-yl)propoxy) 2,2-dimethylchroman-4-one.

Melting ^{point: 103-105 ° C o X H NMR} (CDCI 3) δ 1.46 (s, 6Η), 2.03-2.05 (m, 2H), 2.60 (t, 2H, = 8 Hz),

2.67-2.70 (m, 8H), 3.13 (s, br, 4H), 3.88 (s, 3H), 4.08 (t, 2H, 7=8 Hz), 6.40 (d, IH, = 4 Hz), 6.54- 6.57

(m, IH), 6.87-7.02 (m, 4H), 7.80 (d, IH, J = 8 Hz). MS ( ESI ) m/z 425.3 ([M+H]+) Example 16 7-((4-(4-4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)cyclohexyl)methoxy) 2,2 - Dimethylchroman-4-one (16)

The target compound 16 was prepared by the method of Example 12 using 1,4-bis(bromomethyl)cyclohexane instead of 1,4-dibromobutane. 7-((4-(4- 4-(6-fluoro)) Benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)cyclohexyl)methoxy) 2,2-dimethylchroman-4-one.

Melting point: 126-128 ° C. ^X H NMR (CDCI ₃ ) δ 1.23-1.27 (m, 4Η) 1.46 (s, 6H), 1.69-1.88 (m, 5H), 2.09-2.11 (m, 7H), 2.50 (t, 2H, = 8 Hz ), 2.68 (s, 2H), 3.10-3.12 (m, 3H), 4.04 (t, 2H, 7=8 Hz), 6.38 (d, 1H, = 4 Hz), 6.54-6.57 (m, 1H), 7.04-7.09 (m, 1H), 7.24-7.26 (m, 1H), 7.71-7.74 (m, 1H), 7.81 (d, 1H, J =8 Hz). MS ( ESI ) m/z 521.3 ([M +H] ⁺ ) Example 17 7-(2-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethoxy)ethoxylate 2,2-dimethylchroman-4-one (17)

The target compound 17 was prepared as in Example 12 by substituting 2-bromoethyl ether for 1,4-dibromobutane. 7-(2-(2-(4-(6-fluorobenzo[d]]) Oxazol-3-yl)piperidin-1-yl)ethoxy)ethoxy) 2,2-dimethylchroman-4-one. Melting point: 128-130°. . NMR (CDCI ₃ ) δ 1.46 (s, 6H), 1.69-1.88 (m, 4H), 2.09-2.11 (m, 6H), 2.42-2.53 (m, 6H), 2.69 (s, 2H), 3.10-3.12 (m, 1H), 3.62 (t, 2H, 7=8 Hz), 3.80 (t, 2H, 7=8 Hz), 4.19 (t, 2H, J= 8 Hz), 6.39 (d, 1H, = 4 Hz), 6.54-6.56 (m, 1H), 7.04-7.09 (m, 1H), 7.24-7.26 (m, 1H), 7.71-7.74 (m, 1H), 7.80 (d, 1H, =8 Hz). MS (ESI) m/z 483.3 ([M+H] ⁺ ) Example 18, (E) 7- (4-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperidine Small base) 2-buten-1-yl)oxy) helical [chroman-2-Γ-cyclopentane]-4-one (18)

The title compound 18 was prepared as in Example 1 by substituting 1,4-dibromo-2-butene for 1,4-dibromobutane. (E) 7- (4-(4-(6-fluorobenzene) And [d] isoxazol-3-yl)piperidin-1-yl) 2-buten-1-yl)oxy) Helical [chroman-2-1'-cyclopentanyl]-4-one. Melting point: 125-127 °C. NMR (CDCI ₃ ) δ 1.62-1.92 (m, 12H), 2.41-2.50 (m, 4H), 2.78 (s, 2H), 3.00-3.09 (m, 3H), 4.63 (d, 2H, = 8 Hz) , 5.97-6.12 (m, 2H), 6.39 (d, 1H, J = 4Hz), 6.54-6.56 (m, 1H), 7.05-7.10 (m, 1H), 7.23-7.25 (m, 1H), 7.70- 7.75 (m, 1H), 7.80 (d, 1H, 7=8 Hz). MS ( ESI ) m/z 491.3 ([M+H] ⁺ ) Example 19, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) Helical [color full -2-4'- Piperidine]-4-ketohydrochloride (19)

(1) 2,4-dihydroxyacetophenone 7.6 g, N-Boc-4-piperidone 19.9 g, tetrahydropyrrole 7.1 g, anhydrous acetonitrile 50 ml, and reacted at 50 ° C for 12 h. After the reaction was completed, the reaction was completed, and the mixture was cooled to room temperature. The solution was evaporated to dryness. EtOAc was evaporated, evaporated, evaporated, evaporated. White solid, dried product 7.2 g, mp 166-168. , yield 43.4%.

(2) Take the first step product 3.3g, anhydrous potassium carbonate 6g, acetone 50ml, 1,4-dibromobutane 8.2g, heat reflux reaction for 6 hours, cool to room temperature, filter, evaporate the solvent, elute Petroleum ether: ethyl acetate 8:1 was passed through a column to give 2.6 g of colorless oil.

