CN115246801A

CN115246801A - Free base crystal form containing piperazine polycyclic derivative and preparation method and application thereof

Info

Publication number: CN115246801A
Application number: CN202210385499.7A
Authority: CN
Inventors: 陈金瑶; 李媛媛
Original assignee: Shanghai Hansoh Biomedical Co Ltd
Current assignee: Shanghai Hansoh Biomedical Co Ltd
Priority date: 2021-04-28
Filing date: 2022-04-13
Publication date: 2022-10-28

Abstract

The invention relates to a free alkali crystal form containing piperazine polycyclic derivatives, and a preparation method and application thereof. In particular to a crystal form of a compound shown in a general formula (I) and a stereoisomer free alkali thereof, a preparation method, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and application of the crystal form as a G protein-coupled receptor regulator in treating or preventing central nervous system diseases and/or mental diseases.

Description

Free base crystal form containing piperazine polycyclic derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of biological medicines, and particularly relates to a free alkali crystal form containing piperazine polycyclic derivatives, and a preparation method and application thereof.

Background

Dopamine D3 receptor is a member of the G-protein coupled receptor family, a subtype of dopamine receptor, and is a D2-like inhibitory receptor that belongs to the same family as dopamine D2 and D4 receptors and, upon binding to DA, reduces cAMP levels by inhibiting G-protein. D3 receptors are mainly distributed in the mesolimbic system, especially nucleus accumbens, olfactory tubercles and calleja islands, which are not involved in motor function, and highly active D3 receptor modulators may have very good anti-schizophrenic activity. The D3 receptor has close relationship with emotion, cognition, spirit, addiction and the like, and can better improve the negative symptoms of the schizophrenia patient. The D3 receptor may play a role in regulating cognition by regulating the release of acetylcholine and regulating a glutamate receptor, and partial activation of the D3 receptor plays a role in improving cognition.

The 5-hydroxytryptamine 2A receptor (5-HT 2A) receptor is a member of G protein coupled receptor family, is a main excitatory receptor subtype of 5-HT receptor, has distribution in the center and periphery, is closely related to spirit, emotion, learning, memory and the like, and the high-activity 5-HT2A receptor inhibitor has obvious effect of resisting schizophrenia and can reduce the side effect of extrapyramidal tract.

Schizophrenia is the most prevalent psychosis, has a slow course, is prone to repeated attacks, exacerbations or exacerbations, and causes severe burden and adverse consequences to patients and their families. The mental patients can have positive symptoms such as delusions, hallucinations, thought language and behavior disorder and the like, negative symptoms such as no emotion and expression, poor speech, lack of pleasure and the like and symptoms such as cognitive disorder and the like. Although the development and clinical application of anti-schizophrenia drugs have been greatly developed in the past decades, the conventional antipsychotics (first generation) (haloperidol, methiopyridazine, etc.) and atypical antipsychotics (second generation) (clozapine, risperidone, olanzapine, aripiprazole, etc.) are both effective in treating positive symptoms, and are not ideal in improving negative symptoms and cognitive disorders, so that there is an urgent need to develop anti-schizophrenia drugs that can improve not only positive symptoms but also negative symptoms and cognitive disorders. The high-activity dopamine D3 receptor regulator has an improvement effect on negative symptoms, positive symptoms and cognitive disorder of schizophrenia patients, and has no side effects of extrapyramidal tract and weight gain of first-generation and second-generation anti-mental drugs.

The D3 receptor antagonist or partial agonist has good curative effect on improving positive symptoms and negative symptoms of schizophrenia and cognitive dysfunction. International applications WO2007093540, WO2009013212A2, WO2010031735A1 and WO2012117001A1 report D3 receptors and 5HT _2A Dual modulator compounds, but wherein the compounds are at the D3 receptor and 5HT _2A Most of the binding activity Ki of (2) is above 10 nM; hengsu Hengyi patent WO2014086098A1 reports D3 selective inhibitors, but 5HT does not exist _2A The binding activity of (4); a D3 antagonist Cariprazine developed by Gedeon Richter corporation is marketed in 2015, and an international patent WO2005012266A1 is applied, the Cariprazine has stronger D3 receptor agonist activity, and has a remarkable advantage over the existing drugs for treating negative symptoms, but the Cariprazine has weaker inhibitory activity on a 5-HT2A receptor, so that the Cariprazine has more serious Extrapyramidal (ESP) side effects, and therefore, the development of a D3 receptor modulator with high activity and optimized 5HT is urgently needed _2A To reduce extrapyramidal side effects while enhancing the effects on negative symptoms of schizophrenia and cognitive improvement.

The compound not only has strong D3 receptor agonism activity, but also has 5-HT2A inhibition activity which is obviously superior to that of Cariprazine, and has good treatment effects on negative symptoms of schizophrenia and the like and can obviously reduce the occurrence risk of EPS side effects in clinical prediction.

PCT patent (application number: PCT/CN 2020/124609) and Chinese patent (application number: CN 202080006212.4) disclose structures of a series of quadricyclic derivative regulators, and in subsequent research and development, in order to facilitate the processing, filtration and drying of products, and seek suitable crystals which are convenient to store, stable for a long time and high in bioavailability, the invention comprehensively researches free base crystal forms of the compounds.

Disclosure of Invention

All references to patents PCT/CN2020/124609 and CN202080006212.4 are hereby incorporated by reference.

The invention aims to provide a crystal form of a compound shown as a general formula (I) or a stereoisomer thereof:

wherein:

R ^a each independently selected from hydrogen, deuterium or C _1-6 An alkyl group;

R ₁ selected from hydrogen, deuterium, cyano, halogen, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl or C _1-6 An alkoxy group;

R ₂ selected from hydrogen, deuterium, cyano, halogen, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl or C _1-6 An alkoxy group;

or, R ₁ And R ₂ And the carbon atoms to which they are attached are linked together to form a 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

R ₃ selected from hydrogen, deuterium or C _1-6 An alkyl group;

R ₄ selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl, 5-14 membered heteroaryl, - (CH) ₂ ) _n1 R _a 、-(CH ₂ ) _n1 C(O)R _a 、-(CH ₂ ) _n1 C(O)NR _a R _b 、-C(O)(CHR _a ) _n1 R _b 、-C(O)NR _a (CH ₂ ) _n1 R _b 、-(CH ₂ ) _n1 S(O) ₂ R _a 、-(CH ₂ ) _n1 S(O) ₂ NR _a R _b Or- (CH) ₂ ) _n1 C(O)OR _a The amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

or, R ₃ And R ₄ And the nitrogen atom to which they are attached are linked together to form a 3-6 membered heterocyclyl or 5-6 membered heteroaryl, said 3-6 membered heterocyclyl and 5-6 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

R _a and R _b Each independently selected from hydrogen, deuterium, amino, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroAryl, said amino, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further selected from hydrogen, deuterium, halogen, hydroxy, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

x is 0, 1,2 or 3;

n is 0, 1 or 2; and is

n1 is 0, 1,2 or 3.

In a further preferred embodiment of the present invention, said general formula (I) is further represented by general formula (Ia) or general formula (Ib):

in a further preferred embodiment of the present invention, the general formula (I) is further represented by general formula (II):

wherein:

R ^a selected from hydrogen, deuterium or C _1-6 An alkyl group; hydrogen, deuterium or methyl are preferred.

In a further preferred embodiment of the present invention, said general formula (II) is further represented by general formula (IIa) or general formula (IIb):

R ₂ selected from hydrogen, deuterium, halogen or C _1-3 An alkyl group; preferably fluorine, chlorine or bromine;

or, R ₁ And R ₂ And the carbon atoms to which they are attached are linked together to form a 5-6 membered sulfur-containing heteroaryl;

preferably R ₁ And R ₂ And the carbon atoms to which they are attached are linked together to form a thienyl group.

In a further preferred embodiment of the invention, R is ₃ Selected from hydrogen, deuterium or C _1-3 An alkyl group;

in a further preferred embodiment of the present invention, the acid salt of the compound represented by the above general formula or a stereoisomer thereof, or a crystal form thereof, the R ₃ Selected from hydrogen, deuterium or methyl;

in a further preferred embodiment of the invention, R is ₄ Selected from hydrogen, deuterium, C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 R _a 、-C(O)R _a 、-C(O)NR _a R _b 、-C(O)(CHR _a ) _n1 R _b 、-C(O)NR _a (CH ₂ ) _n1 R _b 、-S(O) ₂ R _a 、-S(O) ₂ NR _a R _b OR-C (O) OR _a Said C is _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, cyano, halogen, hydroxy, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy;

or, R ₃ And R ₄ Linked to form a 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said 3-8 membered heterocyclyl and 5-10 membered heteroaryl being optionally further selected from halogen, amino, cyano, hydroxy, oxo, thio, C _1-6 Alkyl radical, C _3-8 Alkoxy radical, C _3-8 Haloalkoxy and C _3-8 Substituted with one or more substituents in hydroxyalkyl;

R _a and R _b Each independently selected from hydrogen, deuterium, amino, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further selected from halogen, hydroxy, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl; and is

n1 is 0, 1,2 or 3.

In a further preferred embodiment of the present invention, formula (II) is further represented by formula (III):

wherein:

R ₅ selected from hydrogen, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclic group or 5-10 membered heteroaryl, said amino group, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 Substituted with one or more substituents in hydroxyalkyl;

preferably, R ₅ Selected from hydrogen, amino, C _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl containing one nitrogen or oxygen atom or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, said amino, C _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl radical, C _6-10 Aryl radicals a,3-8 membered heterocyclyl containing one nitrogen or oxygen atom or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally further substituted by deuterium, halogen, hydroxy, cyano, oxo, C _1-3 Alkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents in hydroxyalkyl;

more preferably, R ₅ Selected from hydrogen, amino, C _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl, phenyl, oxiranyl, thienylalkyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, said amino, C.C.sub.Cxft 5363-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl, phenyl, oxiranyl, thienylalkyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, optionally further deuterium, halogen, hydroxy, cyano, oxo, C _1-3 Alkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents in hydroxyalkyl;

further preferably, R ₅ Selected from the following groups:

H-、(CH ₃ ) ₂ N-、CH ₃ NH-、CH ₃ -、CH ₃ O-、CH ₃ CH ₂ -、CH ₃ CH ₂ NH-、CH ₃ CH ₂ N(CH ₃ )-、(CH ₃ ) ₂ C(OH)-、(CH ₃ ) ₂ C(OH)CH ₂ -、CH ₃ OCH ₂ -、

and is provided with

v is 0 or 1.

