Quinolinone compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a quinolinone compound, a preparation method therefor and the use thereof. Specifically, the quinolinone compound as represented by general formula (I) provided in the present invention has an antagonistic effect on a 5-hydroxytryptamine transporter, has good regulatory activity against a 5-hydroxytryptamine 1A(5-HT1A) receptor, can be used for treating various central nervous system diseases, and does not cause central or peripheral side effects resulting from the full agonism of the 5-HT1A receptor. In addition, the compound of the present invention has strong activity and high oral bioavailability, has characteristics such as a low effective dosage and low levels of toxicity and few side effects, and is effective in diseases in the field of central nervous systems.

Description

Quinolinone compounds, preparation methods and uses thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to a class of quinolinone compounds represented by general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, preparation methods thereof, pharmaceutical compositions thereof and their use in preparing drugs for central nervous system diseases. Background Art

[0002] With the rapid development of society and the increasing pace and pressure of people's lives, mental illness has become a serious disease that affects human health, bringing serious consequences to patients and their families. Due to factors such as susceptibility to suicide, lack of medical care, and a higher risk of complications, the average life expectancy of patients with mental illness is shortened. Numerous studies have shown that mental illness is associated with abnormal function of multiple central neurotransmitters and receptors. For example, monoamine transmitters in the brain, especially the dopamine (DA) system and the serotonin (5-HT) system, are closely related to normal mental activity in the human body. When the DA and 5-HT systems are dysfunctional, it is easy to lead to the occurrence of a variety of neuropsychiatric diseases, such as schizophrenia, depression, neuropathic pain, mania, anxiety, Parkinson's disease, etc.

[0003] The 5-HT transporter is an important target for antidepressant and antianxiety drugs. Existing SSRIs (selective 5-HT reuptake inhibitors) drugs selectively inhibit the 5-HT transporter, increase the 5-HT concentration in the synaptic cleft, and thus exert antidepressant and antianxiety effects. 1A The 5-HT receptor is the most widely distributed 5-HT receptor subtype in the brain and is involved in many brain-related diseases, including depression, anxiety, and cognitive impairment. 1A The combined use of 5-HT receptor partial agonists (such as buspirone and tandurone) and 5-HT transporter inhibitors can enhance the antidepressant effect of 5-HT transporter inhibitors, possibly because the two drugs can synergistically activate 5-HT 1A Therefore, compounds that combine these two effects will have good research and development prospects. Such compounds can take effect quickly and may be more effective than 5-HT alone. 1A Receptor agonists and SSRIs are significant. The new drug vilazodone launched in the United States in 2011 is 5-HT 1A A dual-target drug that stimulates 5-HT receptors and inhibits 5-HT transporters. It takes effect within 1 week and has no adverse reactions such as sexual dysfunction.

[0004] Therefore, finding compounds that can balance and regulate multiple targets including 5-HT transporters and 5-HT receptors is beneficial to better regulate the balance of multiple neurotransmitters in the brain, regulate the DA / 5-HT system, and thus better treat diseases in the central nervous system.

[0005] In view of this, the present invention is proposed.

[0006] Summary of the Invention

[0007] Purpose of the Invention

[0008] The purpose of the present invention is to provide a class of 5-hydroxytryptamine transporter antagonists and 5-hydroxytryptamine 1A (5-HT 1A ) receptors have good regulatory activity.

[0009] An object of the present invention is to provide a quinolinone compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0010] Another object of the present invention is to provide a method for preparing the quinolinone compound represented by general formula (I).

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof.

[0012] Another object of the present invention is to provide the use of the quinolinone compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts, and the above-mentioned pharmaceutical composition in the preparation of drugs for preventing and / or treating central nervous system diseases.

[0013] Technical Solution

[0014] According to one aspect of the present invention, there is provided a quinolinone compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0015] in:

[0016] X on the benzene ring is a halogen, preferably F;

[0017] Y is NH, O or S, preferably O or S;

[0018] W is CH, CH2 or O;

[0019] represents a single bond or a double bond;

[0020] When W is CH2 or O, the Represents a single bond; when W is CH, the represents a double bond;

[0021] Z on the heterocycle is hydrogen, cyano, aminoC1-C6 alkanoyl, or aminoC1-C6 alkyl substituted aminoC1-C6 alkyl acyl. Preferably, Z is hydrogen, cyano, aminoC1-C4 alkanoyl, or aminoC1-C4 alkanoyl substituted C1-C4 alkyl (preferably N-methylcarbamoyl), more preferably hydrogen, cyano, carbamoyl, or N-methylcarbamoyl.

[0022] When connected with R6, R7, R8, R9 When it represents a single bond, R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino, or acetamido, preferably hydrogen, deuterium, halogen, or hydroxyl; or one of R6 and R7, one of R8 and R9, and the two carbon atoms to which they are connected form a 3- to 6-membered carbocyclic ring, preferably a 3-membered carbocyclic ring, and the other two are as defined above;

[0023] When connected with R6, R7, R8, R9 When it represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetamido, preferably hydrogen, deuterium, halogen, and R7 and R9 are absent; or R6 and R8 and the two carbon atoms to which they are connected form a 3-6 membered carbocyclic ring, preferably a 4-6 membered carbocyclic ring, and R7 and R9 are absent;

[0024] Provided that the following compounds are not included:

[0025] 1) 7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one;

[0026] 2) 7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one.

[0027] In some preferred embodiments, X is F.

[0028] In some preferred embodiments, Y is O or S.

[0029] In some preferred embodiments, Z is hydrogen, cyano, amino C1-C4 acyl or C1-C4 alkyl substituted amino C1-C4 alkanoyl (preferably N-methylcarbamoyl); preferably, Z is hydrogen, cyano, N-methylcarbamoyl or carbamoyl.

[0030] In some preferred embodiments, R6, R7, R8, R9 are connected represents a single bond, and R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, or hydroxyl.

[0031] In some preferred embodiments, R6, R7, R8, R9 are connected to represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen or hydroxyl, and R7 and R9 do not exist.

[0032] In some preferred embodiments, R6, R7, R8, R9 are connected to represents a single bond, R6 and R8 and the two carbon atoms to which they are connected form a 3-membered carbocyclic ring; R7 and R9 are hydrogen or deuterium.

[0033] In some preferred embodiments, X is F and Y is O.

