A kind of piperazine derivative, preparation method and application thereof

Abstract

The present invention provides a piperazine derivative, as shown in formula (I) or its stereoisomers and pharmaceutically acceptable salts thereof; the piperazine derivative provided by the present invention has a strong affinity for dopamine D2, D3, and 5-HT1A, 5-HT2A receptors of 5-hydroxytryptamine, and has a medium affinity for dopamine D4 and 5-HT2C, 5-HT7 of 5-hydroxytryptamine and α1-adrenaline, histamine H1 receptors, and also has a medium affinity for 5-hydroxytryptamine reuptake sites, and has no obvious affinity for cholinergic muscarinic receptors. Functionally, it is a partial agonist of D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors, and can be used to treat or prevent diseases that require regulation of one or more of dopamine D2 receptors, 5-HT1 receptors, 5-HT2 receptors, 5-HT7 receptors, α1-adrenaline receptors, histamine H1 receptors and 5-hydroxytryptamine reuptake sites.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical medicines, and in particular relates to a piperazine derivative, a preparation method and application thereof. Background Art

[0002] With the development of society, the improvement of the public health system and the improvement of the security level, people will pay more and more attention to schizophrenia. Schizophrenia treatment drugs will have a broader prospect and the market size will exceed 2 billion US dollars.

[0003] At present, there is still a lack of sufficiently good treatments in the field of mental illnesses such as schizophrenia. The launch of Cariprazine can alleviate the urgent need of patients for such drugs. In 2004, Richter and Forest Laboratories reached a cooperation agreement on the research and development of the drug. In 2014, Actavis acquired Forest Laboratories for US$25 billion and obtained the rights to the drug. This shows that the development of schizophrenia drugs still has great prospects and potential.

[0004] Cariprazine is a partial agonist of D2 and D3 receptors, with a more significant affinity for D3 receptors; it partially agonizes 5-HT1A receptors and antagonizes 5-HT2A and 5-HT2B receptors. In contrast to the complete antagonism of dopamine receptors, partial agonism of dopamine can reduce the risk of akathisia, tardive dyskinesia, extrapyramidal symptoms and abnormal prolactin levels. Regulation of D3 receptors can improve cognition and reduce negative symptoms. Smaller antagonism of histamine receptors reduces the risk of sedation and weight gain. Despite this, cariprazine still has certain defects as a schizophrenia drug. After taking cariprazine, the blood concentration of cariprazine is unstable, which affects treatment; the hydroxy metabolites of cariprazine are active substances, which pose safety risks. In view of the defects of cariprazine, further research on schizophrenia drugs has potential market prospects. Summary of the invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a piperazine derivative, a preparation method and application thereof.

[0006] The present invention provides a piperazine derivative as shown in formula (I) or its stereoisomers and pharmaceutically acceptable salts thereof:

[0007]

[0008] n is an integer of 1 to 6, preferably an integer of 2 to 4, more preferably 2 or 4; m is 0 or 1;

[0009] -Ar is a substituent represented by V1 or V2:

[0010]

[0011] a and b are each independently an integer of 0 to 3, more preferably an integer of 0 to 2, further preferably 1 or 1, and most preferably 0; R 1 With R 2 Each is independently selected from halogen, C1-C10 alkyl, more preferably halogen, C1-C6 alkyl, further preferably halogen, C1-C4 alkyl, most preferably fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; X 1 With X 2 Each independently is C or a heteroatom, more preferably X 1 With X 2 At least one is a heteroatom, preferably X 1 With X 2 At least one of them is a heteroatom and X 1 With X 2 The heteroatom is preferably N, O or S.

[0012] R is one of the substituents represented by V3 to V5:

[0013]

[0014] X 3 is C or a heteroatom; the heteroatom is preferably N, O or S, more preferably N.

[0015] R 3 ~R 7 Each is independently halogen, C1-C10 alkyl or hydroxyl, preferably halogen, C1-C8 alkyl or hydroxyl, more preferably halogen, C1-C6 alkyl or hydroxyl, further preferably halogen, C1-C4 alkyl or hydroxyl, most preferably fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or hydroxyl.

[0016] In the present invention, preferably, the piperazine derivative is one or more of the compounds represented by formula (I-1) to formula (I-5) or their stereoisomers and pharmaceutically acceptable salts thereof:

[0017]

[0018] More preferably, the piperazine derivative is preferably one or more of the compounds represented by formula (M-1) to formula (M-12) or their stereoisomers and pharmaceutically acceptable salts thereof:

[0019]

[0020] Among them, the above-mentioned pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt; the inorganic acid salt is preferably one or more of sulfate, hydrochloride, nitrate, phosphate and hydrobromide; the organic acid salt is preferably one or more of acetate, format, methanesulfonate, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzenesulfonate, benzoate, lactate, malate and amino acid salt; the amino acid salt is preferably one or more of aspartate, glutamate, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, asparagine, glutamine and threonine.

[0021] The piperazine derivative provided by the present invention has a strong affinity for dopamine D2, D3, and 5-HT1A, 5-HT2A receptors of 5-hydroxytryptamine, and has a medium affinity for dopamine D4, 5-HT2C, 5-HT7, α1-adrenaline, and histamine H1 receptors of 5-hydroxytryptamine, and also has a medium affinity for 5-hydroxytryptamine reuptake sites, and has no obvious affinity for cholinergic muscarinic receptors. Functionally, it is a partial agonist of D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors, and can be used to treat or prevent diseases that require regulation of one or more of dopamine D2 receptors, 5-HT1 receptors, 5-HT2 receptors, 5-HT7 receptors, α1-adrenaline receptors, histamine H1 receptors and 5-hydroxytryptamine reuptake sites.

[0022] The present invention also provides a method for preparing the above-mentioned piperazine derivative, comprising:

[0023] The compound represented by formula (II) is reacted with the compound represented by formula (III-1) whose amino group is protected to obtain the compound represented by formula (IV) whose amino group is protected;

[0024] Deprotecting the amino group of the compound represented by formula (IV), and reacting the compound represented by formula (V) to obtain the compound represented by formula (VI);

[0025]

[0026] R 1 ' is a C1-C3 alkyl, a C1-C3 haloalkyl or an alkyl-substituted phenyl; X 1 ' is a halogen.

