Free base crystalline form of a piperazine polycyclic derivative and methods of making and using the same

Abstract

The present application relates to a free base crystal form of a piperazine polycyclic derivative and its preparation method and application. Specifically, it relates to a crystal form of a free base of a compound having the general formula (I) and its stereoisomer, a preparation method and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and its use as a G protein-coupled receptor modulator in the treatment or prevention of central nervous system diseases and / or mental diseases.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a free base crystal form containing piperazine polycyclic derivatives, its preparation method, and its application. Background Technology

[0002] Dopamine D3 receptors are members of the G protein-coupled receptor family and are a subtype of dopamine receptors. Like dopamine D2 and D4 receptors, they are D2-like inhibitory receptors. Upon binding to dopamine (DA), they reduce cAMP levels by inhibiting G-proteins. D3 receptors are mainly distributed in the mesolimbic system, particularly in the nucleus accumbens, olfactory tubercle, and calleja's islet, which are unrelated to motor function. Highly active D3 receptor modulators may have good antipsychotic activity. D3 receptors are closely related to mood, cognition, mental state, and addiction, and can effectively improve negative symptoms in patients with schizophrenia. D3 receptors may regulate cognition by modulating acetylcholine release and glutamate receptor regulation; partial activation of D3 receptors may improve cognition.

[0003] The 5-hydroxytryptamine 2A receptor (5-HT2A) is a member of the G protein-coupled receptor family and a major excitatory receptor subtype of 5-HT receptors. It is distributed in both the central and peripheral nervous systems and is closely related to mental state, mood, learning, and memory. Highly active 5-HT2A receptor inhibitors have significant antipsychotic effects and can reduce the side effects of extrapyramidal symptoms.

[0004] Schizophrenia is the most prevalent mental illness, characterized by a slow progression and a tendency to relapse, worsen, or deteriorate, placing a heavy burden on patients and their families. Patients with schizophrenia experience positive symptoms such as delusions, hallucinations, and disordered thought, speech, and behavior; negative symptoms such as lack of emotion and expression, impoverished speech, and lack of pleasure; and cognitive impairment. Although significant progress has been made in the research and clinical application of antipsychotic drugs over the past few decades, traditional first-generation antipsychotics (haloperidol, fluperidone, thioridazine, etc.) and atypical second-generation antipsychotics (clozapine, risperidone, olanzapine, aripiprazole, etc.) are effective in treating positive symptoms but less effective in improving negative symptoms and cognitive impairment. Therefore, there is an urgent need to develop antipsychotic drugs that can improve not only positive symptoms but also negative symptoms and cognitive impairment. Highly active dopamine D3 receptor modulators have been shown to improve negative symptoms, positive symptoms, and cognitive impairment in schizophrenia patients without the extrapyramidal tract and weight gain side effects associated with first- and second-generation antipsychotics.

[0005] D3 receptor antagonists or partial agonists have shown good efficacy in improving positive and negative symptoms and cognitive impairment in schizophrenia. International patent applications WO2007093540, WO2009013212A2, WO2010031735A1, and WO2012117001A1 report the effects of D3 receptors and 5HT. 2A Dual regulator compounds, but some of these compounds affect the D3 receptor and 5HT. 2A The binding activity of Ki is mostly above 10 nM; Jiangsu Hengyi's patent WO2014086098A1 reported a selective D3 inhibitor, but not 5HT. 2A The binding activity study; Cariprazine, a D3 antagonist developed by Gedeon Richter, was launched in 2015 and has applied for an international patent WO2005012266A1. Cariprazine has strong D3 receptor agonist activity and has a significant advantage over existing drugs in the treatment of negative symptoms of schizophrenia. However, Cariprazine has weak inhibitory activity on 5-HT2A receptors, resulting in severe extrapyramidal (ESP) side effects. Therefore, there is an urgent need to develop highly active D3 receptor modulators that also have optimized 5-HT2A receptor binding activity. 2A The binding activity is used to reduce extrapyramidal side effects while improving the efficacy against negative symptoms and cognitive improvement in schizophrenia.

[0006] The compound of this invention not only has potent D3 receptor agonist activity, but also exhibits significantly superior 5-HT2A inhibitory activity compared to Cariprazine. Clinically, it is expected to have good therapeutic effects on negative symptoms of schizophrenia and significantly reduce the risk of EPS side effects.

[0007] PCT patent (application number: PCT / CN2020 / 124609) and Chinese patent (application number: CN202080006212.4) disclose the structures of a series of four-membered ring derivative modifiers. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store, have long-term product stability and high bioavailability, this invention has conducted a comprehensive study on the free base crystal forms of the above compounds. Summary of the Invention

[0008] All contents relating to patents PCT / CN2020 / 124609 and CN202080006212.4 are incorporated herein by reference.

[0009] The object of this invention is to provide a crystal form of the compound of general formula (I) or its stereoisomers:

[0010]

[0011] in:

[0012] R a Each is independently selected from hydrogen, deuterium, or C. 1-6 alkyl;

[0013] R1 is selected from hydrogen, deuterium, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy;

[0014] R2 is selected from hydrogen, deuterium, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy;

[0015] Alternatively, R1 and R2, along with their attached carbon atoms, may be linked together to form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group may optionally be further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0016] R3 is selected from hydrogen, deuterium, or C. 1-6 alkyl;

[0017] R4 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 R a -(CH2) n1 C(O)R a -(CH2) n1 C(O)NR a Rb -C(O)(CHR) a ) n1 R b -C(O)NR a (CH2) n1 R b -(CH2) n1 S(O)2R a -(CH2) n1 S(O)2NR a R b Or -(CH2) n1 C(O)OR a The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, C 6-14 aryl and 5-14 heteroaryl groups, optionally further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0018] Alternatively, R3 and R4, along with the nitrogen atom they are attached to, are linked together to form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally further selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0019] R a and R b Each is independently selected from hydrogen, deuterium, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further selected by hydrogen, deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0020] x is 0, 1, 2, or 3;

[0021] n is 0, 1, or 2; and

[0022] n1 can be 0, 1, 2 or 3.

[0023] In a further preferred embodiment of the present invention, the general formula (I) is further shown as in general formula (Ia) or general formula (Ib):

[0024]

[0025] In a further preferred embodiment of the present invention, general formula (I) is further shown as general formula (II):

[0026]

[0027] in:

[0028] R a Selected from hydrogen, deuterium, or C 1-6 Alkyl; preferably hydrogen, deuterium or methyl.

[0029] In a further preferred embodiment of the invention, the general formula (II) is further shown as in general formula (IIa) or general formula (IIb):

[0030]

[0031] R2 is selected from hydrogen, deuterium, halogen, or C. 1-3 Alkyl group; preferably fluorine, chlorine, or bromine;

[0032] Alternatively, R1 and R2, along with the carbon atoms they are attached to, can link together to form a 5-6 member sulfur-containing heteroaryl group;

[0033] Preferably, R1 and R2, along with the carbon atoms they are linked together, form a thiophene group.

[0034] In a further preferred embodiment of the present invention, R3 is selected from hydrogen, deuterium, or C. 1-3 alkyl;

[0035] In a further preferred embodiment of the present invention, the compound or its stereoisomer represented by the above general formula is an acid salt or its crystal form, wherein R3 is selected from hydrogen, deuterium or methyl;

[0036] In a further preferred embodiment of the present invention, R4 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 R a -C(O)R a -C(O)NR a R b -C(O)(CHR) a ) n1 R b -C(O)NR a (CH2) n1 R b -S(O)2R a -S(O)2NR a R b or -C(O)OR a The C mentioned 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further selected from hydrogen, deuterium, cyano, halogen, hydroxyl, C 1-6 Alkyl and C 1-6 One or more substituents in the alkoxy group are substituted;

[0037] Alternatively, R3 and R4 are linked to form a 3-8 membered heterocyclic group or a 5-14 membered heteroaryl group, wherein the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group are optionally further selected from halogen, amino, cyano, hydroxyl, oxo, thio, C 1-6 Alkyl, C3-8 Alkoxy, C 3-8 Halogenated alkoxy groups and C 3-8 One or more substituents in the hydroxyalkyl group are substituted;

[0038] R a and R b Each is independently selected from hydrogen, deuterium, amino, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further selected by halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents of a 5-14 heteroaryl group are substituted; and

[0039] n1 can be 0, 1, 2 or 3.

[0040] In a further preferred embodiment of the present invention, general formula (II) is further shown as in general formula (III):

[0041]

[0042] in:

[0043] R5 is selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 3-8 membered heterocyclic or 5-10 membered heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6Alkoxy and C 1-6 One or more substituents in the hydroxyalkyl group are substituted;

[0044] Preferably, R5 is selected from hydrogen, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 3-8 membered heterocyclic group containing one nitrogen or oxygen atom, or 5-10 membered heteroaryl group containing 1-3 nitrogen, oxygen, or sulfur atoms, wherein the amino group, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 3-8 membered heterocyclic group containing one nitrogen or oxygen atom, or 5-10 membered heteroaryl group containing 1-3 nitrogen, oxygen, or sulfur atoms, optionally further substituted with deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 One or more substituents in the hydroxyalkyl group are substituted;

[0045] More preferably, R5 is selected from hydrogen, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, phenyl, ethylene oxide, cyclothioalkyl, aziridine propane, oxacyclobutane, aziridine, thiobutane, tetrahydrofuranyl, tetrahydrothiopheneyl, furanyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, 1,3,5-triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, benzimidazolyl, indazoleyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, wherein the amino group, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl, phenyl, ethylene oxide, cyclothioalkyl, aziridine propane, oxacyclobutane, aziridine butane, thiobutane, tetrahydrofuranyl, tetrahydrothiopheneyl, furanyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, 1,3,5-triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, benzimidazolyl, inzolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, optionally further oxidized by deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy and C1-3 One or more substituents in the hydroxyalkyl group are substituted;

[0046] More preferably, R5 is selected from the following groups:

[0047] H-, (CH3)2N-, CH3NH-, CH3-, CH3O-, CH3CH2-, CH3CH2NH-, CH3CH2N(CH3)-, (CH3)2C(OH)-, (CH3)2C(OH)CH2-, CH3OCH2-, and

[0048] v is 0 or 1.

[0049] In a further preferred embodiment of the invention, formula (III) is further shown as in formula (IIIa) or formula (IIIb):

[0050]

[0051] In a further preferred embodiment of the present invention, the crystal form of the compound or its stereoisomer represented by general formula (I) is selected from the following compounds:

[0052]

[0053]

[0054]

[0055]

[0056] In a preferred embodiment of the present invention, a crystal form of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (Example 12A) is provided, and the structure of the compound is as follows:

[0057]

[0058] In a further preferred embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A of the N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide exhibits a diffraction peak at 7.1 ± 0.2°; or at 25.8 ± 0.2°; or at 24.3 ± 0.2°; or at 20.0 ± 0.2°; or at 23.5 ± 0.2°. The diffraction peaks are: either at 15.6±0.2°, or at 13.6±0.2°, or at 15.1±0.2°, or at 22.3±0.2°, or at 18.1±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7, or 8 of them.

[0059] Preferably, the X-ray powder diffraction pattern of crystal form A includes at least one or more diffraction peaks located at 2θ of 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, and 20.0±0.2°, preferably two, more preferably three; optionally, it may further include at least one peak at 2θ of 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, and 22.3±0.2°, preferably two, three, four, or five.

[0060] For example, the X-ray powder diffraction pattern of crystal form A shows diffraction peaks at the following positions with a 2θ value:

[0061] At 20.0±0.2° and 23.5±0.2°,

[0062] Alternatively, at 7.1±0.2° and 25.8±0.2°,

[0063] Alternatively, at 7.1±0.2° and 24.3±0.2°,

[0064] Alternatively, at 7.1±0.2°, 25.8±0.2°, and 24.3±0.2°,

[0065] Alternatively, at 7.1±0.2°, 24.3±0.2°, and 22.3±0.2°,

[0066] Alternatively, at 25.8±0.2°, 20.0±0.2°, and 23.5±0.2°,

[0067] Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, and 23.5±0.2°,

[0068] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, and 20.0±0.2°,

[0069] Alternatively, at 7.1±0.2°, 24.3±0.2°, 25.8±0.2°, and 23.5±0.2°,

[0070] Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 15.6±0.2°, and 13.6±0.2°,

[0071] Alternatively, at 7.1±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, and 15.6±0.2°,

[0072] Alternatively, at 7.1±0.2°, 24.3±0.2°, 25.8±0.2°, 23.5±0.2°, and 15.6±0.2°,

[0073] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 15.6±0.2°, and 13.6±0.2°,

[0074] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, and 15.6±0.2°,

[0075] Alternatively, at 7.1±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 13.6±0.2°, and 22.3±0.2°,

[0076] Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 15.6±0.2°, 13.6±0.2°, and 15.1±0.2°,

[0077] Alternatively, at 7.1±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, and 22.3±0.2°;

[0078] More preferably, the X-ray powder diffraction pattern of crystal form A may optionally include one or more diffraction peaks located at 2θ of 18.1±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, 10.4±0.2°, 11.1±0.2°, and 13.1±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0079] For example, the X-ray powder diffraction pattern of crystal form A shows diffraction peaks at the following positions with a 2θ value:

[0080] 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 10.4±0.2°, 11.1±0.2° and 13.1±0.2°,

[0081] Or 7.1±0.2°, 25.8±0.2°, 23.5±0.2°, 15.6±0.2°, 18.1±0.2°, 16.5±0.2°, 26.7±0.2° and 21.2±0.2°,

[0082] Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, and 13.1±0.2°;

[0083] More preferably, the X-ray powder diffraction pattern of crystal form A includes one or more diffraction peaks located at 2θ of 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, 10.4±0.2°, and 11.1±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0084] For example, the X-ray powder diffraction pattern of crystal form A shows diffraction peaks at the following positions with a 2θ value:

[0085] At 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, and 20.0±0.2°,

[0086] Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, and 23.5±0.2°,

[0087] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, and 23.5±0.2°,

[0088] Alternatively, at 24.3±0.2°, 20.0±0.2°, 15.6±0.2°, and 13.6±0.2°,

[0089] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, and 15.6±0.2°,

[0090] Alternatively, at 25.8±0.2°, 24.3±0.2°, 23.5±0.2°, 15.6±0.2°, 15.1±0.2°, and 18.1±0.2°,

[0091] Alternatively, at 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, and 15.1±0.2°,

[0092] Alternatively, at 7.1±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, and 15.1±0.2°,

[0093] Alternatively, at 25.8±0.2°, 24.3±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, and 26.7±0.2°,

[0094] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, and 15.1±0.2°,

[0095] Alternatively, at 7.1±0.2°, 25.8±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, and 18.1±0.2°,

[0096] Alternatively, at 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 15.1±0.2°, 22.3±0.2°, 16.5±0.2°, and 26.7±0.2°,

[0097] Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, and 18.1±0.2°,

[0098] Alternatively, at 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, and 26.7±0.2°,

[0099] Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, and 26.7±0.2°,

[0100] Alternatively, at 7.1±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, and 26.7±0.2°;

[0101] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 1.