In a further preferred embodiment of the present invention, the formula (III) is further represented by formula (IIIa) or formula (IIIb):

in a further preferred embodiment of the present invention, said crystalline form of the compound of formula (I) or a stereoisomer thereof is selected from the following compounds:

in a preferred embodiment of the invention, there is provided a crystalline form of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (example 12A) having the structure:

in a further preferred embodiment of the invention, said N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide has crystalline form a, an X-ray powder diffraction pattern having a diffraction peak at 7.1 ± 0.2 °; or a diffraction peak at 25.8 ± 0.2 °; or a diffraction peak at 24.3 ± 0.2 °; or a diffraction peak at 20.0 ± 0.2 °; or a diffraction peak at 23.5 ± 0.2 °; or a diffraction peak at 15.6 ± 0.2 °; or a diffraction peak at 13.6 ± 0.2 °; or a diffraction peak at 15.1 ± 0.2 °; or a diffraction peak at 22.3 ± 0.2 °; or a diffraction peak at 18.1 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

preferably, form a has an X-ray powder diffraction pattern comprising at least one or more diffraction peaks, preferably 2, more preferably 3, located at 2 Θ at 7.1 ± 0.2 °,25.8 ± 0.2 °,24.3 ± 0.2 ° and 20.0 ± 0.2 °; optionally, the compound further comprises at least one position with 2 theta of 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees and 22.3 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions,

for example, the X-ray powder diffraction pattern of form a has diffraction peaks at the following positions 2 θ:

at 20.0 +/-0.2 degrees and 23.5 +/-0.2 degrees,

or at 7.1 +/-0.2 degrees and 25.8 +/-0.2 degrees,

or at 7.1 +/-0.2 degrees and 24.3 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg. and 24.3 + -0.2 deg.,

or at 7.1 +/-0.2 degrees, 24.3 +/-0.2 degrees and 22.3 +/-0.2 degrees,

or 25.8 +/-0.2 degrees, 20.0 +/-0.2 degrees and 23.5 +/-0.2 degrees,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees and 23.5 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg. and 20.0 + -0.2 deg.,

or at 7.1 + -0.2 deg., 24.3 + -0.2 deg., 25.8 + -0.2 deg. and 23.5 + -0.2 deg.,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 15.6 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg. and 15.6 + -0.2 deg.,

or at 7.1 + -0.2 deg., 24.3 + -0.2 deg., 25.8 + -0.2 deg., 23.5 + -0.2 deg. and 15.6 + -0.2 deg.,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 15.6 + -0.2 deg. and 13.6 + -0.2 deg.,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg. and 15.6 + -0.2 deg.,

or at 7.1 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 13.6 + -0.2 deg. and 22.3 + -0.2 deg.,

or 25.8 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg., and 15.1 + -0.2 deg.,

or at 7.1 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg. and 22.3 + -0.2 deg.;

more preferably, the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 2 Θ 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 at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any of 2,3, 4, 5, 6, 7,

for example, form a has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

7.1 +/-0.2 degrees, 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.1 +/-0.2 degrees and 13.1 +/-0.2 degrees,

or 7.1 +/-0.2 degrees, 25.8 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 18.1 +/-0.2 degrees, 16.5 +/-0.2 degrees, 26.7 +/-0.2 degrees and 21.2 +/-0.2 degrees,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.5 +/-0.2 degrees, 26.7 +/-0.2 degrees, 21.2 +/-0.2 degrees and 13.1 +/-0.2 degrees;

further preferably, the X-ray powder diffraction pattern of form a comprises diffraction peaks at one or more of positions with 2 θ 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, the compound comprises diffraction peaks at 4, 5, 6, 8 and 10;

at 7.1 +/-0.2 degrees, 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees and 20.0 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg. and 23.5 + -0.2 deg.,

or 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 15.6 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.1 +/-0.2 degrees and 18.1 +/-0.2 degrees,

or 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees and 15.1 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg. and 15.1 + -0.2 deg.,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 22.3 +/-0.2 degrees, 18.1 +/-0.2 degrees and 26.7 +/-0.2 degrees,

or at the positions of 7.1 +/-0.2 degrees, 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees and 15.1 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg., 15.1 + -0.2 deg., 22.3 + -0.2 deg. and 18.1 + -0.2 deg.,

or 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.5 +/-0.2 degrees and 26.7 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg., 15.1 + -0.2 deg., 22.3 + -0.2 deg., and 18.1 + -0.2 deg.,

or 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 22.3 +/-0.2 degrees, 18.1 +/-0.2 degrees, 16.5 +/-0.2 degrees and 26.7 +/-0.2 degrees,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 22.3 +/-0.2 degrees, 18.1 +/-0.2 degrees, 16.5 +/-0.2 degrees and 26.7 +/-0.2 degrees,

or 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 °;

characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 1.

TABLE 1

The X-ray powder diffraction pattern of the crystal form A is basically shown in figure 1; the DSC pattern is basically shown in figure 2.

In a further preferred embodiment of the invention, there is provided crystalline form B of the compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (example 12A) having a diffraction peak at 11.3 ± 0.2 ° in an X-ray powder diffraction pattern; or a diffraction peak at 18.7 ± 0.2 °; or a diffraction peak at 22.5 ± 0.2 °; or a diffraction peak at 19.3 ± 0.2; or a diffraction peak at 13.9 ± 0.2 °; or a diffraction peak at 28.2 ± 0.2 °; or a diffraction peak at 24.5 ± 0.2 °; or a diffraction peak at 13.5 ± 0.2 °; or a diffraction peak at 21.1 ± 0.2 °; or a diffraction peak at 17.4 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

preferably, form B has an X-ray powder diffraction pattern comprising at least one or more diffraction peaks, preferably 2, more preferably 3, located at 2 Θ at 11.3 ± 0.2 °,18.7 ± 0.2 °,22.5 ± 0.2 ° and 19.3 ± 0.2 °; optionally, the compound further comprises at least one position with 2 theta of 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees and 21.1 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions,

for example, form B has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

at 18.7 +/-0.2 degrees and 22.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees and 18.7 +/-0.2 degrees,

or 11.3 +/-0.2 degrees and 13.9 +/-0.2 degrees,

or 18.7 +/-0.2 degrees and 22.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees and 22.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 22.5 +/-0.2 degrees and 19.3 +/-0.2 degrees,

or at 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees and 19.3 +/-0.2 degrees,

or at 22.5 + -0.2 deg., 19.3 + -0.2 deg. and 13.9 + -0.2 deg.,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees and 19.3 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees and 28.2 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees and 13.9 +/-0.2 degrees,

or 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees and 13.9 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees and 13.9 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 22.5 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees and 13.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees and 28.2 +/-0.2 degrees,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg. and 28.2 + -0.2 deg.,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees and 28.2 +/-0.2 degrees,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg. and 13.5 + -0.2 deg.,

or 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees and 13.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees and 24.5 +/-0.2 degrees,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 24.5 + -0.2 deg. and 13.5 + -0.2 deg.,

or 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees and 21.1 +/-0.2 degrees;

more preferably, the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 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 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any of 2,3, 4, 5, 6, 7,

for example, the X-ray powder diffraction pattern of form B has diffraction peaks at the following positions 2 θ:

11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 17.4 +/-0.2 degrees and 24.2 +/-0.2 degrees,

or 11.3 + -0.2 deg., 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 21.1 + -0.2 deg., 24.2 + -0.2 deg., and 20.1 + -0.2 deg.,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 24.5 + -0.2 deg., 13.5 + -0.2 deg., 21.1 + -0.2 deg. and 17.4 + -0.2 deg.,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 17.4 +/-0.2 degrees, 24.2 +/-0.2 degrees, 201 +/-0.2 degrees and 27.0 +/-0.2 degrees;

further preferably, the X-ray powder diffraction pattern of form B comprises diffraction peaks at one or more 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 ° of 2 Θ; preferably, the compound comprises diffraction peaks at 4, 5, 6, 8 and 10;

at 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees and 22.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 28.2 +/-0.2 degrees and 24.5 +/-0.2 degrees,

or 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees and 28.2 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 19.3 +/-0.2 degrees, 28.2 +/-0.2 degrees and 24.5 +/-0.2 degrees,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg. and 24.5 + -0.2 deg.,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees and 13.5 +/-0.2 degrees,

or 18.7 +/-0.2 degrees, 19.3 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees and 17.4 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees and 13.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees and 17.4 +/-0.2 degrees,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 24.5 + -0.2 deg., 13.5 + -0.2 deg., 24.2 + -0.2 deg., and 20.1 + -0.2 deg.,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 24.5 + -0.2 deg., 13.5 + -0.2 deg., and 21.1 + -0.2 deg.,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees and 17.4 +/-0.2 degrees,

or 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 17.4 +/-0.2 degrees, 24.2 +/-0.2 degrees and 20.1 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 24.2 +/-0.2 degrees and 20.1 +/-0.2 degrees,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 24.5 + -0.2 deg., 13.5 + -0.2 deg., 21.1 + -0.2 deg., 17.4 + -0.2 deg. and 24.2 + -0.2 deg.,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees, 19.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 28.2 +/-0.2 degrees, 24.5 +/-0.2 degrees, 13.5 +/-0.2 degrees, 21.1 +/-0.2 degrees, 17.4 +/-0.2 degrees, 24.2 +/-0.2 degrees and 20.1 +/-0.2 degrees,

or 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 °;

characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 2.

TABLE 2

The X-ray powder diffraction pattern of the crystal form B is basically shown in figure 3; the DSC pattern is basically shown in figure 4; the TGA profile is substantially as shown in FIG. 5.