[0034] In some preferred embodiments,

[0035] represents a single bond or a double bond;

[0036] X is halogen; Y is O or S; W is CH, CH2 or O; Z is hydrogen, cyano, carbamoyl or C1-C6 alkyl-substituted carbamoyl;

[0037] When connected with R6, R7, R8, R9 When it represents a single bond, R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino, or acetamido; or one of R6 and R7, one of R8 and R9, and the two carbon atoms to which they are connected form a 3-6 membered carbocyclic ring, and the other two are as defined above;

[0038] When connected with R6, R7, R8, R9 When it represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetylamino, preferably hydrogen, deuterium, halogen, and R7 and R9 are absent; or R6 and R8 and the two carbon atoms to which they are connected form a 4-6 membered carbocyclic ring.

[0039] In some preferred embodiments,

[0040] represents a single bond or a double bond;

[0041] X is F; Y is O; W is CH, CH2 or O; Z is hydrogen, cyano, carbamoyl or C1-C6 alkyl-substituted carbamoyl;

[0042] When connected with R6, R7, R8, R9 When it represents a single bond, R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino, or acetamido; or one of R6 and R7, one of R8 and R9, and the two carbon atoms to which they are connected form a 3-6 membered carbocyclic ring, and the other two are as defined above;

[0043] When connected with R6, R7, R8, R9 When it represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetylamino, preferably hydrogen, deuterium, halogen, and R7 and R9 are absent; or R6 and R8 and the two carbon atoms to which they are connected form a 4-6 membered carbocyclic ring.

[0044] In some embodiments, the quinolinone compound represented by formula (I) is selected from the following structures:

[0045] in, Z, R6, R7, R8, and R9 are as defined above.

[0046] In some preferred embodiments, the quinolinone compound represented by general formula (I) is selected from the following structures:

[0047] in, Z, R6, R7, R8, and R9 are as defined above.

[0048] In some more preferred embodiments, the quinolinone compound represented by the general formula (I) is selected from (I-1), (I-2), and (I-5).

[0049] In some most preferred embodiments, the quinolinone compound represented by general formula (I) is selected from the following structures:

[0050] in, Z, R6, R7, R8, and R9 are as defined above.

[0051] Among the quinolinone compounds represented by general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, the following compounds or pharmaceutically acceptable salts thereof are most preferred:

[0052] (1) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0053] (2) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0054] (3) 7-(2-(4-(5-fluorobenzofuran-7-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0055] (4) 7-(2-(4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0056] (5) 7-(2-(4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0057] (6) 7-(2-(4-(5-fluorobenzofuran-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0058] (7) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0059] (8) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0060] (9) 5-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinolin-2-one;

[0061] (10) 5-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinolin-2-one;

[0062] (11) 7-(2-(4-(5-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0063] (12) 7-(2-(4-(7-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0064] (13) 7-(2-(4-(4-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0065] (14) 7-(2-(4-(6-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0066] (15) 7-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0067] (16) 7-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0068] (17) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one;

[0069] (18) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one;

[0070] (19) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,4-d2;

[0071] (20) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3-d2;

[0072] (21) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,4-d2;

[0073] (22) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3-d2;

[0074] (23) 6-fluoro-4-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide;

[0075] (24) 6-fluoro-4-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide;

[0076] (25) 6-fluoro-4-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide;

[0077] (26) 6-fluoro-4-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide;

[0078] (27) 6-fluoro-N-methyl-4-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide;

[0079] (28) 7-(2-(4-(5-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0080] (29) 7-(2-(4-(7-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one;

[0081] (30) 7-(2-(4-(4-Fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one;

[0082] (31) 7-(2-(4-(6-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one;

[0083] (32) 6-fluoro-N-methyl-4-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide;

[0084] (33) 5-fluoro-7-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide;

[0085] (34) 5-fluoro-7-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide;

[0086] (35) 5-fluoro-7-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide;

[0087] (36) 5-fluoro-7-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide;

[0088] (37) 5-fluoro-7-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carbonitrile;

[0089] (38) 5-fluoro-7-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carbonitrile;

[0090] (39) 7-(2-(4-(6-fluorobenzo[d][1,3]dicyclopentadienyl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one;

[0091] (40) 7-(2-(4-(6-fluorobenzo[d][1,3]cyclopentadien-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one;

[0092] (41) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-4,4-d2;

[0093] (42) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-4,4-d2;

[0094] (43) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3,4,4-d4;

[0095] (44)-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3,4,4-d4;

[0096] (45) 7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one;

[0097] (45-1) R-7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one;

[0098] (45-2)S-7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one;

[0099] The compounds of the present invention have 5-HT 1A The multi-target effects on receptors and monoamine transporters make the drug more drugable than the compounds in patent application WO2015131856A1, and can be used to treat various central nervous system diseases, especially depression, bipolar disorder, schizophrenia, anxiety, phobia, autism, Alzheimer's disease, bipolar disorder, hysteria, obsessive-compulsive disorder, ADHD and other diseases.

[0100] According to a second aspect of the present invention, a method for preparing a quinolinone compound represented by general formula (I) is provided. The preparation method can be carried out by one of the following methods 1-2.

[0101] Method 1:

[0102] The compound represented by formula (II) or its salt is subjected to N-alkylation reaction with the compound represented by formula (III) or its salt, as shown in Reaction Formula 1:

[0103] in, X, Y, W, Z, R6, R7, R8 and R9 are as defined and preferred above;

[0104] X1 represents a leaving group, such as halogen, C1-C6 alkylsulfonyloxy, benzenesulfonyloxy, naphthylsulfonyloxy, and the above C1-C6 alkylsulfonyloxy, benzenesulfonyloxy, and naphthylsulfonyloxy may be further substituted with one or more groups selected from halogen, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkanoyl;

[0105] X1 is preferably halogen, C1-C4 alkylsulfonyloxy, benzenesulfonyloxy, or naphthalenesulfonyloxy, and the above C1-C4 alkylsulfonyloxy, benzenesulfonyloxy, or naphthalenesulfonyloxy may be further substituted with one or more groups selected from halogen, hydroxy, amino, nitro, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkanoyl;

[0106] Most preferably, X1 is chlorine, bromine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, methylbenzenesulfonyloxy, nitrobenzenesulfonyloxy, aminobenzenesulfonyloxy, chlorobenzenesulfonyloxy, bromobenzenesulfonyloxy and methoxybenzenesulfonyloxy.

[0107] The N-alkylation reaction between the compound represented by formula (II) or a salt thereof and the compound represented by formula (III) or a salt thereof is carried out in the presence or absence of a solvent, or in the presence or absence of a base. The solvent includes water; ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, xylene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; other types such as dimethyl sulfoxide, acetonitrile, etc.; or mixtures of the above solvents.