[0027] The present invention has no special restrictions on the sources of all raw materials, and any raw materials available on the market can be used. 1 ~R 4 Same as above, no further elaboration is given here;1 ' is preferably a C1-C2 alkyl, a C1-C3 haloalkyl or a C1-C3 alkyl-substituted phenyl, more preferably a methyl, a halomethyl or a methylphenyl; the halomethyl is preferably a fluoromethyl, more preferably a trifluoromethyl; the X 1 ' is halogen, preferably fluorine, chlorine or bromine, more preferably chlorine.

[0028] The compound represented by formula (II) is reacted with the compound represented by formula (III-1) in which the amino group is protected to obtain the compound represented by formula (IV) in which the amino group is protected; the compound represented by formula (III-1) in which the amino group is protected by an amino protecting group. In the present invention, the amino protecting group is preferably a tert-butyloxycarbonylamino protecting group.

[0029] Then, the compound represented by formula (IV) with protected amino group is deprotected and then reacted with the compound represented by formula (V) to obtain the compound represented by formula (VI); the method of deprotecting the amino group can be selected according to the amino protecting group used.

[0030] Alternatively, the compound represented by formula (II) is reacted with the compound represented by formula (III-2) to obtain the compound represented by formula (VII);

[0031]

[0032] X 2 ' is halogen, preferably fluorine, chlorine or bromine, more preferably chlorine.

[0033] R 2 ' is a substituent represented by V4 or V5;

[0034] X 3 is selected from C or a heteroatom; the heteroatom is preferably N, O or S, more preferably N.

[0035] The preparation method of the piperazine derivative provided by the invention is simple and has high yield.

[0036] The present invention also provides the use of the above-mentioned piperazine derivatives in preparing drugs for treating schizophrenia.

[0037] The present invention also provides the use of the above-mentioned piperazine derivatives in the preparation of drugs for treating or preventing diseases that require regulation of one or more of dopamine D2 receptors, 5-HT1 receptors, 5-HT2 receptors, 5-HT7 receptors, α1-adrenaline receptors, histamine H1 receptors and 5-hydroxytryptamine reuptake sites.

[0038] Among them, the 5-HT1 receptor is preferably a 5-HT1A receptor; the 5-HT2 receptor is preferably a 5-HT2A receptor and / or a 5-HT2C receptor.

[0039] The present invention also provides a pharmaceutical composition, comprising the above-mentioned piperazine derivative and a pharmaceutically acceptable inorganic salt or organic salt thereof. Preferably, the composition also comprises a pharmaceutically acceptable excipient, such as a carrier or an excipient. In certain embodiments, the composition is used orally, by injection, transdermally, nasally, by mucosal, or by inhalation.

[0040] The pharmaceutical composition of the present invention may contain one or more piperazine derivatives provided by the present invention. In addition, the pharmaceutical composition may optionally further contain one or more other pharmaceutically active compounds.

[0041] According to the present invention, the pharmaceutical composition comprises the piperazine derivative of the present invention and a conventional pharmaceutical carrier or excipient. The pharmaceutical composition can be administered by, for example, oral or parenteral routes. The pharmaceutical composition of the present invention can be prepared into various dosage forms according to conventional methods in the art, including but not limited to tablets, capsules, solutions, suspensions, granules or injections, and can be administered by, for example, oral or parenteral routes.

[0042] The pharmaceutical composition of the present invention may be present in a unit dosage form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain 0.001 to 1000 mg, for example, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 10 mg, 20 mg, 50 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg or 1000 mg of the piperazine derivative of the present invention, depending on the disease to be treated, the route of administration and the age, weight and symptoms of the subject, or the pharmaceutical composition may be present in a unit dosage form containing a predetermined amount of active ingredient per unit dose. In another embodiment, the unit dose composition is those containing a daily dose or subdose as described herein or an appropriate fraction thereof of an active ingredient. In addition, such a pharmaceutical composition may be prepared by any method known to those skilled in the art.

[0043] The present invention provides a piperazine derivative, as shown in formula (I) or its stereoisomers and pharmaceutically acceptable salts thereof; compared with the prior art, the piperazine derivative provided by the present invention has a stronger affinity for dopamine D2, D3, and 5-HT1A, 5-HT2A receptors of 5-hydroxytryptamine, and has a moderate affinity for dopamine D4, 5-HT2C, 5-HT7, α1-adrenaline, and histamine H1 receptors of 5-hydroxytryptamine, and also has a moderate affinity for 5-hydroxytryptamine reuptake sites, and has no obvious affinity for cholinergic muscarinic receptors. Functionally, it is a partial agonist of D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors, and can be used to treat or prevent diseases that require regulation of one or more of dopamine D2 receptors, 5-HT1 receptors, 5-HT2 receptors, 5-HT7 receptors, α1-adrenaline receptors, histamine H1 receptors and 5-hydroxytryptamine reuptake sites. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 is the hydrogen spectrum of the compound represented by formula (M-1) obtained in Example 1 of the present invention;

[0045] Figure 2 is the LC-MS / MS spectrum of the compound represented by formula (M-1) obtained in Example 1 of the present invention;

[0046] Figure 3 is the hydrogen spectrum of the compound represented by formula (M-2) obtained in Example 2 of the present invention;

[0047] Figure 4 is the LC-MS / MS spectrum of the compound represented by formula (M-2) obtained in Example 2 of the present invention;

[0048] Figure 5 is the hydrogen spectrum of the compound represented by formula (M-3) obtained in Example 3 of the present invention;

[0049] Figure 6 is the LC-MS / MS spectrum of the compound represented by formula (M-3) obtained in Example 3 of the present invention;

[0050] Figure 7 is the hydrogen spectrum of the compound represented by formula (M-4) obtained in Example 4 of the present invention;

[0051] Figure 8 is the LC-MS / MS spectrum of the compound represented by formula (M-4) obtained in Example 4 of the present invention;

[0052] Fig. 9 is the hydrogen spectrum of the compound represented by formula (M-5) obtained in Example 5 of the present invention;

[0053] Fig.10is the LC-MS / MS spectrum of the compound represented by formula (M-5) obtained in Example 5 of the present invention;

[0054] Fig.11 is the hydrogen spectrum of the compound represented by formula (M-6) obtained in Example 6 of the present invention;

[0055] Fig.12 is the LC-MS / MS spectrum of the compound represented by formula (M-6) obtained in Example 6 of the present invention;

[0056] Fig.13 is the hydrogen spectrum of the compound represented by formula (M-7) obtained in Example 7 of the present invention;

[0057] Fig.14 is the LC-MS / MS spectrum of the compound represented by formula (M-7) obtained in Example 7 of the present invention;

[0058] Fig.15 The hydrogen spectrum of the compound represented by formula (M-8) obtained in Example 8 of the present invention;