[0102] Table 1

[0103]

[0104]

[0105] The crystal form A described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 1 As shown; its DSC spectrum is basically as follows Figure 2 As shown.

[0106] In a further preferred embodiment of the invention, crystal form B of compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (Example 12A) is provided, and its X-ray powder diffraction pattern shows a diffraction peak at 11.3 ± 0.2°; or at 18.7 ± 0.2°; or at 22.5 ± 0.2°; or at 19.3 ± 0.2°; or at 13.9 ± 0.2°. The diffraction peak is present at 28.2 ± 0.2°; or at 24.5 ± 0.2°; or at 13.5 ± 0.2°; or at 21.1 ± 0.2°; or at 17.4 ± 0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 6, 7, or 8 diffraction peaks are included.

[0107] Preferably, the X-ray powder diffraction pattern of crystal form B includes at least one or more diffraction peaks located at 2θ of 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, and 19.3±0.2°, preferably two, more preferably three; optionally, it may further include at least one peak at 2θ of 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, and 21.1±0.2°, preferably two, three, four, or five.

[0108] For example, the X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0109] At 18.7±0.2° and 22.5±0.2°,

[0110] Alternatively, at 11.3±0.2° and 18.7±0.2°,

[0111] Alternatively, at 11.3±0.2° and 13.9±0.2°,

[0112] Alternatively, at 18.7±0.2° and 22.5±0.2°,

[0113] Alternatively, at 11.3±0.2°, 18.7±0.2°, and 22.5±0.2°,

[0114] Alternatively, at 11.3±0.2°, 22.5±0.2°, and 19.3±0.2°,

[0115] Alternatively, at 18.7±0.2°, 22.5±0.2°, and 19.3±0.2°,

[0116] Alternatively, at 22.5±0.2°, 19.3±0.2°, and 13.9±0.2°,

[0117] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, and 19.3±0.2°,

[0118] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, and 28.2±0.2°,

[0119] Alternatively, at 11.3±0.2°, 22.5±0.2°, 19.3±0.2°, and 13.9±0.2°,

[0120] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, and 13.9±0.2°,

[0121] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, and 13.9±0.2°,

[0122] Alternatively, at 11.3±0.2°, 22.5±0.2°, 28.2±0.2°, 24.5±0.2°, and 13.5±0.2°,

[0123] Alternatively, at 11.3±0.2°, 18.7±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°,

[0124] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°,

[0125] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 19.3±0.2°, and 13.9±0.2°,

[0126] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°,

[0127] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°,

[0128] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, and 13.5±0.2°,

[0129] Alternatively, at 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, and 13.5±0.2°,

[0130] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, and 24.5±0.2°,

[0131] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, and 13.5±0.2°,

[0132] Alternatively, at 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, and 21.1±0.2°;

[0133] More preferably, the X-ray powder diffraction pattern of crystal form B optionally includes one or more diffraction peaks located at 2θ of 17.4±0.2°, 24.2±0.2°, 20.1±0.2°, 27.0±0.2°, 5.6±0.2°, 24.8±0.2°, and 15.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0134] For example, the X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0135] At angles of 11.3±0.2°, 18.7±0.2°, 13.9±0.2°, 28.2±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, and 24.2±0.2°,

[0136] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 21.1±0.2°, 24.2±0.2°, and 20.1±0.2°,

[0137] Alternatively, at 18.7±0.2°, 22.5±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°,

[0138] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 17.4±0.2°, 24.2±0.2°, 201±0.2°, and 27.0±0.2°;

[0139] More preferably, the X-ray powder diffraction pattern of crystal form B includes one or more diffraction peaks located at 2θ of 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, 24.2±0.2°, 20.1±0.2°, 27.0±0.2°, 5.6±0.2°, and 24.8±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0140] For example, the X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value:

[0141] At 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, and 22.5±0.2°,

[0142] Alternatively, at 11.3±0.2°, 18.7±0.2°, 28.2±0.2°, and 24.5±0.2°,

[0143] Alternatively, at 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°,

[0144] Alternatively, at 11.3±0.2°, 19.3±0.2°, 28.2±0.2°, and 24.5±0.2°,

[0145] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°,

[0146] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, and 24.5±0.2°,

[0147] Alternatively, at 11.3±0.2°, 18.7±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, and 13.5±0.2°,

[0148] Alternatively, at 18.7±0.2°, 19.3±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°,

[0149] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, and 13.5±0.2°,

[0150] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°,

[0151] Alternatively, at 18.7±0.2°, 22.5±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 24.2±0.2°, and 20.1±0.2°,

[0152] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, and 21.1±0.2°,

[0153] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°,

[0154] Alternatively, at 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, 24.2±0.2°, and 20.1±0.2°,

[0155] Alternatively, at 11.3±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 24.2±0.2°, and 20.1±0.2°,

[0156] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, and 24.2±0.2°,

[0157] Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, 24.2±0.2°, and 20.1±0.2°,

[0158] Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, 27.0±0.2°, 5.6±0.2°, and 24.8±0.2°;

[0159] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 2.

[0160] Table 2

[0161]

[0162] The crystal form B described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 3 As shown; its DSC spectrum is basically as follows Figure 4 As shown; its TGA spectrum is basically as follows. Figure 5 As shown.

[0163] In a further preferred embodiment of the invention, the crystal form C of compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (Example 12A) is provided, and its X-ray powder diffraction pattern shows a diffraction peak at 19.0 ± 0.2°; or at 23.7 ± 0.2°; or at 24.2 ± 0.2°; or at 12.1 ± 0.2°; or at 14.3 ± 0.2°. The diffraction peak is present at 2°; or at 27.2±0.2°; or at 20.0±0.2°; or at 26.8±0.2°; or at 11.8±0.2°; or at 17.4±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks are included; more preferably, any 6, 7, or 8 of the above diffraction peaks are included.

[0164] Preferably, the X-ray powder diffraction pattern of crystal form C includes at least one or more diffraction peaks located at 2θ of 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, and 12.1±0.2°, preferably two, more preferably three; optionally, it may further include at least one peak at 2θ of 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°, preferably two, three, four, or five.

[0165] For example, the X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0166] At 19.0±0.2° and 23.7±0.2°,

[0167] Alternatively, at 12.1±0.2° and 27.2±0.2°,

[0168] Alternatively, at 14.3±0.2° and 20.0±0.2°,

[0169] Alternatively, at 19.0±0.2°, 23.7±0.2°, and 27.2±0.2°,

[0170] Alternatively, at 23.7±0.2°, 24.2±0.2°, and 20.0±0.2°,

[0171] Alternatively, at 24.2±0.2°, 12.1±0.2°, and 11.8±0.2°,

[0172] Alternatively, at 19.0±0.2°, 23.7±0.2°, 14.3±0.2°, and 11.8±0.2°,

[0173] Alternatively, at 19.0±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°,

[0174] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, and 20.0±0.2°,

[0175] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, and 11.8±0.2°,

[0176] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 20.0±0.2°, and 26.8±0.2°,

[0177] Alternatively, at 19.0±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°,

[0178] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°,

[0179] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 26.8±0.2°, and 11.8±0.2°,

[0180] Alternatively, at 19.0±0.2°, 23.7±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°,

[0181] Alternatively, at 23.7±0.2°, 24.2±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°,

[0182] Alternatively, at 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 23.5±0.2°;

[0183] More preferably, the X-ray powder diffraction pattern of crystal form C optionally includes one or more diffraction peaks located at 2θ of 17.4±0.2°, 29.1±0.2°, 22.9±0.2°, 20.5±0.2°, 14.7±0.2°, 18.0±0.2°, and 25.4±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0184] For example, the X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0185] At 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°,

[0186] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°,

[0187] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, and 17.4±0.2°;

[0188] More preferably, the X-ray powder diffraction pattern of crystal form C includes one or more diffraction peaks located at 2θ of 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, 22.9±0.2°, 20.5±0.2°, 14.7±0.2°, and 18.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0189] For example, the X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value:

[0190] At 19.0±0.2°, 23.7±0.2°, 24.2±0.2° and 12.1±0.2°,

[0191] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, and 14.3±0.2°,

[0192] Alternatively, at 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°,

[0193] Alternatively, at 19.0±0.2°, 24.2±0.2°, 14.3±0.2°, and 27.2±0.2°,

[0194] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°,

[0195] Alternatively, at 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°,

[0196] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, and 20.0±0.2°,

[0197] Alternatively, at 19.0±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°,

[0198] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°,

[0199] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°,

[0200] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, and 22.9±0.2°,

[0201] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, and 17.4±0.2°,

[0202] Alternatively, at 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, and 22.9±0.2°,

[0203] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 29.1±0.2°, and 22.9±0.2°,

[0204] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, and 22.9±0.2°,

[0205] Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, and 22.9±0.2°,

[0206] Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 20.5±0.2°, 14.7±0.2°, and 18.0±0.2°;

[0207] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 3.

[0208] Table 3

[0209]

[0210]

[0211] The X-ray powder diffraction pattern of crystal form C described in this invention is basically as follows: Figure 6 As shown; its DSC spectrum is basically as follows Figure 7 As shown; its TGA spectrum is basically as follows. Figure 8 As shown.

[0212] In a further preferred embodiment of the invention, the crystal form D of compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (Example 12A) is provided, and its X-ray powder diffraction pattern shows a diffraction peak at 20.8 ± 0.2°; or at 16.9 ± 0.2°; or at 22.7 ± 0.2°; or at 14.5 ± 0.2°; or at 13.6 ± 0.2°. The diffraction peak is present at 2°; or at 15.8±0.2°; or at 22.3±0.2°; or at 16.2±0.2°; or at 17.9±0.2°; or at 29.4±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 diffraction peaks are included; more preferably, any 6, 7, or 8 diffraction peaks are included.

[0213] Preferably, the X-ray powder diffraction pattern of crystal form D includes at least one or more diffraction peaks located at 2θ of 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, and 14.5±0.2°, preferably two, more preferably three; optionally, it may further include at least one peak at 2θ of 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, and 17.9±0.2°, preferably two, three, four, or five.

[0214] For example, the X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0215] At 16.9±0.2° and 22.7±0.2°,

[0216] Alternatively, at 20.8±0.2° and 13.6±0.2°,

[0217] Alternatively, at 14.5±0.2° and 15.8±0.2°,

[0218] Alternatively, at 16.9±0.2°, 22.7±0.2°, and 13.6±0.2°,

[0219] Alternatively, at 20.8±0.2°, 22.7±0.2°, and 15.8±0.2°,

[0220] Alternatively, at 14.5±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0221] Alternatively, at 16.9±0.2°, 22.7±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0222] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, and 13.6±0.2°,

[0223] Alternatively, at 20.8±0.2°, 14.5±0.2°, 22.7±0.2°, and 15.8±0.2°,

[0224] Alternatively, at 16.9±0.2°, 22.7±0.2°, 13.6±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0225] Alternatively, at 20.8±0.2°, 22.7±0.2°, 13.6±0.2°, 15.8±0.2°, and 22.3±0.2°,

[0226] Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, and 22.3±0.2°,

[0227] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 13.6±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0228] Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0229] Alternatively, at 20.8±0.2°, 22.7±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0230] Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, and 22.3±0.2°,

[0231] Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, and 17.9±0.2°;

[0232] More preferably, the X-ray powder diffraction pattern of crystal form D optionally includes one or more diffraction peaks located at 2θ of 29.4±0.2°, 31.1±0.2°, 17.5±0.2°, 15.0±0.2°, 21.8±0.2°, 16.4±0.2°, and 23.4±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 of these peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks.

[0233] For example, the X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0234] At 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 29.4±0.2°, and 31.1±0.2°,

[0235] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 16.2±0.2°, 29.4±0.2°, and 31.1±0.2°,

[0236] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 16.2±0.2°, 29.4±0.2°, 31.1±0.2°, and 17.5±0.2°;

[0237] More preferably, the X-ray powder diffraction pattern of crystal form D includes one or more diffraction peaks located at 2θ of 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, 31.1±0.2°, 17.5±0.2°, 15.0±0.2°, 21.8±0.2°, and 23.4±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations.

[0238] For example, the X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value:

[0239] At 20.8±0.2°, 16.9±0.2°, 22.7±0.2° and 14.5±0.2°,

[0240] Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, and 15.8±0.2°,

[0241] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, and 15.8±0.2°,

[0242] Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0243] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 15.8±0.2°, and 22.3±0.2°,

[0244] Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, and 22.3±0.2°,

[0245] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0246] Alternatively, at 20.8±0.2°, 16.9±0.2°, 15.8±0.2°, 22.3±0.2°, 31.1±0.2°, and 17.5±0.2°,

[0247] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0248] Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, and 17.9±0.2°,

[0249] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°,

[0250] Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 29.4±0.2°,

[0251] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 29.4±0.2°,

[0252] Alternatively, at 16.9±0.2°, 22.7±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, and 31.1±0.2°,

[0253] Alternatively, at 20.8±0.2°, 16.9±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 31.1±0.2°, and 17.5±0.2°,

[0254] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 29.4±0.2°,

[0255] Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 17.5±0.2°,

[0256] Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, and 17.5±0.2°,

[0257] Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, 31.1±0.2°, and 17.5±0.2°,

[0258] Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, and 31.1±0.2°;

[0259] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 4.