[0108] The base can be selected from inorganic bases or organic bases. Inorganic bases include alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate; alkali metals, such as potassium and sodium; others, such as sodium amide, potassium amide, sodium hydride, and potassium hydride; organic bases include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, trisodium iodide, and thiazolinone. Ethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO). These bases can be used alone or in combination of two or more.

[0109] If necessary, the above reaction may be carried out by adding an alkali metal iodide such as potassium iodide and sodium iodide as a reaction promoter.

[0110] The above reaction is usually carried out at room temperature to 200°C, preferably at room temperature to 150°C, and is usually completed in about 1 to 30 hours, preferably in 5 to 20 hours.

[0111] Method 2:

[0112] The compound represented by formula (IV) or its salt is subjected to a coupling reaction with the compound represented by formula (V) or its salt, as shown in Reaction Formula 2:

[0113] in, X, Y, W, Z, R6, R7, R8 and R9 are as defined and preferred above;

[0114] X2 represents halogen or trifluoromethanesulfonyloxy, preferably bromine, iodine, chlorine or trifluoromethanesulfonyloxy;

[0115] The coupling reaction is carried out in the presence of a palladium catalyst and a base, with or without a solvent.

[0116] The palladium catalyst is selected from palladium acetate (Pd(OAc)2), bis(triphenylphosphine) palladium dichloride ((Ph3P)2PdCl2), bis(benzonitrile) palladium chloride ((PhCN)2PdCl2), tetrakis(triphenylphosphine) palladium (Pd(PPh3)4), bis(triphenylphosphine) palladium acetate ((Ph3P)2Pd(OAc)2), 1,2-bis(diphenylphosphino)ethane palladium dichloride ((PdCl2(dppe)2 )), bis(1,2-bis(diphenylphosphino)ethane)palladium (Pd(dppe)2), bis(dibenzylideneacetone)palladium (Pd(dba)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), [1,3-bis(diphenylphosphino)propane]dichloropalladium (PdCl2(dippp)) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2).

[0117] The base is one or more selected from sodium bis(trimethylsilyl)amide, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium fluoride, sodium fluoride, tetrabutylammonium fluoride (TBAF), sodium acetate, potassium acetate, cesium carbonate, potassium carbonate and sodium carbonate.

[0118] The solvent is not particularly limited as long as it does not interfere with the reaction, and includes water; ethers, such as dioxane, tetrahydrofuran, etc.; aromatic hydrocarbons, such as toluene, xylene, etc.; alcohols, such as tert-butanol, etc.; ketones, such as acetone, etc.; amides, such as N,N-dimethylformamide, etc.; others, such as dimethyl sulfoxide, acetonitrile, etc.; or mixtures of the above solvents.

[0119] If necessary, a suitable ligand can be added as a reaction promoter to carry out the above reaction. Suitable ligands include 2,2'-diphenylphosphino-1,1'-binaphthyl (BINAP), tri-tert-butyl (P(t-Bu)3), 1,1'-bis-(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (x-phos), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (Xantphos), tri-tert-butylphosphine tetrafluoroborate, and tri(2-methylphenyl)phosphine (P(o-tolyl)3).

[0120] The compounds of formula (II), formula (III), formula (IV) and formula (V) are commercially available compounds or are prepared according to methods known in the art or according to the synthesis methods of similar compounds.

[0121] The starting compound used in each of the above reaction formulas may be a suitable salt, including alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, calcium salts, magnesium salts, etc.; organic base salts, such as pyridinium salts, triethylamine salts, etc.; inorganic acid salts, such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, etc.; organic acid salts, such as formates, acetates, propionates, glycolates, oxalates, malonates, succinates, fumarates, maleates, lactates, malates, citrates, tartrates, picrates, glutamates, methanesulfonates, and benzenesulfonates, etc.;

[0122] Furthermore, the starting compounds used in the above reaction formulae may include solvate forms such as hydrates, alcoholates, and the like.

[0123] The quinolinone compound represented by the general formula (I) of the present invention and its stereoisomers also include their solvate forms, such as hydrates, alcoholates, etc., and the solvates are included in the scope of the present invention.

[0124] The pharmaceutically acceptable salts of the quinolinone compounds represented by general formula (I) and their stereoisomers of the present invention refer to the quinolinone compounds represented by general formula (I) or their stereoisomers converted into therapeutically active non-toxic addition salt forms by treating them with an appropriate acid. Such salts include hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, nitrate, phosphate or acid phosphate, perchlorate, formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, maleate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, ascorbate, camphorate or camphorsulfonate. Conversely, the salt form can also be converted into the free base form by treating it with an alkali.

[0125] The term "pharmaceutically acceptable salts" used above also includes their solvates, and said solvates are included in the scope of the present invention. Examples of solvates include, for example, hydrates, alcoholates, and the like.

[0126] Each target compound obtained by each reaction formula can be separated and purified from the reaction mixture by the following methods, for example: after cooling the reaction mixture, the crude product is separated by methods such as filtration, extraction or concentration, and then purified by conventional methods such as column chromatography, beating method or recrystallization.

[0127] According to the third aspect of the present invention, there is also provided a pharmaceutical composition comprising a therapeutically effective amount of the quinolinone compound represented by the above general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and an optional pharmaceutically acceptable carrier.

[0128] According to a fourth aspect of the present invention, there is also provided a method for preparing a pharmaceutical composition, comprising mixing the quinolinone compound represented by the above general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable carrier.

[0129] In the pharmaceutical composition of the present invention, a variety of pharmaceutical preparation forms can be selected according to the therapeutic purpose, including but not limited to: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols and injections (such as fat-soluble or oil-soluble injections), etc.

[0130] According to a fifth aspect of the present invention, there is also provided a use of the quinolinone compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a drug for preventing and / or treating central nervous system diseases.

[0131] According to the sixth aspect of the present invention, there is also provided a method for treating and / or preventing central nervous system diseases, which comprises administering to humans or animals the quinolinone compound represented by the above-mentioned general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof.

[0132] The above-mentioned central nervous system diseases are selected from the group consisting of: schizophrenia; affective disorders; psychotic disorders; mood disorders; bipolar I disorder; bipolar II disorder; depression; dysthymic disorder; cyclothymic disorder; panic disorder; obsessive-compulsive disorder; impulsive disorder; post-traumatic stress disorder; anxiety disorder; hysteria; anorexia nervosa; sleep disorder; adjustment disorder; cognitive disorder; autism; neuralgic headache; mania; Parkinson's disease; Huntington's disease; various dementias; memory disorders; ADHD; attention deficit / hyperactivity disorder and tics, etc.