[0059] Fig.16 is the LC-MS / MS spectrum of the compound represented by formula (M-8) obtained in Example 8 of the present invention;

[0060] Fig.17 is the hydrogen spectrum of the compound represented by formula (M-9) obtained in Example 9 of the present invention;

[0061] Fig.18 is the LC-MS / MS spectrum of the compound represented by formula (M-9) obtained in Example 9 of the present invention;

[0062] Fig.19 is the hydrogen spectrum of the compound represented by formula (M-10) obtained in Example 10 of the present invention;

[0063] Fig. 20 is the LC-MS / MS spectrum of the compound represented by formula (M-10) obtained in Example 10 of the present invention;

[0064] Fig.21 is the hydrogen spectrum of the compound represented by formula (M-11) obtained in Example 11 of the present invention;

[0065] Fig. 22 is the LC-MS / MS spectrum of the compound represented by formula (M-11) obtained in Example 11 of the present invention;

[0066] Fig.23 is the hydrogen spectrum of the compound represented by formula (M-12) obtained in Example 12 of the present invention;

[0067] Fig.24This is the LC-MS / MS spectrum of the compound represented by formula (M-12) obtained in Example 12 of the present invention. DETAILED DESCRIPTION

[0068] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0069] Definition of terms

[0070] As used herein, the term "compound" refers to a compound of formula (I) as defined above, in any form, including various stereoisomers, any salt or non-salt form (for example, as a free acid or free base, or as a salt, especially a pharmaceutically acceptable salt thereof) and any physical form thereof (for example, including non-solid forms (for example, liquid or semi-solid forms) and solid forms (for example, amorphous or crystalline forms)), as well as mixtures of various forms.

[0071] In order to further illustrate the present invention, a piperazine derivative provided by the present invention, its preparation method and application are described in detail below in conjunction with examples.

[0072] The reagents used in the following examples are all commercially available.

[0073] Example 1 Preparation of the compound represented by formula (M-1)

[0074] 1. Process route:

[0075]

[0076] 2. Operation method

[0077] (1) Weigh 20.0 g of compound 1 in a reaction flask; weigh 100.0 ml of ethanol and add it to the reaction flask. The system becomes turbid; weigh 13.4 g of NaOH in 100.0 ml of H 2 O, completely dissolved; sodium hydroxide aqueous solution was added dropwise to the reaction bottle, the system became turbid; the temperature was raised to 80°C and stirred overnight; TLC (petroleum ether: ethyl acetate = 2:1) monitored the completion of the reaction; after the reaction was completed, the reaction solution was suspended to dryness; 300.0 ml of water was added, the system became turbid; 300.0 ml of ethyl acetate was measured for washing; the aqueous phase was adjusted to pH 4-5 with 1M dilute hydrochloric acid, and a large amount of white solid precipitated; filtration was performed to obtain 14.0 g of white solid.

[0078] The yield was calculated according to the following formula, and the yield was 65%; wherein: W2 is the weight of compound 2; 238.33 is the molecular weight of compound 1; W1 is the weight of compound 1; 257.33 is the molecular weight of compound 2.

[0079]

[0080] (2) Weigh 13.0 g of compound 2 into a three-necked flask; add 130.0 ml of THF into the reaction flask, the system becomes turbid; add ice to cool to 0°C; at T = 0°C, add 7.7 ml of BH 3 (dimethyl sulfide), the system gradually becomes clear; stir at room temperature overnight; TLC (PE:EA=3:1) monitors the completion of the reaction; after the reaction is completed, add 30.0ml of methanol to quench; add 1.0M dilute hydrochloric acid to adjust to pH=5; take 400.0ml of ethyl acetate for extraction; dry over anhydrous sodium sulfate, and hang the organic phase to dryness; purify by column, polar (PE:EA=5:1~1:1), and obtain 6.0g of white solid.

[0081] The calculated yield was 49%.

[0082] (3) Weigh 1.0g of compound 3 in a reaction bottle; add 20.0ml of DCM to the reaction bottle, and the system becomes clear; weigh 1.7g of triethylamine to the reaction bottle, and the system becomes clear; cool to 0℃ with ice; T=0℃, drop 962.0mg of MsCl; stir at room temperature; monitor the reaction by TLC; after the reaction is complete, add 20.0ml of water to quench; extract three times with 30.0ml*3 of dichloromethane; dry with anhydrous sodium sulfate; dry the organic phase to obtain 1.3g of light yellow solid. The calculated yield is 98%.

[0083] (4) Weigh 0.7 g of compound 4A into a reaction bottle; add 20.0 ml of acetonitrile to the reaction bottle, and the system becomes turbid; weigh 1.3 g of compound 4 into the reaction bottle, and the system becomes turbid; add 1.0 g of triethylamine, 1.4 g of potassium carbonate and 0.5 g of KI in sequence, and the system becomes turbid; heat to 80°C and stir overnight; monitor the completion of the reaction by LCMS; after the reaction is completed, add 100.0 ml of water to the reaction solution and quench with 20.0 ml of water; extract twice with 30.0 ml*2 ethyl acetate; dry over anhydrous sodium sulfate; hang the organic phase to dryness to obtain 1.5 g of crude product; add 10.0 ml of methyl tert-butyl ether to the crude product and stir at room temperature; filter and collect the solid to obtain 1.2 g of product, with a yield of 84.3%.

[0084] (5) Weigh 1.2 g of compound 5 into a reaction flask; add 12.0 ml of dichloromethane to the reaction flask to dissolve the system; add 12.0 ml of HCl / EtOH dropwise to dissolve the system; stir at room temperature; monitor the completion of the reaction by TLC; after the reaction is completed, dry the mixture to obtain 0.8 g of a crude light yellow solid; the yield is 86%.

[0085] (6) Weigh 800.0 mg of compound 6 into a reaction flask; add 16.0 ml of dichloromethane to the reaction flask to dissolve the system; weigh 1.2 g of TEA to the reaction flask to dissolve the system; cool to 0°C; T = 0°C, add 492.0 mg of dimethylaminoformyl chloride dropwise to dissolve the system; stir at room temperature overnight; monitor the completion of the reaction by LCMS; after the reaction is completed, prepare and purify to obtain 68.0 mg of an off-white solid with a purity of 98.1604%, which is the compound represented by formula (M-1); the yield is 7%.