[0260] Table 4

[0261]

[0262]

[0263] The crystal form D of the compound described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 9 As shown.

[0264] In a further preferred embodiment of the present invention, the crystal form of the compound or its stereoisomer represented by general formula (I) is a solvent-containing or solvent-free crystal form, wherein the solvent is selected from one or more of water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, n-heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, or isopropyl ether.

[0265] In a further preferred embodiment of the present invention, the number of solvents is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0266] The present invention also provides a method for preparing the compound of general formula (I) or its stereoisomer crystal form, specifically comprising the following steps:

[0267] 1) Weigh an appropriate amount of the compound and suspend it in a poor solvent; the preferred suspension density is 50–200 mg / mL;

[0268] 2) The suspension obtained above is shaken at a certain temperature for a certain period of time; the preferred temperature is 0-50℃, and the preferred time is 1-10 days;

[0269] 3) Centrifuge the above suspension rapidly, remove the supernatant, and dry to constant weight to obtain the target product;

[0270] in:

[0271] The undesirable solvent is selected from one or more of methanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, methyl tert-butyl ether, n-heptane, benzene, toluene, chlorobenzene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butanol, 2-butanone, or 3-pentanone;

[0272] The preferred materials are one or more of ethyl formate, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dichloromethane, isopropyl acetate, or isopropanol.

[0273] The present invention also provides a method for preparing the compound of general formula (I) or its stereoisomer crystal form, specifically comprising the following steps:

[0274] 1) Weigh out an appropriate amount of free base and dissolve it in a good solvent;

[0275] 2) Add the antisolvent to the solution obtained above at a certain temperature and stir until a solid precipitates. The temperature is selected from 0 to 50°C.

[0276] 3) Centrifuge the above suspension quickly to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50°C until constant weight to obtain the target product;

[0277] in:

[0278] The benign solvent is selected from one or more of methanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, ethanol, 88% acetone, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butanol, 2-butanone, or 3-pentanone;

[0279] Preferably, one or more of dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, or 2-butanone are used;

[0280] The antisolvent is selected from one or more of methanol, ethanol, ethyl acetate, acetone, isopropanol, toluene, n-heptane, water, isopropyl acetate, cyclohexane, methyl tert-butyl ether, or isopropyl ether;

[0281] Preferably, one or more of water, n-heptane, cyclohexane, or methyl tert-butyl ether are used.

[0282] Another object of the present invention is to provide a pharmaceutical composition comprising a crystal form of any of the compounds described above a therapeutically effective dose and their stereoisomers, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0283] The present invention also aims to provide crystal forms of the compounds described above and their stereoisomers, as well as pharmaceutical compositions thereof, in the preparation of G protein-coupled receptor modulators, particularly in the preparation of dopamine D3 receptor and 5-HT2A receptor modulator drugs.

[0284] The present invention also aims to provide the use of the above-described pharmaceutical compositions in the preparation of medicaments for the treatment or prevention of central nervous system diseases and / or mental illnesses or conditions; wherein the nervous system diseases and / or mental illnesses are preferably schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and / or cognitive disorders, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, tinnitus, depression, autism, Alzheimer's disease, epileptic seizures, neuralgia or drug withdrawal symptoms, major depressive disorder, and mania, etc. Attached Figure Description

[0285] Figure 1 XRPD diagram of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form A

[0286] Figure 2 DSC illustration of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form A

[0287] Figure 3 XRPD illustration of the free base crystal form B of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide

[0288] Figure 4 DSC illustration of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B

[0289] Figure 5 TGA illustration of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B

[0290] Figure 6XRPD diagram of the free base crystal form C of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide

[0291] Figure 7 DSC illustration of the free base crystal form C of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide

[0292] Figure 8 TGA illustration of the free base crystal form C of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide

[0293] Figure 9 XRPD diagram of the free base crystal form D of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide Detailed Implementation

[0294] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0295] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, hydroxy-substituted alkyl, and cyano-substituted alkyl.

[0296] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl. The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclic alkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0297] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyl, pyrrolyl, pyrrolidone, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., with oxobutyl, pyrrolidone, tetrahydrofuranyl, pyrrolidone, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring. The heterocyclic group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups.

[0298] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, carboxyl, or carboxylic acid ester group.

[0299] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably oxazolyl, oxadiazole, tetrazolyl, triazolyl, thiophene, imidazolyl, pyridinyl, pyrimidinyl, or thiazolyl; more preferably oxazolyl, oxadiazole, tetrazolyl, triazolyl, thiophene, pyridinyl, thiazolyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0300] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above. Alkoxy groups containing 1 to 8 carbon atoms are preferred, alkoxy groups containing 1 to 6 carbon atoms are more preferred, and alkoxy groups containing 1 to 3 carbon atoms are most preferred. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0301] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0302] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0303] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0304] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0305] "Hydroxy" refers to the -OH group.

[0306] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0307] "Amino" refers to -NH2.

[0308] “Cyano” refers to -CN.

[0309] "Nitro" refers to -NO2.

[0310] "THF" refers to tetrahydrofuran.

[0311] “EtOAc” refers to ethyl acetate.

[0312] "DMSO" refers to dimethyl sulfoxide.

[0313] "LDA" refers to lithium diisopropylamine.

[0314] "DMAP" refers to 4-dimethylaminopyridine.

[0315] “EtMgBr” refers to ethyl magnesium bromide.

[0316] “HOSu” refers to N-hydroxysuccinimide.

[0317] “EDCl” refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0318] "IPA" refers to isopropyl alcohol.

[0319] “MeOH” refers to methanol.

[0320] “EtOH” refers to ethanol.

[0321] "DMF" refers to N,N-dimethylformamide.

[0322] "DIPEA" refers to N,N-diisopropylethylamine.

[0323] “HEPES” refers to 4-hydroxyethylpiperazine ethanesulfonic acid.

[0324] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0325] "Optional" or "optionally" means that the event or situation described below may, but does not have to, occur, and the description includes the circumstances under which the event or situation may or may not occur.

[0326] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0327] "Stereoheterogeneity" includes three categories: geometric heterogeneity (cis-trans heterogeneity), optical heterogeneity, and conformational heterogeneity.

[0328] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0329] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0330] X-ray powder diffraction (XRPD) refers to the experimentally observed diffraction pattern or parameters derived from it, characterized by peak positions (x-axis) and peak intensities (y-axis). Those skilled in the art will understand that experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray diffraction patterns typically change with instrument conditions, and appropriate error tolerances for XRPD can be: 2θ ± 0.5°; 2θ ± 0.4°; 2θ ± 0.3°; 2θ ± 0.2°. It is particularly important to note that the relative intensities of the X-ray diffraction pattern can also vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. Furthermore, the influence of experimental factors such as sample height can cause an overall shift in peak angles, which is generally permissible. Therefore, those skilled in the art will understand that any crystal form with characteristic peaks identical or similar to those of the patterns of this invention falls within the scope of this invention.

[0331] "TGA" refers to thermogravimetric analysis (TGA) experiments.

[0332] "DSC" refers to the Differential Scanning Calorimetry (DSC) experiment.

[0333] "HPLC" refers to High Performance Liquid Chromatography (HPLC) experiments.

[0334] "PK" refers to pharmacokinetic (PK) experiments.

[0335] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0336] I. Preparation of Compounds

[0337] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0338] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0339] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0340] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0341] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0342] compound a

[0343] 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0344]

[0345] Step 1: tert-butyl (3-oxocyclobutyl) carbamate

[0346]

[0347] 3-O-cyclobutylcarboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol), and toluene (30 mL) were added sequentially to a 100 mL round-bottom flask. Diphenyl azidophosphate (4.0 g, 14.5 mmol) was then slowly added at -5 °C to 0 °C. The reaction mixture was stirred at 0 °C for 16 hours. The mixture was washed with saturated sodium bicarbonate aqueous solution (30 mL x 1) and saturated sodium chloride aqueous solution (30 mL x 1) at 0 °C, and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was then added to the organic phase, and the reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain tert-butyl (3-oxocyclobutyl)carbamate (500 mg, yield: 20.5%).

[0348] 1 H NMR (400MHz, CDCl3) δ4.86(s,1H),4.27(s,1H),3.50–3.33(m,2H),3.11–2.97(m,2H),1.46(s,9H).

[0349] Step 2: 2-(3-((tert-butoxycarbonyl)amino)cyclobutylene)methyl acetate

[0350]

[0351] In a 50 mL round-bottom flask, tert-butyl (3-oxocyclobutyl)carbamate (450 mg, 2.43 mmol) and toluene (20 mL) were added sequentially, followed by the slow addition of methoxyformylmethylenetriphenylphosphine (1.22 g, 3.64 mmol). The reaction mixture was refluxed under nitrogen protection for 16 hours, cooled, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 6 / 1) to give methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylene)acetate (450 mg, yield: 76.8%).

[0352] 1 H NMR(400MHz, CDCl3)δ5.76–5.66(m,1H),4.80(br,1H),4.24(s,1H),3.69(s,3H),3.6 3–3.49(m,1H),3.27–3.10(m,1H),3.00–2.86(m,1H),2.82–2.64(m,1H),1.45(s,9H).

[0353] Step 3: 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)methyl acetate

[0354]

[0355] In a 50 mL round-bottom flask, methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylene)acetate (450 mg, 1.9 mmol) and methanol (10 mL) were added sequentially. Under nitrogen protection, palladium on carbon (45 mg, containing 10% palladium and 50% water) was slowly added. The reaction mixture was stirred at hydrogen (1 atm) for 5 hours. The solvent was removed by filtration, and the mixture was evaporated to dryness to obtain crude methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylene)acetate (450 mg), which was used directly in the next step.

[0356] MS m / z(ESI): 244.2 [M+H] + .

[0357] Step 4: (3-(2-hydroxyethyl)cyclobutyl)carbamate tert-butyl ester

[0358]

[0359] In a 50 mL round-bottom flask, methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)acetate (450 mg, 1.9 mmol) and dry tetrahydrofuran (10 mL) were added sequentially. Under nitrogen protection at 0 °C, lithium aluminum hydride (210 mg, 5.6 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 2 hours, then quenched with a saturated sodium bicarbonate solution. Anhydrous sodium sulfate was added directly for drying, and the mixture was stirred for 15 minutes. The organic phase was filtered and evaporated to dryness to obtain crude tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate (450 mg), which was used directly in the next step.

[0360] MS m / z (ESI): 216.2 [M+H] + .

[0361] Step 5: 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonic acid

[0362]

[0363] In a 50 mL round-bottom flask, tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate (450 mg, 2.1 mmol), triethylamine (634 mg, 6.3 mmol), and dichloromethane (10 mL) were added sequentially, followed by the slow addition of 4-toluenesulfonyl chloride (438 mg, 2.3 mmol). The reaction mixture was stirred overnight at room temperature. Dichloromethane (20 mL) was added, and the mixture was washed with water (30 mL x 1). The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to give 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonic acid (710 mg, yield: 84%).

[0364] MS m / z (ESI): 370.2 [M+H] + .

[0365] Step 6: (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)tert-butyl carbamate

[0366]

[0367] In a 50 mL round-bottom flask, 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonic acid (350 mg, 0.95 mmol), potassium carbonate (392 mg, 2.84 mmol), and acetonitrile (10 mL) were added sequentially. Then, 1-(2,3-dichlorophenyl)piperazine (219 mg, 0.95 mmol) was slowly added. The reaction mixture was refluxed overnight. After cooling, dichloromethane (20 mL) was added, followed by washing with water (30 mL x 3). The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 50 / 1) to obtain tert-butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (310 mg, yield: 76%).

[0368] MS m / z (ESI): 428.2 [M+H] + .

[0369] Step 7: 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride

[0370]

[0371] In a 25 mL round-bottom flask, tert-butyl (310 mg, 0.72 mmol) of (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate was added sequentially, followed by ethyl acetate (2 mL). Ethyl hydrochloride solution (10 mL, 4 M) was then added at 0 °C. After stirring the reaction mixture at room temperature for 1 hour, the solvent was removed by rotary evaporation to obtain crude 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (310 mg). The crude product was used directly in the next step.

[0372] MS m / z(ESI): 328.1 [M+H] + .

[0373] Step 8: 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0374]

[0375] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50 mg, 0.11 mmol), triethylamine (69 mg, 0.69 mmol), and dichloromethane (2 mL) were added sequentially to a 10 mL reaction flask. Dimethylcarbamoyl chloride (18.4 mg, 0.17 mmol) was then added with stirring. The reaction mixture was stirred at room temperature for 12 hours, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was separated by preparative HPLC to obtain 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (11 mg, yield: 24%).

[0376] 1 H NMR (400MHz, CDCl3) δ7.23–7.10(m,2H),7.08–6.91(m,1H),4.61–3.93(m,2H) ,3.56–3.02(m,4H),3.03–2.64(m,8H),2.65–2.31(m,3H),2.31–1.21(m,7H).

[0377] MS m / z(ESI): 399.2 [M+H] + .