[0133] Preferably, the central nervous system disease is selected from the group consisting of: refractory, intractable or chronic schizophrenia; intrinsic depression; major depression; refractory depression; panic attack; social phobia; acute stress disorder; and Alzheimer's disease.

[0134] The compounds of the present invention have the following beneficial effects:

[0135] 1) The compounds of the present invention have a good inhibitory effect on the 5-HT transporter and can be used to treat various central nervous system diseases.

[0136] 2) The compounds of the present invention have an effect on 5-HT 1A The receptor has a good regulatory effect, EC 50 or IC 50Reaching the level of 0.1 to 10 nM, it can be used to treat various central nervous system diseases without causing complete excitation of 5-HT 1A Central or peripheral side effects caused by receptors.

[0137] 3) The compounds of the present invention are not only highly active but also orally effective (high bioavailability), have the characteristics of low effective dose and minimal toxic side effects, and are effective in treating diseases of the central nervous system, especially major depressive disorder (MDD), anxiety, negative symptoms of schizophrenia, cognitive dysfunction, Parkinson's disease, ADHD and other diseases.

[0138] In summary, compared with the compounds disclosed in the prior art, the compounds of the present invention have the advantages of multi-target effects, lower effective doses, fewer toxic side effects, better safety and tolerability, good overall drugability, and good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0139] FIG1 shows the results of the forced swimming test of Test Example 5, wherein * indicates P<0.05, and ** indicates P<0.01 (tested by one-way analysis of variance). DETAILED DESCRIPTION

[0140] The following preparation examples, examples and pharmacological activity test examples further illustrate the present invention, but do not limit the scope of the present invention.

[0141] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples and experimental examples are conventional raw materials, reagents, and methods in the art.

[0142] Preparation Example

[0143] Example 1 Preparation of 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

[0144] (1) Synthesis of compound 1-b:

[0145] Under nitrogen, 3-fluoro-5-bromophenol (6 g, 1 eq), 2-bromo-1,1-dimethoxyethane (7.44 g, 1.4 eq), and potassium carbonate (6.51 g, 1.5 eq) were dissolved in 50 ml of DMF. The mixture was heated to 100°C and stirred overnight. The reaction mixture was poured into water and extracted three times with ethyl acetate (EA). The organic phase was then washed twice with saturated sodium bicarbonate. The organic phase was dried and concentrated to afford compound 1-b, 10.7 g of a brownish-red oil, in a yield of >99%.

[0146] (2) Synthesis of compound 1-c:

[0147] Under nitrogen, 1-b (10.7 g, 1 eq) and polyphosphoric acid (PPA) (38 g, 3 eq) were dissolved in toluene and heated under reflux at 110°C for 2 h. The reaction mixture was poured into water, and the organic phase was washed 2-3 times with water and then 1-2 times with saturated sodium bicarbonate solution. The organic phase was dried, concentrated, and purified by column chromatography to afford compound 1-c as an oil (4.734 g, 57% yield).

[0148] (3) Synthesis of compound 1-d

[0149] Under nitrogen, 1-c (4.734 g, 1 eq), tris(dibenzylideneindeneacetone)dipalladium (Pd2(dba)3) (1.8 g, 0.1 eq), potassium tert-butoxide (6.16 g, 2.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) (1.25 g, 0.1 eq), and 1-Boc-piperazine (4.9 g, 1.2 eq) were dissolved in toluene. The mixture was refluxed at 100°C and the reaction progress was monitored by TLC. After completion of the reaction, the mixture was filtered. The filtrate was concentrated and purified by column chromatography to afford compound 1-d as a yellow oil (1.604 g, 22% yield).

[0150] (4) Synthesis of compound 1-e

[0151] Dissolve 1-d (800 mg, 1 eq) in 2 ml of ethanol, add 2 M ethanolic hydrogen chloride solution (5 ml), and stir at room temperature overnight. Concentrate under reduced pressure to remove the solvent, then add isopropyl acetate to slurry, filter, and dry the filter cake to obtain compound 1-e as a yellow solid (hydrochloride salt, 600 mg), in a yield of 93%.

[0152] (5) Synthesis of Compound 1

[0153] To a 50 mL single-necked bottle, add 1-e (600 mg, 1 eq), 1-f (823 mg, 1.3 eq), sodium bicarbonate (1 g, 5.0 eq), sodium iodide (360 mg, 1 eq), and DMF (6 mL). Under nitrogen, react at 80°C overnight. Add water and stir, extract twice with EA, dry the organic phase, and concentrate under reduced pressure. Purify by column chromatography to yield 710 mg of the product.

[0154] 1H NMR (400MHz, DMSO-d6) δ10.07 (s, 1H), 7.96 (d, J = 2.3Hz, 1H), 7.13–7.08 (m, 2H), 7.04(d,J=2.2Hz,1H),6.85(dd,J=7.6,1.7Hz,1H),6.79(d,J=1.7Hz,1H),6.59(d d,J=12.5,2.2Hz,1H),3.24(t,J=4.7Hz,4H),2.87(t,J=7.5Hz,2H),2.77–2.68( m,6H),2.63–2.59(m,2H),2.48(dd,J=8.5,6.5Hz,2H).ESI-MS(m / z):394.3[M+H] +

[0155] Example 2 Preparation of 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

[0156] (1) Synthesis of compound 2-a

[0157] Dissolve 1-d (0.437 g, 1 eq) in 5 ml of methanol and add 5% palladium on carbon (40 mg, 10% wt). Pressurize the mixture to 2.5 MPa with hydrogen and stir at 40°C overnight. Filter and concentrate the filtrate, followed by column chromatography to afford compound 2-a as a light yellow solid (302 mg, 68% yield).

[0158] (2) Synthesis of compound 2-b

[0159] 2-a (302 mg, 1 eq) was dissolved in 5 ml of ethanol, and 2 M ethanolic hydrogen chloride solution (8 ml) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove the solvent, and isopropyl acetate was added to slurry. The mixture was filtered and the filter cake was dried to obtain compound 2-b as a yellow solid (hydrochloride salt, 156 mg) in a yield of 64%.

[0160] (3) Synthesis of Compound 2

[0161] To a 25 mL three-necked flask, add 2-b (200 mg, 1.0 eq), 1-f (340 mg, 1.5 eq), DMF (6 mL), sodium bicarbonate (378 mg, 5.0 eq), and sodium iodide (140 mg, 1.0 eq) under nitrogen. Heat to 80°C and stir overnight. Add water and extract twice with EA. Combine the organic phases, dry, concentrate under reduced pressure, and purify by column chromatography to yield 200 mg of the product.