[0086] The compound represented by formula (M-1) obtained in Example 1 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Figure 1 As shown, HNMR MeOD-d 4 :8.48(br s,1H),7.85-7.83(d,1H),7.80-7.78(d,1H),7.72-7.5(m,2H),6.94(s,1H),3.55-3.50(m,1H),3.33- 3.32(m,8H),3.02-2.99(m,2H),2.89(s,6H),1.95-1.86(m,4H),1.67-1.64(m,2H),1.33-1.13(m,5H).

[0087] The compound represented by formula (M-1) obtained in Example 1 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Figure 2 As shown, LC-MS: (ES, m / z): [M+1]=415.2.

[0088] Example 2 Preparation of the compound represented by formula (M-2)

[0089] 1. Process route:

[0090]

[0091] 2. Operation method

[0092] (1) Weigh 10.0 g of compound 1 into a reaction bottle; weigh 27.2 g of NaOAc and add it into the reaction bottle; weigh 100.0 ml of ethanol and add it into the reaction bottle; weigh NH 2OH.HCl was added to the reaction flask, heated to 45°C, and stirred for reaction; TLC monitored the completion of the reaction; after the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with 50.0 ml of ethyl acetate, and the filtrate was concentrated to obtain 11.4 g of crude product; the yield was 100%.

[0093] (2) Weigh 11.4 g of compound 2 into a reaction flask; add 114.0 ml of DMF to the reaction flask and cool to 0°C; weigh 11.7 g of NCS and slowly add it to the reaction flask, with the internal temperature not exceeding 5°C; after the addition of NCS, stir at room temperature; monitor the completion of the reaction by TLC; after the reaction, add 500.0 ml of water to the reaction solution and extract with MTBE (200.0 ml); dry over anhydrous sodium sulfate, and hang the organic phase to dryness to obtain 15.0 g of crude yellow oil, which is directly used in the next step without purification, and the crude yield is greater than 100%.

[0094] (3) Weigh 10.0 g of compound 3 into a reaction flask; weigh 100.0 ml of DCM and add it to the reaction flask; weigh 10.6 g of triethylamine and add it to the reaction flask, there is slight heat release, and the temperature is lowered to 10°C; weigh 18.1 g of piperazine and add it to the reaction flask, the internal temperature does not exceed 15°C; after the addition is completed, stir the reaction at room temperature, and a large amount of solid precipitates; monitor the completion of the reaction by TLC; after the reaction is completed, add 200.0 ml of water to the reaction solution and extract; hang the organic phase to dryness to obtain 20.0 g of crude product; the crude product is purified by column chromatography, polarity: DCM / MeOH: 1 / 0-20 / 1, to obtain 5.5 g of brown solid product; the yield is 43.6%.

[0095] (4) Weigh 3.9 g of compound 4 and add it to a 250.0 ml autoclave; weigh 60.0 ml of dioxane and 20.0 ml of water and add them to a reaction flask; weigh 2.7 g of KOH and add it to the reaction flask, raise the temperature to 120°C for reaction; monitor the reaction by TLC, which shows that most of the raw materials remain; weigh 6.0 g of KOH and add it to the reaction flask, raise the temperature to 120°C, and continue the reaction; monitor the reaction by TLC until it is complete; after the reaction is completed, add 200.0 ml of water and 50.0 ml of ethyl acetate to the filtrate; dry the organic phase to obtain 1.4 g of light yellow solid, which is directly used in the next step.

[0096] (5) Weigh 670.0 mg of compound 5 in a reaction flask; add 20.0 ml of acetonitrile to the reaction flask to dissolve the system; weigh 1.3 g of compound 5A in the reaction flask to dissolve the system; weigh 1.0 g of triethylamine to the reaction flask to clarify the system; stir at room temperature overnight, monitor the reaction by LCMS (HYKR00652009S-1021-01), most of which is raw material; heat to 8°C and stir overnight; monitor the completion of the reaction by LCMS (HYKR00652009S-1022-01); after the reaction is completed, the organic phase is suspended to dryness; the crude product is purified by column chromatography, polarity: n-heptane-n-heptane / ethyl acetate 3 / 1, to obtain 600.0 mg of light yellow solid; the yield is 42%.

[0097] (6) Weigh 600.0 mg of compound 6 into a reaction flask; add 6.0 ml of dichloromethane into the reaction flask; add 6.0 ml of HCl / MeOH into the reaction flask and stir at room temperature; monitor the completion of the reaction by TLC; after the reaction is completed, the organic phase is suspended to dryness to obtain 400.0 mg of a crude white solid, which is directly used in the next step.

[0098] (7) Weigh 400.0 mg of compound 7 into a reaction flask; weigh 606.0 mg of triethylamine and add it into the reaction flask; weigh 12.0 ml of DCM and add it into the reaction flask; cool the reaction solution to 5°C; weigh 257.0 mg of dimethylaminoformyl chloride and add it into the reaction flask, with the internal temperature not exceeding 10°C; after the addition is complete, react at room temperature overnight; monitor the completion of the reaction by LCMS; after the reaction is complete, prepare and purify, and lyophilize to obtain 110.0 mg of an off-white solid with a purity of 98.7676%, which is the compound represented by formula (M-2); the yield is 23%.

[0099] The compound of formula (M-2) obtained in Example 2 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Figure 3 As shown, HNMR MeOD-d 4 :8.40(br s,1H),7.91-7.89(d,1H),7.62-7.60(t,1H),7.53-7.51(d,1H),7.35-7.32(t,1H),3.76-3.74(m,4H),3. 22-3.20(m,4H),2.99-2.95(m,2H),2.89(s,6H),1.94-1.84(m,4H),1.66-1.62(m,2H),1.32-1.2(m,5H).

[0100] The compound represented by formula (M-2) obtained in Example 2 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Figure 4 As shown, LC-MS: (ES, m / z): [M+1]=400.2.

[0101] Example 3 Preparation of the compound represented by formula (M-3)

[0102] 1. Process route:

[0103]

[0104] 2. Operation method

[0105] (1) Weigh 5.0 g of compound 1 into a reaction flask; add 20.0 ml of triethylamine into the reaction flask and stir; concentrate the triethylamine and suspend it to dryness; weigh 5.0 g of compound 1A into the reaction flask; weigh 5.0 g of potassium carbonate into the reaction flask; add 50.0 ml of diethylene glycol dimethyl ether into the reaction flask, heat to 160° C. and react; monitor the completion of the reaction by TLC; after the reaction is completed, add 500.0 ml of water and extract with 200.0 ml of ethyl acetate; purify by column, polarity: n-heptane / ethyl acetate 3 / 1-ethyl acetate / methanol 10 / 1, and obtain 3.0 g of product; yield 50.8%.