In a further preferred embodiment of the present invention, there is provided crystalline form C of the compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (example 12A) having a diffraction peak at 19.0 ± 0.2 ° X-ray powder diffraction pattern; or a diffraction peak at 23.7 ± 0.2 °; or a diffraction peak at 24.2 ± 0.2 °; or a diffraction peak at 12.1 ± 0.2 °; or a diffraction peak at 14.3 ± 0.2 °; or a diffraction peak at 27.2 ± 0.2 °; or a diffraction peak at 20.0 ± 0.2 °; or a diffraction peak at 26.8 ± 0.2 °; or a diffraction peak at 11.8 ± 0.2 °; or a diffraction peak at 17.4 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

preferably, form C has an X-ray powder diffraction pattern comprising at least one or more diffraction peaks, preferably 2 thereof, more preferably 3 thereof, located at 2 Θ at 19.0 ± 0.2 °,23.7 ± 0.2 °,24.2 ± 0.2 ° and 12.1 ± 0.2 °; optionally, the compound further comprises at least one position with 2 theta of 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees and 11.8 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions,

for example, form C has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

19.0 +/-0.2 degrees and 23.7 +/-0.2 degrees,

or 12.1 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or, at 14.3 + -0.2 deg. and 20.0 + -0.2 deg.,

or at 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or at 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 20.0 +/-0.2 degrees,

or at 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees and 11.8 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 14.3 +/-0.2 degrees and 11.8 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or at 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees and 20.0 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees and 11.8 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 12.1 + -0.2 deg., 20.0 + -0.2 deg. and 26.8 + -0.2 deg.,

or 19.0 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 12.1 + -0.2 deg., 14.3 + -0.2 deg., 26.8 + -0.2 deg. and 11.8 + -0.2 deg.,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees and 26.8 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 27.2 + -0.2 deg., 20.0 + -0.2 deg., 26.8 + -0.2 deg. and 11.8 + -0.2 deg.,

or 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees and 23.5 +/-0.2 degrees;

more preferably, the X-ray powder diffraction pattern of form C optionally further comprises one or more diffraction peaks at 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 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4, 5, 6, 7,

19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees and 26.8 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees and 11.8 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 11.8 +/-0.2 degrees and 17.4 +/-0.2 degrees;

further preferably, the X-ray powder diffraction pattern of form C comprises diffraction peaks at one or more 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 ° of 2 Θ; preferably, the compound comprises diffraction peaks at 4, 5, 6, 8 and 10;

19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees and 12.1 +/-0.2 degrees,

or at 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees and 14.3 +/-0.2 degrees,

or 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 24.2 +/-0.2 degrees, 14.3 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees and 26.8 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 12.1 + -0.2 deg., 14.3 + -0.2 deg., 27.2 + -0.2 deg. and 20.0 + -0.2 deg.,

or 19.0 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees and 26.8 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees and 26.8 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 12.1 + -0.2 deg., 14.3 + -0.2 deg., 27.2 + -0.2 deg., 20.0 + -0.2 deg., 26.8 + -0.2 deg. and 11.8 + -0.2 deg.,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 29.1 +/-0.2 degrees and 22.9 +/-0.2 degrees,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 11.8 +/-0.2 degrees and 17.4 +/-0.2 degrees,

or 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees, 14.3 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 29.1 +/-0.2 degrees and 22.9 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 12.1 + -0.2 deg., 14.3 + -0.2 deg., 27.2 + -0.2 deg., 20.0 + -0.2 deg., 26.8 + -0.2 deg., 11.8 + -0.2 deg., 29.1 + -0.2 deg. and 22.9 + -0.2 deg.,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 29.1 +/-0.2 degrees and 22.9 +/-0.2 degrees,

or 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 °;

characteristic diffraction peaks of X-rays expressed in terms of 2. Theta. Angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 3.

TABLE 3

The X-ray powder diffraction pattern of the crystal form C is basically shown in figure 6; the DSC pattern is basically shown in figure 7; the TGA profile is substantially as shown in figure 8.

In a further preferred embodiment of the invention, there is provided crystalline form D of the compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (example 12A) having a diffraction peak at 20.8 ± 0.2 ° in an X-ray powder diffraction pattern; or a diffraction peak at 16.9 ± 0.2 °; or a diffraction peak at 22.7 ± 0.2 °; or a diffraction peak at 14.5 ± 0.2 °; or a diffraction peak at 13.6 ± 0.2 °; or a diffraction peak at 15.8 ± 0.2 °; or a diffraction peak at 22.3 ± 0.2 °; or a diffraction peak at 16.2 ± 0.2 °; or a diffraction peak at 17.9 ± 0.2 °; or a diffraction peak at 29.4 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

preferably, form D has an X-ray powder diffraction pattern comprising at least one or more diffraction peaks, preferably 2, more preferably 3, located at 2 Θ at 20.8 ± 0.2 °,16.9 ± 0.2 °,22.7 ± 0.2 ° and 14.5 ± 0.2 °; optionally, the compound further comprises at least one position with 2 theta of 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees and 17.9 +/-0.2 degrees, preferably comprises 2,3, 4 or 5 positions,

for example, form D has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:

16.9 +/-0.2 degrees and 22.7 +/-0.2 degrees,

or 20.8 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or, at 14.5 + -0.2 deg. and 15.8 + -0.2 deg.,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 22.7 +/-0.2 degrees and 15.8 +/-0.2 degrees,

or at 14.5 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 14.5 +/-0.2 degrees, 22.7 +/-0.2 degrees and 15.8 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 13.6 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 22.7 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees and 22.3 +/-0.2 degrees,

or 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees and 22.3 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 13.6 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 22.7 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees and 22.3 +/-0.2 degrees,

or 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees and 17.9 +/-0.2 degrees;

more preferably, the X-ray powder diffraction pattern of form D optionally further comprises one or more 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 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4, 5, 6, 7,

20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 29.4 +/-0.2 degrees and 31.1 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.2 +/-0.2 degrees, 29.4 +/-0.2 degrees and 31.1 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 31.1 +/-0.2 degrees and 17.5 +/-0.2 degrees;

further preferably, the X-ray powder diffraction pattern of form D comprises diffraction peaks at one or more 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 ° of 2 Θ; preferably, the compound comprises diffraction peaks at 4, 5, 6, 8 and 10;

20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees and 14.5 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees and 15.8 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees and 15.8 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.8 +/-0.2 degrees and 22.3 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 31.1 +/-0.2 degrees and 17.5 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees and 17.9 +/-0.2 degrees,

or 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees and 29.4 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees and 29.4 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 29.4 +/-0.2 degrees and 31.1 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 31.1 +/-0.2 degrees and 17.5 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees and 29.4 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees and 17.5 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 29.4 +/-0.2 degrees and 17.5 +/-0.2 degrees,

or 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 29.4 +/-0.2 degrees, 31.1 +/-0.2 degrees and 17.5 +/-0.2 degrees,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 29.4 +/-0.2 degrees and 31.1 +/-0.2 degrees;

characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K alpha radiation are shown in Table 4.

TABLE 4

The X-ray powder diffraction pattern of the crystal form D of the compound is basically shown as figure 9.

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

In a further preferred embodiment of the invention, the number of solvents is from 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.

The invention also provides a method for preparing the compound shown in the general formula (I) or the stereoisomer crystal form thereof, which comprises the following steps:

1) Weighing a proper amount of compound, and suspending with a poor solvent; the suspension density is preferably 50-200 mg/mL;

2) Shaking the obtained suspension for a certain time at a certain temperature; the temperature is preferably 0-50 ℃, and the time is preferably 1-10 days;

3) Quickly centrifuging the suspension, removing supernatant, and drying to constant weight to obtain a target product;

wherein:

the adverse 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-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-propanol, ethyl formate, isopropyl acetate, tert-butanol, 2-butanone or 3-pentanone;

preferably one or more of ethyl formate, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dichloromethane, isopropyl acetate or isopropanol.

1) Weighing a proper amount of free alkali, and dissolving the free alkali in a good solvent;

2) Adding an anti-solvent into the obtained solution at a certain temperature, and stirring until a solid is separated out, wherein the temperature is selected from 0-50 ℃;

3) Quickly centrifuging the suspension, removing supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain a target product;

wherein:

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

preferably one or more of dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetonitrile or 2-butanone;

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;

one or more of water, n-heptane, cyclohexane or methyl tert-butyl ether are preferred.

It is also an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the above and crystalline forms of its stereoisomers, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also aims to provide application of the compound, the crystal form of the stereoisomer thereof and the pharmaceutical composition thereof in preparing G protein-coupled receptor modulators, in particular in preparing medicines of dopamine D3 receptors and 5-HT2A receptor modulators.

The invention also aims to provide the application of the pharmaceutical composition in preparing medicines for treating or preventing central nervous system diseases and/or mental diseases or symptoms; the nervous system disease and/or mental disease is preferably diseases such as schizophrenia, sleep disorder, mood disorder, schizophrenia spectrum disorder, spastic disorder, memory disorder and/or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus, depression, autism, senile dementia, alzheimer's disease, epileptic seizure, neuralgia or drug withdrawal symptom major depression and mania.

Drawings

FIG. 1 is a graphic representation of the XRPD of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form A

FIG. 2 is a DSC representation of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form A

FIG. 3 is a graphic representation of the XRPD of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form B

FIG. 4 is a DSC representation of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form B

FIG. 5 is a TGA representation of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form B

FIG. 6 is a graphic representation of the XRPD of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form C

FIG. 7 is a DSC representation of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form C

FIG. 8 is a TGA representation of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form C

FIG. 9 is a graphic representation of the XRPD of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form D

Detailed Description

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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, 4924-and the like, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, hydroxy-substituted alkyl and cyano-substituted alkyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl. The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the rings. The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl and the like, preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferred are oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, pyridyl, thiazolyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more 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 carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Alkoxy groups having 1 to 8 carbon atoms are preferred, alkoxy groups having 1 to 6 carbon atoms are more preferred, and alkoxy groups having 1 to 3 carbon atoms are most preferred. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"DMSO" refers to dimethyl sulfoxide.

"LDA" refers to lithium diisopropylamide.

"DMAP" refers to 4-dimethylaminopyridine.

"EtMgBr" refers to ethyl magnesium bromide.

"HOSu" refers to N-hydroxysuccinimide.

"EDCl" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

"IPA" refers to isopropanol.

"MeOH" refers to methanol.

"EtOH" refers to ethanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to N, N-diisopropylethylamine.

"HEPES" means 4-hydroxyethylpiperazine ethanesulfonic acid.

Different terms such as "X is A, B, or C", "X is A, B and C", "X is A, B or C", "X is A, B and C" all express the same meaning, i.e. X can be any one or more of A, B, C.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"stereoisomerism" encompasses the three classes geometric isomerism (cis-trans isomerism), optical isomerism and conformational isomerism.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

X-ray powder diffraction pattern (XRPD), which refers to the experimentally observed diffraction pattern or a parameter derived therefrom, is characterized by peak position (abscissa) and peak intensity (ordinate). Those skilled in the art will appreciate that the experimental error therein will depend on the conditions of the instrument, the sample preparation and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns will generally vary with the conditions of the instrument, and those skilled in the art will appreciate that a suitable error tolerance for XRPD may be: 2 theta +/-0.5 degrees; 2 theta +/-0.4 degrees; 2 theta +/-0.3 degrees; 2 theta +/-0.2 deg. It is particularly noted that the relative intensities of the X-ray diffraction patterns may also vary with the experimental conditions, so that the order of the peak intensities cannot be considered as the sole or determining factor. In addition, due to the influence of experimental factors such as sample height, an overall shift in peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that any crystalline form having the same or similar characteristic peaks as the present profile is within the scope of the present invention.

