A 2-imidazolone derivative and its application

Abstract

The present invention relates to the field of chemical medicine, and particularly relates to a 2-imidazolone derivative and its application. A 2-imidazolone derivative provided by the present invention is a compound shown in Formula I, which acts on 5-HT2A and 5-HT2C receptors, and has a selectivity for 5-HT2A superior to or similar to that of pimavanserin. It is used for treating schizophrenia or behavioral disorders and psychosis related to Parkinson's disease and dementia. The antipsychotic activity of the compound of this application is equivalent to that of pimavanserin, and its cardiotoxicity is less than that of pimavanserin.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and particularly relates to a 2-imidazolone derivative and its application. Background Art

[0002] Schizophrenia has a hidden onset and a low admission rate, with a relatively high lifetime prevalence. Currently, about 0.3-0.7% of the world's population is affected by schizophrenia in their lifetime, and it is estimated that there are more than 21 million schizophrenia patients globally in 2016. Currently, the main antipsychotic drugs for schizophrenia are typical antipsychotic drugs and atypical antipsychotic drugs. However, the current drugs for treating schizophrenia strongly block dopamine receptors, resulting in adverse reactions such as extrapyramidal reactions (EPS), tardive dyskinesia, and increased prolactin. In the medical field, although there are various types of active compounds acting on different targets available for the treatment of sleep disorders, adverse reactions such as addiction, drug resistance, and residual effects are still unsolved problems.

[0003] Traditionally, antipsychotic drugs that exert pharmacological effects by blocking dopamine D 2 receptors are called first-generation antipsychotic drugs, that is, "typical" antipsychotic drugs (such as haloperidol). They have a breakthrough in treating the positive symptoms of schizophrenia, but fail to treat negative symptoms and cognitive disorders. Typical antipsychotic drugs generally have severe EPS side effects and are ineffective in one-third of schizophrenia patients.

[0004] After the 1960s, a series of new-generation antipsychotic drugs were successively developed, including ziprasidone, risperidone, etc., which are called second-generation antipsychotic drugs, that is, new antipsychotic drugs. Although their respective pharmacological effects are not completely the same, they have common pharmacological characteristics, that is, their affinities for 5-hydroxytryptamine (5-HT) receptors (5-HT 1A、2A、2C ) and norepinephrine (NA) receptors (α 1 , α 2 ) are much higher than those for D 2 receptors. Their clinical effects have more advantages compared with first-generation antipsychotic drugs. They are not only as effective as traditional antipsychotic drugs for positive symptoms, but also effective for negative symptoms and cognitive deficit symptoms, with a wider spectrum of action. However, these drugs have adverse reactions such as QT interval prolongation, hyperprolactinemia, and weight gain. Therefore, finding drugs that are effective for the positive and negative symptoms and cognitive disorders of schizophrenia and have few side effects is a current research hotspot.

[0005] The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A . Recently, it has been demonstrated that the PFC and NMDA receptor channels are targets of 5-HT 1A R, and these two receptors regulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data indicate that 5-HT 1A R may be a new target for the development of antipsychotic drugs. The high affinity of atypical antipsychotics (such as olanzapine, aripiprazole, etc.) for 5-HT 1A R and their low EPS side effects all indicate that the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A . Recent studies have shown that 5-HT 1A agonists are related to the treatment of atypical antipsychotics and can improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, it has been found that 5-HT 2A plays a very important role, involving all aspects of perception, emotional regulation, and motor control. Blocking the 5-HT 2A receptor can normalize the release of dopamine and play an antipsychotic role. In addition, the 5-HT 2C receptor is closely related to weight gain.

[0006] Pimavanserin is an inverse agonist with high affinity for 5-HT 2A , a 5-HT 2C antagonist. The in vitro experimental results show that its affinity for the 5-HT 2A receptor [inhibition constant (Ki) is 0.4 nm] is higher than that for 5-HT 2C (Ki = 16 nm), and it has no obvious affinity for 5-HT 2B receptors, dopamine receptors (including D 2 receptors), adrenergic receptors, muscarinic receptors, or calcium channel receptors (Ki > 300 nm). This drug was approved by the US Food and Drug Administration for marketing in April 2016 and is mainly used for the treatment of Parkinson's psychosis symptoms such as hallucinations and illusions.

[0007] Therefore, there is a need to find an antipsychotic drug that is effective against both positive and negative symptoms, can improve cognitive impairment, and can prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease; and can reduce weight gain. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, an object of the present invention is to provide a 2-imidazolone derivative, such as the compound of formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R 3 is a straight-chain or branched-chain alkyl group of C 1 -C 3 ;

[0011] R 4 is selected from a straight-chain or branched-chain alkyl group of C 1 -C 5 ;

[0012] Z is selected from C, O, N;

[0013] The bond represents a single bond or a double bond;

[0014] R 1 , R 2 are each independently selected from hydrogen, the structure of formula II, R 1 forms a carbonyl group with the adjacent carbon; or R 2 forms a carbonyl group with the adjacent carbon;

[0015]

[0016] In formula II, n1 is an integer from 0 to 3;

[0017] R 5 is selected from one of hydrogen, halogen, or a straight-chain or branched-chain alkyl group of C 1 -C 5 .