[0162] 1H NMR (400MHz, DMSO-d6) δ10.01(s,1H),7.06(d,J=7.6Hz,1H),6.78(dd,J=7.6,1.7Hz,1H),6.71(d,J=1.7Hz,1H),6.27–6.18(m,2H),4.52(t,J=8.5 Hz,2H),3.08–2.99(m,6H),2.82(t,J=7.5Hz,2H),2.67(t,J=7.7Hz,2H), 2.56–2.54(m,6H),2.42(dd,J=8.5,6.5Hz,2H).ESI-MS(m / z):394.3[M+H] +

[0163] Example 9 Preparation of 5-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinolin-2-one

[0164] (1) Preparation of compound 9-b

[0165] Compound 9-a (10 g, 1.0 eq), potassium persulfate (28.3 g, 2.0 eq), and copper sulfate pentahydrate (1.3 g, 0.1 eq) were added to acetonitrile (100 mL) and water (100 mL), heated to 80°C, and stirred for 3 hours. The reaction solution was cooled to room temperature and extracted with methyltetrahydrofuran. The organic phase was dried and concentrated to dryness under reduced pressure. 50 mL of ethanol was added to the mixture, and the mixture was slurried for 30 minutes. The mixture was filtered and the filter cake was dried to obtain compound 9-b as a 3.6 g yellow solid.

[0166] (2) Preparation of compound 9-c

[0167] Compound 9-b (3.6 g, 1.0 eq) was added to N,N-dimethylformamide (DMF) (36 mL), cooled to 0°C under nitrogen, and stirred. NaH (3.0 g, 4.0 eq) was slowly added. After addition, the mixture was stirred for 1 hour. p-Methoxybenzyl chloride (PMBCl) (12.0 g, 4.0 eq) was slowly added. After addition, the mixture was warmed to room temperature and reacted for 3 hours. Water was slowly added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried and purified by column chromatography to obtain compound 9-c as a 2.4 g yellow solid.

[0168] (3) Synthesis of compound 9-d

[0169] Trimethylsulfoxide iodide (5.1 g, 10.0 eq) was added to tetrahydrofuran (THF) (50 mL), and the mixture was cooled to 0°C under nitrogen. n-Butyllithium (9.3 mL, 10.0 eq) was slowly added and the mixture was kept warm for 30 min. Compound 9-c (1.0 g, 1.0 eq) in THF (5 mL) was slowly added and the mixture was heated to 70°C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to dryness under reduced pressure to obtain compound 9-d as a 1 g yellow solid.

[0170] (4) Synthesis of compound 9-e

[0171] Compound 9-d (1.0 g, 1.0 eq) was added to trifluoroacetic acid (10 mL) and stirred at 70°C for 3 hours. The reaction solution was directly concentrated under reduced pressure to remove the solvent, quenched by adding amine methanol solution, filtered, and the mother liquor was concentrated and purified by column chromatography to obtain compound 9-e as an off-white solid (320 mg).

[0172] (5) Synthesis of compound 9-f

[0173] Compound 9-e (320 mg, 1.0 eq) and triethylamine (TEA) (230 mg, 1.5 eq) were added to dichloromethane (DCM) (3 mL). A solution of methanesulfonic anhydride (320 mg, 1.2 eq) in DCM (2 mL) was slowly added dropwise at 0°C. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with water and stirred with 20 mL of n-heptane. The precipitated solid was filtered and dried to obtain compound 9-f as an off-white solid (280 mg).

[0174] (6) Synthesis of Compound 9

[0175] Compound 9-f (100 mg, 1.0 eq), compound 9-g (130 mg, 1.1 eq), and potassium carbonate (120 mg, 2.0 eq) were added to acetonitrile (3 mL) and stirred at 80°C for 13 hours. The reaction solution was quenched with water to precipitate a solid, which was filtered and dried to obtain compound 9 as an off-white solid (125 mg).

[0176] 1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),7.67(d,J=5.5Hz,1H),7.51(d,J=8.8Hz,1H ),7.38(d,J=5.6Hz,1H),7.28(d,J=7.7Hz,1H),6.90–6.79(m,1H),6.80–6.71(m, 2H),3.11(s,4H),2.72–2.68(m,6H),2.59–2.55(m,2H),2.50–2.47(m,1H),2.00– 1.95(m,1H),1.58–1.53(m,1H),0.48(q,J=4.7Hz,1H).ESI-MS(m / z):422.1[M+H] + .

[0177] Example 10 Preparation of 5-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinolin-2-one

[0178] (1) Synthesis of compound 10-b

[0179] Under nitrogen, compound 10-a (5.0 g, 1.0 eq), ethyl mercaptoacetate (2.7 g, 1.0 eq), and potassium carbonate (6.2 g, 2.0 eq) were added to DMF (50 mL) and stirred at 60°C for 2 hours. The reaction was quenched by the addition of 150 mL of water to precipitate an off-white solid, which was filtered, dried, and recrystallized from ethanol, filtered, and dried to obtain compound 10-b as an off-white solid (4.7 g, 69% yield).

[0180] (2) Synthesis of compound 10-c

[0181] Compound 10-b (4.0 g, 1.0 eq) and sodium hydroxide (1.0 g, 2.0 eq) were added to a mixed solvent of THF (50 mL), methanol (15 mL), and water (20 mL) and stirred at room temperature for 12 hours. The organic phase was concentrated under reduced pressure and the pH was adjusted to 2-3 by adding 1 M HCl. An off-white solid precipitated, which was filtered and the filter cake dried to afford compound 10-c as an off-white solid (3.4 g, 94% yield).

[0182] (3) Synthesis of compound 10-d

[0183] Under nitrogen, compound 10-c (3.4 g, 1.0 eq) and cuprous oxide (5.4 g, 3.0 eq) were added to N,N-dimethylformamide (30 mL), and the mixture was stirred at 145°C for 6 hours. The reaction mixture was filtered, and purified water was added to the filtrate. The mixture was stirred at room temperature for crystallization, filtered, and the filter cake was dried to obtain compound 10-d as a yellow solid (0.8 g).

[0184] (4) Synthesis of compound 10-e

[0185] Under nitrogen, compound 10-d (400 mg, 1.0 eq), N-Boc piperazine (480 mg, 1.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) (108 mg, 0.1 eq), Pd2(dba)3 (159 mg, 0.1 eq), and potassium tert-butoxide (388 mg, 2.0 eq) were added to toluene (10 ml), and the mixture was stirred at 100°C for 12 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the organic phase was purified by column chromatography to obtain compound 10-e as an off-white solid (220 mg).