[0378] Compound b

[0379] 1-Cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea

[0380]

[0381] Step 1: 1-Cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea

[0382]

[0383] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (33 mg, 0.09 mmol), triethylamine (46 mg, 0.45 mmol), and N'N-carbonyldiimidazole (22 mg, 0.16 mmol) were dissolved in dichloromethane (2 mL). After stirring the reaction solution at room temperature for 2 hours, the starting material disappeared. Cyclopropylamine (10 mg, 0.18 mmol) was added, and the reaction solution was stirred at 35 °C for 48 hours. The solvent was evaporated to dryness, and the crude product was separated by preparative HPLC to obtain 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea (12 mg, yield: 32.2%).

[0384] 1 H NMR (400MHz, CDCl3) δ7.20–7.12(m,2H),6.97(dd,J=7.0,2.4Hz,1H),5.08(dd,J=28. 8,7.3Hz,1H),4.64(s,1H),4.43–4.09(m,1H),3.14(s,4H),2.73(s,4H),2.56(ddd,J =16.2,7.4,2.8Hz,2H),2.43(s,3H),2.05(dddd,J=33.4,24.1,16.7,8.5Hz,4H),1.8 3–1.68(m,2H),1.48(dt,J=9.6,6.0Hz,2H),0.76(q,J=6.3Hz,2H),0.61–0.53(m,2H).

[0385] MS m / z(ESI): 411.2 [M+H] + .

[0386] Compound C

[0387] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxamide

[0388]

[0389] Step 1: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxamide

[0390]

[0391] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1H-indole-2-carboxylic acid (30 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol) were added. The reaction was stirred overnight at room temperature. The solvent was evaporated to dryness, and the crude product was separated by high performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxamide.

[0392] MS m / z (ESI): 471.2 [M+H] + .

[0393] compound d

[0394] 3-(3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0395]

[0396] Step 1: tert-butyl(3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutane)carbamate

[0397]

[0398] In a 50 mL round-bottom flask, 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (200 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol), and acetonitrile (10 mL) were added sequentially. Then, 1-(benzo[b]thiophene-4-yl)piperazine (118 mg, 0.54 mmol) was slowly added. The reaction mixture was refluxed overnight. After cooling, dichloromethane (20 mL) was added, followed by washing with water (30 mL x 3). The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 50 / 1) to obtain tert-butyl (3-(2-(4-(benzo[b]thiophene-4-yl)piperazine-1-yl)ethyl)cyclobutane)carbamate (120 mg, yield: 53%).

[0399] MS m / z (ESI): 416.2 [M+H] + .

[0400] Step 2: 3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride

[0401]

[0402] In a 25 mL round-bottom flask, tert-butyl(3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutane)carbamate (120 mg, 0.29 mmol) and ethyl acetate (1 mL) were added sequentially. Then, ethyl acetate hydrochloride solution (6 mL, 4 M) was added at 0 °C. After stirring the reaction mixture at room temperature for 1 hour, the solvent was removed by rotary evaporation to obtain crude hydrochloride (110 mg), which was used directly in the next step.

[0403] MS m / z (ESI): 316.1 [M+H] + .

[0404] Step 3: 3-(3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0405]

[0406] 3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50 mg, 0.12 mmol), triethylamine (71 mg, 0.70 mmol), and dichloromethane (2 mL) were added sequentially to a 10 mL reaction flask, followed by the addition of dimethylcarbamoyl chloride (19 mg, 0.18 mmol) with stirring. The reaction mixture was stirred at room temperature for 12 hours, then evaporated to dryness to remove the solvent, yielding the crude product. The crude product was further separated by preparative HPLC to obtain 3-(3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (17 mg, yield: 37%).

[0407] MS m / z (ESI): 387.2 [M+H] + .

[0408] Example 1

[0409] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carboxamide

[0410]

[0411] Referring to compound a, step 8 yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carboxamide (23 mg, white solid, yield: 28.3%).

[0412] 1 H NMR(400MHz,Chloroform-d)δ7.21–7.12(m,2H),7.01–6.96(m,2H),6.39(dd,J=34 .1,8.0Hz,1H),6.11–6.06(m,1H),4.52(dq,J=84.5,8.0Hz,1H),3.23–3.05(m,4H) ,2.76(s,4H),2.59(td,J=7.4,6.8,2.2Hz,1H),2.48–2.46(m,1H),2.35(s,3H),2. 24–2.13(m,2H),2.04–1.97(m,1H),1.84–1.75(m,2H),1.62(qd,J=9.1,2.8Hz,2H).

[0413] MS m / z (ESI): 436.1 [M+H] + .

[0414] Example 2

[0415] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide

[0416]

[0417] Referring to compound a, step 8 yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide (29 mg, white solid, yield: 33%).

[0418] 1 H NMR(400MHz,Chloroform-d)δ7.19–7.12(m,2H),6.97(dd,J=7.0,2.5Hz,1H),6.63(dd,J =42.2,8.2Hz,1H),4.42(dq,J=87.5,7.9Hz,1H),3.86(d,J=4.7Hz,2H),3.42(d,J=2.5Hz ,3H),3.22–3.06(m,4H),2.81–2.61(m,4H),2.58–2.52(m,1H),2.45–2.32(m,2H),2.21– 2.03(m,2H),2.02–1.91(m,1H),1.79–1.73(m,1H),1.70–1.67(m,1H),1.57–1.49(m,1H).

[0419] MS m / z (ESI): 400.1 [M+H] + .

[0420] Example 3

[0421] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)nicotinamide

[0422]

[0423] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)nicotinamide (25 mg, white solid, yield: 29%).

[0424] 1H NMR(400MHz,Chloroform-d)δ8.97(d,J=2.2Hz,1H),8.72(dd,J=4.8,1.8Hz,1H),8.12(dq, J=8.0,2.0Hz,1H),7.44–7.34(m,1H),7.19–7.12(m,2H),6.97(dt,J=7.0,2.7Hz,1H),6.41 (dd,J=14.4,7.5Hz,1H),4.85–4.34(m,1H),3.12(t,J=5.0Hz,4H),2.78–2.66(m,4H),2.46 –2.39(m,2H),2.27–2.16(m,2H),2.13–2.02(m,1H),1.87–1.79(m,1H),1.79–1.57(m,3H).

[0425] MS m / z(ESI): 433.1 [M+H] + .

[0426] Example 4

[0427] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropionamide

[0428]

[0429] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropionamide (32 mg, white solid, yield: 30%).

[0430] MS m / z (ESI): 414.1 [M+H] + .

[0431] Example 5

[0432] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyacridine-1-carboxamide

[0433]

[0434] Reference compound b yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyacridine-1-carboxamide (22 mg, white solid, yield: 23%).

[0435] 1H NMR(400MHz,Chloroform-d)δ7.18–7.12(m,2H),6.96(dd,J=7.1,2.6Hz,1H),4.41–4.2 2(m,1H),4.21–4.15(m,2H),4.11–4.06(m,2H),3.85–3.78(m,2H),3.29(s,3H),3.16–3. 08(m,4H),2.69(s,4H),2.55–2.49(m,1H),2.42–2.35(m,2H),2.11(ddd,J=11.5,7.3,2 .9Hz,1H),2.04–1.85(m,2H),1.71(dq,J=32.8,7.8Hz,2H),1.44(td,J=9.2,2.9Hz,1H).

[0436] MS m / z(ESI): 441.1 [M+H] + .

[0437] Example 6

[0438] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0439]

[0440] Step 1: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0441]

[0442] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxycyclopropane-1-carboxylic acid (18 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol) were added. The reaction was stirred overnight at room temperature. The solvent was evaporated to dryness, and the crude product was separated by high performance liquid chromatography to give N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide (13 mg, white solid, yield: 21%).

[0443] 1H NMR(400MHz,Chloroform-d)δ7.20–7.12(m,2H),7.07(dd,J=28.3,8.0Hz,1H),6.96(dd,J=7.1,2 .5Hz,1H),4.38(dq,J=87.6,7.9Hz,1H),3.20–3.05(m,4H),2.72(s,4H),2.56(dd,J=8.9,2.9Hz, 1H),2.41(dd,J=9.5,6.3Hz,2H),2.25(d,J=8.4Hz,1H),2.19–2.06(m,2H),1.99(dd,J=14.2,6.4 Hz,1H),1.82–1.69(m,2H),1.55(dd,J=9.1,2.9Hz,1H),1.35–1.30(m,2H),1.01(q,J=4.6Hz,2H).

[0444] MS m / z(ESI): 412.1 [M+H] + .

[0445] Example 6A

[0446] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0447]

[0448] Step 1: N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide urea

[0449]

[0450] Starting with intermediate 1-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide urea was obtained under the reaction conditions of Example 6.

[0451] 1H NMR(400MHz,Chloroform-d)δ7.20–7.13(m,2H),7.07(d,J=8.0Hz,1H),6.97(dd,J=7.0,2.6Hz,1H),4.56–4.44(m,1H),3.22–3.07(m,4H ),2.86–2.66(m,4H),2.50–2.41(m,2H),2.32–2.24(m,1H),2.20–2.05(m,5H),1.84–1.76(m,2H),1.38–1.32(m,2H),1.06–1.00(m,2H).

[0452] MS m / z(ESI): 412.1 [M+H] + .

[0453] Example 6B

[0454] N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0455]

[0456] Step 1: N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide urea

[0457]

[0458] Starting with intermediates 1-2, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide urea was obtained under the reaction conditions of Example 6.

[0459] MS m / z(ESI): 412.1 [M+H] + .

[0460] 1 H NMR(400MHz,Chloroform-d)δ7.24–7.15(m,2H),7.09(d,J=7.8Hz,1H),7.02–6.98(m,1H),4.36–4.25(m,1H),3.33(s,4H),3.18 –2.95(m,3H),2.73–2.65(m,2H),2.63–2.54(m,2H),2.05–1.89(m,4H),1.71–1.59(m,3H),1.36–1.30(m,2H),1.06–1.00(m,2H).

[0461] Example 7

[0462] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide

[0463]

[0464] Step 1: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide

[0465] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), and thiazolyl-2-carboxylic acid (23 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol) were added. The reaction was stirred overnight at room temperature. The solvent was evaporated to dryness, and the crude product was separated by high performance liquid chromatography to give N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazolyl-2-carboxamide (21 mg, white solid, yield: 32%).

[0466] 1 H NMR(400MHz,Chloroform-d)δ7.86(dd,J=3.1,1.5Hz,1H),7.57(d,J=3.1Hz,1H),7.40(dd,J=42.4,8.2Hz,1H),7.20–7.12(m,2H),7.01–6.93(m,1H),4 .73–4.28(m,1H),3.18–3.03(m,4H),2.78–2.54(m,6H),2.44–2.35(m,2H), 2.24–2.19(m,1H),2.10–1.98(m,1H),1.81–1.75(m,1H),1.71–1.65(m,2H).

[0467] MS m / z(ESI): 439.1 [M+H] + .

[0468] Example 7A

[0469] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide

[0470]

[0471] Step 1: N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide

[0472]

[0473] Starting with intermediate 1-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide (21 mg, white solid, yield: 32%) was obtained under the reaction conditions of Example 7.

[0474] 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=3.1Hz,1H),7.57(d,J=3.1Hz,1H),7.45(d,J=8.0Hz,1H),7.21–7.13(m,2H),7.00–6.95(m,1H) ,4.74–4.59(m,1H),3.18–3.02(m,4H),2.79–2.58(m,4H),2.47–2.38(m,2H),2.35–2.27(m,1H),2.25–2.18(m,4H),1.87–1.77(m,2H).

[0475] MS m / z(ESI): 439.1 [M+H] + .

[0476] Example 8

[0477] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-hydroxy-3-methylbutanamide

[0478]

[0479] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-hydroxy-3-methylbutanamide (21 mg, white solid, yield: 20%).

[0480] 1H NMR(400MHz,Chloroform-d)δ7.21–7.13(m,2H),6.96(dd,J=7.0,2.7Hz,1H),6.08(dd ,J=21.6,7.5Hz,1H),4.51–4.19(m,2H),3.10(d,J=6.2Hz,4H),2.76–2.62(m,4H),2.5 6(ddd,J=8.9,5.9,2.7Hz,1H),2.42–2.36(m,2H),2.29(d,J=6.4Hz,2H),2.05–1.96(m ,3H),1.72(dq,J=28.0,7.6Hz,2H),1.51(td,J=9.1,2.8Hz,1H),1.27(d,J=2.2Hz,6H).

[0481] MS m / z (ESI): 428.1 [M+H] + .

[0482] Example 9

[0483] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(5-methyloxazol-2-yl)acetamide

[0484]

[0485] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(5-methyloxazol-2-yl)acetamide (15 mg, white solid, yield: 16%).

[0486] MS m / z (ESI): 451.1 [M+H] + .

[0487] Example 10

[0488] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(3-methylisothiazo-5-yl)acetamide

[0489]

[0490] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(3-methylisothiazo-5-yl)acetamide (26 mg, white solid, yield: 28%).

[0491] MS m / z (ESI): 451.1 [M+H] + .

[0492] Example 11

[0493] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide

[0494]

[0495] Step 1: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide

[0496]

[0497] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (40 mg, 0.11 mmol), triethylamine (44 mg, 0.44 mmol), and cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) were dissolved in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 12 hours, and the solvent was evaporated to dryness. The crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide (15 mg, yield: 31.6%).

[0498] 1 H NMR (400MHz, CDCl3) δ7.20–7.10(m,2H),7.00–6.92(m,1H),4.75–4.60(m,1H),4.14–3.73(m,1H),3.09(s,4H),2.67(s,4H) ,2.62–2.49(m,2H),2.42–2.29(m,3H),2.25–1.89(m,5H),1.79–1.54(m,4H),1.16(d,J=4.8Hz,2H),0.99(q,J=6.8Hz,2H).

[0499] MS m / z(ESI): 432.0 [M+H] + .

[0500] Example 12

[0501] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide

[0502]

[0503] Step 1: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide

[0504]

[0505] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), and oxazol-2-carboxylic acid (20 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol) were added. The reaction was stirred overnight at room temperature. The solvent was evaporated to dryness, and the crude product was separated by high performance liquid chromatography to give N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (13 mg, white solid, yield: 21%).