"TGA" refers to a thermogravimetric analysis (TGA) experiment.

"DSC" refers to a Differential Scanning Calorimetry (DSC) experiment.

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

"PK" refers to Pharmacokinetic (PK) experiments.

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

1. Preparation of the Compounds

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) Internal standard is Tetramethylsilane (TMS).

Agilent 1200 for measuring LC-MS (liquid chromatography-mass spectrometry) by using chromatographyInfinity Series mass spectrometer. HPLC was measured using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C) ₁₈ 150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by a thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.

Compound a

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

The first step is as follows: tert-butyl (3-oxocyclobutyl) carbamate

3-Oxocyclobutanecarboxylic acid (1.5g, 13.2mmol), triethylamine (2.0mL, 14.5mmol) and toluene (30 mL) were sequentially added to a 100mL eggplant-shaped bottle, and diphenyl phosphorazidate (4.0g, 14.5mmol) was slowly added thereto at-5 ℃ to 0 ℃. The reaction solution was stirred at 0 ℃ for 16 hours. At 0 ℃, the organic phase was washed with saturated aqueous sodium bicarbonate (30 mLx 1), saturated aqueous sodium chloride (30 mLx 1) and dried over anhydrous sodium sulfate. Then, t-butanol (7.5mL, 74.8mmol) was added to the organic phase, and the reaction mixture was heated to 100 ℃ and stirred for 16 hours. And (4) spin-drying the post-reaction liquid to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to give tert-butyl (3-oxocyclobutyl) carbamate (500 mg, yield: 20.5%).

¹ H NMR(400MHz,CDCl ₃ )δ4.86(s,1H),4.27(s,1H),3.50–3.33(m,2H),3.11–2.97(m,2H),1.46(s,9H).

The second step is that: 2- (3- ((tert-Butoxycarbonyl) amino) cyclobutyl) acetic acid methyl ester

To a 50mL eggplant-shaped bottle were added (3-oxocyclobutyl) tert-butyl carbamate (450mg, 2.43mmol) and toluene (20 mL) in this order, and then slowly added methoxycarbonylmethylenetriphenylphosphine (1.22g, 3.64mmol). And refluxing the reaction liquid for 16 hours under the protection of nitrogen, cooling the reaction liquid, and spin-drying to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 6/1) to give methyl 2- (3- ((tert-butoxycarbonyl) amino) cyclobutylidene) acetate (450 mg, yield: 76.8%).

¹ H NMR(400MHz,CDCl ₃ )δ5.76–5.66(m,1H),4.80(br,1H),4.24(s,1H),3.69(s,3H),3.63–3.49(m,1H),3.27–3.10(m,1H),3.00–2.86(m,1H),2.82–2.64(m,1H),1.45(s,9H).

The third step: 2- (3- ((tert-Butoxycarbonyl) amino) cyclobutyl) acetic acid methyl ester

Methyl 2- (3- ((tert-butoxycarbonyl) amino) cyclobutylidene) acetate (450mg, 1.9mmol) and methanol (10 mL) were added sequentially in a 50mL eggplant-shaped bottle, and palladium on carbon (45 mg, 10% palladium and 50% water) was slowly added under nitrogen. The reaction was stirred under hydrogen (1 atm) for 5 hours, filtered to remove the solvent and spin-dried to give crude methyl 2- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) acetate (450 mg) which was used directly in the next step.

MS m/z(ESI):244.2[M+H] ⁺ .

The fourth step: (3- (2-hydroxyethyl) cyclobutyl) carbamic acid tert-butyl ester

A50 mL eggplant-shaped bottle was charged with methyl 2- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) acetate (450mg, 1.9 mmol) and dried tetrahydrofuran (10 mL) in that order, and lithium aluminum hydride (210mg, 5.6 mmol) was slowly added thereto at 0 ℃ under a nitrogen atmosphere. After the reaction mixture was stirred at 0 ℃ for 2 hours, it was quenched with a saturated aqueous solution of sodium hydrogencarbonate, dried by directly adding anhydrous sodium sulfate, and stirred for 15 minutes. The organic phase was filtered and spin dried to give crude tert-butyl (3- (2-hydroxyethyl) cyclobutyl) carbamate (450 mg) which was used directly in the next step.

MS m/z(ESI):216.2[M+H] ⁺ .

The fifth step: 4-Methylbenzenesulfonic acid 2- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) ethyl ester

To a 50mL eggplant-shaped bottle were added tert-butyl (3- (2-hydroxyethyl) cyclobutyl) carbamate (450mg, 2.1mmol), triethylamine (634mg, 6.3mmol) and dichloromethane (10 mL) in this order, and 4-toluenesulfonyl chloride (438mg, 2.3mmol) was slowly added. The reaction mixture was stirred at room temperature overnight, dichloromethane (20 mL) was added to the reaction mixture, washed with water (30 mLx 1), the organic phase was dried and spun dry to give 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-methylbenzenesulfonate (710 mg, yield: 84%).

MS m/z(ESI):370.2[M+H] ⁺ .

And a sixth step: (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) carbamic acid tert-butyl ester

A50 mL round bottom flask was charged with 2- (3- ((tert-butoxycarbonyl) amino) cyclobutyl 4-methylbenzenesulfonate (350mg, 0.95mmol), potassium carbonate (392mg, 2.84mmol) and acetonitrile (10 mL) in that order, and 1- (2,3-dichlorophenyl) piperazine (219mg, 0.95mmol) was added slowly. The reaction was refluxed overnight. The reaction was cooled, dichloromethane (20 mL) was added, washed with water (30 mLx 3), the organic phase was dried and spun-dried to give the crude product. The crude product was purified by column chromatography (dichloromethane/methanol: 50/1) to give (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) carbamic acid tert-butyl ester (310 mg, yield: 76%).

MS m/z(ESI):428.2[M+H] ⁺ .

The seventh step: 3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride

To a 25mL round bottom flask were added tert-butyl (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) carbamate (310mg, 0.72mmol) and ethyl acetate (2 mL) in this order, and to the mixture was added ethyl acetate hydrochloride solution (10mL, 4M) at 0 ℃. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed by spin-drying to obtain crude 3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride (310 mg), which was used directly in the next step.

MS m/z(ESI):328.1[M+H] ⁺ .

Eighth step: 3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1,1-dimethylurea

To a 10mL reaction flask were added 3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride (50mg, 0.11mmol), triethylamine (69mg, 0.69mmol), and dichloromethane (2 mL) in that order, and dimethylcarbamoyl chloride (18.4mg, 0.17mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, the solvent was removed by spin-drying to obtain a crude product. The crude product was isolated by preparative HPLC to give 3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1,1-dimethylurea (11 mg, yield: 24%).

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):399.2[M+H] ⁺ .

Compound b

1-cyclopropyl-3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) urea

The first step is as follows: 1-cyclopropyl-3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) urea

3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride (33mg, 0.09mmol), triethylamine (46mg, 0.45mmol) and N' N-carbonyldiimidazole (22mg, 0.16mmol) were dissolved in dichloromethane (2 mL). After the reaction mixture was stirred at room temperature for 2 hours, the starting material was removed, cyclopropylamine (10mg, 0.18mmol) was added, and the reaction mixture was stirred at 35 ℃ for 48 hours. The solvent was spun dry and the crude product was isolated by preparative HPLC to give 1-cyclopropyl-3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) urea (12 mg, yield: 32.2%).

¹ H NMR(400MHz,CDCl ₃ )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),1.83–1.68(m,2H),1.48(dt,J＝9.6,6.0Hz,2H),0.76(q,J＝6.3Hz,2H),0.61–0.53(m,2H).

MS m/z(ESI):411.2[M+H] ⁺ .

Compound c

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

The first step is as follows: n- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1H-indole-2-carboxamide

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

MS m/z(ESI):471.2[M+H] ⁺ .

Compound d

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

The first step is as follows: tert-butyl (3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutane) carbamate

2- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) ethyl 4-methylbenzenesulfonate (200mg, 0.54mmol), potassium carbonate (224mg, 1.62mmol) and acetonitrile (10 mL) were added successively to a 50mL eggplant-shaped bottle, and 1- (benzo [ b ] thiophen-4-yl) piperazine (118mg, 0.54mmol) was slowly added. The reaction was refluxed overnight. The reaction was cooled, dichloromethane (20 mL) was added, washed with water (30 mLx 3), the organic phase was dried and spun-dried to give the crude product. The crude product was purified by column chromatography (dichloromethane/methanol: 50/1) to give tert-butyl (3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutane) carbamate (120 mg, yield: 53%).

MS m/z(ESI):416.2[M+H] ⁺ .

The second step is that: 3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride

To a 25mL eggplant-shaped bottle were added tert-butyl (3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutane) carbamate (120mg, 0.29mmol) and ethyl acetate (1 mL) in this order, and to the solution at 0 ℃ was added ethyl acetate hydrochloride (6 mL, 4M). After the reaction was stirred at room temperature for 1 hour, the solvent was removed by rotary drying to give a crude hydrochloride (110 mg) which was used directly in the next step.

MS m/z(ESI):316.1[M+H] ⁺ .

The third step: 3- (3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutyl) -1,1-dimethylurea

A10 mL reaction flask was charged with 3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride (50mg, 0.12mmol), triethylamine (71mg, 0.70mmol) and dichloromethane (2 mL) in this order, and dimethylformamide (19mg, 0.18mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, the solvent was removed by spin-drying to obtain a crude product. The crude product was isolated by preparative HPLC to give 3- (3- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) cyclobutyl) -1,1-dimethylurea (17 mg, yield: 37%).

MS m/z(ESI):387.2[M+H] ⁺ .

Example 1

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

The eighth step of reference compound a gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -5-methylfuran-2-carboxamide (23 mg, white solid, yield: 28.3%).

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).

MS m/z(ESI):436.1[M+H] ⁺ .

Example 2

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

The eighth step of reference Compound a gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-methoxyacetamide (29 mg, white solid, yield: 33%).

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).

MS m/z(ESI):400.1[M+H] ⁺ .

Example 3

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

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

¹ H 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).

MS m/z(ESI):433.1[M+H] ⁺ .

Example 4

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-hydroxy-2-methylpropanamide

Reference compound c gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-hydroxy-2-methylpropanamide (32 mg, white solid, yield: 30%).