[0186] (5) Synthesis of compound 10-f

[0187] Compound 10-e (220 mg, 1.0 eq) was dissolved in 2 ml of ethanol, and 2 M ethanolic hydrogen chloride solution (5 ml) was added. The mixture was stirred at room temperature overnight. The organic phase was concentrated, and water was added to adjust the pH to 7-8. The mixture was extracted with ethyl acetate, dried, and concentrated under reduced pressure to obtain compound 10-f as a 150 mg yellow solid.

[0188] (6) Synthesis of Compound 10

[0189] Compound 9-f (100 mg, 1.0 eq), compound 10-f (130 mg, 1.1 eq), and potassium carbonate (120 mg, 2.0 eq) were added to acetonitrile (3 mL) and stirred at 80°C for 13 hours. The reaction mixture was quenched with water to precipitate a solid, which was filtered and dried to yield 50 mg of an off-white solid.

[0190] 1H NMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 7.82 (d, J = 5.4Hz, 1H), 7.42 (d, J = 5.4Hz, 1H), 7. 35(dd,J=9.1,2.3Hz,1H),7.27(d,J=7.7Hz,1H),6.85–6.81(m,2H),6.73(d,J=1.6Hz, 1H),3.19(t,J=4.7Hz,4H),2.71–2.64(m,6H),2.58–2.54(m,2H),2.50–2.47(m,1H),2 .00–1.94(m,1H),1.58–1.52(m,1H),0.48(q,J=4.7Hz,1H).ESI-MS(m / z):422.2[M+H] + .

[0191] The following table shows the compounds in Examples 3 to 8 and 11 to 45. These compounds can be prepared using the same methods as in the above examples, except that the starting materials and intermediates corresponding to the final products are used.

[0192] For the compound of Example 45, isomers 45-1 and 45-2 were chirally separated by HPLC, wherein the chromatographic conditions were:

[0193] Test Example 1. 5-HT 1A Receptor agonist activity test

[0194] Using LANCE TM The cAMP 384 Kit (PerkinElmer, USA) was used to test the effects of the compounds on the expression of human recombinant 5-HT 1A 5-HT receptor in CHO-K1 cells 1A The inhibitory effect of the test compounds on cAMP production in CHO-K1 cells was used to evaluate the 5-HT receptor agonist activity of the compounds. 1A Receptor agonism. 8-OH-DPAT was used as a positive control. The specific operation is as follows:

[0195] a) Prepare the compounds (test compound and positive control) in DMSO to a stock concentration of 10 mM. Prepare forskolin to a stock concentration of 10 mM. 8-OH-DPAT should be tested starting at 1 μM using a 3X dilution. Test compound should be tested starting at 0.1 μM using a 3X dilution. Repeat twice for each concentration. Use an Echo to transfer 100 nL of compound and 10 nL of forskolin to the assay plate. Final DMSO concentration should be <1%.

[0196] b) 5-HT 1A Remove the stably transfected cells from the incubator and observe their status. When the cell density reaches 80%-90%, discard the culture medium and wash the cells with 5 mL of DPBS. Remove the DPBS, add 2 mL of trypsin, and incubate at 37°C in a CO2 incubator for 2-5 minutes. Add 10 mL of complete culture medium to harvest the cells, centrifuge at 1000 rpm for 4 minutes, and discard the supernatant. Adjust the cell suspension to a density of 1000 cells / well using Stimulation Buffer (HBSS + 5 mM HEPES + 0.5 mM IBMX + 0.1% BSA).

[0197] c) Transfer 10 μl of the prepared cell solution to the assay plate containing the compound.

[0198] d) Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for one hour.

[0199] e) Add 5 μL 4X Eu-cAMP tracer solution and 5 μL 4X ULight TM -anti-cAMP solution, centrifuge at 600 rpm for 3 minutes, and incubate at room temperature for one hour.

[0200] f) Read the data using the multifunctional microplate reader EnVision, EC 50 The results were calculated using Graphpad Prism software and are shown in Table 1.

[0201] Table 1:

[0202] *Note: The compound of Example 85 in patent application WO2015131856A1 (7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one).

[0203] As can be seen from the table above, the compounds of Examples 1-3, 5, 12, 14-16 of the present invention and the control compound have comparable 5-HT 1A Receptor agonist activity.

[0204] Test Example 2. 5-HT transporter inhibitory activity test

[0205] Transporter inhibition was tested in HEK-293 cells expressing human SERT using a Neurotransmitter transporter uptake assay kit (Molecular Devices). The assay was performed according to the kit instructions, using citalopram as a positive control. The specific procedures were as follows:

[0206] a) HEK-hSERT cells were seeded into 384-well plates at 20,000 cells / well and then transferred to a culture incubator and incubated overnight at 37°C.

[0207] b) The next day, dilute the compounds (test compounds and positive control) from a 20 mM DMSO solution to working concentrations. Transfer each test compound and citalopram to a 384-well plate using assay buffer containing 0.1% BSA. Citalopram should be tested starting at a 1 μM concentration and diluted 3X. Test compounds should be tested starting at a 10 μM concentration and diluted 4X. Repeat twice for each concentration.

[0208] c) Remove the 384-well cell culture plate from the incubator, aspirate the culture medium from each well, and add 25 μL / well of the test compound solution. Incubate at 37°C for 30 minutes. After incubation, add 25 μL of the dye solution to each well and incubate at 37°C for 30 minutes.

[0209] d) Fluorescence values ​​were read on Flexstation 3 and the data were analyzed using Graphpad Prism. The results are shown in Table 2.

[0210] Table 2:

[0211] *Note: The compound of Example 85 in patent application WO2015131856A1.

[0212] As can be seen from the table above, both the example compounds and the control compounds of the present invention have strong 5-HT transporter inhibitory activity. In particular, when Y in the general formula is an oxygen atom, the 5-HT transporter inhibitory activity of the compounds is even better.

[0213] Test Example 3. Pharmacokinetic Experiment in Mice

[0214] Animals: Male ICR mice were randomly assigned to treatment groups and fasted for 12 h before dosing.

[0215] Drug: The compound was dissolved in a solvent (0.5% CMC-Na). The intravenous (iv) dose was 0.3 mg / kg in a volume of 5 ml / kg; the oral (po) dose was 1 mg / kg in a volume of 10 mL / kg body weight.

[0216] Sample Collection and Bioanalysis: After administration, blood was collected from the mouse orbits at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours (n = 3 per time point) into EP tubes containing sodium heparin. Mice were immediately sacrificed by vertebral dislocation after blood collection, and the brains of the mice at the corresponding time points were removed. All samples were immediately collected, quickly frozen, and stored at -70°C until use.