[0506] 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=1.9Hz,1H),7.24–7.14(m,4H),6.98(m,2.0Hz,1H),4.68–4.59(m,0.4H),4.48–4.38(m,0.7H),3 .26–3.15(m,4H),2.98–2.81(m,3H),2.64–2.56(m,3H),2.22(t,J=7.0Hz,2H),2.07–1.99(m,1H),1.89–1.80(m,2H),1.75–1.67(m,2H).

[0507] MS m / z(ESI): 423.1M+H] + .

[0508] Examples 12A and 12B

[0509] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (12A)

[0510] N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (12B)

[0511]

[0512] Example 12 prepared N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (12A) and N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (12B) by resolution.

[0513] Chiral preparation conditions:

[0514] instrument SFC-80 (Thar, Waters) Column AD 20*250mm, 10um (Daicel) Column pressure 100 bar mobile phase <![CDATA[CO2 / EtOH(1%Methanol Ammonia)=50 / 50]]> Flow rate 80g / min Detection wavelength UV 214nm Column temperature 35℃

[0515] Example 12A: t R =2.473min

[0516] 1 H NMR(400MHz,Chloroform-d)δ7.79(s,1H),7.24–7.20(m,2H),7.17–7.11(m,2H),6.97(dd,J=6.4,3.1Hz,1H),4.69–4.58( m,1H),3.16–3.02(m,4H),2.76–2.58(m,4H),2.41–2.36(m,2H),2.36–2.28(m,1H),2.24–2.17(m,4H),1.82–1.73(m,2H).

[0517] MS m / z(ESI): 423.1M+H] + .

[0518] Example 12B: t R =1.782min

[0519] 1 H NMR(400MHz,Chloroform-d)δ7.79(s,1H),7.22(s,1H),7.19–7.10(m,3H),6.97(dd,J=7.0,2.5Hz,1H),4.49–4.37(m, 1H),3.28–3.03(m,4H),2.84–2.67(m,3H),2.67–2.54(m,3H),2.53–2.35(m,2H),2.15–2.02(m,1H),1.75–1.63(m,4H).

[0520] MS m / z(ESI): 423.1M+H] + .

[0521] Example 13

[0522] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide

[0523]

[0524] Reference compound c yields N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide.

[0525] 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.23–7.09(m,2H),7.05–6.91(m,1H),6.75–6.51(m,1H),4.70–4.33(m ,1H),3.41–3.00(m,4H),2.90–2.54(m,4H),2.54–2.40(m,2H),2.34(s,3H),2.26–2.02(m,3H),1.91–1.58(m,4H).

[0526] MS m / z (ESI): 437.1 [M+H] + .

[0527] Example 13A

[0528] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide

[0529]

[0530] Starting with intermediate 1-1, and referring to the reaction conditions of compound c, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide (13A) (21 mg, white solid, yield: 25%) was obtained.

[0531] 1 H NMR(400MHz,Chloroform-d)δ8.17(s,1H),7.22–7.09(m,2H),7.02–6.90(m,1H),6.71(d,J=7.5Hz,1H),4.69–4.54(m,1H),3. 30–3.00(m,4H),2.86–2.58(m,4H),2.53–2.39(m,2H),2.34(s,3H),2.33–2.27(m,1H),2.26–2.12(m,4H),1.91–1.72(m,2H).

[0532] MS m / z (ESI): 437.1 [M+H] + .

[0533] Example 13B

[0534] N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide

[0535]

[0536] Starting with intermediates 1-2, and referring to the reaction conditions of compound c, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide (35B) was obtained.

[0537] MS m / z (ESI): 437.1 [M+H] + .

[0538] Example 14

[0539] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisothiazolyl-5-carboxamide

[0540]

[0541] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisothiazolyl-5-carboxamide (21 mg, white solid, yield: 32%).

[0542] 1 H NMR(400MHz,Chloroform-d)δ7.21–7.11(m,2H),7.02–6.93(m,1H),6.77–6.57(m,2H),4.69–4.33(m,1H),3.30–3.01 (m,4H),2.89–2.56(m,5H),2.49–2.38(m,2H),2.36(s,3H),2.27–2.15(m,1H),2.10–1.99(m,1H),1.87–1.57(m,4H).

[0543] MS m / z(ESI): 437.0 [M+H] + .

[0544] Example 15

[0545] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-5-carboxamide

[0546]

[0547] Reference compound c yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-5-carboxamide (14 mg, white solid, yield: 22%).

[0548] 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J=1.6Hz,1H),7.21–7.11(m,2H),7.06–6.87(m,2H),6.84–6.77(m,1H),4.70–4.34( m,1H),3.24–3.01(m,4H),2.76–2.57(m,5H),2.46–2.35(m,2H),2.34–2.14(m,2H),2.11–1.99(m,1H),1.83–1.59(m,3H).

[0549] MS m / z(ESI): 423.0 [M+H] + .

[0550] Example 15A

[0551] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-5-carboxamide

[0552]

[0553] Starting with intermediate 1-1, and referring to the reaction conditions of compound c, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-5-carboxamide (37A) (white solid) was obtained.

[0554] 1 H NMR(400MHz,Chloroform-d)δ8.34(d,J=1.8Hz,1H),7.22–7.11(m,2H),6.98(dd,J=6.7,2.9Hz,1H),6.91(d,J=1.9Hz,1H),6.78(d,J=7.6Hz ,1H),4.70–4.57(m,1H),3.28–3.02(m,4H),2.86–2.56(m,4H),2.50– 2.39(m,2H),2.39–2.30(m,1H),2.28–2.14(m,4H),1.88–1.76(m,2H).

[0555] MS m / z(ESI): 423.2 [M+H] + .

[0556] Example 16

[0557] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-5-carboxamide

[0558]

[0559] Reference compound c yields N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-5-carboxamide.

[0560] 1 H NMR (400MHz, CDCl3) δ7.55(s,1H),7.16(dd,J=7.2,4.3Hz,2H),6.96(dd,J=6.6,2.8Hz,1H),6.28(d,J=7.7Hz,1H),4.47–4.32(m,1H),3.09(s,4H), 2.68–2.58(m,7H),2.41–2.33(m,2H),2.18(td,J=20.3,12.2Hz,2H),2.02 (dd,J=15.7,8.3Hz,1H),1.78(dd,J=15.3,7.6Hz,1H),1.71–1.55(m,3H).

[0561] MS m / z (ESI): 437.1 [M+H] + .

[0562] Example 17

[0563] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-3-carboxamide

[0564]

[0565] Reference compound c yields N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-3-carboxamide.

[0566] 1 H NMR(400MHz, CDCl3)δ8.33(d,J=1.7Hz,1H),7.19–7.14(m,2H),7.02–6.93(m,1H),6.91(d,J=1.6Hz,1H),4.48-4.64(m, 1H),3.29-3.11(m,4H),2.79–2.60(m,4H),2.45–2.39(m,2H),2.26-2.22(m,2H),2.05-2.01(m,1H),1.76-1.60(m,4H).

[0567] MS m / z(ESI): 423.1 [M+H] + .

[0568] Example 17A

[0569] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazolyl-3-carboxamide

[0570]

[0571] Starting with intermediate 1-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-3-carboxamide was obtained under the same reaction conditions as compound c.

[0572] 1 H NMR (400MHz, CDCl3) δ8.46(d,J=1.4Hz,1H),7.22-7.17(m,2H),7.00(d,J=6.8Hz,2H),6.81(d,J=1.4Hz,1H),4.64(d d,J=15.1,7.5Hz,1H),3.29(s,4H),2.79-2.77(m,4H),2.36(s,2H),2.24(d,J=7.0Hz,2H),2.01(s,1H),1.60(s,4H).

[0573] MS m / z(ESI): 423.1 [M+H] + .

[0574] Example 18

[0575] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-4-carboxamide

[0576]

[0577] Referring to compound c in Example 1, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-4-carboxamide (white solid) was obtained.

[0578] 1H NMR(400MHz,Chloroform-d)δ8.06(d,J=1.6Hz,1H),7.17–7.13(m,2H),7.05–6.90(m,2H),4.66–4.36(m,1H),3.19–3.05(m,4H),2. 74–2.63(m,3H),2.64–2.53(m,2H),2.50–2.46(m,3H),2.42–2.34(m,2H),2.21–2.13(m,1H),2.08–1.94(m,1H),1.68–1.60(m,4H).

[0579] MS m / z(ESI): 437.1M+H] + .

[0580] Example 18A

[0581] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-4-carboxamide

[0582]

[0583] Starting with intermediate 1-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-4-carboxamide was obtained under the same reaction conditions as compound c.

[0584] 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.20–7.11(m,2H),7.05–6.92(m,2H),4.67–4.54(m,1H),3.1 9–3.06(m,4H),2.76–2.63(m,4H),2.48(s,3H),2.44–2.41(m,2H),2.21–2.11(m,5H),1.84–1.75(m,2H).

[0585] MS m / z(ESI): 437.1M+H] + .

[0586] Example 19

[0587] N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide

[0588]

[0589] Reference compound c was used to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide (35 mg, white solid) in the first step.

[0590] 1 H NMR(400MHz,Chloroform-d)δ8.96(dd,J=4.2,1.7Hz,1H),8.76(d,J=8.7Hz,1H) ,8.25–8.16(m,1H),7.75–7.67(m,2H),7.51–7.45(m,1H),7.16(dd,J=7.0,2.0H z,2H),7.03–6.95(m,1H),6.29–6.15(m,1H),4.84–4.52(m,1H),3.23–3.05(m,4 H),2.80–2.67(m,4H),2.52–2.41(m,2H),2.35–2.04(m,3H),1.70–1.57(m,4H).

[0591] MS m / z(ESI): 483.1M+H] + .

[0592] Example 19A

[0593] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide

[0594]

[0595] Starting with intermediate 1-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide was obtained under the same reaction conditions as compound c.

[0596] 1H NMR(400MHz,Chloroform-d)δ8.96(dd,J=4.3,1.7Hz,1H),8.76(d,J=8.6Hz,1H),8.25–8.14( m,1H),7.69(d,J=5.0Hz,2H),7.47(dd,J=8.6,4.2Hz,1H),7.19–7.14(m,2H),6.98(dd,J=7.2, 2.4Hz,1H),6.29(d,J=7.5Hz,1H),4.84–4.71(m,1H),3.22–3.14(m,4H),2.94–2.88(m,1H),2 .86–2.74(m,4H),2.56–2.50(m,2H),2.32–2.26(m,2H),2.25–2.18(m,2H),1.93–1.84(m,2H).

[0597] MS m / z(ESI): 483.1M+H] + .

[0598] Example 20

[0599] 1-Cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methylurea

[0600]

[0601] Referring to compound a, step 8 yielded 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methylurea (43 mg, white solid, yield: 33%).

[0602] 1 H NMR(400MHz,Chloroform-d)δ7.22–7.11(m,2H),7.03–6.92(m,1H),5.32(dd,J=36 .5,7.6Hz,1H),4.45–4.10(m,1H),3.25–3.02(m,4H),2.88(d,J=1.7Hz,3H),2.82– 2.57(m,4H),2.57–2.51(m,1H),2.47–2.32(m,3H),2.24–2.10(m,1H),2.08–1.90( m,1H),2.06–1.75(m,2H),1.50–1.39(m,1H),0.88–0.78(m,2H),0.75–0.67(m,2H).

[0603] MS m / z (ESI): 425.1 [M+H] +.

[0604] Example 21

[0605] 1-Cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide

[0606]

[0607] The first step of the reaction with reference to compound c yielded 1-cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide (31 mg, white solid).

[0608] 1 H NMR(400MHz,Chloroform-d)δ7.19–7.12(m,2H),7.00–6.94(m,1H),6.56–6.36(m,1H),4.54–4.17(m,1H),3.21–3.02(m,4H),2.79–2.60(m ,4H),2.57–2.53(m,1H),2.43–2.36(m,2H),2.18–2.12(m,1H),2.06– 1.95(m,1H),1.68–1.65(m,3H),1.63–1.56(m,3H),1.51–1.45(m,2H).

[0609] MS m / z(ESI): 421.1M+H] + .

[0610] Example 22

[0611] (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropionamide

[0612]

[0613] Step 1: (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[0614]

[0615] Using 1-bromo-2,3-dichlorobenzene and (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester as starting materials, tert-butyl(R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylic acid ester (600 mg, yellow solid, yield: 32.6%) was obtained from reference compound a in the first step.

[0616] MS m / z (ESI): 345.1 [M+H] + .

[0617] 1 H NMR (400MHz, Chloroform-d) δ7.26–7.21(m,1H),7.21–7.11(m,1H),7.11–6.94(m,1H),3.99–3.00(m,7H),1.49(s,9H),0.91(d,J=6.3Hz,3H).

[0618] Step 2: (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine

[0619]

[0620] Using (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylic acid tertiary ester as the starting material, (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%) was obtained in step 2 from reference compound a.

[0621] MS m / z (ESI): 245.1 [M+H] + .

[0622] 1 H NMR(400MHz,Methanol-d4)δ7.36–7.29(m,1H),7.27–7.16(m,2H),3.60–3.44(m,1 H),3.42–3.27(m,2H),3.21–3.13(m,2H),3.02–2.81(m,2H),0.88(d,J=6.3Hz,3H).

[0623] Step 3: (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutane-1-amine

[0624]

[0625] Referring to steps six and seven of compound a, (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutane-1-amine (280 mg) was obtained.

[0626] MS m / z(ESI): 342.1 [M+H] + .

[0627] Step 4: (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropionamide

[0628]

[0629] (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropionamide (18 mg) was obtained with reference to Example 4.