(3) Take the second step product 0.92g, add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride 0.58g, anhydrous potassium carbonate 2g, potassium iodide 0.2g And 30 ml of acetonitrile, and the mixture was heated to reflux for 12 hours, cooled to room temperature, and the solvent was evaporated to dryness. The mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Column chromatography gave 0.89 g of a white solid, m.p.: 89-91.

(4) Take the product of the third step, 0.8 g, add 20 ml of ethyl acetate, stir to dissolve, add 10 ml of saturated ethyl acetate hydrochloric acid at room temperature, continue stirring for 4 h, stop the reaction, spin dry the solvent, add diethyl ether, and filter. A white solid was obtained which crystallised from isopropyl alcohol to yield white crystals (yield: EtOAc: EtOAc: ^X H NMR (DMSO-d6) δ 1.81-2.20 (m, 10H), 2.48 (t, 2H, = 8 Hz), 2.80 (s, 2H), 3.11-3.16 (m, 7H), 3.50-3.63 (m , 3H), 4.10 (t, 2H, 7=8 Hz), 6.67 (d, 1H, = 4 Hz), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 2H), 8.29 (d, 1H) , J = 8 Hz). 11.25 (s, br, 1H). MS

( ESI ) m/z 508.3 ([M+H] ⁺ ) Example 20, 7- - (4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2-methylchroman-4-one (20 )

(1) Resorcinol llg and 17.2g of crotonic acid were added to 15 g of anhydrous zinc chloride and heated to 180 ° C for 30 minutes. After the completion of the reaction, the reaction was quenched, cooled to room temperature, poured into water, ethyl acetate (200 ml), EtOAc (EtOAc) Melting point: 173-175 ° C.

(2) Take the first step product 3g, anhydrous potassium carbonate 6g, acetone 50ml, 1,4-dibromobutane 8.2g, heated to reflux for 6 hours, cooled to room temperature, filtered, evaporated to dryness, eluent Petroleum ether: ethyl acetate 8:1 was passed through a column to yield 2.6 g of colorless oil.

(3) Take the second step product 0.62g, add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride 0.51g, anhydrous potassium carbonate 2g, potassium iodide 0.2g And 30 ml of acetonitrile, heating and refluxing for 10 hours, cooling to room temperature, evaporation of the solvent, adding appropriate amount of dichloromethane, washing with water, separating the aqueous layer, drying the organic layer with anhydrous magnesium sulfate, evaporation of solvent, column chromatography Solid 7- (4- (4-

(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2-methylchroman-4-one 0.71 g, m.p.: 95-97 ° C, The rate is 63.4%. NMR (CDCI ₃ ) δ 1.47-1.50 (m, 5H), 1.67-1.93 (m, 6H), 2.41-2.51 (m, 4H), 2.78-2.81 (m, 2H), 3.01-3.06 (m, 3H) , 4.05 (t, 2H, 7=8 Hz), 4.38-4.41(m, 1H), 6.39 (d, 1H, = 4 Hz), 6.54-6.57 (m, 1H), 7.05-7.10 (m, 1H) , 7.25-7.27 (m, 1H), 7.70-7.74 (m, 1H), 7.80 (d, 1H, J = 8 Hz). MS (ESI) m/z 453.3 ([M+H]+) Example 21 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-2-methyl-8-chlorochroman-4-one (21) Using 2-chlororesorcin instead of resorcin, the target compound 21 was prepared as in Example 20: 7-(4-(4-(6-fluorobenzo[d]isoxazole- 3-yl)piperidin-1-yl)butoxy) 2-methyl-8-chlorochroman-4-one.

XH NMR (CDCI ₃ ) δ 1.47-1.50 (m, 5H), 1.67-1.93 (m, 6H), 2.41-2.51 (m, 4H), 2.78-2.81 (m, 2H), 3.01-3.06 (m, 3H ), 4.05 (t, 2H, 7=8 Hz), 4.38-4.41 (m, 1H), 6.54-6.56 (m, 1H), 7.05-7.11 (m, 1H), 7.24-7.27 (m, 1H), 7.71-7.74 (m, 1H), 7.81 (d, 1H, J = 8 Hz). MS ( ESI ) m/z 486.2 ([M+H]+) Example 22, 7-(4-(4-(6-Fluorobenzox)isoxazol-3-yl)piperidin-1-yl)butoxy)chroman-4-one (22)

(1) 10.5 g of resorcinol llg and 3-chloropropionic acid, 50 g of trifluoromethanesulfonic acid was added, and heated to 80 ° C for 1 h. After the reaction was completed, the reaction was stopped, and the mixture was cooled to room temperature, poured into water, and ethyl acetate (200 ml) was evaporated to ethyl acetate, and the organic layer was combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to give the product 13.6 g, yield 74.8%. One step reaction. The product at the front at 5 °C

13.6 g was slowly added to the 2N sodium hydroxide solution, and after the addition, the reaction was carried out at room temperature for 2 h. After completion of the reaction, _P H was adjusted to 2 with dilute hydrochloric acid in an ice bath, and a solid was precipitated, allowed to stand for 30 minutes, filtered, and the solid was dried to obtain 9.0 g of a product, yield 80%.