[0018] Furthermore, the compound of formula I is as follows:

[0019]

[0020] Z is selected from O.

[0021] In the above structure, the halogen is selected from fluorine, chlorine, bromine, and iodine. The straight-chain or branched-chain alkyl group of C 1 -C 5 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. The C1 -C 3 The straight-chain or branched-chain alkyl group of which is selected from methyl, ethyl, propyl, and isopropyl.

[0022] Furthermore, the compound of Formula I is as follows:

[0023]

[0024] Wherein, R 3 is methyl, ethyl, propyl or isopropyl;

[0025] R 4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl;

[0026] Z is O;

[0027] R 1 and R 2 are each independently selected from hydrogen, the structure of Formula II or R 1 forms a carbonyl group with the connected carbon; or R 2 forms a carbonyl group with the connected carbon;

[0028]

[0029] In Formula II, n1 is 0, 1, 2 or 3;

[0030] R 5 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and the substitution site is the para-position or meta-position.

[0031] The compound of Formula I as described above or a pharmaceutically acceptable salt thereof, and the compound is selected from any one of the following compounds: 4-benzyl-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one; 4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one;

[0032] 4-(3-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one;

[0033] 4-benzyl-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one;

[0034] (S)-4-(4-Fluorophenyl)-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)imidazolidin-2-one; (S)-5-(4-Fluorophenyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)imidazoline-2,4-dione.

[0035] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I as described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0036] On the other hand, the present invention provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating mental diseases. The mental diseases are schizophrenia. The mental diseases are Parkinson's disease, behavioral disorders associated with dementia, and psychosis.

[0037] Term Explanation:

[0038] The term "comprising" is an open-ended expression, that is, it includes the content specified in the present invention, but does not exclude other aspects. It should be understood that the term "comprising" can cover a closed meaning, that is, "consisting of".

[0039] As described in the present invention, the compounds of the present invention can optionally be substituted by one or more substituents, such as the general formula compounds above or specific examples and subclasses in the examples. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, the optionally substituted group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be the same or different at each position.

[0040] In addition, it should be noted that unless otherwise explicitly indicated, the description method "are each independently" used in the present invention should be understood in a broad sense, which can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0041] In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. In particular, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1 -C 5 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4Alkyl, C 5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), etc.

[0042] The ranges recited herein (such as numerical ranges) can cover every value within the range and each sub-range formed by the individual values. Thus, for example, the statement “n 2 is any integer between 0 and 3” includes, for example, any integer between 0 and 2, any integer between 2 and 3, etc., such as 1, 2, 3.

[0043] The statement “one or more” can mean 1, 2, 3, 4, 5, 6 or more.

[0044] The term “hydrogen (H)” represents a single hydrogen atom. Such an atomic group can be connected to other groups, for example, connected to an oxygen atom to form a hydroxyl group.

[0045] The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0046] The bond represents either a single bond or a double bond.

[0047] “Carbonyl” is R 1 forming a carbonyl with the connected carbon; or R 2 forming a carbonyl with the connected carbon.

[0048] The term “pharmaceutically acceptable salt” refers to an organic or inorganic salt of the compounds of the present invention.

[0049] Compound of formula I

[0050]

[0051] wherein, R 3 is a straight-chain or branched-chain alkyl of C 1 -C 3 ;

[0052] R 4 is selected from straight-chain or branched-chain alkyl of C 1 -C 5 ;

[0053] Z is selected from C, O, N;

[0054] The bond represents either a single bond or a double bond;

[0055] R 1 , R 2 are each independently selected from hydrogen, the structure of formula II, or R 1 forming a carbonyl with the connected carbon; or R 2 forming a carbonyl with the connected carbon;

[0056]

[0057] In formula II, n1 is an integer from 0 to 3;

[0058] R 5 is selected from hydrogen, halogen, C 1 -C 5 linear or branched alkyl.

[0059] In one embodiment, Z is selected from C, O, N. In a preferred embodiment, Z is selected from O, N. In a particularly preferred embodiment, Z is O.

[0060] In one embodiment, R 3 is C 1 -C 3 linear or branched alkyl. In a preferred embodiment, R 3 is selected from methyl, ethyl, propyl, isopropyl. In a more preferred embodiment, R 3 is selected from methyl, ethyl. In a particularly preferred embodiment, R 3 is methyl.

[0061] In one embodiment, R 4 is C 1 -C 5 linear or branched alkyl, in a preferred embodiment, R 4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl. In a more preferred embodiment, R 4 is selected from isopropyl, butyl, isobutyl. In a particularly preferred embodiment, R 4 is isobutyl.

[0062] In one embodiment, the bond in the compound of formula I exists as a single bond or a double bond. In a specific embodiment, the bond in the compound of formula I exists as a single bond. In another specific embodiment, the bond in the compound of formula I exists as a double bond.

[0063] In one embodiment, R 1 , R 2 are each independently selected from hydrogen or the structure of formula II, or R 1 forms a carbonyl group with the adjacent carbon; or R 2 forms a carbonyl group with the adjacent carbon;

[0064]

[0065] In formula II, n1 is an integer of 0, 1, 2 or 3;

[0066] R5 Selected from hydrogen, a halogen, or C 1 -C 5 and is a straight-chain or branched-chain alkyl group.