[0217] Plasma samples were obtained by whole blood centrifugation. 10 μL of plasma was then mixed with 190 μL of internal standard solution (20 ng / mL metolazone dissolved in acetonitrile containing 0.1% formic acid). After mixing, the mixture was centrifuged at 13,000 rpm for 10 minutes. 120 μL of the supernatant was collected from each sample, and 0.5-10 μL (depending on the sensitivity of the compound) was removed for drug analysis using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method appropriate for the intended use. Standards for each analyte were used for calibration and identification.

[0218] According to the ratio of brain tissue: extract (50% acetonitrile water) = 1 (g): 8 (ml), 5 3mm magnetic beads were used for homogenization in an OMNI Bead Ruptor 24Elite homogenizer at a speed of 3.2 m / s for 2 minutes. The mixture was centrifuged at 4°C and 3000g for 3 minutes. 50uL of the supernatant was collected and 200uL of internal standard solution (20ng / mL dissolved in 80% acetonitrile water) was added and mixed. After mixing, the mixture was centrifuged at 13000rpm for 10 minutes. 120μL of supernatant was collected for each sample, and then 0.5-10μl (depending on the sensitivity of the compound) of the supernatant was removed and analyzed using an appropriate LC-MS / MS method. The standard of each analyte was used for calibration and identification.

[0219] Data Analysis: Drug concentrations below the lower limit of quantification (LLOQ) were recorded as zero. Pharmacokinetic data were analyzed in PK Solver using a non-compartmental, bolus, or extravascular infusion analysis model. Data points below the LLOQ were excluded from analysis to improve t 1 / 2 The results of pharmacokinetic parameters in plasma are shown in Table 3 below. max The data are shown in Table 4:

[0220] Table 3

[0221] Table 4

[0222] *Note: The compound of Example 85 in patent application WO2015131856A1.

[0223] As shown in Tables 3 and 4 above, the compounds of Examples 1-2 of the present invention exhibited higher maximum blood concentrations and bioavailability in mice after oral administration compared to the control compound. Following oral administration at a dose of 1 mg / kg, the compounds of the present invention exhibited better brain penetration and higher brain concentrations in mice compared to the control compound.

[0224] Test Example 4. Pharmacokinetic Experiment in Rats

[0225] The compound of Example 2 was used in a pharmacokinetic study in rats (non-fasted SD male rats). The compound of the present invention was dissolved in a solvent (0.5% CMC-Na). The intravenous (iv) dose was 1 mg / kg in a volume of 5 ml / kg; the oral (po) dose was 3 mg / kg in a volume of 10 mL / kg body weight. Approximately 0.3 mL of blood was collected from the jugular vein of the rats at the following time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration (n=3 at each time point). The collected blood was stored under ice-cooling, and the plasma was quickly separated by centrifugation and a precipitant was added. The concentration of the test compound was quantified by LCMS. The experimental results are shown in Table 5 below:

[0226] Table 5

[0227] *Note: The compound of Example 85 in patent application WO2015131856A1.

[0228] As can be seen from the above table, the compound of Example 2 of the present invention has higher oral maximum blood concentration and bioavailability in rats than the control compound.

[0229] Test Example 5. Forced Swim Test:

[0230] Drug: The compound of the present invention and the positive control compound (vortioxetine) were mixed with 5% DMSO and then added Mix HS 15 and add 90% normal saline to prepare a solution of appropriate concentration for immediate use.

[0231] Animals: Male C57 mice, approximately 22 g. The animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Each group of mice was intraperitoneally injected with the vehicle formulation or each test drug.

[0232] Experimental procedures: 0.5 h after administration, mice were subjected to a forced swimming test. The water level in the forced swimming apparatus was 45 cm and the water temperature was 25°C. The mice were placed in the experimental room to adapt to the environment for 1 h before the experiment began. At the beginning of the experiment, the mice were placed in the apparatus for 6 minutes. The entire process was recorded with a camera, and only the last 4 minutes of the mice's immobility time were counted when analyzing the data. The compounds of the present invention showed significant antidepressant-like effects within the dose range of 0.01 to 0.1 mg / kg, with a low onset dose. In particular, as shown in Figure 1, compound 2 (0.01 mg / kg dose) and the positive control vortioxetine (10 mg / kg dose) were able to significantly reduce the immobility time of mice compared to the vehicle control group, and had an antidepressant-like effect.

Claims

1. A quinolinone compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: X on the benzene ring is a halogen; Y is NH, O or S; W is CH, CH2 or O; represents a single bond or a double bond; When W is CH2 or O, the represents a single bond; when W is CH, represents a double bond; Z on the heterocyclic ring is hydrogen, cyano, amino C1-C6 alkanoyl or amino C1-C6 alkyl substituted with C1-C6 alkyl; When connected with R6, R7, R8, R9 When it represents a single bond, R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino, or acetylamino; or one of R6 and R7 and one of R8 and R9 and the two carbon atoms connected thereto form a 3-6 membered carbocyclic ring, and the other two are as defined above; When connected with R6, R7, R8, R9 When it represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetylamino, and R7 and R9 do not exist; or R6 and R8 and the two carbon atoms connected thereto form a 3-6 membered carbon ring, and R7 and R9 do not exist; Provided that the following compounds are not included: 1) 7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one; 2) 7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one.

2. The quinolinone compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: X is F; and / or Y is O or S; and / or Z is hydrogen, cyano, amino C1-C4 acyl or amino C1-C4 alkanoyl substituted by C1-C4 alkyl (preferably N-methylcarbamoyl); preferably, Z is hydrogen, cyano, N-methylcarbamoyl or carbamoyl; and / or Connected to R6, R7, R8, R9 represents a single bond, R6, R7, R8, R9 are each independently selected from hydrogen, deuterium, halogen or hydroxyl; or R6 and R8 and the two carbon atoms connected to them form a 3-membered carbocyclic ring, R7 and R9 are hydrogen or deuterium; or R6, R7, R8, R9 connected to represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen or hydroxyl, and R7 and R9 do not exist.

3. The quinolinone compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: represents a single or double bond; X is a halogen; Y is O or S; W is CH, CH2 or O; Z is hydrogen, cyano, carbamoyl or carbamoyl substituted by a C1-C6 alkyl group; When connected with R6, R7, R8, R9 When it represents a single bond, R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino, or acetylamino; or one of R6 and R7 and one of R8 and R9 and the two carbon atoms connected thereto form a 3-6 membered carbocyclic ring, and the other two are as defined above; When connected with R6, R7, R8, R9 When it represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetylamino, preferably hydrogen, deuterium, halogen, and R7 and R9 do not exist; or R6 and R8 and the two carbon atoms to which they are connected form a 4-6 membered carbocyclic ring, and R7 and R9 do not exist.