(2) Take the first step product 2.5g, anhydrous potassium carbonate 6g, acetone 50ml, 1,4-dibromobutane 8.2g, heat reflux reaction for 6 hours, cool to room temperature, filter, evaporate the solvent, elute The petroleum ether: ethyl acetate 8:1 was passed through a column to give a colorless oil of 2.1 g, yield 51.2%.

(3) Take the second step product 0.6g, add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride 0.52g, anhydrous potassium carbonate 2g, potassium iodide 0.2g And 30 ml of acetonitrile, and the mixture was heated to reflux for 12 hours, cooled to room temperature, and the solvent was evaporated to dryness. The mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Column chromatography gave 0.5 g of a colorless oil, which is 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) Full-4-ketone, yield 58.1%. NMR (CDCI ₃ ) δ δ 1.35-1.41 (m, 2H), 1.69-1.92 (m, 6H), 2.43-2.52 (m, 4H), 2.78-2.81 (m, 1H), 2.95-3.06 (m, 4H) ), 4.06 (t, 2H, 7=8 Hz), 4.42 (t, 2H, 7=8 Hz), 6.38 (d, 1H, = 4 Hz), 6.53-6.56 (m, 1H), 7.06-7.11 ( m, 1H), 7.24-7.26 (m, 1H), 7.71-7.75 (m, 1H), 7.80 (d, 1H, J = 8 Hz). MS ( ESI ) m/z 439.3 ([M+H]+ Example 23, 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 5-methylchroman-4- The ketone (23) was prepared by substituting 5-methyl resorcinol for resorcinol to obtain the target compound 23 by the method of Example 22: 7-(4-(4-(6-fluorobenzo[d]] Zyrid-3-yl)piperidin-1-yl)butoxy) 5-methylchroman-4-one.

Melting point: 85-87°C o ^X H NMR(CDCI ₃ ) δ δ 1.33-1.40 (m, 2Η), 1.67-1.93 (m, 6Η), 2.39 (s, 3H),

2.43-2.52 (m, 7H), 2.77-2.80 (m, 1H), 2.96-3.07 (m, 4H), 4.07 (t, 2H, 7=8 Hz), 4.45 (t, 2H, 7=8 Hz) , 6.39 (d, IH, = 4 Hz), 6.54-6.57 (m, 1H) „ 7.06-7.11 (m, IH), 7.23-7.25 (m, IH), 7.71-7.75 (m, IH). MS ( ESI ) m/z 453.3 ([M+H] ⁺ ) Example 24, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy 6-methylchroman-4-one (24) Using 4-methyl resorcinol instead of resorcin, the target compound 24 was prepared as in Example 22: 7- (4- (4- (6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 6-methylchroman-4-one.

Melting point: 91-93 °C. NMR (CDCI ₃ ) δ 1.35-1.41 (m, 2H), 1.68-1.91 (m, 6H), 2.38 (s, 3H), 2.43-2.52

(m, 4H), 2.77-2.80 (m, IH), 2.99-3.08 (m, 4H), 4.06 (t, 2H, 7=8 Hz), 4.46 (t, 2H, 7=8 Hz), 6.38 ( d, IH, J

= 4 Hz), 7.07-7.12 (m, IH), 7.24-7.26 (m, IH), 7.70-7.74 (m, IH), 7.80 (d, IH, J = 8 Hz). MS ( ESI ) m/ z

453.2 ([M+H]+) Example 25, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 8 -methylchroman-4-one (25) Using 2-methyl resorcinol instead of resorcin, the target compound 25 was prepared as in Example 22: 7-(4-(4-(6-fluoro) Benzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 8-methylchroman-4-one.

Melting point: 88-90 °C. NMR (CDCI ₃ ) δ 1.36-1.41 (m, 2H), 1.69-1.91 (m, 6H), 2.40 (s, 3H), 2.44-2.55

(m, 4H), 2.79-2.82 (m, IH), 3.01-3.08 (m, 4H), 4.06 (t, 2H, 7=8 Hz), 4.45 (t, 2H, 7=8 Hz), 6.54- 6.57 (m,

IH), 7.07-7.12 (m, IH), 7.24-7.26 (m, IH), 7.70-7.74 (m, IH), 7.80 (d, IH, J = 8 Hz). MS ( ESI ) m/z

453.2 ([M+H]+) Example 26, 7 Full-4-ketone (26)

(1) 16.6 g of 2,4-dihydroxypropiophenone, 70 ml of acetic anhydride, 8.3 g of anhydrous sodium acetate was added, and the mixture was heated under reflux for 14 h. After the reaction is completed, it is cooled to room temperature, and the reaction liquid is poured into water, and the organic layer is combined with methylene chloride 100 ml×3 times, dried, and the solvent is dried. A yellow solid was obtained in a yield of 95%. Melting point: 98-100 ° C.