[0067] In a preferred embodiment, R 1 , R 2 are each independently selected from hydrogen, a structure of Formula II, or R 1 forms a carbonyl group with the adjacent carbon; or R 2 forms a carbonyl group with the adjacent carbon;

[0068]

[0069] In Formula II, n1 is an integer of 0, 1, or 2;

[0070] R 5 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, and isopropyl.

[0071] In a more preferred embodiment, R 1 , R 2 are each independently selected from hydrogen, a structure of Formula II; or R 1 forms a carbonyl group with the adjacent carbon; or R 2 forms a carbonyl group with the adjacent carbon;

[0072]

[0073] In Formula II, n1 is 0 or 1;

[0074] R 5 is selected from hydrogen and fluorine.

[0075] In a specific embodiment, R 1 is selected from H, phenyl, fluorophenyl, and forms a carbonyl group with the adjacent carbon. In a more specific embodiment, R 1 is selected from H, phenyl, and forms a carbonyl group with the adjacent carbon. In a particularly specific embodiment, R 1 is H. In another particularly specific embodiment, R 1 is phenyl. In another particularly specific embodiment, R 1 is In another particularly specific embodiment, R 1 is In another particularly specific embodiment, R 1 is In yet another particularly specific embodiment, R 1 is In yet another particularly specific embodiment, R 1 forms a carbonyl group with the attached carbon.

[0076] In a specific embodiment, R 2 is selected from H, phenyl, fluorophenyl, forms a carbonyl group with the attached carbon. In a more specific embodiment, R 2 is selected from H, phenyl, forms a carbonyl group with the attached carbon. In a particularly specific embodiment, R 2 is H. In another particularly specific embodiment, R 2 is phenyl. In another particularly specific embodiment, R 2 is In another particularly specific embodiment, R 2 is In another particularly specific embodiment, R 2 is In yet another particularly specific embodiment, R 2 is In yet another particularly specific embodiment, R 2 forms a carbonyl group with the attached carbon.

[0077] In a specific embodiment, C 1 -C 5 the straight-chain or branched-chain alkyl group and C 1 -C 3 the straight-chain or branched-chain alkyl group are each independently selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl, and isopentyl. In a more specific embodiment, C 1 -C 5 the straight-chain or branched-chain alkyl group and C 1 -C 3 the straight-chain or branched-chain alkyl group are each independently selected from methyl, ethyl, propyl, and isobutyl.

[0078] In an embodiment, the propyl group includes but is not limited to n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), or isopropyl (i-Pr, -CH(CH 3 )) 2 ). The butyl group includes but is not limited to n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ) or tert-butyl (t-Bu, -C(CH 3 ) 3 ). The pentyl group includes but is not limited to n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ) or 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ).

[0079] In a specific embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0080] In a specific embodiment, Z is O, R 1 , R 2 , R 3 , R 4 , R 5 , n1 and bonds are defined as above. In a more specific embodiment, Z is O, R 3 is methyl; R 4 is isobutyl; R 5 is selected from H or fluorine; R 1 and R 2 are each independently selected from H, phenyl,[[]] or form a carbonyl with the attached carbon.

[0081] Advantageous technical effects of the present invention:

[0082] The compound provided by the present invention acts on 5-HT2A and 5-HT2C receptors, and its selectivity for 5-HT2A is better than or similar to that of pimavanserin. It is used to treat schizophrenia or behavioral disorders and psychosis related to Parkinson's disease and dementia. The antipsychotic activity of the compound of this application is comparable to that of pimavanserin, and its cardiotoxicity is less than that of pimavanserin. Specific implementation methods

[0083] The following examples are for illustrative purposes only and are not intended to limit the present invention.

[0084] Table 1 Compound structure

[0085]

[0086]

[0087]

[0088] The synthesis examples are for illustrative purposes and should not be considered as limitations of the present invention.

[0089] Examples of synthesis

[0090] Example 1. 4-Benzyl-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (1)

[0091] Reaction formula 1

[0092]

[0093] 1.1 Preparation of benzyl 4–(prop-2-yn-1-ylamino)piperidine-1-carboxylate

[0094] Add 4-aminopiperidine-1-carboxylic acid benzyl ester (10.00 g, 42.681 mmol) and dimethylformamide (100 mL) to a 500 mL three-necked round-bottom flask. Under nitrogen protection, cool the temperature below 0 °C, add potassium methoxybenzoate (17.83 g, 128.042 mmol), stir at a temperature of 0 °C, and slowly add propargyl bromide (5.08 g, 42.681 mmol). After the addition, allow the reaction to proceed at room temperature for 3 hours. After the reaction is completed, add 100 mL of ice water to the system to quench the reaction, extract with ethyl acetate (3 x 100 mL), wash the organic phase with 200 mL of saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by column chromatography (EA:PE = 3:7) to obtain 5.5 g of benzyl 4–(prop-2-yn-1-ylamino)piperidine-1-carboxylate, with a yield of 47.32%, as a pale yellow oil.