MS m/z(ESI):414.1[M+H] ⁺ .

Example 5

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -3-methoxyazetidine-1-carboxamide

Reference compound b gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -3-methoxyazetidine-1-carboxamide (22 mg, white solid, yield: 23%).

¹ H NMR(400MHz,Chloroform-d)δ7.18–7.12(m,2H),6.96(dd,J＝7.1,2.6Hz,1H),4.41–4.22(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).

MS m/z(ESI):441.1[M+H] ⁺ .

Example 6

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

The first step is as follows: n- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-hydroxycyclopropane-1-carboxamide

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

¹ H 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＝14.2,6.4Hz,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).

MS m/z(ESI):412.1[M+H] ⁺ .

Example 6A

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

The first step is as follows: n- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-hydroxycyclopropane-1-carboxamide urea

The intermediate 1-1 was used as a starting material, and N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-hydroxycyclopropane-1-carboxamide urea was obtained under the reaction conditions in example 6.

¹ H 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).

MS m/z(ESI):412.1[M+H] ⁺ .

Example 6B

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

The first step is as follows: n- (cis-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-hydroxycyclopropane-1-carboxamide urea

The intermediate 1-2 was used as a starting material, and N- (cis-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-hydroxycyclopropane-1-carboxamide urea was obtained under the reaction conditions in example 6.

MS m/z(ESI):412.1[M+H] ⁺ .

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).

Example 7

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

The first step is as follows: n- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) thiazole-2-carboxamide

3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine (50mg, 0.15mmol) was dissolved in N, N-dimethylformamide (3 mL), thiazole-2-carboxylic acid (23mg, 0.18mmol), HATU (86mg, 0.23mmol) and diisopropylethylamine (58mg, 0.45mmol) were added, and the reaction was stirred at room temperature overnight. The solvent was dried by spinning, 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) thiazole-2-carboxamide (21 mg, white solid, yield: 32%).

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).

MS m/z(ESI):439.1[M+H] ⁺ .

Example 7A

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

The first step is as follows: n- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) thiazole-2-carboxamide

Starting from intermediate 1-1, reaction conditions of reference example 7 gave N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) thiazole-2-carboxamide (21 mg, white solid, yield: 32%).

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).

MS m/z(ESI):439.1[M+H] ⁺ .

Example 8

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

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

¹ H 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),2.56(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).

MS m/z(ESI):428.1[M+H] ⁺ .

Example 9

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

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

MS m/z(ESI):451.1[M+H] ⁺ .

Example 10

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2- (3-methylisothiazol-5-yl) acetamide

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

MS m/z(ESI):451.1[M+H] ⁺ .

Example 11

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

The first step is as follows: n- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) cyclopropanesulfonamide

3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride (40mg, 0.11mmol), triethylamine (44mg, 0.44mmol) and cyclopropylsulfonyl chloride (31mg, 0.22mmol) were dissolved in dichloromethane (2 mL), the reaction was stirred at room temperature for 12 hours, the solvent was spun dry and the crude product was isolated by preparative HPLC to give N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) cyclopropanesulfonamide (15 mg, yield: 31.6%)

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):432.0[M+H] ⁺ 。

Example 12

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide

The first step is as follows: n- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide

3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine (50mg, 0.15mmol) was dissolved in N, N-dimethylformamide (3 mL), oxazole-2-carboxylic acid (20mg, 0.18mmol), HATU (86mg, 0.23mmol) and diisopropylethylamine (58mg, 0.45mmol) were added, and the reaction was stirred at room temperature overnight. The solvent was dried by spinning, 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) oxazole-2-carboxamide (13 mg, white solid, yield: 21%).

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).

MS m/z(ESI):423.1M+H] ⁺ .

Example 12A and example 12B

N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (12A)

N- (cis-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (12B)

Example 12 was resolved to provide N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (12A) and N- (cis-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide (12B).

Chiral preparation conditions are as follows:

instrument for measuring the position of a moving object	SFC-80(Thar,Waters)
		Column shape	AD	20*250mm,10um(Daicel)
Column pressure	100bar
		Mobile phase	CO ₂ /EtOH(1％Methanol Ammonia)＝50/50
Flow rate of flow	80g/min
		Detection wavelength	UV 214nm
Column temperature
		35℃

Example 12A: t is t _R ＝2.473min

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).

MS m/z(ESI):423.1M+H] ⁺ .

Example 12B: t is t _R ＝1.782min

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).

MS m/z(ESI):423.1M+H] ⁺ .

Example 13

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -4-methylisothiazole-5-carboxamide

Reference compound c gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -4-methylisothiazole-5-carboxamide.

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).

MS m/z(ESI):437.1[M+H] ⁺ .

Example 13A

N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -4-methylisothiazole-5-carboxamide

Starting from intermediate 1-1, reference compound c reaction conditions yielded N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -4-methylisothiazole-5-carboxamide (13A) (21 mg, white solid, yield: 25%).

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).

MS m/z(ESI):437.1[M+H] ⁺ .

Example 13B

N- (cis-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -4-methylisothiazole-5-carboxamide

Taking the intermediate 1-2 as an initial raw material, and referring to the reaction conditions of the compound c to obtain the N- (cis-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) -4-methylisothiazole-5-formamide (35B).

MS m/z(ESI):437.1[M+H] ⁺ .

Example 14

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -3-methylisothiazole-5-carboxamide

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

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).

MS m/z(ESI):437.0[M+H] ⁺ .

Example 15

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) isothiazole-5-carboxamide

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

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).

MS m/z(ESI):423.0[M+H] ⁺ .

Example 15A

N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) isothiazole-5-carboxamide

Taking the intermediate 1-1 as a starting material, and referring to the reaction conditions of the compound c, obtaining N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) isothiazole-5-formamide (37A) (white solid).

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).

MS m/z(ESI):423.2[M+H] ⁺ .

Example 16

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-methyloxazole-5-carboxamide

The reference compound c gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-methyloxazole-5-carboxamide.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):437.1[M+H] ⁺ .

Example 17

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) isothiazole-3-carboxamide

The reference compound c gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) isothiazole-3-carboxamide.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):423.1[M+H] ⁺ .

Example 17A

N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) isothiazole-3-carboxamide

Taking the intermediate 1-1 as a starting material, and referring to the reaction conditions of the compound c to obtain the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) isothiazole-3-formamide.

¹ H NMR(400MHz,CDCl ₃ )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(dd,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).

MS m/z(ESI):423.1[M+H] ⁺ .

Example 18

N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-methyloxazole-4-carboxamide

Compound c of the reference example gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-methyloxazole-4-carboxamide (white solid).

¹ H 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).

MS m/z(ESI):437.1M+H] ⁺ .

Example 18A

N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -2-methyloxazole-4-carboxamide

Taking the intermediate 1-1 as an initial raw material, and referring to the reaction conditions of the compound c to obtain the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) -2-methyloxazole-4-formamide.

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),3.19–3.06(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).

MS m/z(ESI):437.1M+H] ⁺ .

Example 19

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

Reference compound c gave N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) quinoline-5-carboxamide (35 mg, white solid) in a first step.

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＝7.0,2.0Hz,2H),7.03–6.95(m,1H),6.29–6.15(m,1H),4.84–4.52(m,1H),3.23–3.05(m,4H),2.80–2.67(m,4H),2.52–2.41(m,2H),2.35–2.04(m,3H),1.70–1.57(m,4H).

MS m/z(ESI):483.1M+H] ⁺ .

Example 19A

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

Taking the intermediate 1-1 as an initial raw material, and referring to the reaction conditions of the compound c to obtain the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) quinoline-5-formamide.

¹ H 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).

MS m/z(ESI):483.1M+H] ⁺ .

Example 20

1-cyclopropyl-3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-methylurea

Reference compound a obtained 1-cyclopropyl-3- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) -1-methylurea in the eighth step (43 mg, white solid, yield: 33%).

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).

MS m/z(ESI):425.1[M+H] ⁺ .

Example 21

1-cyano-N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) cyclopropane-1-carboxamide

Reference compound c gave 1-cyano-N- (3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) cyclopropane-1-carboxamide (31 mg, white solid) in the first step.

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).

MS m/z(ESI):421.1M+H] ⁺ .

Example 22

(R) -N- (3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) cyclobutyl) -2-hydroxy-2-methylpropanamide

The first step is as follows: (R) -4- (2,3-dichlorophenyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester

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

MS m/z(ESI):345.1[M+H] ⁺ .

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).

The second step is that: (R) -1- (2,3-dichlorophenyl) -2-methylpiperazine

(R) -4- (2,3-dichlorophenyl) -3-methylpiperazine-1-carboxylic acid tert-ester as starting material the second step of reference compound a gave (R) -1- (2,3-dichlorophenyl) -2-methylpiperazine (420 mg, yellow solid, yield: 98.8%).

MS m/z(ESI):245.1[M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d4)δ7.36–7.29(m,1H),7.27–7.16(m,2H),3.60–3.44(m,1H),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).

The third step: (R) -3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) cyclobutane-1-amine

The sixth and seventh steps of reference Compound a gave (R) -3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) cyclobutane-1-amine (280 mg).

MS m/z(ESI):342.1[M+H] ⁺ .

The fourth step: (R) -N- (3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) cyclobutyl) -2-hydroxy-2-methylpropanamide

Reference example 4 gave (R) -N- (3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) cyclobutyl) -2-hydroxy-2-methylpropanamide (18 mg).

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).

MS m/z(ESI):428.1[M+H] ⁺ .

Example 23

(R) -N- (3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) cyclobutyl) -carbamic acid tert-butyl ester

Reference example 22 gave (R) -tert-butyl N- (3- (2- (4- (2,3-dichlorophenyl) -3-methylpiperazin-1-yl) ethyl) carbamate.

MS m/z(ESI):441.3[M+H] ⁺ .

Example 24

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

1- (benzo [ b ] thiophene-4-yl) piperazine is used as a raw material and a reference compound d is used to obtain 3- (3- (2- (4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl) ethyl) cyclobutyl) -1-ethyl-1-methylurea.

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).

MS m/z(ESI):401.2[M+H] ⁺ .

Example 25

N- (3- (2- (4- (2,3-dichlorophenyl) -1,4-diazohepten-1-yl) ethyl) cyclobutyl) furan-2-carboxamide

Synthesis of example 25 reference example 12.

MS m/z(ESI):436.2[M+H] ⁺ .

2. Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.

1. Radioligand receptor binding assays

Test example 1 determination of the binding Capacity of Compounds of the invention to dopamine D3 receptor

1. Purpose of the experiment:

the purpose of this test example was to measure the affinity of the compound to the dopamine D3 receptor.