(2) Take 4 g of the first step product and add to a saturated sodium hydrogencarbonate solution: methanol (1:1, 50 ml). The reaction was stirred at room temperature for 3 h. The reaction mixture was filtered, and washed with EtOAc. Melting point 192-194 ° C.

(3) Take 3 g of the second step product, add 30 ml of methanol, stir to dissolve, and add 10% Pd-C 0.3 g. The reaction was carried out at room temperature for 12 h. The reaction was quenched, filtered, and the solvent was evaporated to ethylamine.

(4) Take the third step product 1.9g, anhydrous potassium carbonate 6g, acetone 50ml, 1,4-dibromobutane 8.2g, heated to reflux for 6 hours, cooled to room temperature, filtered, evaporated to dryness Petroleum ether: ethyl acetate 6:1 was passed through a column to give a colorless oil of 2.2 g, yield 61.1%.

(5) Take the fourth step product 0.7g, add 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride 0.52g, anhydrous potassium carbonate 2g, potassium iodide 0.2g And 30 ml of acetonitrile, and the mixture was heated to reflux for 12 hours, cooled to room temperature, and the solvent was evaporated to dryness. The mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Column chromatography gave the product 0.8 g, m.p.: 82-84. , yield 86.1%. ^ NMRiCDCI^ S Ul^l im' SH), 1.69-1.92 (m, 6H), 2.44-2.55 (m, 4H), 2.78-2.82 (m, IH), 3.01-3.03 (m, 2H), 3.69 ( m, IH) 4.06 (t, 2H, 7=8 Hz), 4.45 (m, IH), 6.38 (d, IH, 7 = 4 Hz), 6.54-6.58 (m, IH), 7.08-7.13 (m, IH), 7.24-7.26 (m, IH), 7.71-7.75 (m, IH), 7.80 (d, IH, J = 8 Hz). MS ( ESI ) m/z 467.2 ([M+H] ⁺ )

61

B. Examples of pharmacological aspects

Example 27

Preparation of s-HU

Rats were decapitated, operated on ice, and the cortex was quickly taken. Add 3 ml of buffer (0.05 M Tris-HCI buffer containing 0.1% ascorbic acid, ΙΟμιη eugenin and 4 mM CaCI ₂ ) in 4 3-4 s. Homogenize, homogenize 4 times, then add 5 ml buffer (0.05 M Tris-HCI buffer containing 0.1% ascorbic acid, ΙΟμΓΠ eugenin and 4 mM CaCI ₂ ), incubate for 10 min at 37 ° C, and incubate the test tube Adjust the weight with a balance, centrifuge at 12000r, 4 °C for 20 min, discard the supernatant, add 3 ml of B solution, mix with a vortex mixer, add 5 ml of buffer, centrifuge, repeat three times of centrifugation, centrifuge, and discard the supernatant. The solution was stored at -80 ° C until use.

Receptor binding experimental materials:

Isotope ligand ³ H-8-OH-DPAT (67.0 Ci/mmol), purchased from PerkinElmer; 5-HT, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO POPOP was purchased from Shanghai Reagent No. 1 Plant; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.

experimental method:

(1) Firstly, the prepared membrane was uniformly dispersed by a homogenizer with a suitable amount of buffer, and 15 tubes were mixed into a 100 ml container, and a suitable amount of a buffer solution of 50 ml of the membrane was added thereto for use.

(2) Each reaction tube was separately added with a membrane preparation of 100 μM, and a buffer of 100 μί.

(3) the total binding tube (ΤΒ) was added 100μΙ_ buffer, non-specific binding tubes (ΝΒ) was added 5-ΗΤ ΙΟΟμί (final concentration of 10- ⁵ Μ), each test compound specifically binds tube (SB) was added 100μΙ_ test compound (final concentration of 10- ⁵ M);

(4) Each reaction tube was separately added with radioligand ³ H-8-OH-DPAT 10 μΙ_ (two parallel tubes were set for each reaction tube, and each tube was placed on ice when the sample was applied).

(5) Incubate each reaction tube at 37 ° C for 10 min, the reaction is completed, and the combined ligand is rapidly filtered by decompression, using ice-cold The test buffer is thoroughly washed, the filter is taken out and placed in a 3 ml scintillation cup, 2 ml of toluene scintillation liquid is added and mixed; (6) The scintillation bottle is placed in a liquid scintillation counter.

Inhibition rate (I %) = (total binding tube _cpm - compound cpm) / (total binding tube _cpm - non-specific binding tube _cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2. Example 28

Preparation of 5-HT _2/ J

Rats were decapitated, operated on ice, and the cortex was quickly taken. Add 3 ml of buffer (0.05 M Tris-HCI buffer: 6.05 g of Tris dissolved in 1000 ml of double distilled water and adjusted to pH 7.5 with concentrated HCI). -4 s homogenate, homogenate 4 times, then add 5ml buffer, incubate at 37 °C for 10min, after the hatching, adjust the weight with the balance, centrifuge at 12000r, 4 °C for 20 min, discard the supernatant, add 3ml Buffer, mix with a vortex mixer, add 5 ml of buffer, centrifuge, (three times of centrifugation), centrifuge, discard the supernatant, store the pellet at -80 °C for later use.