[0095] Preparation of Benzyl 4 - [(3 - phenyl - 2 - ethyn - 1 - yl)amino]piperidine - 1 - carboxylate

[0096] Into a 250 mL three - necked round - bottom flask, add benzyl 4 - (prop - 2 - yn - 1 - ylamino)piperidine - 1 - carboxylate (5.50 g, 20.195 mmol), tetrahydrofuran (60.00 mL), iodobenzene (6.18 g, 30.292 mmol), triethylamine (6.13 g, 60.584 mmol), copper(I) iodide (0.38 g, 2.019 mmol) and Pd(PPh 3 ) 2 Cl 2 (2.83 g, 4.032 mmol). Under nitrogen protection, heat the mixture to 50 °C and stir for 3 hours. After the reaction is completed, extract the reaction solution with ethyl acetate (3 x 50 mL), dry the organic phase with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and purify by column chromatography (EA:PE = 1:4) to obtain 4.1 g of benzyl 4 - [(3 - phenyl - 2 - ethyn - 1 - yl)amino]piperidine - 1 - carboxylate, with a yield of 59.18%, as a yellow oil.

[0097] Preparation of Benzyl 4 - [[([4 - (2 - methylpropoxy)phenyl]methyl]carbamoyl)(3 - phenylprop - 2 - yn - 1 - yl)amino]piperidine - 1 - carboxylate

[0098] To a 50 mL three-necked round-bottom flask, 1-[4-(2-methylpropoxy)phenyl]methylamine (1.29 g, 7.175 mmol), dichloromethane (25.00 mL), triphosgene (1.06 g, 3.587 mmol) and triethylamine (1.45 g, 14.349 mmol) were added respectively. Under nitrogen protection, the temperature was lowered to -30 °C and the reaction was carried out for 30 minutes. After the reaction was completed, the solvent was concentrated under reduced pressure to dryness. The residue was dissolved in 10 mL of dichloromethane, and benzyl 4-[(3-phenyl-2-yn-1-yl)amino]piperidine-1-carboxylate (2.50 g, 7.175 mmol) dissolved in 10 mL was slowly added dropwise thereto, and triethylamine (1.45 g, 14.349 mmol) was added. The reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the reaction was quenched by adding water, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and purification was carried out by column chromatography (EA:PE = 2:3) to obtain 2 g of benzyl 4-[([[4-(2-methylpropoxy)phenyl]methyl]carbamoyl)(3-phenylprop-2-yn-1-yl)amino]piperidine-1-carboxylate, with a yield of 50.34%, as a yellow solid. Preparation of 1.4 benzyl 4-(4-benzyl-3-[[4-(2-methylpropoxy)phenyl]methyl]-2-oxoimidazol-1-yl)piperidine-1-carboxylate

[0099] To a 25 mL sealed tube, benzyl 4-[([[4-(2-methylpropoxy)phenyl]methyl]carbamoyl)(3-phenylprop-2-yn-1-yl)amino]piperidine-1-carboxylate (1.10 g, 1.987 mmol), MeCN (10 mL) and silver 2-methylpropane-2-sulfonate (0.49 g, 1.987 mmol) were added respectively. Under nitrogen protection, the temperature was raised to 100 °C and the reaction was carried out overnight. After the reaction was completed, the solvent was removed by distillation under pressure, and purification was carried out by column chromatography (DCM:MeOH = 30:1) to obtain 310 mg of benzyl 4-(4-benzyl-3-[[4-(2-methylpropoxy)phenyl]methyl]-2-oxoimidazol-1-yl)piperidine-1-carboxylate, with a yield of 28.18%, as a light yellow solid.

[0100] 1.5 Preparation of 4-benzyl-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]imidazol-2-one

[0101] To a 25 mL round-bottom flask were added benzyl 4-(4-benzyl-3-[[4-(2-methylpropoxy)phenyl]methyl]-2-oxoimidazol-1-yl)piperidine-1-carboxylate (330.00 mg, 0.596 mmol), methanol (4.00 mL), formaldehyde (17.90 mg, 0.596 mmol) and Pd / C (30.00 mg, 0.282 mmol). Hydrogen gas was introduced into the reaction system, and the reaction was carried out at room temperature overnight. After completion of the reaction, the mixture was filtered to obtain a solution. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 30:1) to obtain 137.5 mg of compound 4-benzyl-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]imidazol-2-one, with a yield of 53.21%. 1 H NMR(400MHz,Methanol-d 4 )δ7.32–7.26(m,2H),7.26–7.20(m,1H),7.15–7.10(m,2H),7.04–6.99(m,2H),6.88–6.82(m,2H),6.27(d,J=1.2Hz,1H),4.68(s,2H),4.03(tt,J=11.7,4.4Hz,1H),3.73(d,J=6.5Hz,2H),3.66(s,2H),3.06–2.94(m,2H),2.34(s,3H),2.21(td,J=12.1,2.8Hz,2H),2.06(hept,J=6.6Hz,1H),1.96–1.77(m,4H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):434[M+H] + 。

[0102] Example 2. 4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (2)