2. Laboratory instruments and reagents:

2.1 Experimental apparatus:

vortex mixer (IKA; MS3 basic)

Electric constant temperature incubator (Shanghai Yiheng; DHP-9032)

Micro-plate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer；NTX)

Universal Harvester(PerkinElmer；UNIFILTER-96)

2.2 Experimental reagents and consumables:

[ ³ H]-methylspiperone(PerkinElmer；NET856250UC)

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

GR 103691(Sigma；162408-66-4)

ULTIMA GOLD(Perkin Elmer；77-16061)

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

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

polyethylene imine

branched(Sigma；408727)

Centrifuge tube (BD, 352096

Loading slot(JET BIOFIL；LTT001050)

Pipette tip (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S)

Magnesium chloride (Sigma, 7786-30-3)

Tris-base(Sigma，77-86-1)

HCl(Beijing XingJing Precision Chemical Technology CO.,LTD)。

3. The experimental method comprises the following steps:

experiment buffer solution: 50mM Tris-HCl pH7.4, 10mm MgCl ₂ 1; washing liquid: 50mM Tris-HCl pH7.4,4 ℃ storage; 0.5% PEI solution:0.5g PEI dispolve in 100mL ddH ₂ O，4℃storage of spare。

mu.L of test compound (0.005 nM-100nM, 10 concentrations) and 100. Mu.L of buffer were added to the 96-well assay plate. mu.L of cell membrane and 300. Mu.L of buffer were added to each well and shaken at 600rpm for 5min. Each well was filled with 100. Mu.L of a buffer solution ³ H]A mixed solution of-methylspiperone (final concentration of 0.5 nM) was added to the reaction system, shaken at 600rpm for 5min, and incubated at 27 ℃ for 30min. UNIFILTER-96GF/B filter plate preincubated for 1h with 0.5% PEI was washed 2 times with 1ml/well buffer and the cell membrane suspension was added to the UNIFILTER-96GF/B filter plate and washed 4 times, incubated for 10min at 55 ℃ and 40. Mu.L of ULTIMA GOLD per well and counted by liquid scintillation.

4. The experimental data processing method comprises the following steps:

CPM (Counts per minute) values were read by TopCount. Percent inhibition [ 2 ] calculated from the readings of the High control (DMSO control) and Low control (100 nM positive compound) test groups ³ H]-Methylpiperone binding data {% inhibition rate = (CPM) _sample -CPM _{low control} )/(CPM _{high control} -CPM _{low control} ) X 100}. The concentration of the compound was 100nM to 0.005nM in 10 diluted 3-fold in the reaction system. IC of compounds was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula ₅₀ The value is obtained.

5. The experimental results are as follows:

the D3 binding activity of the compounds of the present invention was determined by the above assay, and the measured IC ₅₀ The values are shown in Table 5.

TABLE 5 binding Activity of Compounds of the invention on D3 IC ₅₀

6. And (4) experimental conclusion:

the compound has good affinity with dopamine receptor D3.

Test example 2 determination of the binding Capacity of Compounds of the invention to 5-HT2A receptor

1. Purpose of the experiment:

the purpose of this test example was to measure the affinity of the compound to the 5-HT2A receptor.

2. Laboratory instruments and reagents:

2.1 Instrument:

vortex mixer (IKA; MS3 basic)

Electric constant temperature incubator (Shanghai Yiheng; DHP-9032)

Micro-plate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer；NTX)

Universal Harvester(PerkinElmer；UNIFILTER-96)

2.2 Experimental reagents and consumables:

[ ³ H]-Ketanserin(PerkinElmer NET791)

Human Dopamine 5-HT2A Receptor membrane(PerkinElmer)

ULTIMA GOLD(Perkin Elmer；77-16061)

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

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

polyethyleneimine, branched (Sigma; 408727)

Centrifuge tube (BD, 352096

Loading slot(JET BIOFIL；LTT001050)

Pipette tip (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S)

Magnesium chloride (Sigma, 7786-30-3)

Calcium chloride (Sigma)

Tris-base(Sigma，77-86-1)

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

L-Ascorbic acid(Tianjin Guangfu)

3. The experimental method comprises the following steps:

experiment buffer: 50mM Tris-HCl pH7.4, 4mM CaCl ₂ 1; washing liquid: 50mM Tris-HCl pH7.4,4 ℃ storage; 0.5% PEI solution:0.5g PEI dispolve in 100mL ddH ₂ O，4℃storage of spare

mu.L of test compound (0.005 nM-100nM, 10 concentrations) and 100. Mu.L of buffer were added to the 96-well assay plate. mu.L of cell membrane and 300. Mu.L of buffer were added to each well. Shaking at 600rpm for 5min. Each well was filled with 100. Mu.L of a buffer solution and [ 2 ] ³ H]A mixture of Ketanserin (final concentration of 2 nM) was added to the reaction system, shaken at 600rpm for 5min, and incubated at 27 ℃ for 30min. UNIFILTER-96GF/B filter plate preincubated for 1h with 0.5% PEI was washed 2 times with 1mL/well buffer and the cell membrane suspension was added to the UNIFILTER-96GF/B filter plate and washed 4 times and incubated for 10min at 55 ℃. Add 40. Mu.L of ULTIMA GOLD to each well and perform liquid scintillation counting.

4. The experimental data processing method comprises the following steps:

percentage inhibition calculated from readings of High control (DMSO control) and Low control (100 nM positive compound) test groups by TopCount reading CPM (Counts per minute) values ³ H]Data of Ketanserin binding {% inhibition = (CPM) _sample -CPM _{low control} )/(CPM _{high control} -CPM _{low control} ) X 100, concentration of compound 10 after 3-fold dilution of the reaction system from 100nM to 0.005nM, IC of compound calculated using GraphPad prism fitting percent inhibition and ten-point concentration data to parametric nonlinear logical equations ₅₀ The value is obtained.

5. The experimental results are as follows:

compound pair 5 of the present inventionthe-HT 2A binding Activity is determined by the above assay, the IC determined ₅₀ The values are shown in Table 6.

TABLE 6 IC of the binding Capacity of the Compounds of the invention to 5-HT2A ₅₀ Value of

6. And (4) experimental conclusion:

the above data show that the compounds of the invention have good affinity for 5-HT 2A.

2. Cell function test

Test example 1 determination of Effect of Compounds of the present invention on cAMP content in cells stably expressing D3 receptor

1. Purpose of the experiment:

the activation of the D3 receptor by the compound is measured.

2. Laboratory instruments and reagents:

2.1 Instrument:

384 well-assay plates (Perkin Elmer; 6007680);

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

EnVision(Perkin Elmer)。

2.2 reagent:

Fetal Bovine Serum(Gibco，10999141)；

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

Penicillin-Streptomycin，Liquid(Gibco；15140122)；

G418(invitrogen；0131-027)；

Forskolin(Selleck，S2449)；

BSA stabilizer(Perkin Elmer；CR84-100)；

cAMP kit(Cisbio；62AM4PEC)；

IBMX(Sigma；I5879)；

HEPES(Gibco；15630080)；

HBSS(Gibco；14025076)；

TrypLE(ThermoFisher；12604021)。

3. the experimental method comprises the following steps:

1. preparing a buffer solution: 1 × HBSS +20mM HEPES +0.1% BSA +500 μ M IBMX.

Complete medium: ham's F K +10% fetal bovine serum + 1x penicillin streptomycin +400 μ g/mLG418.

2. Culturing the CHO-D3 cell line at 37 ℃ and 5% CO ₂ In complete medium under ambient conditions; after TrypLE digestion, cells were resuspended in experimental buffer, seeded into 384 cell culture plates at 8000 density per well.

3. Preparation of experiment buffer 1 × HBSS,0.1% BSA, 2mM HEPES and 500. Mu.M IBMX; diluting the compound with buffer; add 2.5. Mu.L of compound per well, incubate 10 minutes at 37 ℃; forskolin was diluted to 8 μ M (8 x) with assay buffer; 2.5 μ L of diluted 8 × forskolin was added and incubated at 37 ℃ for 30 min; the cAMP-d2 and Anti-cAMP-Eu3+ are frozen and thawed, and diluted by 20 times by using lysine buffer; add 10. Mu.L cAMP-d2 to the experimental well, then add 10. Mu.L Anti-cAMP-Eu3+ to the experimental well; the reaction plate was centrifuged at 200g for 30s at room temperature and allowed to stand at 25 ℃ for 1 hour, and data were collected by Envision

The experimental data processing method comprises the following steps:

1)Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；

2)CVMax＝(SDMax/MeanMax)*100％；

3)CVMin＝(SDMin/MeanMin)*100％；

4)S/B＝Singal/Background；

5) Compound EC was calculated using GraphPad non-linear fitting equation ₅₀ ：

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

X: log value of compound concentration; y: activation%

4. The experimental results are as follows:

EC of Table 7 Compounds on cAMP content in cells stably expressing D3 receptor ₅₀ Value of

Example numbering	EC ₅₀ (nM)
		Carilazine	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

5. And (4) experimental conclusion:

as can be seen from the data in the table, the compounds of the examples shown in the present invention showed good agonistic activity in the experiment of the effect of stably expressing D3 receptor cells on cAMP.

Test example 2 determination of the Effect of the Compounds of the invention on the calcium ion flux in cells stably expressing 5-HT2A receptor

1. Purpose of the experiment:

the inhibitory effect of the compounds on the 5-HT2A receptor was measured.

2. Laboratory instruments and reagents:

2.1 Instrument:

384 well-assay plate (Corning; 3712);

FLIPR(Molecular Devices)。

2.2 reagent:

DMEM(Invitrogen；11965)；

fetal bovine serum (Biowest; S1810-500);

dialyzed serum (S-FBS-AU-065;

penicillin and streptomycin (Biowest; L0022-100);

hygromycin B (CABI ℃ HEM, 400052);

Matrigel(BD；354230)；

DMSO(Sigma；D2650)；

HBSS(Invitrogen；14065)；

HEPES(Invitrogen；15630080)；

Probenecid(Sigma；P8761)；

BSA(renview；FA016)；

TrypLE(ThermoFisher；12604021)。

3. the experimental method comprises the following steps:

1) Preparing a buffer solution: 1x HBSS,20mM HEPES,2.5mM probenecid (probenecid is 400mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh the day of the experiment. The experimental buffer comprises a dye buffer, a compound dilution buffer and the like.