Receptor binding experimental materials:

Isotope ligand [ ³ H]- Ketanserin ( 67.0 Ci/mmol ), purchased from PerkinElmer; Methysergide, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP purchased from Shanghai Reagent No. 1; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.

experimental method:

(1) Firstly prepare the prepared membrane with an appropriate amount of buffer, and uniformly disperse it in a homogenizer. Mix 15 tubes into a 100 ml container, add a suitable amount of buffer to a 50 ml membrane suspension, and set aside.

(3) Total binding tube (ΤΒ) was added with 100 μΙ buffer, non-specific binding tube (ΝΒ) was added to Methysergide 100 μΙ (final concentration 10 - ⁵ Μ), and each test compound specific binding tube (SB) was added to 100 μΙ. compound (final concentration of 10- ⁵ M);

(4) The radioactive ligands ³ H-Ket _{a nSer} in ΙΟμί were added to each reaction tube (two parallel tubes were set for each reaction tube, and each tube was placed on ice when the sample was applied).

(5) Each reaction tube was incubated at 37 ° C for 15 min. After the reaction was completed, the combined ligand was rapidly filtered by decompression, and thoroughly washed with ice-cold test buffer. The filter was taken out and placed in a 3 ml scintillation cup, and 2 ml was added. Toluene scintillation solution and mix;

(6) Put the scintillation bottle into the liquid scintillation counter

Inhibition rate (I %) = (total binding tube _cpm - compound cpm) / (total binding tube _cpm - non-specific binding tube _cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2. Example 29

0 ₂ film preparation

Rats were decapitated, operated on ice, and the brain striatum was quickly taken. Add 3 ml of buffer (0.05 M Tris-HCI buffer containing NaCI 120 mM, KCI 5 mM, MgCI 2 lmM, CaCI 2 ImM) in 4 steps 3-4 s homogenate, homogenate 4 times, then add 5ml buffer, adjust the weight of the homogenized test tube with a balance, centrifuge at 12000r, 4 °C for 20 min, discard the supernatant, add 3ml of B solution, mix with a vortex mixer Evenly, add 5 ml of buffer, centrifuge, repeat three times of centrifugation, centrifuge, and discard the supernatant. Store the pellet at -80 °C for later use.

Receptor binding experimental materials:

Isotope ligand ³ H-Spiperone (67.0 Ci/mmol), purchased from PerkinElmer; Butaclamol, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP from Shanghai reagent One plant; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.

experimental method:

(3) the total binding tube (ΤΒ) was added 100μΙ_ buffer, non-specific binding tubes (ΝΒ) was added 100μΙ_ Butaclamol (final concentration of 10- ⁵ M), each test compound specifically binds tube (SB) was added 100μΙ_ test compound (final concentration of 10- ⁵ M);

(4) Each reaction tube was separately added with a radioactive ligand ^-Spiperone ΙΟμί (two parallel tubes were set for each reaction tube, and each tube was placed on ice when the sample was applied).

(5) Each reaction tube was incubated at 37 ° C for 20 min. After the reaction was completed, the combined ligand was rapidly filtered by decompression, and thoroughly washed with ice-cold test buffer. The filter was taken out and placed in a 3 ml scintillation cup, and 2 ml was added. Toluene scintillation solution and mix;

(6) Put the scintillation bottle into the liquid scintillation counter

Inhibition rate (I %) = (total binding tube _cpm - compound cpm) / (total binding tube _cpm - non-specific binding tube _cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2. Example 30

Preparation of histamine receptor membrane

Rats were decapitated, operated on ice, quickly took the rat cerebellum, added homogenate F, mixed with a vortex mixer, centrifuged at 48000 g, 4 ° C for 10 min, discard the supernatant, take the precipitate, and then add the homogenate F Wash, repeat three times of centrifugation, and centrifuge, The supernatant was discarded and the pellet was stored at -80 ° C until use.

Receptor binding experimental materials:

Isotope ligand ³ H-pyrilamine (67.0 Ci/mmol), purchased from PerkinElmer; promethazine, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP purchased from Shanghai reagent One plant; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.

experimental method:

The first step: firstly prepare the prepared membrane with an appropriate amount of homogenate F, and uniformly disperse it with a homogenizer. Mix 15 tubes into a 100 ml container, add a proper amount of the homogenate to a suspension of 50 ml membrane, and set aside.

Step 2: Each reaction tube was separately added to the membrane preparation 100 μί.