[0103] The reaction raw material iodobenzene was replaced with p-fluoroiodobenzene, and the target compound was prepared according to the method of Example 1. The structural formula is shown as No. (2) in Table 1. 1 H NMR(400MHz,Methanol-d 4)δ8.44(s,1H),7.12(ddd,J=8.5,5.3,2.6Hz,2H),7.04–6.95(m,3H),6.87-6.79(m,2H),6.24(d,J=1.3Hz,1H),4.83(s,1H),4.71(s,2H),4.18(tt,J=10.4,5.1Hz,1H),3.73(d,J=6.5Hz,2H),3.66(s,2H),3.41(d,J=12.5Hz,2H),2.88(t,J=11.8Hz,2H),2.73(s,3H),2.09(s,3H),2.09–1.98(m,1H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):452[M+H] + 。

[0104] Example 3. 4-(3-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (3)

[0105] Replace the reaction raw material iodobenzene with 3-fluoroiodobenzene, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (3) in Table 1. 1 H NMR(400MHz,Methanol-d4)δ7.28(td,J=8.0,5.9Hz,1H),7.04–6.89(m,4H),6.86–6.77(m,3H),6.36(s,1H),4.69(s,2H),4.04(tt,J=11.8,4.5Hz,1H),3.75–3.67(m,4H),3.06–2.97(m,2H),2.35(s,2H),2.22(td,J=12.1,2.8Hz,2H),2.05(hept,J=6.7Hz,1H),1.98-1.78(m,4H),1.04(d,J=6.7Hz,5H),1.02(s,1H).LCMS(ES,m / z):452[M+H] + 。

[0106] Example 4. 4-(3-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (4)

[0107] Replace the reaction raw material benzyl 4-aminopiperidine-1-carboxylate with 1-[4-(2-methylpropoxy)phenyl]methanamine, and replace 1-[4-(2-methylpropoxy)phenyl]methanamine with 1-methylpiperidin-4-amine, and prepare the target compound according to the method of Example 1. The structural formula is shown as No. (4) in Table 1.1 H-NMR(400MHz, Methanol-d 4 ): δ 7.53 (d, J = 7.7 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 8.4 Hz, 3H), 7.01 (d, J = 8.5 Hz, 2H), 6.05 (s, 1H), 4.74 (s, 1H), 4.54 (s, 2H), 4.20 (s, 1H), 3.78 (d, J = 6.5 Hz, 2H), 3.70 (d, J = 12.7 Hz, 2H), 3.28 (s, 2H), 2.96 (s, 3H), 2.44 (d, J = 14.2 Hz, 2H), 2.08 (dt, J = 13.4, 6.7 Hz, 3H), 1.05 (d, J = 6.7 Hz, 6H). LCMS(ES, m / z): 434 [M + H] + 。

[0108] Example 5. (S)-4-(4-Fluorophenyl)-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)imidazolidin-2-one (5)

[0109] Reaction Scheme 2

[0110]

[0111] 5.1 Preparation of (S)-[(tert-butoxycarbonyl)amino](4-fluorophenyl)acetic acid

[0112] To a 250 mL round-bottom flask were added (S)-amino(4-fluorophenyl)acetic acid (5.00 g, 29.559 mmol), acetonitrile (75 mL) and water (25 mL). The temperature was lowered to 0 °C, and triethylamine (5.98 g, 59.117 mmol) was slowly added dropwise. After stirring for 30 minutes, Boc2O (7.74 g, 35.470 mmol) was added, and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, water was added to the system to quench the reaction, and the pH was adjusted to 5 with 1 M HCl solution. The mixture was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 7.5 g of compound (S)-[(tert-butoxycarbonyl)amino](4-fluorophenyl)acetic acid, with a yield of 94.23%, as a white solid.

[0113] 5.2 tert-Butyl (S)-(1-(4-fluorophenyl)-2-((4-isobutoxybenzyl)amino)-2-oxoethyl)carbamate

[0114] (S)-[(tert-Butoxycarbonyl)amino](4-fluorophenyl)acetic acid (3.00 g, 11.141 mmol), 1-[4-(2-methylpropoxy)phenyl]methanamine (2.00 g, 11.141 mmol), HATU (6.35 g, 16.712 mmol) and DIEA (2.88 g, 22.282 mmol) were added to 30 mL of DMF, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water, extracted with ethyl acetate, the solvent was removed under reduced pressure, and purified by column chromatography (PE:EA = 3:1) to obtain 3 g of tert-butyl (S)-(1-(4-fluorophenyl)-2-((4-isobutoxybenzyl)amino)-2-oxoethyl)carbamate, with a yield of 62.55%, as a yellow solid.

[0115] 5.3 Preparation of (2S)-2-amino-2-(4-fluorophenyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide

[0116] (2S)-2-Amino-2-(4-fluorophenyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide (3.00 g, 6.977 mmol) was added to 4M HCl / dioxane (30 mL) solution, and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain 3 g of crude (2S)-2-amino-2-(4-fluorophenyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide, with a yield of 130.43%.

[0117] 5.4 Preparation of (2S)-2-(4-fluorophenyl)-2-[(1-methylpiperidin-4-yl)amino]-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide

[0118] (2S)-2-Amino-2-(4-fluorophenyl)-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide (3.00 g, 9.080 mmol), 1-methylpiperidin-4-one (1.03 g, 9.080 mmol) and HOAc (4 mL) were added to 20 mL of ethanol solution, and then NaBH 3 CN (0.86 g, 13.620 mmol) was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was poured into saturated NaHCO 3 solution, extracted with ethyl acetate, the solvent was removed under reduced pressure, and purified by column chromatography (MeOH:DCM = 1:10) to obtain 2 g of (2S)-2-(4-fluorophenyl)-2-[(1-methylpiperidin-4-yl)amino]-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide, with a yield of 51.52%, as a white solid.