[0630] 1 H NMR(400MHz,Chloroform-d)δ7.25–7.20(m,1H),7.16(t,J=7.9Hz,1H),7.10–7.04(m,1H),6.91 –6.75(m,1H),4.49–4.14(m,1H),3.47–3.34(m,1H),3.21–3.13(m,1H),2.91–2.82(m,1H),2.83– 2.68(m,2H),2.59–2.48(m,2H),2.38–2.31(m,2H),2.24–2.12(m,2H),2.11–1.93(m,2H),1.82– 1.73(m,1H),1.70–1.65(m,1H),1.56–1.46(m,2H),1.44(d,J=2.4Hz,6H),0.90(d,J=6.2Hz,3H).

[0631] MS m / z (ESI): 428.1 [M+H] + .

[0632] Example 23

[0633] (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-carbamate tert-butyl ester

[0634]

[0635] (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)carbamate tert-butyl ester was obtained with reference to Example 22.

[0636] MS m / z (ESI): 441.3 [M+H] + .

[0637] Example 24

[0638] 3-(3-(2-(4-(benzo[b]thiophene-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea

[0639]

[0640] Using 1-(benzo[b]thiophen-4-yl)piperazine as a starting material, reference compound d yielded 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea.

[0641] 1 H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.0Hz,1H),7.40(d,J=3.7Hz,2H),7.31–7 .26(m,1H),6.90(d,J=7.6Hz,1H),4.54–4.09(m,2H),3.41–3.15(m,6H),2.85(d,J =4.0Hz,3H),2.82–2.63(m,4H),2.59–2.51(m,1H),2.48–2.35(m,2H),2.28–2.07( m,1H),2.07–1.87(m,2H),1.85–1.62(m,2H),1.53–1.40(m,1H),1.22–1.02(m,3H).

[0642] MS m / z (ESI): 401.2 [M+H] + .

[0643] Example 25

[0644] N-(3-(2-(4-(2,3-dichlorophenyl)-1,4-diazoylheptane-1-yl)ethyl)cyclobutyl)furan-2-carboxamide

[0645]

[0646] The synthesis of Example 25 is based on Example 12.

[0647] MS m / z (ESI): 436.2 [M+H] + .

[0648] II. Biological Testing Evaluation

[0649] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0650] I. Radioligand-receptor binding experiment

[0651] Test Example 1: Determination of the binding affinity of the compounds of the present invention to dopamine D3 receptors

[0652] 1. Experimental objective:

[0653] The purpose of this test case is to measure the affinity of the compound for the dopamine D3 receptor.

[0654] 2. Experimental instruments and reagents:

[0655] 2.1 Experimental Apparatus:

[0656] Vortex mixer (IKA; MS3 basic)

[0657] Electric thermostatic incubator (Shanghai Yiheng; DHP-9032)

[0658] Microplate vibrating screen (VWR; 12620-928)

[0659] TopCount(PerkinElmer; NTX)

[0660] Universal Harvester (PerkinElmer; UNIFILTER-96)

[0661] 2.2 Experimental reagents and consumables:

[0662] [ 3 H]-methylspiperone (PerkinElmer; NET856250UC)

[0663] Human Dopamine D3 Receptor membrane (PerkinElmer; ES-173-M400UA)

[0664] GR 103691 (Sigma; 162408-66-4)

[0665] ULTIMA GOLD (Perkin Elmer; 77-16061)

[0666] 96round deep well plate 1.1mL (Perkin Elmer; P-DW-11-C)

[0667] UNIFILTER-96GF / B filter plate (PerkinElmer; 6005174)

[0668] Polyethyleneimine

[0669] branched(Sigma; 408727)

[0670] Centrifuge tubes (BD, 352096; 352070)

[0671] Loading slot(JET BIOFIL;LTT001050)

[0672] Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS)

[0673] Magnesium chloride (Sigma, 7786-30-3)

[0674] Tris-base (Sigma, 77-86-1)

[0675] HCl (Beijing XingJing Precision Chemical Technology CO., LTD).

[0676] 3. Experimental methods:

[0677] Experimental buffer: 50mM Tris-HCl pH 7.4, 10mm MgCl2; Washing buffer: 50mM Tris-HCl pH 7.4, stored at 4℃; 0.5% PEI solution: 0.5g PEI dissolve in 100mL ddH2O, storage of spare at 4℃.

[0678] Add 5 μL of the test compound (0.005 nM-100 nM, 10 concentrations in total) and 100 μL of buffer to each well of a 96-well plate. Add 1 μL of cell membrane and 300 μL of buffer to each well, and vortex at 600 rpm for 5 min. Add 100 μL of buffer and [[] to each well] 3 Add the mixture of H]-methylspiperone (final concentration 0.5 nM) to the reaction system, shake at 600 rpm for 5 min, and incubate at 27 °C for 30 min. Wash the UNIFILTER-96GF / B filter plate, which has been pre-incubated with 0.5% PEI for 1 h, twice with 1 ml / well buffer, add the cell membrane suspension to the UNIFILTER-96GF / B filter plate, wash 4 times, incubate at 55 °C for 10 min, add 40 μL ULTIMA GOLD to each well, and perform liquid scintillation counting.

[0679] 4. Experimental data processing methods:

[0680] CPM (Counts per minute) values ​​were read using TopCount. Percentage inhibition was calculated based on readings from the High control (DMSO control) and Low control (100 nM positive compound) experimental groups. 3 Data on H]-methylspiperone binding {% inhibition rate = (CPM)} sample -CPM low control ) / (CPM high control -CPM low control The concentrations of the compound, after being diluted 3-fold in the reaction system, ranged from 100 nM to 0.005 nM. The IC50 of the compound was calculated using a nonlinear logic formula fitted with the percentage inhibition rate and the ten concentration data points to the parameters using GraphPad Prism. 50 value.

[0681] 5. Experimental Results:

[0682] The D3 binding activity of the compound in this invention was determined by the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 5.

[0683] Table 5. D3 binding activity IC of the compounds in this invention 50

[0684]

[0685] 6. Experimental Conclusion:

[0686] The compound of this invention has a good affinity for dopamine receptor D3.

[0687] Test Example 2: Determination of the binding affinity of the compounds of the present invention to the 5-HT2A receptor

[0688] 1. Experimental objective:

[0689] The purpose of this test case is to measure the affinity of the compound for the 5-HT2A receptor.

[0690] 2. Experimental instruments and reagents:

[0691] 2.1 Instruments:

[0692] Vortex mixer (IKA; MS3 basic)

[0693] Electric thermostatic incubator (Shanghai Yiheng; DHP-9032)

[0694] Microplate vibrating screen (VWR; 12620-928)

[0695] TopCount(PerkinElmer; NTX)

[0696] Universal Harvester (PerkinElmer; UNIFILTER-96)

[0697] 2.2 Experimental reagents and consumables:

[0698] [ 3 H]-Ketanserin (PerkinElmer NET791)

[0699] Human Dopamine 5-HT2A Receptor membrane(PerkinElmer)

[0700] ULTIMA GOLD (Perkin Elmer; 77-16061)

[0701] 96round deep well plate 1.1mL (Perkin Elmer; P-DW-11-C)

[0702] UNIFILTER-96GF / B filter plate (PerkinElmer; 6005174)

[0703] Polyethyleneimine, branched (Sigma; 408727)

[0704] Centrifuge tubes (BD, 352096; 352070)

[0705] Loading slot(JET BIOFIL;LTT001050)

[0706] Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS)

[0707] Magnesium chloride (Sigma, 7786-30-3)

[0708] Calcium chloride (Sigma)

[0709] Tris-base (Sigma, 77-86-1)

[0710] HCl(Beijing XingJing Precision Chemical Technology CO.,LTD)

[0711] L-Ascorbic acid (Tianjin Guangfu)

[0712] 3. Experimental methods:

[0713] Experimental buffer: 50mM Tris-HCl pH 7.4, 4mM CaCl2; Washing buffer: 50mM Tris-HCl pH 7.4, stored at 4℃; 0.5% PEI solution: 0.5g PEI dissolve in 100mL ddH2O, stored at 4℃.

[0714] Add 5 μL of the test compound (0.005 nM-100 nM, 10 concentrations in total) and 100 μL of buffer to each well of a 96-well plate. Add 1.5 μL of cell membrane and 300 μL of buffer to each well. Shake at 600 rpm for 5 min. Add 100 μL of buffer and [[] to each well] 3 Add the [H]-Ketanserin (final concentration 2 nM) mixture to the reaction system, shake at 600 rpm for 5 min, and incubate at 27°C for 30 min. Wash the UNIFILTER-96GF / B filter plate, which has been pre-incubated with 0.5% PEI for 1 h, twice with 1 mL / well buffer, add the cell membrane suspension to the UNIFILTER-96GF / B filter plate, wash 4 times, and incubate at 55°C for 10 min. Add 40 μL of ULTIMA GOLD to each well for liquid scintillation counting.

[0715] 4. Experimental data processing methods:

[0716] The percentage inhibition was calculated based on the CPM (Counts per minute) values ​​read by TopCount, according to the readings of the High control (DMSO control) and Low control (100 nM positive compound) experimental groups. 3 H]-Ketanserin binding data {% inhibition rate = (CPM) sample -CPM low control ) / (CPM high control -CPM low control The concentrations of the compound, after being diluted 3-fold in the reaction system, ranged from 100 nM to 0.005 nM. The IC50 of the compound was calculated using a nonlinear logic formula fitted with the percentage inhibition rate and the ten concentration data points to the parameters using GraphPad Prism. 50 value.

[0717] 5. Experimental Results:

[0718] The binding activity of the compound to 5-HT2A in this invention was determined by the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 6.

[0719] Table 6 IC50 values ​​of the binding affinity of the compounds in this invention to 5-HT2A 50 value

[0720]

[0721] 6. Experimental Conclusion:

[0722] The data above show that the compound of the present invention has a good affinity for 5-HT2A.

[0723] II. Cell Function Experiments

[0724] Test Example 1: Determination of the effect of the compound of the present invention on cAMP levels in cells stably expressing the D3 receptor.

[0725] 1. Experimental objective:

[0726] The activation effect of the compound on the D3 receptor was measured.

[0727] 2. Experimental instruments and reagents:

[0728] 2.1 Instruments:

[0729] 384-well test plate (Perkin Elmer; 6007680);

[0730] 96-well conical btm PP Plt nature RNASE / Dnase-free plate (ThermoFisher; 249944);

[0731] EnVision (Perkin Elmer).

[0732] 2.2 Reagents:

[0733] Fetal Bovine Serum (Gibco, 10999141);

[0734] Ham's F-12K (Kaighn's) Medium (Hyclone; SH30526.01);

[0735] Penicillin-Streptomycin, Liquid (Gibco; 15140122);

[0736] G418(invitrogen;0131-027);

[0737] Forskolin (Selleck, S2449);

[0738] BSA stabilizer (Perkin Elmer; CR84-100);

[0739] cAMP kit (Cisbio; 62AM4PEC);

[0740] IBMX (Sigma; I5879);

[0741] HEPES (Gibco; 15630080);

[0742] HBSS (Gibco; 14025076);

[0743] TrypLE (ThermoFisher; 12604021).

[0744] 3. Experimental methods:

[0745] 1. Buffer preparation: 1*HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX.

[0746] Complete culture medium: Ham's F12K + 10% fetal bovine serum + 1* penicillin-streptomycin + 400μg / mLG418.

[0747] 2. The CHO-D3 cell line was cultured in a complete medium at 37°C and 5% CO2. After TrypLE digestion, the cells were resuspended in the experimental buffer and seeded into 384 cell culture plates at a seeding density of 8000 cells per well.

[0748] 3. Prepare experimental buffer: 1*HBSS, 0.1% BSA, 20mM HEPES, and 500μM IBMX; dilute the compounds with the buffer; add 2.5μL of the compound to each well and incubate at 37℃ for 10 minutes; dilute forskolin to 8μM (8*) with experimental buffer; add 2.5μL of the diluted 8*forskolin and incubate at 37℃ for 30 minutes; freeze-thaw cAMP-d2 and Anti-cAMP-Eu3+, and dilute them 20-fold with lysis buffer; add 10μL of cAMP-d2 to the experimental wells, and then add 10μL of Anti-cAMP-Eu3+ to the experimental wells; centrifuge the reaction plate at 200g for 30s at room temperature, incubate at 25℃ for 1h, and collect data using Envision.

[0749] Experimental data processing methods:

[0750] 1)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin);

[0751] 2)CVMax=(SDMax / MeanMax)*100%;

[0752] 3)CVMin=(SDMin / MeanMin)*100%;

[0753] 4) S / B = Single / Background;

[0754] 5) Calculate compound EC using GraphPad nonlinear fitting formula. 50 :

[0755] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0756] X: Log value of compound concentration; Y: Activation%

[0757] 4. Experimental Results:

[0758] Table 7. Effects of compounds on cAMP levels in EC3 cells stably expressing the D3 receptor. 50 value

[0759] Example number <![CDATA[EC 50 (nM)]]> Caliprazine 1.69 1 3.5 2 2.2 3 1.2 4A 0.4 5 2.4 6 2.9 6A 0.6 7 2.8 7A 1.0 10 1.2 12 1.7 12A 0.6 12B 0.7 13 3.4 13A 1.1 14 1.2 14A 0.9 15 1.7 15A 0.7 16 0.7 16A 1.7 17 3.1 17A 1.1 18 3.9 18A 1.4 19 1.0 19A 1.6 20 1.0 21 3.3 22 0.4 24 0.9

[0760] 5. Experimental Conclusion:

[0761] As can be seen from the data in the table, the compounds in the embodiments of the present invention showed good agonistic activity in the experiment on the effect of stable D3 receptor cells on cAMP.

[0762] Test Example 2: Determination of the effect of the compound of the present invention on calcium ion mobility in cells stably expressing the 5-HT2A receptor.

[0763] 1. Experimental objective:

[0764] The inhibitory effect of the compound on the 5-HT2A receptor was measured.