The third step: The total binding tube (ΤΒ) was added 100μΙ_ homogenate F, nonspecific binding tube (NB) was added 100μΙ_ promethazine (final concentration of 10- ⁵ M), each test compound specifically binds tube (SB) was added 100μΙ_ test compound (final concentration of 10- ⁵ M);

Step 4: Each reaction tube was separately added with radioligand ³ H- _P y _r ilami _ne l (^L (each reaction tube was provided with 2 parallel tubes, and each tube was placed on ice when the sample was applied).

Step 5: Incubate each reaction tube at 30 ° C for 60 min. After the reaction is completed, the combined ligand is rapidly filtered by decompression, thoroughly washed with ice-cold test buffer, and the filter is taken out and placed in a 3 ml scintillation cup. 2ml of toluene scintillation fluid and mix well;

Step 6: Put the scintillation bottle into the liquid scintillation counter

Inhibition rate (I %) = (total binding tube _cpm - compound cpm) / (total binding tube _cpm - non-specific binding tube _cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2.

In vitro experiments showed that compounds 2, 4, 5, 11 and 12 were superior to risperidone and Abaperidone for the three receptors (D ₂ , 5-HT _1A , and 5-HT _2A ). Moreover, the affinity of the compounds 2, 4, 5, 11 and 12 is low, and the side effects of producing weight gain are less likely than those of risperidone and Abaperidone. Example 31, In vivo anti-schizophrenia activity of highly active compounds induced by MK-801

Laboratory animals and reagents

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

Ascorbic acid, Sinopharm Chemical Reagent Co., Ltd.;

MK-801, produced by Sigma, USA, preparation method: 0.1% vitamin C is formulated into a 1mg/ml solution; Positive drugs tested: haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine; Tween 80, concentration 10%.

experimental method

The well-qualified mice were randomly divided into a blank group, a model group, a positive control group (risperidone group), and a drug group. The empty group and the model group were given 10% Tween 0.1ml/10g, and the positive control group was given risperidone 0.1mg/kg. The drug group was given the corresponding dose of drugs. After administration, the blank group was intraperitoneally injected with 0.1% ascorbic acid 0.1ml/10g, the model group, the positive control group (30min), and the drug group were intraperitoneally injected with MK-801 solution 0.1mg/kg. Thereafter, spontaneous activity of each group of mice was measured within 90 minutes. The results are shown in Table 3.

The results of this experiment show that compared with the model group, risperidone, compounds 2, 4, 11, 12 and 14 can significantly improve the high activity induced by MK-801, and can effectively improve apomorphine-induced climbing. Symptoms, and do not cause EPS at an effective dose, indicating that it has significant anti-schizophrenia effects. Moreover, compounds 12 and 14 have a stronger effect than Abaperidone, and the therapeutic index is greater. Example 32: Apomorphine-induced mouse climbing experiment

Experimental animal

Healthy KM mice, male, weighing 18~22g, provided by Nanjing Qinglongshan Animal Breeding Center.

Primary reagent

Positive drugs tested: haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine; apomorphine, supplied by Sigma, 0.9% before use (containing 0.1% vitamin C) dissolved, ready for use; vitamin C, F20061113, Sinopharm Chemical Reagent Co., Ltd.;

Sodium Chloride Injection, H32026305, Xuzhou Fifth Pharmaceutical Factory Co., Ltd.

The instrument clamps the climbing cage, the stopwatch.

Experimental method: apomorphine induced mouse climbing experiment

KM mice, male, weighing 18~22g, were randomly divided into negative control group, model group, positive drug group (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, fluoride). Piperidinol, clozapine and compound dose groups (see table below for specific doses), 10 in each group. The negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (first adding a small amount of acetic acid and then adding double distilled water), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound. The volume of the gavage was 0.1 ml/10 g. One hour after the intragastric administration, apomorphine (1 mg/kg) was injected subcutaneously in a volume of 0.1 ml/10 g. Immediately after the injection of apomorphine, put it into a climbing cage for 5 minutes and observe the 10th-11 after the injection of apomorphine. 20-21, 30-31 minutes of behavior and score, the scoring criteria: four feet scored 0 on the floor; two forefoot scored 1 on the cage; four feet scored 2 on the cage. Example 33, method of catalepsy

Experimental animal

Healthy Kunming mice, male and female, (22 ± 2) g, provided by Nanjing Qinglongshan Animal Culture Center.

Main reagents:

Test drug, haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone

Instrument:

Self-made grab bar equipment: A stainless steel rod with a diameter of 0.3 cm and a height of 5 cm above the table is placed in the mouse box.

experimental method:

KM mice, male and female, weighing 20~24g, were randomly divided into negative control group, model group and positive drug group (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine). , haloperidol, clozapine) and compound dose groups, 10 in each group. The negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (adding a small amount of acetic acid and then adding double distilled water when dissolved), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound. When the intragastric volume was O.lml/lOgo for 30min, 60min, 90min, the two front paws of the mouse were gently placed on a long 20cm, 0.3cm in diameter, which was higher than the 5.5cm of the table. The hind limbs of the animals were lightly placed on the bottom of the box, and the duration of the posture of the two forepaws of the mice on the stick was recorded, and the positive reaction was confirmed by the 30s stiffness. If the mouse's forepaws have not been lowered, the observation is terminated at 60 s. The number of positive animals in each compound dose group was counted. Example 34, Acute Toxicity Study

Sequential method limit experiment KM mice, male and female, were randomly divided into several groups, each group of 2-5, each group of 2000mg/kg and solvent group, administered by 0.2ml/10g. Observe the animal's death within 3 days. (If the animal survives in 3 or more days within 3 days and there is no obvious abnormality in the state of life, continue to observe until the end of the experiment after 7 days. If the animal dies 3 or more in 3 days, the median lethal dose method is used. Determine its LD50.)