4. The quinolinone compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: represents a single or double bond; X is F; Y is O; W is CH, CH2 or O; Z is hydrogen, cyano, carbamoyl or carbamoyl substituted by a C1-C6 alkyl group; When connected with R6, R7, R8, R9 When it represents a single bond, R6, R7, R8, and R9 are each independently selected from hydrogen, Deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetylamino; or one of R6 and R7 and one of R8 and R9 and the two carbon atoms connected to them form a 3-6 membered carbocyclic ring, and the other two are as defined above; When connected with R6, R7, R8, R9 When it represents a double bond, R6 and R8 are each independently selected from hydrogen, deuterium, halogen, methyl, ethyl, hydroxyl, amino or acetylamino, preferably hydrogen, deuterium, halogen, and R7 and R9 do not exist; or R6 and R8 and the two carbon atoms to which they are connected form a 4-6 membered carbocyclic ring, and R7 and R9 do not exist.

5. The quinolinone compound represented by general formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The quinolinone compound represented by general formula (I) is selected from the following structures: in, Z, R6, R7, R8 and R9 are as defined in claims 1-4 respectively.

6. The quinolinone compound represented by general formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The quinolinone compound represented by general formula (I) is selected from the following structures: Alternatively, the quinolinone compound represented by general formula (I) is selected from the following structures: in, Z, R6, R7, R8 and R9 are as defined in claims 1-4 respectively.

7. The quinolinone compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The quinolinone compound represented by the general formula (I) is selected from the following compounds or pharmaceutically acceptable salts thereof: (1) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (2) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (3) 7-(2-(4-(5-fluorobenzofuran-7-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (4) 7-(2-(4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (5) 7-(2-(4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (6) 7-(2-(4-(5-fluorobenzofuran-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (7) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (8) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (9) 5-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinolin-2-one; (10) 5-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-1,1a,3,7b-tetrahydro-2H-cyclopropyl[c]quinolin-2-one; (11) 7-(2-(4-(5-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (12) 7-(2-(4-(7-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (13) 7-(2-(4-(4-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (14) 7-(2-(4-(6-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (15) 7-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (16) 7-(2-(4-(5-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (17) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one; (18) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one; (19) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,4-d2; (20) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3-d2; (21) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,4-d2; (22) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3-d2; (23) 6-fluoro-4-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide; (24) 6-fluoro-4-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide; (25) 6-fluoro-4-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide; (26) 6-fluoro-4-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide; (27) 6-fluoro-N-methyl-4-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide; (28) 7-(2-(4-(5-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (29) 7-(2-(4-(7-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one; (30) 7-(2-(4-(4-Fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one; (31) 7-(2-(4-(6-fluorobenzo[b]thiophen-7-yl)piperazin-1-yl)ethyl)-quinolin-2(1H)-one; (32) 6-fluoro-N-methyl-4-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide; (33) 5-fluoro-7-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide; (34) 5-fluoro-7-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carboxamide; (35) 5-fluoro-7-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide; (36) 5-fluoro-7-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide; (37) 5-fluoro-7-(4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carbonitrile; (38) 5-fluoro-7-(4-(2-(2-oxo-1,2-dihydroquinolin-7-yl)ethyl)piperazin-1-yl)benzo[b]thiophene-2-carbonitrile; (39) 7-(2-(4-(6-fluorobenzo[d][1,3]dicyclopentane-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (40) 7-(2-(4-(6-fluorobenzo[d][1,3]cyclopentadienyl)piperazin-1-yl)ethyl)quinolin-2(1H)-one; (41) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-4,4-d2; (42) 7-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-4,4-d2; (43) 7-(2-(4-(6-fluorobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3,4,4-d4; (44)-(2-(4-(6-fluoro-2,3-dihydrobenzofuran-4-yl)piperazin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one-3,3,4,4-d4; (45) 7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one; (45-1) R-7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one; (45-2) S-7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one; 8. A method for preparing a quinolinone compound represented by the general formula (I) according to any one of claims 1 to 7, the preparation method being carried out by one of the following methods 1 to 2: Method 1: The compound represented by formula (II) or its salt is subjected to N-alkylation reaction with the compound represented by formula (III) or its salt, as shown in reaction formula 1: in, X, Y, R6, R7, R8 and R9 have the same definitions as in the corresponding claims; X1 represents a leaving group, such as halogen, C1-C6 alkylsulfonyloxy, benzenesulfonyloxy, naphthylsulfonyloxy, and the above C1-C6 alkylsulfonyloxy, benzenesulfonyloxy, naphthylsulfonyloxy may be further substituted with one or more groups selected from halogen, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 alkanoyl; Preferably, the reaction is carried out in the presence or absence of a solvent, or in the presence or absence of a base; The reaction temperature is from room temperature to 200°C, and the reaction time is from 1 to 30 hours; Method 2: The compound represented by formula (IV) or its salt is coupled with the compound represented by formula (V) or its salt, as shown in Reaction Formula 2: in, X, Y, W, Z, R6, R7, R8 and R9 have the same definitions as in the corresponding claims; X2 represents halogen or trifluoromethanesulfonyloxy; Preferably, the reaction is carried out in the presence of a base in the presence of palladium catalysis, or in the presence or absence of a solvent; Preferably, the reaction temperature is from room temperature to 200° C., and the reaction time is from 1 to 30 hours.

9. A pharmaceutical composition comprising a therapeutically effective amount of a quinolinone compound represented by the general formula (I) selected from any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and an optional pharmaceutically acceptable carrier.

10. Use of the quinolinone compound represented by the general formula (I) according to any one of claims 1 to 7, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a central nervous system disease; Preferably, the central nervous system disease is selected from the group consisting of: schizophrenia; affective disorder; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; dysthymic disorder; cyclothymic disorder; panic disorder; obsessive-compulsive disorder; impulsive disorder; post-traumatic stress disorder; anxiety disorder; hysteria; anorexia nervosa; sleep disorder; adjustment disorder; cognitive disorder; autism; neuralgic headache; mania; Parkinson's disease; Huntington's disease; various dementias; memory disorders; ADHD; attention deficit / hyperactivity disorder and tics; More preferably, the central nervous system disease is selected from: refractory, intractable or chronic schizophrenia; intrinsic depression; major depression; refractory depression; panic attack; social phobia; acute stress disorder; Alzheimer's disease.

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