2) Cell culture medium: ham's F-12K +10% fetal calf serum +600ug/ml hygromycin B +1 penicillin and streptomycin;

inoculating a culture medium: ham's F-12K +10% dialyzed serum; assay buffer:1x HBSS +20mM HEPES; cell lines: flp-In-CHO-5HT2A stable pool.

3) The cell line was cultured in complete medium at 37 ℃ and 5% CO ₂ To 70% -90% fusion. Digested with TrypLE and then digested at 1X 10 ⁴ The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).

4) Freeze-thaw 20 XComponent A to room temperature, dilute it to 2 Xworking concentration with assay buffer containing 5mM Probenecid, and leave at room temperature until use.

5) The cell culture plates were removed, allowed to stand at room temperature for 10min, FBS was diluted to 0.03% using Apricot and assay buffer, leaving 20. Mu.L of final in 3764 plates, followed by addition of 20. Mu.L of 2X Component A containing 5mM Probenecid to each experimental well, 200g, RT centrifugation for 3-5sec, and incubation at 37 ℃ for 2hr.

6) Positive control compound and test compound working solutions (6X) were prepared in DMSO.

7) Taking out the cell culture plate and standing for 10 minutes at room temperature; add 10. Mu.L of the 6 Xcompound working solution from step 5 to the corresponding experimental wells of 384-well cell culture plates and incubate for 30min at room temperature.

8) 5HT was diluted to 6n μm (6X) with assay buffer, 50. Mu.L was transferred to 384 well plates (Corning, 3657), and left at room temperature for use. 10ul of diluted 5HT was added to each experimental well using FLIPR Tetra and the values read.

4. The experimental data processing method comprises the following steps:

calcium signal values were read by FLIPR. The calculated output for each sampling time point in the experiment is the ratio of the 340/510nm to 380/510nm wavelength signals. The maximum minus the minimum is calculated from the ratio signal curve. IC of compound was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula ₅₀ The value is obtained.

5. The experimental results are as follows:

table 8: IC of compound for stably expressing calcium ion flowing ability of 5-HT2A receptor cell ₅₀ Value of

6. And (4) experimental conclusion:

as can be seen from the data in the table, the compounds of the examples of the present invention showed good inhibitory activity in the calcium flux assay for stably expressing 5-HT2A cell function.

3. Balb/C mouse pharmacokinetic assay

1. The research aims are as follows:

Balb/C mice were used as test animals to study the pharmacokinetic behavior of the compounds of the examples of the invention administered orally at a dose of 5mg/kg in vivo (plasma and brain tissue) in mice.

2. The experimental scheme is as follows:

2.1 Experimental drugs:

the compound of the embodiment of the invention is prepared by self.

2.2 Experimental animals:

Balb/C Mouse group was 12 animals per group, male, shanghai Jitsie laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

2.3 preparation prescription:

0.5% CMC-Na (1% Tween 80), sonicated, and formulated as a clear solution or a homogeneous suspension.

2.4 administration:

12 mice per group, male, balb/C; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10mL/kg.

2.5 sample collection:

mice were dosed with CO before and after dosing at 1,2, 4, 8 and 24 hours ₂ Sacrifice, blood sampling 0.2mL of the heart, placing in EDTA-K ₂ Centrifuging at 4 deg.C and 6000rpm for 6min in a test tube to separate plasma, and storing at-80 deg.C; the whole brain tissue was taken out, weighed, placed in a 2mL centrifuge tube, and stored at-80 ℃.

2.6 sample treatment:

1) Plasma samples 40uL were precipitated by addition of 160uL acetonitrile, mixed and centrifuged at 3500 Xg for 5-20 minutes.

2) Plasma and brain homogenate samples 30. Mu.L were precipitated by adding 90. Mu.L acetonitrile containing internal standard (100 ng/mL), mixed and centrifuged at 13000rpm for 8 minutes.

3) 70uL of the treated supernatant solution was added to 70uL of water, vortexed and mixed for 10 minutes, and then 20 uL of the supernatant solution was subjected to LC/MS/MS analysis for the concentration of the test compound, and the LC/MS/MS analyzer: AB Sciex API4000Qtrap.

2.7 liquid phase analysis:

liquid phase conditions: shimadzu LC-20AD pump

Column chromatography: agilent ZORBAX XDB-C18 (50X 2.1mm,3.5 μm) mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile

Flow rate: 0.4mL/min

Elution time: 0-4.0 min, eluent as follows:

3. experimental results and analysis:

the major pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in table 9 below:

table 9: mouse pharmacokinetic experiment results

4. And (4) experimental conclusion:

as can be seen from the results of the mouse pharmacokinetic experiments in the table: the compounds of the embodiment of the invention show good metabolic properties, exposure AUC and maximum blood concentration C _max All performed well.

4. Drug effect model for rat active escape experiment

1. Purpose of experiment

The anti-schizophrenia effect of the compound is evaluated by utilizing a rat active escape experiment pharmacodynamic model.

2. Laboratory apparatus and reagent

2.1 Instrument:

serial number	Name of the deviceBalance	Model of the device	Source	Manufacturer of the product
					1	Active and passive shuttle device	MED-APA-D1R	An inlet	Med Associates，Inc.
2	Constant temperature magnetic stirrer	85-2	Made in China	Shanghai Si le instruments Ltd
					3	Vortex instrument	H-101	Made in China	Shanghai Kanghe photoelectric Instrument Co Ltd
4	Ultrasonic cleaner	KQ3200DE	Made in China	KUNSHAN ULTRASONIC INSTRUMENTS Co.,Ltd.

2.2 reagent:

serial number

Name (R)

Purity of

Batch number

Storage conditions

Manufacturer of the product

1

CMC-Na

100％

SLBV9664

RT

Sigma

2

Tween 80

100％

BCBV8843

RT

Sigma

2.3 test Compounds

The compound of the embodiment of the invention is prepared by self.

3. Experimental animals:

animal species	Line of	Age (age)	Sex	Suppliers of goods
					Rat	F344	6-8weeks	Male sex	Beijing vitamin Tonglihua

4. Solvent and compound preparation:

4.1 solvent (0.5% CMC-Na +1%

Weighing a certain mass (such as 1.0 g) of CMC-Na into a glass bottle, adding a certain volume (such as 200 mL) of purified water, stirring to uniformly disperse the CMC-Na, adding 1% (v/v) of Tween80 according to the volume of the solution, stirring overnight to obtain a clear and uniform clear solution, and storing at 2-8 ℃ for later use.

4.2 compound preparation:

the prescribed amount of the compound was weighed out, added to 0.5% by volume of CMC-Na +1% by volume of Tween80 solution, prepared before administration, stored at 2 to 8 ℃ and used within 4 days.

The compound solution preparation and administration need to calculate the actual sample amount, and the conversion formula is as follows: compound actual sample size = theoretical sample size purity/salt factor.

5. And (3) experimental operation:

after the animals reached the experimental facility, the experiment was started one week after acclimatization.

5.1 establishing a drug effect model:

5.1.1 animals are placed in a shuttle box, and after 5 seconds of adaptation, sound and light stimulation is given for 10 seconds;

5.1.2 if the animal avoids to the other side under the stimulation of sound and light for 10 seconds, no electric shock is carried out, recording as active avoidance (avoids), and ending the single training;

5.1.3 if the animal does not move to the other side after the 10-second sound and illumination stimulation is finished, giving an electric shock, wherein the current intensity is 0.6mA, the duration time is 10 seconds, and if the animal escapes to the other side within 10 seconds of the electric shock duration, the electric shock stops, recording as passive escape (escapes), and finishing the single training;

5.1.4 if the animal has not been avoided within 10 seconds of the shock, the shock is stopped, recording as an escape failure (escape failures), and the single training is finished;

5.1.5 Each animal was trained 30 times a day, and after training was completed, the animals were returned to their cages for 6 days.

5.2 Baseline testing and grouping

The day before the compound screening test, a baseline test is required, the test flow is 5.1.1-5.1.3, the number of the baseline test is 20, animals with the number of active escape times reaching 16 (80%) are grouped according to the number of the active escape times, and each group is 10 animals; the first group was given vehicle orally and the remaining groups were given the corresponding test compounds according to the experimental design.

5.3 Compound screening assay

The drug is administered one hour before the test begins, the drug administration mode is oral administration, 5mL/kg;

the test flow is the same as 5.1.1-5.1.4, and the test times are 20 times.

6. Data processing

The software collected the following data for data analysis:

number of active escapes (avoids) for animals;

number of times the animal failed to escape (escape failures);

latency for passive escape of the animal (escape);

all dosing data are expressed as Mean ± standard error (Mean ± SEM) and the significance of the difference is considered as significantly different as p < 0.05 using test analysis in Graphpad 6 statistical software.

7. The experimental results are as follows:

watch 10

8. Conclusion of the experiment

The data show that the compound of the embodiment of the invention has better effect in a rat active evasion experiment pharmacodynamic model, and shows that the compound has the effect of resisting schizophrenia.

3. Study of Crystal forms

1.1 Experimental instruments

1.1.1 some parameters of the physicochemical measuring Instrument

1. Preparation of different crystal forms

1.1 preparation of free base form A

The compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide is prepared, separated and freeze-dried by HPLC to obtain the crystal form A. By detection and analysis, the XRPD pattern shown in figure 1 and the DSC pattern shown in figure 2 are obtained.

1.2 preparation of free base form B

The compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide gave form B after column chromatography (mobile phase: DCM/MeOH = 10) freeze-drying. By detection analysis, it has XRPD pattern as shown in figure 3, DSC pattern as shown in figure 4 and TGA pattern as shown in figure 5.

1.3 preparation of free base form C

Weighing 10mg of free alkali crystal form B, adding 100 mu L of ethyl formate solvent, pulping for a week at 50 ℃, centrifuging, and drying in vacuum at 50 ℃ to constant weight to obtain crystal form C. By detection analysis, it has XRPD pattern as shown in figure 6, DSC pattern as shown in figure 7 and TGA pattern as shown in figure 8.

1.4 preparation of free base form D

Weighing 10mg of free base crystal form B, adding 200 mu L of methanol solvent, dissolving at 50 ℃ until the mixture is clear, and adding 1mL of isopropyl ether at room temperature to obtain a crystal form D. Upon detection analysis, it had an XRPD pattern as shown in figure 9.

2. Solid stability test

2.1 purpose of experiment:

the physicochemical stability of the compound under the conditions of 5000lx of illumination, 60 ℃ high temperature, 92.5% RH and 75% RH at 50 ℃ high temperature, high humidity, was examined for N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystal form B, and the storage of the compound was provided.