KM mice were pre-tested by median lethal dose method, male and female, randomly divided into several groups, 4 in each group, respectively, each group of 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, according to 0.2ml/10g The drug was administered by gavage and the animals were observed for death within 1-3 days.

Results: The LD _{5Q of} mice in a single administration was greater than 2000 mg/kg, with aripiprazole (93 mg/kg) and ziprasidone ( > 2000mg/kg) equivalent, higher than risperidone (82.1mg/kg) and Abaperidone (160 mg/kg), with less acute toxicity. Table 2 Inhibition rate of each compound to the receptor (repeated three times, ± SD) No. D ₂ Inhibition rate % 5-ΗΤ _1Α Inhibition rate % 5-ΗΤ _2Α Inhibition rate % ^ Inhibition rate %

1 88.8±10.1 100.0±9.5 119.1±12.3 -

2 122·2±12·3 99.0±9.1 125.5±12.6 95.5±10.4

4 125·3±12·3 100.8±9.5 120.7±12.2 92.7±9.3

6 42.0±5.1 99·3±10·2 70.8±8.1 -

7 34.3±4.0 88.7±9.1 48.9±5.6 -

9 2.5±0.3 90.8±8.9 71.5±7.9 -

10 48.9±4.6 96·6±10·3 118·3±12·8 -

12 120.6±12.6 106·9±10·8 128·3±12·3 87.4±9.1

13 79.5±8.6 96.0±9.9 82.1±8.5 -

14 94.8±7.1 98.3±9.9 96.9±9.8 -

16 72.7±7.9 99·3±10·5 115·1±12·5 -

17 19.5±2.3 88.9±8.6 97.2±10.3 -

18 109·5±12·5 98.9±9.5 99.3±10.2 -

19 99.5±11.2 96.1±8.6 92.2±101 -

20 148.2±15.1 88.6±9.7 111.2±9.9 -

22 100·3±10·1 92.3±8.6 99.8±9.1 -

24 101.3±10.2 99.3±8.9 100.8±9.6 -

25 100·1±12·0 99.6±9.9 99·5±10·6 -

Abaperidone 106·3±13·2 90.3±9.1 95.3±8.9 112.3±12.1 Risperidone 106.9±11.6 82.9±11.3 109.8±12.3 101·2±10·2 Table 3. In vivo animal model test results for preferred compounds

c Composition Examples

Example 35, tablet

Active ingredient (compound of the invention) lOOmg

Microcrystalline cellulose 50mg

Lactose lOOmg

Povidone K30 9 mg

Carboxymethyl starch sodium 12 mg

Silica 2.5mg

Magnesium stearate 1.5mg

The original auxiliary material has been sieved for 80 mesh, and the prescribed amount of active ingredient, microcrystalline cellulose, lactose, povidone K30 is weighed, added to the high-speed mixing machine, mixed at low speed, uniformly mixed, added with appropriate amount of purified water, low-speed stirring, high-speed cutting Granulation, wet granules 60 Dry at °C for 3h, sieve through 24 mesh, add the prescribed amount of sodium carboxymethyl starch, silica and magnesium stearate, mix thoroughly, and compress by tablet press. The compound of the present invention as an active ingredient is any one of the compound compounds 26. Example 36, capsule (230 mg)

Active ingredient (compound of the invention) lOOmg

Lactose 80 mg

Starch 40 mg

Povidone K30 7 mg

Silica 2 mg

Magnesium stearate 1 mg

The original auxiliary material has been sieved for 80 mesh, and the active ingredients, lactose, starch and povidone K30 are weighed into the high-speed mixing machine. The mixture is mixed at low speed, and the appropriate amount of purified water is added. The mixture is stirred at a low speed and cut at a high speed. The wet granules were dried at 60 ° C for 3 h, sieved through a 24 mesh sieve, and the prescribed amount of silica and magnesium stearate were added, and the mixture was mixed, and the capsule was filled with a capsule filling machine. The compound of the present invention as an active ingredient is any one of the compound compounds 26.