[0106] (2) Weigh 700.0 mg of compound 2 into a reaction bottle; add 20.0 ml of acetonitrile to the reaction bottle; add 1.3 g of compound 2A, 1.4 g of potassium carbonate, and 1.0 g of triethylamine in sequence; stir at 80°C overnight; monitor the completion of the reaction by LCMS; after the reaction is completed, purify by column, polarity: PE / EA: 10 / 1-5 / 1, to obtain 900.0 mg of white solid; the yield is 62%.

[0107] (3) Weigh 900.0 mg of compound 3 into a reaction flask; add 18.0 ml of DCM to the reaction flask to dissolve the system; dropwise add 18.0 ml of HCl / MeOH to gradually make the system turbid; stir at room temperature; monitor the completion of the reaction by TLC; after the reaction is complete, dry the mixture to obtain 600.0 mg of a yellow oil; the yield is 86%.

[0108] (4) Measure 12.0 ml of dichloromethane into a reaction flask; weigh 600.0 mg of compound 4 into the reaction flask, and the system is dissolved; weigh 909.0 mg of triethylamine into the reaction flask, and the system is dissolved; add ice to cool to 0°C; T = 0°C, drop 385.0 mg of dimethylaminoformyl chloride, and the system is dissolved; stir at room temperature overnight; LCMS monitors the completion of the reaction; after the reaction is completed, prepare and purify, and freeze-dry to obtain 303.2 mg of an off-white solid, which is the compound of formula (M-3), with a purity of 97.44% and a yield of 41.2%.

[0109] The compound of formula (M-3) obtained in Example 3 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Figure 5 As shown, HNMR MeOD-d 4:8.20-8.18(d,1H),7.85-7.83(d,1H),7.58-7.56(d,1H),7.49-7.39(m,3H),7.16-7.15(d,1H),5.93-5.90(d,1H),3.55-3.4 9(m,1H),3.17-3.15(m,4H),2.89-2.80(m,10H),2.61-2.57(m,2H),1.92-1.86(m,4H,)1.58-1.52(m,2H),1.37-1.08(m,5H).

[0110] The compound represented by formula (M-3) obtained in Example 3 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Figure 6 As shown, LC-MS: (ES, m / z): [M+1]=409.3.

[0111] Example 4 Preparation of the compound represented by formula (M-4)

[0112] 1. Process route:

[0113]

[0114] 2. Operation method

[0115] (1) Weigh 1.0 g of compound 1 in a reaction bottle; weigh 20.0 ml of acetonitrile and add it to the reaction bottle, the system is dissolved; weigh 1.3 g of compound 1A and add it to the reaction bottle, the system is dissolved; weigh 41.0 mg of KI and add it to the reaction bottle, the system is turbid; weigh 245.0 mg of NaOH and add it to the reaction bottle, the system is turbid; stir at room temperature overnight; LCMS monitors the reaction, most of which is raw material; add 1.0 eq NaOH, 0.08 eq KI and 1.0 eq compound 1A; heat to 45 ° C and stir overnight; LCMS monitors the completion of the reaction; after the reaction is completed, purify by column, polarity: PE / EA: 10 / 1 to 1 / 1, and obtain 370.0 mg of white solid; yield 20%.

[0116] (2) Weigh 148.0 mg of compound 2A into a reaction flask; add 10.0 ml of acetonitrile to the reaction flask, and the system becomes turbid; add 244.0 mg of compound 2, 113.0 mg of KI, and 206.0 mg of triethylamine to the reaction flask in sequence; raise the temperature to 80°C and stir overnight; monitor the completion of the reaction by LCMS; after the reaction is completed, prepare and purify, and lyophilize to obtain 50.0 mg of the compound with a purity of 99.3034%. The white solid is the compound represented by formula (M-4), with a yield of 17%.

[0117] The compound of formula (M-4) obtained in Example 4 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Figure 7As shown (the right figure is a partial enlarged view), HNMR MeOD-d 4 :9.98(s,1H),8.15(s,1H),7.91-7.90(d,1H),7.74-7.72(d,1H),7.37-7.35(m,2H),7.05-7.03(d,1H),6.89(s,1H),6.50-6.48(d, 1H),6.43(s,1H),3.94-3.91(t,2H),3.09-3.00(m,4H),2.79-2.75(t,2H),2.69-2.60(m,4H),2.44-2.39(m,4H),1.75-1.59(m,4H).

[0118] The compound represented by formula (M-4) obtained in Example 4 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Figure 8 As shown, LC-MS: (ES, m / z): [M+1]=436.2.

[0119] Example 5 Preparation of the compound represented by formula (M-5)

[0120] 1. Process route:

[0121]

[0122] 2. Operation method

[0123] (1) Weigh 10.0 g of compound 1 in a reaction flask; weigh 100.0 ml of DCM and add it to the reaction flask; weigh 1.0 g of DMAP and add it to the reaction flask; weigh 16.2 g of TEA and add it to the reaction flask, cool it to 5°C; weigh 11.6 g of compound 1A and slowly add it to the reaction flask; complete the addition; monitor the completion of the reaction by TLC; after the reaction, add 100.0 ml of water to the reaction solution, separate the liquids and extract; collect the organic phase, concentrate it, and obtain 20.0 g of crude product; purify it by column to obtain 16.0 g of white solid; the yield is 95.4%.

[0124] (2) Weigh 16.0 g of compound 2 into a reaction flask; weigh 160.0 ml of Me-THF and add it into the reaction flask, protect with nitrogen, and cool to -70°C; weigh 105.6 ml of n-BuLi and slowly add it dropwise into the reaction flask, the temperature does not exceed -60°C, and a large amount of solid precipitates; after the addition is complete, slowly raise the temperature to 0°C and react for 4 hours; cool the reaction solution to -70°C; weigh 17.3 g of dibromoethane and slowly add it dropwise into the reaction flask; after the addition is complete, slowly raise the temperature to room temperature, the solution becomes clear, and continue the reaction; monitor the completion of the reaction by TLC; after the reaction is complete, add 100.0 ml of ethyl acetate to the reaction solution for extraction; collect the organic phase and concentrate to obtain 20.0 g of yellow-brown solid crude product; purify by column to obtain 14.9 g of white solid; the yield is 65.7%.