[0119] Preparation of 5.5N-[(1S)-1-(4-fluorophenyl)-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)ethyl]-1-methylpiperidin-4-amine

[0120] (2S)-2-(4-Fluorophenyl)-2-[(1-methylpiperidin-4-yl)amino]-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide (200.00 mg, 0.468 mmol) was added to BH3.THF (5 mL), and the reaction was heated to reflux overnight. After the reaction was completed, the reaction was quenched with 3N hydrochloric acid solution. The aqueous phase was washed with ethyl acetate, the pH of the aqueous phase was adjusted to 10 with 6N NaOH solution, and then extracted with dichloromethane. The solvent was removed under reduced pressure to obtain 150 mg of crude product of N-[(1S)-1-(4-fluorophenyl)-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)ethyl]-1-methylpiperidin-4-amine, with a yield of 77.72%.

[0121] Preparation of 5.6(S)-4-(4-fluorophenyl)-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)imidazolidin-2-one

[0122] N-[(1S)-1-(4-Fluorophenyl)-2-([[4-(2-methylpropoxy)phenyl]methyl]amino)ethyl]-1-methylpiperidin-4-amine (150.00 mg, 0.363 mmol) and triethylamine (73.40 mg, 0.725 mmol) were added to 5 mL of tetrahydrofuran, and then CDI (88.21 mg, 0.544 mmol) was added. The reaction was carried out at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the product was purified by column chromatography (DCM:MeOH = 50:1) to obtain 32.7 mg of the compound, with a yield of 20.51%. 1 H NMR(400MHz,DMSO-d 6,): δ 9.92 (s, 1H), 7.42–7.33 (m, 2H), 7.25–7.12 (m, 4H), 6.93–6.85 (m, 2H), 4.72 (dd, J = 9.1, 7.2 Hz, 1H), 4.25 (s, 2H), 3.71 (d, J = 6.5 Hz, 2H), 3.55 (td, J = 8.9, 5.0 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.26 (d, J = 12.3 Hz, 1H), 3.17–2.86 (m, 1H), 2.82 (dd, J = 9.0, 7.2 Hz, 1H), 2.62 (d, J = 4.7 Hz, 3H), 2.27 (td, J = 13.0, 4.0 Hz, 1H), 1.99 (hept, J = 6.7 Hz, 1H), 1.75 (d, J = 13.3 Hz, 1H), 1.65 - 1.55 (m, 2H), 0.97 (d, J = 6.7 Hz, 6H). LCMS (ES, m / z): 440 [M+H] + 。

[0123] Example 6. (S)-5-(4-Fluorophenyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)imidazolidine-2,4-dione (6)

[0124] Reaction Scheme 3

[0125]

[0126] 6.1 Preparation of (2S)-2-(4-Fluorophenyl)-2-[(1-methylpiperidin-4-yl)amino]-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide.

[0127] The target compound (2S)-2-(4-fluorophenyl)-2-[(1-methylpiperidin-4-yl)amino]-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide (210 mg) was prepared according to the method of Example 5.

[0128] 6.2 Preparation of (S)-5-(4-Fluorophenyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)imidazolidine-2,4-dione.

[0129] (2S)-2-(4-Fluorophenyl)-2-[(1-methylpiperidin-4-yl)amino]-N-[[4-(2-methylpropoxy)phenyl]methyl]acetamide (200.00 mg, 0.468 mmol), CDI (91.02 mg, 0.561 mmol) and triethylamine (94.67 mg, 0.936 mmol) were added to 5 mL of tetrahydrofuran and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) to obtain 54.4 mg of compound (S)-5-(4-fluorophenyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)imidazoline-2,4-dione, with a yield of 25.64%. 1 H-NMR(400MHz,DMSO-d 6 ,):δ7.35(dd,J=8.5,5.4Hz,2H),7.25(t,J=8.7Hz,2H),7.19(d,J=8.3Hz,2H),6.89(d,J=8.4Hz,2H),5.38(s,1H),4.62–4.31(m,2H),3.72(d,J=6.5Hz,2H),3.57(s,1H),2.74(d,J=7.6Hz,1H),2.61(d,J=11.5Hz,1H),2.06(s,3H),1.99(dq,J=13.3,6.7Hz,1H),1.77(dd,J=28.1,10.4Hz,2H),1.63(d,J=8.1Hz,1H),1.46(d,J=12.4Hz,1H),1.19(qd,J=12.6,4.4Hz,1H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):454[M+H] + 。

[0130] Example 7 In Vitro Receptor Binding Assay

[0131] 7.1 Experimental Method

[0132] 7.1.1 Preparation of Solutions Required for the Experiment

[0133] A: (For the preparation of 5-HT 2C receptor membrane): 50 mM Tris-HCl buffer: Dissolve 96.8 g of Tris in double-distilled water to a total volume of 4000 ml, adjust the pH to 7.5 with HCl, and dilute to 16000 mL, pH = 7.4

[0134] B: (For the preparation of 5-HT 2A receptor membrane): Weigh 11.7 mg of EDTA and 380.84 mg of MgCl 2, add 50 mM Tris-HCl buffer to a total volume of 400 mL and adjust the pH to 7.4. Make their final concentrations 0.1 mM EDTA and 10 mM MgCl 2 respectively.