Claims

The flavonoid derivative having the structure of the formula (I) or a pharmaceutically acceptable salt thereof is desired to be produced:

ζ is a substituted or unsubstituted c ₂ ～ c ₆ alkylene group,

Or a substituted or unsubstituted c ₂ ～ c ₆ alkenylene group,

Or a (CH ₂ ) _X — A — (CH ₂ ) _y —, wherein A is 0 or a C ₃ —C ₆ cycloalkyl group, and x and y are each independently selected from an integer of 0 to 5, and x+y An integer of =2~7;

Ri R ₂ , R ₃ , R ₄ , R ₅ or R _{6 are} independently hydrogen, halogen, substituted or unsubstituted C _r C ₅ fluorenyl;

Or R1 and R2 together with the carbon atom to which they are bonded form a substituted or unsubstituted C ₄ -C ₆ cyclodecyl or heterocycloalkyl group; the hetero atom of the heterocyclic fluorenyl group is N;

X is CH or

Ar is of formula II or formula II I;

among them:

Q is 0 or S;

R _7, R ₈ or R ₉ are each independently hydrogen, halogen, C _r C ₅ hospital groups, substituted or C _r C alkyl with C _r C ₅ alkoxy group _5.

The flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substituent of the substituted alkyl group is one or more of a halogen, an amino group or a hydroxyl group.

The flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein the substituted _5- alkyl group is a trifluoromethyl group or a hydroxymethyl group.

The flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a n-pentyl group or an isopenic group. Base or neopentyl.

The flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the alkoxy group of C _r C ₅ is a methoxy group, an ethoxy group, a propoxy group, or a butyl group. Oxygen.

The flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine.

The flavonoid derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the R ₂ R ₃ , R ₄ , R ₅ or R _{6 is} independently hydrogen, chlorine or methyl. Base, ethyl, propyl, trifluoromethyl or hydroxymethyl.

The flavonoid derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R ₇ , [1⁄2 or [3⁄4 ₉ independently hydrogen, chlorine, fluorine, methyl, and B Base, trifluoromethyl, methoxy or ethoxy.

The flavonoid derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 together with a carbon atom to which they are bonded form a substituted or unsubstituted C ₄ to C ₆ The substituent on the ring in the cycloalkyl or heterocycloalkyl group is an alkyl group of d- ₅ .

The flavonoid derivative according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 together with a carbon atom to which they are bonded form a substituted or unsubstituted cyclopentane or a ring Hexane or piperidine wherein the substituent is selected from one or more of methyl, ethyl, propyl or butyl.

The flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the Z is a methyl group, an ethyl group, a propyl group, a butyl group, a propylene group, a vinyl group, or a Oxy, propoxy or 1,4-2methylcyclohexane; or Z is a (CH ₂ ) _X -A-(CH ₂ ) _y — wherein A is cyclohexane or cyclopentyl , X and y are each an integer selected from 0 to 5, and an integer of >< _+¥ =2~7.

The compound according to any one of claims 1 to 4, wherein the flavonoid derivative or a pharmaceutically acceptable salt thereof is selected from any of the following compounds or a pharmaceutically acceptable salt thereof:

(1) 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-helix [chroman-2-1'-cyclopentanyl]-4-one;

(3) 7-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-helix [chroman-2-1'-cyclopentanyl]-4-one;

(4) 7-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy) a helix [color full-2-1'-ring Pentamidine]-4-one;

(5) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-helix [color-2-1'-ring酮]-4-one; (6) 7-(4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)butoxy) Helical [color-2-1'-cyclohexan]-4 -ketone;

(7) 7-(4-(4-(2,3-Dimethylphenyl)piperazin-1-yl)butoxy) Helical [color-2-1'-cyclohexan]-4- Ketone

(10) 7- . (3-. (4- • (2-methoxyphenyl) piperazin-1-yl) propoxy) helix [color-2-1'-cyclohexan]-4 Ketone

(11) 7-(3- (4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)helix [color full-2-1'-ring酮]-4-one;

(12) 7-. (4-. (4-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2,2 dimethylchroman -4-ketone;

(13) 7-. (4-. (4-(2-Methoxyphenyl) piperazine-1-yl)butoxy) 2,2-dimethylchroman-4-one;

(14) 7-. (3-. (4-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy) 2,2 dimethylchroman -4-ketone;

(15) 7-. (3-. (4-(2-Methoxyphenyl) piperazine-1-yl)propoxy) 2,2-dimethylchroman-4-one;

(16) 7- -((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)cyclohexyl)methoxy) 2, 2-dimethylchroman-4-one;

(17) 7-(2-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethoxy)ethoxy) 2,2- Dimethyl color

-4-ketone;

(18) (E) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl) 2-buten-1-yl)oxy) Spiral [color full -2-1'-cyclopentan-4-one;

(19) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) Helical [Color-2-4'- Piperidine]-4-one hydrochloride;

(23) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-5-methylchroman-4-one;

(24) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 6-methylchroman-4-one;

(25) 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 8-methylchroman-4-one;

A pharmaceutical composition, which comprises the flavonoid derivative according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

14. The flavonoid derivative of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the preparation of a therapeutic nerve Application in psychotropic drugs.

15. The use according to claim 14, wherein the neuropsychiatric disorder is schizophrenia.