[0125] (3) Weigh 5.0 g of compound 3 into a reaction bottle; weigh 100.0 ml of dioxane and add it to the reaction bottle; weigh 2.7 g of compound 3A and add it to the reaction bottle; weigh 100.0 mg of di(tert-butylphosphine) and add it to the reaction bottle; weigh 100.0 mg of Pd 2 (dba) 3 Add to the reaction bottle; weigh 2.7g DIEA and add to the reaction bottle, protect with nitrogen; heat to 100℃ and react overnight; monitor the completion of the reaction by TLC; after the reaction, filter and concentrate the filtrate to obtain 8.0g yellow solid crude product, which is directly used in the next step.

[0126] (4) Weigh 6.9 g of compound 4 into a reaction flask; weigh 140.0 ml of ethanol and add it to the reaction flask, the system is light yellow; weigh 690.0 mg of Pd / C and add it to the reaction flask, replace the hydrogen, and react at room temperature overnight under a hydrogen balloon; LCMS monitors the completion of the reaction; after the reaction is completed, filter the reaction solution and rinse with 20.0 ml of ethanol; the filtrate is suspended to dryness to obtain 7.0 g of light yellow oil, which is directly used in the next step.

[0127] (5) Weigh 6.0 g of compound 5 into a reaction flask; add 15.0 ml of water into the reaction flask; add 15.0 ml of HCl into the reaction flask, and heat to 100° C. to react; monitor the completion of the reaction by LCMS; after the reaction, concentrate the reaction solution, add 200.0 ml of acetonitrile, and stir; filter and collect the filter cake to obtain 3.1 g of a yellow solid; yield 105%.

[0128] (6) Weigh 1.0 g of compound 6 into a reaction flask; weigh 20.0 ml of DMF and add it to the reaction flask; weigh 1.3 g of compound 6A and add it to the reaction flask; weigh 2.0 g of cesium carbonate and add it to the reaction flask; weigh 276.0 mg of triethylamine and add it to the reaction flask; heat to 80°C and stir; monitor the completion of the reaction by LCMS; after the reaction is completed, add 200.0 ml of water to the reaction solution and extract with 30.0 ml*3 ethyl acetate; hang the organic phase to dryness and purify it by column to obtain 620.0 mg of product; yield 34%.

[0129] (7) Weigh 200.0 mg of compound 7A into a reaction flask; weigh 20.0 ml of acetonitrile and add it into the reaction flask; weigh 272.0 mg of compound 7 and add it into the reaction flask; weigh 151.0 mg of KI and add it into the reaction flask; weigh 276.0 mg of triethylamine and add it into the reaction flask; heat to 80°C and stir overnight; monitor the completion of the reaction by LCMS; after the reaction is completed, filter, suspend the filtrate to dryness, prepare and purify, and lyophilize to obtain 111.9 mg of the white solid with a purity of 98.3498%, which is the compound represented by formula (M-5); the yield is 28%.

[0130] The compound of formula (M-5) obtained in Example 5 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig. 9 As shown, HNMR MeOD-d 4 :8.42(br s,1H),8.05-8.03(d,1H),7.96-7.94(d,1H),7.58-7.55(t,1H),7.49-7.44(m,2H),6.42-6.40(d,1H),4.32-4.31(m, 2H),3.70-3.68(m,4H),3.17-3.15(m,4H),2.96-2.93(m,2H),2.90-2.86(t,2H),2.62-2.58(t,2H)1.87-1.84(m,4H).

[0131] The compound represented by formula (M-5) obtained in Example 5 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig.10 As shown, LC-MS: (ES, m / z): [M+1]=438.2.

[0132] Example 6 Preparation of the compound represented by formula (M-6)

[0133] 1. Process route:

[0134]

[0135] 2. Operation method

[0136] Weigh 200.0 mg of compound 1A in a reaction bottle; weigh 20.0 ml of acetonitrile and add it to the reaction bottle; weigh 294.0 mg of compound 1 and add it to the reaction bottle; weigh 164.0 mg of KI and add it to the reaction bottle; weigh 298.0 mg of triethylamine and add it to the reaction bottle; heat to 80°C and stir overnight; LCMS monitors the completion of the reaction; after the reaction is completed, the filtrate is suspended to dryness, prepared and purified, and freeze-dried to obtain 43.7 mg of a white solid with a purity of 97.5663%. The white solid is the compound represented by formula (M-6); the yield is 10.5%.

[0137] The compound of formula (M-6) obtained in Example 6 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.11 As shown, HNMR MeOD-d 4 :10.23(br s,1H),8.14(br s,1H),7.98-7.96(d,1H),7.58-7.57(d,2H),7.49-7.47(d,1H),7.31-7.27(m,1H),6.36-6.34(d,1H),4.21- 4.18(t,2H),3.48-3.46(m,4H),2.79-2.75(t,2h),2.55-2.54(m,4H),2.46-2.38(m,4H),1.74-1.58(m,4H).

[0138] The compound represented by formula (M-6) obtained in Example 6 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig.12 As shown, LC-MS: (ES, m / z): [M+1]=422.2.

[0139] Example 7 Preparation of the compound represented by formula (M-7)

[0140] 1. Process route:

[0141]

[0142] 2. Operation method

[0143] (1) Weigh 5.0 g of compound 1 into a reaction bottle; weigh 50.0 ml of toluene and add it to the reaction bottle, the system is dissolved; weigh 2.4 g of piperazine and add it to the reaction bottle, the system is dissolved; weigh 6.8 g of sodium tert-butoxide and add it to the reaction bottle, the system is turbid; weigh 500.0 mg of R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) and add it to the reaction bottle, the system is turbid; weigh 500.0 mg of Pd 2 dba 3 Added to the reaction bottle, the system turned black; replaced N 23 times, stirring at 80°C overnight; LCMS monitored the completion of the reaction; after the reaction was completed, column purification was performed, polarity: DCM / MeOH: 50 / 1 to 20 / 1, to obtain 2.5 g of black oil; the yield was 40%.

[0144] (2) Weigh 500.0 mg of compound 2 into a reaction bottle; weigh 10.0 ml of acetonitrile and add it to the reaction bottle, the system is turbid; weigh 630.0 mg of compound 2B and add it to the reaction bottle, the system is turbid; weigh 380.0 mg of KI and add it to the reaction bottle; weigh 700.0 mg of triethylamine and add it to the reaction bottle, the system is turbid; heat to 80°C and react overnight; LCMS monitors the completion of the reaction; after the reaction is completed, prepare and purify, and lyophilize to obtain 450.0 mg of a light yellow solid with a purity of 98.6081%, which is the compound represented by formula (M-7); the yield is 48%.