[0135] C: (for preparing Dopamine receptor membrane): Weigh 2.978 g HEPES, 1.17 g NaCl, 0.119 g MgCl 2 , 36.5 mg EDTA and add pure water to a total volume of 250 ml. Adjust the pH to 7.4. Make their final concentrations 50 mM HEPES, 50 mM NaCl, 5 mM MgCl 2 , 0.5 mM EDTA, pH 7.4.

[0136] 7.2 Preparation of receptor membrane

[0137] 1) CHO-5-HT 2A Preparation of receptor membrane

[0138] CHO-5-HT 2A Take out the CHO-5-HT cells from the -80 °C refrigerator and thaw them naturally. Centrifuge at 2000 g and 4 °C for 15 minutes. Take the precipitate and discard the supernatant. Add solution B to the precipitate. Mix the cells for 20 - 30 seconds, then centrifuge at 50000 g and 4 °C for 25 min. Carefully discard the upper layer of liquid, add solution B again and mix well, then centrifuge at 50000 g and 4 °C for 25 min. Store the precipitate at -80 °C.

[0139] 2) 5-HT 2C Preparation of membrane

[0140] Take out the rat cortex from the -80 °C refrigerator and thaw it naturally. Add solution A and homogenize at speed 4 for 3 - 4 s, homogenize 4 times. Centrifuge at 50000 g and 4 °C for 25 min, discard the supernatant. Add solution A, mix well with a vortex mixer, then centrifuge at 50000 g and 4 °C for 25 min, repeat the centrifugation twice. After centrifugation, discard the supernatant, and store the precipitate at -80 °C for standby.

[0141] 3) CHO-D 2 Preparation of receptor membrane

[0142] CHO-D cells 2 Take out the CHO-D cells from the -80 °C refrigerator and thaw them naturally. Centrifuge at 2000 g for 15 min. Add the homogenate C to the precipitate and mix well with a vortex mixer. Centrifuge at 50000 g and 4 °C for 25 min, discard the supernatant. Take the precipitate, add C buffer again to wash, resuspend and centrifuge. After centrifugation, discard the supernatant, and store the precipitate at -80 °C for standby.

[0143] 7.3 Receptor competition binding experiment

[0144] 1) 5-HT 2A Receptor competitive binding assay

[0145] Step 1: First, prepare the prepared membrane into a suspension of 10 mg / mL membrane with homogenate B for standby.

[0146] Step 2: Add 100 μL of the membrane preparation to each reaction tube.

[0147] Step 3: Add 100 μL of Solution B to the total binding tube (TB), add 100 μL of Methysergide (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB), and add 100 μL of the test compound to each test compound tube (CB).

[0148] Step 4: Add the radioactive ligand 3 10 μL of 3H-Ketanserin, final concentration 2.98 nM, to each reaction tube.

[0149] Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is completed, the bound ligand is quickly filtered under reduced pressure through a Whatman filter paper GF / C plate that has been soaked in 0.5% PEI for more than 1 h. After filtration, dry the filter membrane at 60 °C, stick on the bottom film, add 40 μL of scintillation fluid, seal the top film, and let it stand.

[0150] Step 6: Place the scintillation vial into a liquid scintillation counter for counting.

[0151] 2) 5-HT 2C Receptor competitive binding assay

[0152] Step 1: First, prepare the prepared membrane into a suspension of 210 mg / mL membrane with homogenate B for standby.

[0153] Step 2: Add 100 μL of the membrane preparation to each reaction tube.

[0154] Step 3: Add 100 μL of Solution B to the total binding tube (TB), add 100 μL of Ketanserin (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB), and add 100 μL of the test compound to each test compound tube (CB).

[0155] Step 4: Add the radioactive ligand 3 10 μL of 3H-Mesulergine, final concentration 3 nM, to each reaction tube.

[0156] Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is complete, filter the bound ligand rapidly under reduced pressure. The Whatman GF / C filter paper is saturated with 0.5% PEI solution 1 h in advance, washed thoroughly with ice-cold Tris buffer, the filter disc is taken out and placed into a 4 mL scintillation vial, 1 mL of toluene scintillation fluid is added and mixed well.

[0157] Step 6: Place the scintillation vial into a liquid scintillation counter for counting.

[0158] 3) CHO-D 2 Receptor competition binding assay

[0159] Step 1: First, prepare a suspension of the membrane at 8 mg / mL with homogenate C for standby.

[0160] Step 2: Add 100 μL of the membrane preparation to each reaction tube.

[0161] Step 3: Add 100 μL of solution C to the total binding tube (TB), add 100 μL of Haloperidol (final concentration 1.0×10 -5 M) to the non-specific binding tube (NB), and add 100 μL of the test compound to each test compound binding tube (CB).