[0765] 2. Experimental instruments and reagents:

[0766] 2.1 Instruments:

[0767] 384-well test plate (Corning; 3712);

[0768] FLIPR (Molecular Devices).

[0769] 2.2 Reagents:

[0770] DMEM (Invitrogen; 11965);

[0771] Fetal bovine serum (Biowest; S1810-500);

[0772] Dialysis serum (S-FBS-AU-065; Serana);

[0773] Penicillin and streptomycin (Biowest; L0022-100);

[0774] Hygromycin B (CABI℃HEM, 400052);

[0775] Matrigel (BD; 354230);

[0776] DMSO (Sigma; D2650);

[0777] HBSS (Invitrogen; 14065);

[0778] HEPES (Invitrogen; 15630080);

[0779] Probenecid (Sigma; P8761);

[0780] BSA (renview; FA016);

[0781] TrypLE (ThermoFisher; 12604021).

[0782] 3. Experimental methods:

[0783] 1) Buffer preparation: 1x HBSS, 20mM HEPES, 2.5mM probenecid (400mM stock in 1M NaOH), 0.1% BSA. Add probenecid and BSA fresh on the day of the experiment. Experimental buffers include dye buffers and compound dilution buffers, etc.

[0784] 2) Cell culture medium: Ham's F-12K + 10% fetal bovine serum + 600ug / ml hygromycin B + 1* penicillin and streptomycin;

[0785] Inoculation medium: Ham's F-12K + 10% dialyzed serum; Assay buffer: 1x HBSS + 20mM HEPES; Cell line: Flp-In-CHO-5HT2A stable pool.

[0786] 3) Cell lines were cultured in complete medium at 37°C with 5% CO2 until 70%-90% confluence. After digestion with TrypLE, the cells were sputtered at 1×10⁻⁶ ppm. 4 Seed at a density of 1 cell / well in 384-well plates and incubated for 16–24 hours (at least overnight).

[0787] 4) Freeze-thaw 20X Component A to room temperature, dilute it with experimental buffer to a working concentration of 2X containing 5 mM borobenecid, and store at room temperature until use.

[0788] 5) Remove the cell culture plate and let it stand at room temperature for 10 min. Dilute the FBS concentration to 0.03% using Apricot and experimental buffer, leaving 20 μL in the 3764 culture plate. Then add 20 μL of 2X Component A containing 5 mM Probenecid to each well. Centrifuge at 200g for 3-5 seconds at RT and incubate at 37°C for 2 hours.

[0789] 6) Prepare working solutions (6X) of positive control compound and test compound using DMSO.

[0790] 7) Remove the cell culture plate and let it stand at room temperature for 10 minutes; add 10 μL of the 6X compound working solution from step 5 to the corresponding experimental wells of the 384-well cell culture plate and incubate at room temperature for 30 minutes.

[0791] 8) Dilute 5HT to 6 nM (6X) with experimental buffer, transfer 50 μL to a 384-well plate (Corning, 3657), and let it stand at room temperature. Use FLIPR Tetra to add 10 μL of the diluted 5HT to each well and read the values.

[0792] 4. Experimental data processing methods:

[0793] Calcium signal values ​​were read using FLIPR. The calculated output at each sampling time point was the ratio of the 340 / 510nm to the 380 / 510nm wavelength signals. The maximum value minus the minimum value was derived from the ratio signal curve. The IC50 of the compound was calculated using a non-linear logic formula fitted with the percentage inhibition rate and ten concentration data points using GraphPad Prism. 50 value.

[0794] 5. Experimental Results:

[0795] Table 8: IC of the compounds on calcium mobilization in cells stably expressing 5-HT2A receptors 50 value

[0796]

[0797]

[0798] 6. Experimental conclusion:

[0799] It can be seen from the data in the table that the compounds of the examples of the present invention exhibit good inhibitory activity in the functional calcium mobilization assay of cells stably expressing 5-HT2A.

[0800] III. Determination of pharmacokinetics in Balb / C mice

[0801] 1. Research objective:

[0802] Using Balb / C mice as test animals, the pharmacokinetic behavior of the compounds of the examples of the present invention after oral administration at a dose of 5 mg / kg in mice (plasma and brain tissue) was studied.

[0803] 2. Experimental protocol:

[0804] 2.1 Test drugs:

[0805] The compounds of the examples of the present invention, self-prepared.

[0806] 2.2 Experimental animals:

[0807] 12 male Balb / C mice per group, purchased from Shanghai Jiesijie Laboratory Animal Co., Ltd., with animal production license number (SCXK(Hu)2013-0006N0.311620400001794).

[0808] 2.3 Formulation composition:

[0809] 0.5% CMC-Na (1% Tween 80), dissolved by ultrasonication to prepare a clear solution or a homogeneous suspension.

[0810] 2.4 Administration:

[0811] 12 male Balb / C mice per group; after overnight fasting, the animals were administered p.o. at a dose of 5 mg / kg with an administration volume of 10 mL / kg.

[0812] 2.5 Sample collection:

[0813] Mice were euthanized with CO2 at 1, 2, 4, 8 and 24 hours before and after drug administration. 0.2 mL of blood was collected from the heart and placed in an EDTA-K2 tube. The plasma was separated by centrifugation at 6000 rpm for 6 min at 4 °C and stored at -80 °C. The whole brain tissue was removed, weighed, placed in a 2 mL centrifuge tube, and stored at -80 °C.

[0814] 2.6 Sample preparation:

[0815] 1) Add 40uL of plasma sample to 160uL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5-20 minutes.

[0816] 2) Add 30 μL of plasma and brain homogenate samples to 90 μL of acetonitrile containing internal standard (100 ng / mL) for precipitation, mix, and centrifuge at 13000 rpm for 8 minutes.

[0817] 3) Take 70 μL of the supernatant solution after treatment and add 70 μL of water. Vortex mix for 10 minutes. Then take 20 μL for LC / MS / MS analysis of the concentration of the analyte compound. LC / MS / MS analyzer: AB Sciex API4000Qtrap.

[0818] 2.7 Liquid phase analysis:

[0819] • Liquid phase conditions: Shimadzu LC-20AD pump

[0820] • Column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile

[0821] • Flow rate: 0.4 mL / min

[0822] • Elution time: 0-4.0 minutes, eluent as follows:

[0823]

[0824] 3. Experimental Results and Analysis:

[0825] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiment are shown in Table 9 below:

[0826] Table 9: Results of Pharmacokinetic Experiments in Mice

[0827]

[0828]

[0829] 4. Experimental conclusions:

[0830] As can be seen from the results of the mouse pharmacokinetic experiments in the table, the compounds in the embodiments of this invention exhibit good metabolic properties, with low exposure AUC and maximum plasma concentration C. max They all performed well.

[0831] IV. Rat Active Escape Experimental Pharmacodynamic Model

[0832] 1. Experimental Objective

[0833] The antipsychotic effects of compounds were evaluated using a rat active escape experimental pharmacological model.

[0834] 2. Experimental instruments and reagents

[0835] 2.1 Instruments:

[0836] Serial Number Equipment Name Equipment Model source Manufacturers 1 Active and passive shuttle devices MED-APA-D1R import Med Associates, Inc. 2 Thermostatic magnetic stirrer 85-2 Domestic Shanghai Sile Instruments Co., Ltd. 3 vortex generator H-101 Domestic Shanghai Kanghe Optoelectronic Instruments Co., Ltd. 4 ultrasonic cleaner KQ3200DE Domestic Kunshan Ultrasonic Instruments Co., Ltd.

[0837] 2.2 Reagents:

[0838] Serial Number name purity batch number Storage conditions Manufacturers 1 CMC-Na 100％ SLBV9664 RT Sigma 2 Tween 80 100％ BCBV8843 RT Sigma

[0839] 2.3 Test Compounds

[0840] The compounds used in this invention embodiment are self-made.

[0841] 3. Laboratory animals:

[0842] Animal species strain age gender supplier rats F344 6-8 weeks male Beijing Viton Lihua

[0843] 4. Preparation of solvents and compounds:

[0844] 4.1 Solvent (0.5% CMC-Na+1% Tween80)

[0845] Weigh a certain mass (e.g., 1.0 g) of CMC-Na into a glass bottle, add a certain volume (e.g., 200 mL) of purified water, stir to disperse it evenly, add 1% (v / v) of Tween 80 according to the solution volume, stir overnight to obtain a clear and uniform solution, and store at 2-8℃ for later use.

[0846] 4.2 Compound preparation:

[0847] Weigh the prescribed amount of the compound and add it to the prescribed volume of 0.5% CMC-Na + 1% Tween 80 solution. Prepare before administration, store at 2-8℃, and use within 4 days.

[0848] When preparing and administering compound solutions, the actual sample volume must be calculated. The conversion formula is as follows: Actual sample volume of compound = Theoretical sample volume * Purity / Salt coefficient.

[0849] 5. Experimental Procedure:

[0850] After the animals arrive at the experimental facility, they are allowed to acclimatize for a week before the experiment begins.

[0851] 5.1 Establishment of the pharmacodynamic model:

[0852] 5.1.1 Place the animal in the shuttle box and allow it to adapt for 5 seconds before providing 10 seconds of sound and light stimulation;

[0853] 5.1.2 If the animal avoids to the other side after 10 seconds of sound and light stimulation, no electric shock will be given, and this will be recorded as active avoidance, thus ending the single training session;

[0854] 5.1.3 If the animal does not move to the other side after the 10-second sound and light stimulation, an electric shock is given with a current intensity of 0.6mA for 10 seconds. If the animal escapes to the other side within the 10-second electric shock, the electric shock is stopped and recorded as a passive escape, and the single training session ends.

[0855] 5.1.4 If the animal does not dodge within 10 seconds of the electric shock, the electric shock is stopped, recorded as an escape failure, and the training session ends.

[0856] 5.1.5 Each animal is trained 30 times a day. After the training is completed, the animal is put back into its cage. The training lasts for 6 days.

[0857] 5.2 Baseline Testing and Grouping

[0858] The day before the compound screening test, a baseline test is required. The test procedure is the same as 5.1.1 to 5.1.3. The baseline test is conducted 20 times. Animals that actively escape 16 times (80%) are grouped according to the number of active escapes, with 10 animals in each group. The first group is given the solvent orally, and the other groups are given the corresponding test compounds according to the experimental design.

[0859] 5.3 Compound Screening Test

[0860] Administer the medication one hour before the start of the test, orally, at a dose of 5 mL / kg.

[0861] The testing procedure is the same as 5.1.1 to 5.1.4, and the number of tests is 20.

[0862] 6. Data Processing

[0863] The software collects the following data for data analysis:

[0864] The number of times an animal actively avoids something;

[0865] The number of times an animal fails to escape;

[0866] The escape latency of animals in passive escape;

[0867] All measurement data are expressed as mean ± standard error (Mean ± SEM). Statistical analysis was performed using Graphpad 6 software. A p-value < 0.05 was considered statistically significant.

[0868] 7. Experimental Results:

[0869] Table 10

[0870]

[0871] 8. Experimental Conclusions

[0872] The data above show that the compound in the embodiments of the present invention exhibits good efficacy in the rat active escape experimental pharmacological model, indicating that it has an anti-schizophrenic effect.

[0873] III. Crystal Form Study

[0874] 1.1 Experimental Apparatus

[0875] 1.1.1 Some parameters of physicochemical testing instruments

[0876]

[0877] 1. Preparation of different crystal forms

[0878] 1.1 Preparation of Free Base Crystal Form A

[0879] Compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide was prepared and separated by HPLC, and then lyophilized to obtain crystal form A. Analysis showed that it possessed the following properties: Figure 1 The XRPD diagram shown and as follows Figure 2 The DSC diagram shown.

[0880] 1.2 Preparation of Free Base Crystal Form B

[0881] Compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide was subjected to column chromatography (mobile phase: DCM / MeOH = 10:1), and after lyophilization, crystal form B was obtained. Analysis showed that it possessed the following properties: Figure 3 The XRPD diagram shown is as follows: Figure 4 The DSC diagram shown and as follows Figure 5 The TGA diagram shown.

[0882] 1.3 Preparation of Free Base Crystal Form C

[0883] 10 mg of free alkali crystal form B was weighed and added to 100 μL of ethyl formate solvent. The mixture was stirred at 50°C for one week, centrifuged, and vacuum dried at 50°C to constant weight to obtain crystal form C. Analysis showed that it exhibited the following properties: Figure 6 The XRPD diagram shown is as follows: Figure 7 The DSC diagram shown and as follows Figure 8 The TGA diagram shown.

[0884] 1.4 Preparation of Free Base Crystal Form D

[0885] Weigh 10 mg of free alkali crystal form B, add 200 μL of methanol solvent, dissolve at 50°C until clear, and then add 1 mL of isopropyl ether at room temperature to obtain crystal form D. Analysis shows that it has the following properties: Figure 9 The XRPD diagram shown.

[0886] 2. Solid stability experiment

[0887] 2.1 Experimental Objective:

[0888] The physicochemical stability of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B was investigated under the conditions of 5000 lx light, 60 °C high temperature, 92.5% RH high humidity, and 50 °C high temperature and 75% RH high temperature and high humidity, providing a basis for the storage of the compound.

[0889] 2.2 Experimental Scheme:

[0890] Approximately 1 mg of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B was tested for 5 and 10 days under the following conditions: 5000 lx light, 60°C high temperature, 92.5% RH high humidity, and 50°C high temperature and 75% RH high temperature. The content was determined by HPLC using the external standard method, and the changes in related substances were calculated using the chromatographic peak area normalization method.

[0891] Chromatographic conditions:

[0892]

[0893] 2.3 Experimental Results:

[0894] The physicochemical stability results of the free base crystal form B are shown in Table 11:

[0895] Table 11

[0896]

[0897] 2.4 Experimental Conclusions:

[0898] The above data indicate that the total impurities in N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B increased after 10 days of storage under high humidity conditions, and the single impurities increased significantly after 5 days of storage under light conditions; other conditions remained stable. Therefore, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B needs to be sealed and protected from light during subsequent storage.