[0145] The compound of formula (M-7) obtained in Example 7 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.13 As shown, HNMR MeOD-d 4 :7.83-7.77(m,2H),7.40-7.34(m,2H),6.86(s,1H),3.96-3.92(t,2H),3.33-3. 23(m,4H),2.92-2.82(m,8H),2.67-2.63(m,2H),2.36(s,3H),2.02-1.89(m,4H).

[0146] The compound represented by formula (M-7) obtained in Example 7 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig.14 As shown, LC-MS: (ES, m / z): [M+1]=409.2.

[0147] Example 8 Preparation of the compound represented by formula (M-8)

[0148] 1. Process route:

[0149]

[0150] 2. Operation method

[0151] Weigh 500.0 mg of compound 1 into a reaction bottle; add 10.0 ml of acetonitrile to the reaction bottle, and the system becomes turbid; add 630.0 mg of compound 1A, 460.0 mg of KI, and 700.0 mg of triethylamine to the reaction bottle in sequence, and the system becomes turbid; heat to 80°C and stir overnight; monitor the completion of the reaction by LCMS; after the reaction is completed, suspend to dryness, prepare purification, and lyophilize to obtain 129.0 mg of the white solid with a purity of 99.9538%, which is the compound represented by formula (M-8); the yield is 14%.

[0152] The compound of formula (M-8) obtained in Example 8 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.15 As shown, HNMR MeOD-d 4 :8.39(br s,1H),8.06-8.04(d,1H),7.95-7.93(d,1H),7.58-7.54(t,1H),7.48-7.44(t,1H),3.96-3.93( t,1H),3.68-3.66(m,4H),3.13-3.11(m,4H),2.93-2.87(m,6H),2.36(s,1H),2.02-1.89(m,4H).

[0153] The compound represented by formula (M-8) obtained in Example 8 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig.16 As shown, LC-MS: (ES, m / z): [M+1]=410.2.

[0154] Example 9 Preparation of the compound represented by formula (M-9)

[0155] 1. Process route:

[0156]

[0157] 2. Operation method

[0158] Weigh 500.0 mg of compound 1 in a reaction bottle; measure 20.0 ml of acetonitrile and add it to the reaction bottle; weigh 533.0 mg of compound 1A and add it to the reaction bottle; weigh 399.0 mg of KI and add it to the reaction bottle; weigh 710.0 mg of triethylamine and add it to the reaction bottle; heat to 80°C and stir overnight; LCMS monitors the completion of the reaction; after the reaction is completed, suspend to dryness, prepare purification, and lyophilize to obtain 290.6 mg with a purity of 98.9458%. The white solid is the compound represented by formula (M-9); the yield is 30.7%.

[0159] The compound of formula (M-9) obtained in Example 9 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.17 As shown, HNMR MeOD-d 4:8.39(br s,1H),8.23-8.21(d,1H),7.88-7.86(d,1H),7.59-7.43(m,3H),7.23-7.21(d,1H),3.98-3.95(t,2H),3. 51-3.40(m,8H),3.16-3.12(m,2H),3.01-2.97(m,2H),2.92-2.91(m,2H),2.39(s,3H),2.03-1.91(m,4H).

[0160] The compound represented by formula (M-9) obtained in Example 9 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig.18 As shown, LC-MS: (ES, m / z): [M+1]=425.1.

[0161] Example 10 Preparation of the compound represented by formula (M-10)

[0162] 1. Process route:

[0163]

[0164] 2. Operation method

[0165] 10.0 ml of acetonitrile was added to the reaction bottle; 500.0 mg of compound 1, 678.0 mg of compound 1B, 460.0 mg of KI, and 700.0 mg of triethylamine were added in sequence, and the system became turbid; the temperature was raised to 80°C and stirred overnight; LCMS monitored the completion of the reaction; after the reaction was completed, the mixture was suspended to dryness, prepared for purification, and freeze-dried to obtain 532.0 mg of a light yellow solid with a purity of 97.2169%, which was the compound represented by formula (M-10); the yield was 55%.

[0166] The compound represented by formula (M-10) obtained in Example 10 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.19 As shown, HNMR MeOD-d 4 :8.32(s,1H),8.07-8.05(d,1H),7.96-7.94(d,1H),7.59-7.55(t,1H),7.49-7.45(t,1H),4.63-4.60(m,1H ),4.10-4.03(m,1H),3.89-3.71(5H),3.33-3.27(m,4H),3.01-2.96(m,4H),2.42(s,3H),2.19-1.96(m,4H).

[0167] The compound represented by formula (M-10) obtained in Example 10 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig. 20As shown, LC-MS: (ES, m / z): [M+1]=426.2.

[0168] Example 11 Preparation of the compound represented by formula (M-11)

[0169] 1. Process route:

[0170]

[0171] 2. Operation method

[0172] Weigh 250.0 mg of compound 1 in a reaction bottle; measure 5.0 ml of acetonitrile and add it to the reaction bottle; weigh 298.0 mg of compound 1A and add it to the reaction bottle; weigh 204.0 mg of KI and add it to the reaction bottle; weigh 373.0 mg of triethylamine and add it to the reaction bottle; heat to 80°C and stir overnight; LCMS monitors the completion of the reaction; after the reaction is completed, suspend to dryness, prepare purification, and lyophilize to obtain 17.8 mg with a purity of 96.2577%. The white solid is the compound represented by formula (M-11); the yield is 30.7%.

[0173] The compound represented by formula (M-11) obtained in Example 11 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.21 As shown, HNMR MeOD-d 4 :7.91-7.89(d,1H),7.60-7.51(t,1H),7.50-7.48(d,1H),7.33-7.29(t,1H),4.61-4.59(m,1H),4.07-4.02(m,1 H),3.86-3.82(m,1H),3.63-3.60(m,4H),2.86-2.83(m,6H),2.65-2.61(m,2H),2.40(s,3H),2.18-1.95(m,4H).

[0174] The compound represented by formula (M-11) obtained in Example 11 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig. 22 As shown, LC-MS: (ES, m / z): [M+1]=410.15, [M-1]=408.1.

[0175] Example 12 Preparation of the compound represented by formula (M-12)

[0176] 1. Process route:

[0177]

[0178] 2. Operation method

[0179] Weigh 300.0 mg of compound 1 in a reaction bottle; add 10.0 ml of acetonitrile to the reaction bottle, the system is turbid; weigh 412.0 mg of compound 1A to the reaction bottle, the system is turbid; weigh 232.0 mg of KI to the reaction bottle, the system is turbid; weigh 425.0 mg of triethylamine to the reaction bottle, the system is turbid; heat to 80°C, stir overnight; LCMS monitors the completion of the reaction; after the reaction is completed, suspend to dryness, prepare purification, and lyophilize to obtain 39.0 mg of white solid with a purity of 95.7619%, which is the compound represented by formula (M-12); the yield is 7%.