[0162] Step 4: Add 10 μL of radioactive ligand 3 H-Spiperone to each reaction tube, with a final concentration of 1.176 nM.

[0163] Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is complete, filter the bound ligand rapidly under reduced pressure. The Whatman GF / B filter plate is soaked with 0.5% PEI for more than 1 h in advance. After filtration, dry the filter membrane at 60 °C, stick on the bottom film, add 40 μL of scintillation fluid, seal the top film, and let it stand.

[0164] Step 6: Place the suction filter plate into a liquid scintillation counter for counting.

[0165] 7.4 Experimental results

[0166] Pimavanserin 5-HT 2A 、5-HT 2C receptor Ki values are 0.036 and 2.94 nM respectively. For compound 3, the Ki values for 5-HT 2A 、5-HT 2C receptors are 0.0735 and 193.80 nM respectively. Compared with pimavanserin, it has excellent selectivity. See the following table for details.

[0167] Table 2 In vitro receptor binding activities (Ki values, nM) of each compound

[0168] Compound number <![CDATA[5-HT 2A (Ki value, nM)]]> <![CDATA[5-HT 2C (Ki value, nM)]]> 2C / 2A 3 0.0735 193.80 2637.39 Pimavanserin 0.036 2.94 81.667

[0169] Example 8 In Vitro hERG Experiment

[0170] 8.1 Experimental Procedure

[0171] The stably transfected cells were seeded on glass slides at a cell density of less than 50% and cultured overnight. The experimental cells were transferred to a bath of approximately 1 ml embedded in the stage of an inverted microscope, and the extracellular fluid was perfused at a rate of 2.7 ml / minute. After stabilizing for 5 minutes, the experiment could be started. A HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system were used to record the membrane current (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were completed at room temperature (22 - 24 °C).

[0172] In the experiment, a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) was used to pull the electrodes (BF150-110-10). The inner diameter of the electrodes was 1 - 1.5 mm, and the access resistance after being filled with the internal solution was 2 - 4 MΩ.

[0173] The electrophysiological stimulation protocol for the hERG potassium channel was to first clamp the membrane voltage at -80 mV, apply a +20 mV voltage stimulation to the cells for 2 s to activate the hERG potassium channel, and then repolarize to -50 mV for 5 s to generate an outward tail current, with a stimulation frequency of once every 15 s. The current value was the peak value of the tail current.

[0174] In the experiment, the whole-cell recording mode was used to record the channel current. First, the extracellular fluid was perfused (about 2 ml per minute) and continuously recorded, and waited for the current to stabilize (the current decay (Run-Down) was less than 5% within 5 minutes). At this time, the peak value of the tail current was the control current value. Then, the extracellular fluid containing the drug to be tested was perfused and continuously recorded until the inhibitory effect of the drug on the hERG current reached a steady state. At this time, the peak value of the tail current was the current value after adding the drug. The standard for the steady state was judged by whether the last three consecutive current recording lines coincided. After reaching the steady state, if the hERG current recovered or approached the size before adding the drug after perfusion and rinsing with the extracellular fluid, other concentrations or drugs could be continuously perfused for testing.

[0175] 8.2 Experimental Results

[0176] The IC50 of pimavanserin in the hERG experiment was 208 nM, and the ICs of Compound 1, Compound 2, and Compound 3 in the hERG experiment 50 were 402, 305, and 647 nM respectively, and the cardiotoxicity was less than that of pimavanserin. The results are shown in the following table.

[0177] Table 3 Results of in vitro hERG tests for compounds

[0178] Compound hERG (nM) 1 402.00 2 305.00 3 647.00 Pimavanserin 208 。

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: Wherein, R 3 is C 1 -C 3 a straight-chain or branched-chain alkyl group; R 4 selected from C 1 -C 5 linear or branched alkyl; The key indicates the existence in the form of a double bond; R 1 ,R 2 are each independently selected from hydrogen and the structure of Formula II, and R 1 and R 2 are not simultaneously hydrogen or the structure of Formula II; In formula II, n1 is 1; R 5 selected from hydrogen, a halogen or a C 1 -C 5 linear or branched alkyl group; Z is O.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The halogen is selected from fluorine, chlorine, bromine, and iodine.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The C described above 1 -C 5 The straight-chain or branched-chain alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The described C 1 -C 3 The linear or branched alkyl group is selected from methyl, ethyl, propyl, and isopropyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound of formula I is as follows: Among them, R 3 is methyl, ethyl, propyl, or isopropyl; R 4 selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl; Z is O; R 1 ,R 2 are each independently selected from hydrogen and the structure of Formula II, and R 1 and R 2 are not simultaneously hydrogen or the structure of Formula II; In formula II, n1 is 1; R 5 Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and the substitution site is the para position or the meta position.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein, The compound is selected from any one of the following compounds: 4-Benzyl-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one; 4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one; 4-(3-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one; 4-Benzyl-1-(4-isobutoxybenzyl)-3-(1-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one.

7. A pharmaceutical composition, wherein It contains the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and optionally further contains a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of a drug for treating mental diseases.

9. The use according to claim 8, wherein, The mental disease is schizophrenia or mania.

10. The use according to claim 8, wherein, The mental disease is Parkinson's disease, behavioral disorders and psychosis related to dementia.

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