[0899] 3. Hygroscopicity test

[0900] 3.1 Experimental Objective:

[0901] The hygroscopicity of compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B under different relative humidity conditions was investigated to provide a basis for compound storage. 3.2 Experimental scheme:

[0902] The free base crystal form B of compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide was placed in saturated water vapor with different relative humidities to allow the compound to reach dynamic equilibrium with the water vapor, and the percentage of moisture absorption weight gain of the compound after equilibrium was calculated.

[0903] 3.3 Experimental Results:

[0904] N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B exhibits a moisture absorption weight gain of approximately 0.2079% at 80% RH, indicating slight hygroscopicity. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form B remained unchanged, indicating no crystal form transformation.

[0905] 4. Solubility experiments in different media

[0906] 4.1 Experimental Objective:

[0907] The solubility of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form A in media such as pH 1-8 USP buffer, simulated gastric juice (FaSSGF), fasting simulated intestinal juice (FaSSIF), non-fasting simulated intestinal juice (FeSSIF), and pure water was compared to provide a basis for drugability assessment.

[0908] 4.2 Experimental Procedure:

[0909] Approximately 1.0 mg of N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form A was suspended in different media for 4 hours, and the thermodynamic solubility of the compound at 37 °C was determined by HPLC using the external standard method.

[0910] 4.3 Experimental Results: As shown in Table 12

[0911] Table 12 Solubility of Free Alkali Crystal Form A

[0912] serial number condition Solubility (mg / mL) 1 pH 1 >1 2 pH 2 >1 3 pH 3 0.62 4 pH 4 0.56 5 pH 5 0.89 6 pH 6 0.09 7 pH 7 0.01 8 pH 8 0.00 9 <![CDATA[H2O]]> 0.00 10 FaSSGF >1 11 FaSSIF 0.07 12 FeSSIF 0.81

[0913] 4.4 Experimental Conclusions

[0914] The above results indicate that N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide free base crystal form A has good solubility under acidic conditions.

[0915] 5. Polycrystalline screening and stable crystal form confirmation experiment

[0916] 5.1 Experimental Objective:

[0917] Through polycrystalline screening, relatively stable compound crystal forms were found.

[0918] 5.2 Experimental Procedure:

[0919] Select an organic solvent and water with a certain solubility, suspend the free base crystal form B in the solvent system, stir and slurry at 50°C for 1 week, centrifuge, discard the supernatant, and dry the solid under vacuum at 50°C (-0.1 MPa) overnight. Then, determine the XRPD, DSC and TGA of the solid and compare them.

[0920] 5.3 Experimental Results:

[0921]

[0922]

[0923] 5.4 Experimental Results:

[0924] The free base N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide was slurried, and three crystal forms were obtained by changing the crystallization solvent and crystallization method: crystal form A, crystal form B, and crystal form C. By comparing the DSC spectra of the different amorphous forms, it can be determined that crystal form B is the most thermodynamically stable among these crystal forms.

Claims

1. The crystal form of compound N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide, ， The X-ray powder diffraction pattern of crystal form A shows diffraction peaks including any 6-8 locations from 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, and 18.1±0.2°. The X-ray powder diffraction pattern of crystal form B shows diffraction peaks including any 6-8 locations from 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°. The X-ray powder diffraction pattern of crystal form C shows diffraction peaks including any 6-8 locations from 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, and 17.4±0.2°. The X-ray powder diffraction pattern of crystal form D shows diffraction peaks including any 6-8 locations from 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 29.4±0.2°.

2. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A shows that the diffraction peaks include any 8 locations from 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, and 18.1±0.2°. The X-ray powder diffraction pattern of crystal form B shows that the diffraction peaks include any 8 locations from 1.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°. The X-ray powder diffraction pattern of crystal form C shows that the diffraction peaks include any 8 locations from 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, and 17.4±0.2°. The X-ray powder diffraction pattern of crystal form D shows that the diffraction peaks include any 8 locations from 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 29.4±0.2°.

3. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A shows diffraction peaks at the following positions with a 2θ value: At 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, and 15.6±0.2°, Alternatively, at 7.1±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 13.6±0.2°, and 22.3±0.2°, Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 15.6±0.2°, 13.6±0.2°, and 15.1±0.2°, Alternatively, at 7.1±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, and 22.3±0.2°; The X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value: At 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 19.3±0.2° and 13.9±0.2°, Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°, Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°, Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, and 13.5±0.2°, Alternatively, at 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, and 21.1±0.2°; The X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value: At 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°, Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 26.8±0.2°, and 11.8±0.2°, Alternatively, at 19.0±0.2°, 23.7±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°, Alternatively, at 23.7±0.2°, 24.2±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°, Alternatively, at 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 23.5±0.2°; The X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value: At 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 13.6±0.2°, 22.3±0.2°, and 16.2±0.2°, Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°, Alternatively, at 20.8±0.2°, 22.7±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°, Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, and 22.3±0.2°, Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, and 17.9±0.2°.

4. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A includes any 6-7 diffraction peaks among 18.1±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, 10.4±0.2°, 11.1±0.2°, and 13.1±0.2°. The X-ray powder diffraction pattern of crystal form B includes any 6-7 diffraction peaks among 17.4±0.2°, 24.2±0.2°, 20.1±0.2°, 27.0±0.2°, 5.6±0.2°, 24.8±0.2°, and 15.3±0.2°. The X-ray powder diffraction pattern of crystal form C includes any 6-7 diffraction peaks among 17.4±0.2°, 29.1±0.2°, 22.9±0.2°, 20.5±0.2°, 14.7±0.2°, 18.0±0.2°, and 25.4±0.2°. The X-ray powder diffraction pattern of crystal form D includes any 6-7 diffraction peaks among 29.4±0.2°, 31.1±0.2°, 17.5±0.2°, 15.0±0.2°, 21.8±0.2°, 16.4±0.2°, and 23.4±0.2°.

5. The crystal form according to claim 4, characterized in that, The X-ray powder diffraction pattern of crystal form A contains any 7 diffraction peaks at 18.1±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, 10.4±0.2°, 11.1±0.2° and 13.1±0.2°. The X-ray powder diffraction pattern of crystal form B contains any 7 diffraction peaks from 17.4±0.2°, 24.2±0.2°, 20.1±0.2°, 27.0±0.2°, 5.6±0.2°, 24.8±0.2° and 15.3±0.2°. The X-ray powder diffraction pattern of crystal form C contains any 7 diffraction peaks from 17.4±0.2°, 29.1±0.2°, 22.9±0.2°, 20.5±0.2°, 14.7±0.2°, 18.0±0.2° and 25.4±0.2°. The X-ray powder diffraction pattern of crystal form D contains any 7 diffraction peaks at 29.4±0.2°, 31.1±0.2°, 17.5±0.2°, 15.0±0.2°, 21.8±0.2°, 16.4±0.2°, and 23.4±0.2°.

6. The crystal form according to claim 4, characterized in that, The X-ray powder diffraction pattern of crystal form A shows diffraction peaks at the following positions with a 2θ value: 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 10.4±0.2°, 11.1±0.2° and 13.1±0.2°, Or 7.1±0.2°, 25.8±0.2°, 23.5±0.2°, 15.6±0.2°, 18.1±0.2°, 16.5±0.2°, 26.7±0.2° and 21.2±0.2°, Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, and 13.1±0.2°; The X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value: At angles of 11.3±0.2°, 18.7±0.2°, 13.9±0.2°, 28.2±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, and 24.2±0.2°, Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 21.1±0.2°, 24.2±0.2°, and 20.1±0.2°, Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 17.4±0.2°, 24.2±0.2°, 201±0.2°, and 27.0±0.2°; The X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value: At 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°, Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°, Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, and 17.4±0.2°; The X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value: At 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 29.4±0.2°, and 31.1±0.2°, Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 16.2±0.2°, 29.4±0.2°, and 31.1±0.2°, Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 16.2±0.2°, 29.4±0.2°, 31.1±0.2°, and 17.5±0.2°.

7. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A contains diffraction peak positions at any of 6, 8, or 10 locations selected from 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, 26.7±0.2°, 21.2±0.2°, 10.4±0.2°, and 11.1±0.2°. The X-ray powder diffraction pattern of crystal form B contains diffraction peak positions at any of the following locations: 6, 8, or 10 selected from 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, 24.2±0.2°, 20.1±0.2°, 27.0±0.2°, 5.6±0.2°, and 24.8±0.2°. The X-ray powder diffraction pattern of crystal form C contains diffraction peak positions at any of the following random numbers: 6, 8, or 10, selected from 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, 22.9±0.2°, 20.5±0.2°, 14.7±0.2°, and 18.0±0.2°. The X-ray powder diffraction pattern of crystal form D contains 6, 8, or 10 diffraction peaks selected from 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, 31.1±0.2°, 17.5±0.2°, 15.0±0.2°, 21.8±0.2°, and 23.4±0.2°.

8. The crystal form according to claim 7, characterized in that, The X-ray powder diffraction pattern of crystal form A shows diffraction peaks at the following positions with a 2θ value: At 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, and 15.6±0.2°, Alternatively, at 25.8±0.2°, 24.3±0.2°, 23.5±0.2°, 15.6±0.2°, 15.1±0.2°, and 18.1±0.2°, Alternatively, at 25.8±0.2°, 24.3±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, and 26.7±0.2°, Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, and 15.1±0.2°, Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, and 18.1±0.2°, Alternatively, at 7.1±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, and 26.7±0.2°, Alternatively, at 7.1±0.2°, 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 16.5±0.2°, and 26.7±0.2°, Alternatively, at 25.8±0.2°, 24.3±0.2°, 20.0±0.2°, 23.5±0.2°, 15.6±0.2°, 13.6±0.2°, 15.1±0.2°, 22.3±0.2°, 18.1±0.2°, 21.2±0.2°, 10.4±0.2°, and 11.1±0.2°; The X-ray powder diffraction pattern of crystal form B shows diffraction peaks at the following positions with a 2θ value: At angles of 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, and 28.2±0.2°, Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, and 24.5±0.2°, Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, and 13.5±0.2°, Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, and 21.1±0.2°, Alternatively, at 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, and 17.4±0.2°, Alternatively, at 18.7±0.2°, 22.5±0.2°, 19.3±0.2°, 13.9±0.2°, 28.2±0.2°, 24.5±0.2°, 13.5±0.2°, 21.1±0.2°, 17.4±0.2°, and 24.2±0.2°; The X-ray powder diffraction pattern of crystal form C shows diffraction peaks at the following positions with a 2θ value: At 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, and 27.2±0.2°, Alternatively, at 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°, Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, and 26.8±0.2°, Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, and 17.4±0.2°, Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, and 11.8±0.2°, Alternatively, at 23.7±0.2°, 24.2±0.2°, 12.1±0.2°, 14.3±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 29.1±0.2°, and 22.9±0.2°, Alternatively, at 19.0±0.2°, 23.7±0.2°, 24.2±0.2°, 27.2±0.2°, 20.0±0.2°, 26.8±0.2°, 11.8±0.2°, 17.4±0.2°, 29.1±0.2°, and 22.9±0.2°; The X-ray powder diffraction pattern of crystal form D shows diffraction peaks at the following positions with a 2θ value: At 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, and 15.8±0.2°, Alternatively, at 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°, Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, and 16.2±0.2°, Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, and 17.9±0.2°, Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, and 29.4±0.2°, Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, and 31.1±0.2°; Alternatively, at 20.8±0.2°, 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, 31.1±0.2°, and 17.5±0.2°; Alternatively, at 16.9±0.2°, 22.7±0.2°, 14.5±0.2°, 13.6±0.2°, 15.8±0.2°, 22.3±0.2°, 16.2±0.2°, 17.9±0.2°, 29.4±0.2°, 31.1±0.2°, 21.8±0.2°, and 23.4±0.2°.

9. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A is basically shown in Figure 1, or its DSC pattern is basically shown in Figure 2. The X-ray powder diffraction pattern of crystal form B is basically shown in Figure 3, or its DSC pattern is basically shown in Figure 4, or its TGA pattern is basically shown in Figure 5. The X-ray powder diffraction pattern of crystal form C is basically shown in Figure 6, or its DSC pattern is basically shown in Figure 7, or its TGA pattern is basically shown in Figure 8. The X-ray powder diffraction pattern of crystal form D is shown in Figure 9.

10. A method for preparing the crystal form according to any one of claims 1-9, specifically comprising the following steps: 1) Weigh an appropriate amount of the compound, suspend it in a poor solvent, and shake it. 2) The above suspension is rapidly centrifuged to remove the supernatant and dried to obtain the target product; Alternatively, the specific steps include the following: 1) Weigh out an appropriate amount of free base and dissolve it in a good solvent. 2) Add the antisolvent to the solution obtained above and stir until a solid precipitates. 3) Centrifuge the above suspension rapidly, remove the supernatant, and dry to obtain the target product; in, The unsuitable solvent is selected from one or more of ethyl acetate or ethyl formate; The good solvent is selected from one or more of methanol, ethanol, dichloromethane, isopropanol, n-butanol, isobutanol, n-propanol, or tert-butanol; The antisolvent is isopropyl ether.

11. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1 to 9 of the crystal form, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. The crystal form according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 11, in the preparation of a G protein-coupled receptor modulator drug.

13. The application according to claim 12, characterized in that, G protein-coupled receptors are dopamine D3 receptor and 5-HT2A receptor.

14. Use of the crystal form according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for treating or preventing diseases of the central nervous system and / or mental illnesses or conditions.

15. The use according to claim 14, characterized in that, Central nervous system diseases and / or mental illnesses or conditions include schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory impairment and / or cognitive impairment, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, tinnitus, depression, autism, Alzheimer's disease, seizures, neuralgia or withdrawal symptoms, major depressive disorder and mania.

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