[0180] The compound represented by formula (M-12) obtained in Example 12 was analyzed by nuclear magnetic resonance, and its hydrogen spectrum was obtained as follows: Fig.23 As shown, HNMR MeOD-d 4 :8.40(br s,1H)7.81-7.77(m,2H),7.38-7.32(m,2H),6.89(s,1H),4.60-4.57(m,1H),4.17-4.00(m,1 H),3.85-2.79(m,1H),3.29-2.92(m,8H),2.84-2.76(m,4H),2.45(s,3H),2.16-1.90(m,4H).

[0181] The compound represented by formula (M-12) obtained in Example 12 was analyzed by liquid chromatography-mass spectrometry to obtain its mass spectrum as shown in Fig.24 As shown, LC-MS: (ES, m / z): [M+1]=425.15.

[0182] The piperazine derivatives of the present invention are structurally optimized on the basis of cariprazine, so the pharmacodynamic activity of the piperazine derivatives of the present invention is verified by the affinity of each target with reference to the mechanism of action of cariprazine, and the test is as follows.

[0183] Test Example 1 The activity of the test compound was tested in the 5HT1A receptor cAMP assay.

[0184] Test Example 2 The inhibitory effect of the test compound on the human serotonin receptor 5HT2A was determined using the FLIPR calcium assay.

[0185] Test Example 3 The inhibitory effect of the test compound on the human serotonin receptor 5HT2B was determined using the FLIPR calcium assay.

[0186] Test Example 4 Activity test of the test compound in the D2L receptor cAMP assay.

[0187] Experimental Example 5 Activity test of the test compound in the D3 receptor cAMP assay.

[0188] 1. Cell culture and reagent preparation

[0189]

[0190] 2. Test methods

[0191]

[0192]

[0193] 3. Data Analysis

[0194]

[0195] Table 1 Activity test results of compounds in 5HT1A receptor cAMP assay

[0196]

[0197] As can be seen from Table 1, in the 5HT1A receptor cAMP experiment, M-7, M-5, M-8, M-9, M-10, and M-12 all have corresponding activities, among which the activity of M-9 is higher than that of cariprazine.

[0198] Table 2 Test results of the inhibitory activity of compounds on human serotonin receptor 5HT2A

[0199]

[0200] As can be seen from Table 2, in the inhibitory activity test experiment on human serotonin receptor 5HT2A, compounds M1-M12 all have corresponding activities, and the activities are higher than or equivalent to cariprazine.

[0201] Table 3 Test results of the inhibitory activity of compounds on human serotonin receptor 5HT2B

[0202]

[0203]

[0204] As can be seen from Table 3, in the test experiment of the inhibitory activity of human serotonin receptor 5HT2B, the activities of M-1, M-7, M-8, and M-12 are equivalent to cariprazine, and the activities of M-9 and M-3 are higher than cariprazine.

[0205] Table 4 Activity test results of compounds in D2L receptor cAMP assay

[0206]

[0207] As can be seen from Table 4, in the activity test experiment of the D2L receptor cAMP experiment, the activities of M-3 and M-4 are comparable to that of cariprazine.

[0208] Table 5 Activity test results of compounds in D3 receptor cAMP assay

[0209]

[0210]

[0211] As can be seen from Table 5, compounds M1-M12 were all inactive in the D3 receptor cAMP assay.

[0212] In summary, the experiments show that the pyrazine derivatives provided by the present invention have a strong affinity for dopamine D2, D3 and 5-HT1A, 5-HT2A receptors of serotonin, and also have a moderate affinity for 5-HT reuptake sites, and have no obvious affinity for cholinergic muscarinic receptors. Functionally, it is a partial agonist of D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors, and can be used to treat or prevent diseases that require regulation of one or more of dopamine D2 receptors, 5-HT1 receptors, 5-HT2 receptors and 5-HT reuptake sites, such as schizophrenia.

[0213] As can be seen from Tables 1 to 5, the piperazine derivatives of the present invention have partial or full activity in in vitro efficacy experiments, among which the activity of M-9 is higher than that of cariprazine in the 5HT1A receptor cAMP experiment and the inhibitory activity test of the human serotonin receptor 5HT2B, and its activity is similar to that of cariprazine in other aspects; the activity of M-3 is higher than that of cariprazine in the inhibitory activity test of the human serotonin receptor 5HT2B, and its activity is similar to that of cariprazine in other aspects.

Claims

1. A piperazine derivative, characterized in that: The piperazine derivative is one or more compounds represented by formula (M-3) and formula (M-9):

2. A method for preparing the piperazine derivative according to claim 1, characterized in that: include: The compound represented by formula (II) is reacted with the compound represented by formula (III-1) whose amino group is protected to obtain the compound represented by formula (IV) whose amino group is protected; The compound represented by formula (IV) with protected amino group is deaminated and then reacted with the compound represented by formula (V) to obtain the compound represented by formula (VI); Alternatively, the compound represented by formula (II) is reacted with the compound represented by formula (III-2) to obtain the compound represented by formula (VII); Wherein, n is 2; m is 0; -Ar is selected from the substituents shown in V2: b is selected from 0; said R2 is selected from halogen, C1-C10 alkyl; R1' is selected from C1-C3 alkyl, C1-C3 haloalkyl or alkyl-substituted phenyl; X1' and X2' are each independently selected from halogen; R2' is selected from the substituents shown in V5: R3, R4 and R6 are methyl groups, and R7 is hydrogen.

3. Use of the piperazine derivative according to claim 1 or the piperazine derivative prepared by the preparation method according to claim 2 in the preparation of a drug for treating schizophrenia.

4. Use of the piperazine derivative according to claim 1 or the piperazine derivative prepared by the preparation method according to claim 2 in the preparation of a drug for treating or preventing a disease requiring regulation of one or more of dopamine D2 receptors, 5-HT1 receptors, 5-HT2 receptors, 5-HT7 receptors, α1-adrenaline receptors, histamine H1 receptors and serotonin reuptake sites.

5. The use according to claim 4, characterized in that: The 5-HT1 receptor is a 5-HT1A receptor; the 5-HT2 receptor is a 5-HT2A receptor and / or a 5-HT2C receptor.

6. A pharmaceutical composition, characterized in that The invention comprises the piperazine derivative as claimed in claim 1.

Images