2.2 protocol:

taking about 1mg of N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystal form B, observing 5 days and 10 days under the conditions of 5000lx of light irradiation, 92.5% RH of high temperature and high humidity at 60 ℃, and 75% RH of high temperature and high humidity at 50 ℃, measuring the content by HPLC and external standard method, and calculating the change of related substances by using a chromatographic peak area normalization method.

Chromatographic conditions are as follows:

2.3 Experimental results:

the physicochemical stability results of free base form B are shown in table 11:

TABLE 11

2.4 conclusion of the experiment:

the data show that the total amount of impurities of the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form B is increased after the crystal form B is placed under a high-humidity condition for 10 days, the single impurities are obviously increased after the crystal form B is placed under an illumination condition for 5 days, and other conditions are stable. Therefore, the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form B needs to be sealed and stored in a shading mode in the later storage process.

3 hygroscopicity test

3.1 purpose of experiment:

the hygroscopicity of the compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form B under different relative humidity conditions is examined, and a basis is provided for compound storage. 3.2 Experimental protocol:

placing the compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form B in saturated water vapor with different relative humidity to enable the compound and the water vapor to reach dynamic balance, and calculating the percentage of moisture absorption weight gain of the compound after the balance.

3.3 Experimental results:

n- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form B hygroscopic gained approximately 0.2079% at RH80% with a slight hygroscopicity. And (3) carrying out moisture absorption and moisture desorption circulation for 2 times under the condition of 0-95% relative humidity, wherein the XRPD spectrogram of the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form B is not changed, namely the crystal form is not transformed.

4. Solubility experiments in different media

4.1 purpose of experiment:

the solubility of the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form A in media such as pH1-8 USP buffer solution, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF) and pure water is compared, and a basis is provided for the evaluation of drugability.

4.2 protocol:

about 1.0mg of n- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide free base crystalline form a was suspended in various media for 4 hours and thermodynamic solubility of compound at 37 ℃ was determined by HPLC, external standard method.

4.3 Experimental results: as shown in Table 12

Table 12 free base form a solubility

Numbering	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	H ₂ O	0.00
10	FaSSGF	>1
			11	FaSSIF	0.07
12	FeSSIF	0.81

4.4 conclusion of the experiment

The results show that the N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base crystal form A has better solubility under acidic conditions.

5. Polycrystal screening and stable crystal form confirmation experiment

5.1 purpose of experiment:

and finding a relatively stable compound crystal form through polycrystal screening.

5.2 protocol:

selecting an organic solvent and water with certain solubility, suspending the free alkali crystal form B in a solvent system, stirring and pulping at 50 ℃ for 1 week, centrifuging, discarding a supernatant, vacuum-drying the solid at 50 ℃ (-0.1 Mpa) overnight, and measuring XRPD, DSC and TGA of the solid for comparison.

5.3 Experimental results:

5.4 Experimental results:

n- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazine-1-yl) ethyl) cyclobutyl) oxazole-2-formamide free base is subjected to pulping, and a crystallization solvent, a crystallization mode and the like are changed to obtain 3 crystal forms, namely a crystal form A, a crystal form B and a crystal form C. By comparing DSC spectra of different non-crystal forms, the free alkali crystal form B can be judged to be the most thermodynamically stable crystal form in the crystal forms.

Claims

1. A crystal form of a compound shown in a general formula (I) or a stereoisomer thereof,

wherein:

R ₃ selected from hydrogen, deuterium or C _1-6 An alkyl group;

R ₄ selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl, 5-14 membered heteroaryl, - (CH) ₂ ) _n1 R _a 、-(CH ₂ ) _n1 C(O)R _a 、-(CH ₂ ) _n1 C(O)NR _a R _b 、-C(O)(CHR _a ) _n1 R _b 、-C(O)NR _a (CH ₂ ) _n1 R _b 、-(CH ₂ ) _n1 S(O) ₂ R _a 、-(CH ₂ ) _n1 S(O) ₂ NR _a R _b Or- (CH) ₂ ) _n1 C(O)OR _a Said amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

or, R ₃ And R ₄ And the nitrogen atom to which they are attached are linked together to form a 3-6 membered heterocyclyl or 5-6 membered heteroaryl, said 3-6 membered heterocyclyl and 5-6 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, ammoniaRadical, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

R _a and R _b Each independently selected from hydrogen, deuterium, amino, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further selected from deuterium, halogen, hydroxy, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 A cycloalkyl group, a 3-to 12-membered heterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl;

x is 0, 1,2 or 3;

n is 0, 1 or 2; and is

n1 is 0, 1,2 or 3.

2. A crystalline form according to claim 1, characterized in that formula (I) is further represented by formula (Ia) or formula (Ib):

3. the crystalline form of claim 1, wherein formula (I) is further represented by formula (II):

wherein:

4. A crystalline form according to claim 3, characterized in that formula (II) is further represented by formula (IIa) or formula (IIb):

5. the crystalline form according to any one of claims 1 to 4, characterized in that R ₁ Selected from hydrogen, deuterium, halogen or C _1-3 Alkyl, preferably fluorine, chlorine or bromine;

R ₂ selected from hydrogen, deuterium, halogen or C _1-3 Alkyl, preferably fluorine, chlorine or bromine;

or, R ₁ And R ₂ And the carbon atoms to which they are attached are linked together to form a 5-6 membered sulfur-containing heteroaryl group, preferably a thienyl group.

6. A crystalline form according to any one of claims 1 to 5, characterised in that R ₃ Selected from hydrogen, deuterium or C _1-3 An alkyl group; preferably hydrogen, deuterium or methyl;

R ₄ selected from hydrogen, deuterium, C _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 R _a 、-C(O)R _a 、-C(O)NR _a R _b 、-C(O)(CHR _a ) _n1 R _b 、-C(O)NR _a (CH ₂ ) _n1 R _b 、-S(O) ₂ R _a 、-S(O) ₂ NR _a R _b OR-C (O) OR _a Said C is _1-6 Alkyl radical, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl,optionally further substituted by a group selected from deuterium, cyano, halogen, hydroxy, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of alkoxy;

or, R ₃ And R ₄ Linked to form a 3-8 membered heterocyclyl or 5-14 membered heteroaryl, said 3-8 membered heterocyclyl and 5-14 membered heteroaryl being optionally further selected from halogen, amino, cyano, hydroxy, oxo, thio, C _1-6 Alkyl radical, C _3-8 Alkoxy radical, C _3-8 Haloalkoxy and C _3-8 Substituted with one or more substituents in hydroxyalkyl;

n1 is 0, 1,2 or 3.

7. The crystalline form of claim 3, wherein formula (II) is further represented by formula (III):

wherein:

R ₅ selected from hydrogen, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl or5-10 membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _1-6 Substituted with one or more substituents in hydroxyalkyl;

preferably, R ₅ Selected from hydrogen, amino, C _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl containing one nitrogen or oxygen atom or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, said amino, C _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl radical, C _6-10 Aryl, 3-8 membered heterocyclyl containing one nitrogen or oxygen atom or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur atom, optionally further substituted by deuterium, halogen, hydroxy, cyano, oxo, C _1-3 Alkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents in hydroxyalkyl;

more preferably, R ₅ Selected from hydrogen, amino, C _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl, phenyl, oxiranyl, thienylalkyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, said amino, C.C.sub.Cxft 5363-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl _1-3 Alkyl radical, C _1-3 Alkoxy radical, C _1-3 Hydroxyalkyl radical, C _3-8 Cycloalkyl, phenyl, oxirane, epithioethyl, aziridinyl, oxetanyl, azetidinyl, thietaneAlkyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzotriazolyl, quinolinyl or isoquinolinyl, optionally further deuterium, halogen, hydroxy, cyano, oxo, C _1-3 Alkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents in hydroxyalkyl;

further preferably, R ₅ Selected from the following groups: h-, (CH) ₃ ) ₂ N-、CH ₃ NH-、CH ₃ -、CH ₃ O-、CH ₃ CH ₂ -、CH ₃ CH ₂ NH-、CH ₃ CH ₂ N(CH ₃ )-、(CH ₃ ) ₂ C(OH)-、(CH ₃ ) ₂ C(OH)CH ₂ -、CH ₃ OCH ₂ -、

And is

v is 0 or 1.

8. The crystalline form of claim 7, wherein formula (III) is further represented by formula (IIIa) or formula (IIIb):

9. a crystalline form according to any one of claims 1 to 8, characterized in that the general formula (I) is selected from the following compounds:

10. a crystalline form according to any one of claims 1 to 9, characterized by being a crystalline form of the compound N- (trans-3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutyl) oxazole-2-carboxamide, including form a, form B, form C and form D;

the X-ray powder diffraction pattern of the crystal form A has a diffraction peak at 7.1 +/-0.2 degrees; or a diffraction peak at 25.8 ± 0.2 °; or a diffraction peak at 24.3 ± 0.2 °; or a diffraction peak at 20.0 ± 0.2 °; or a diffraction peak at 23.5 ± 0.2 °; or a diffraction peak at 15.6 ± 0.2 °; or a diffraction peak at 13.6 ± 0.2 °; or a diffraction peak at 15.1 ± 0.2 °; or a diffraction peak at 22.3 ± 0.2 °; or a diffraction peak at 18.1 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

at 20.0 +/-0.2 degrees and 23.5 +/-0.2 degrees,

or at 7.1 +/-0.2 degrees and 25.8 +/-0.2 degrees,

or at 7.1 +/-0.2 degrees and 24.3 +/-0.2 degrees,

or at 7.1 +/-0.2 degrees, 25.8 +/-0.2 degrees and 24.3 +/-0.2 degrees,

or at 7.1 +/-0.2 degrees, 24.3 +/-0.2 degrees and 22.3 +/-0.2 degrees,

or 25.8 +/-0.2 degrees, 20.0 +/-0.2 degrees and 23.5 +/-0.2 degrees,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg. and 20.0 + -0.2 deg.,

or at 7.1 + -0.2 deg., 24.3 + -0.2 deg., 25.8 + -0.2 deg. and 23.5 + -0.2 deg.,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees and 15.1 +/-0.2 degrees,

or 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 °;

more preferably, the X-ray powder diffraction pattern of form a optionally further comprises one or more diffraction peaks at 2 Θ 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 at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4, 5, 6, 7,

further preferably, the X-ray powder diffraction pattern of form a comprises diffraction peaks at one or more of positions at which 2 θ is 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, the compound contains diffraction peaks at 4, 5, 6, 8 and 10,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg. and 15.1 + -0.2 deg.,

or at 7.1 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg., 15.1 + -0.2 deg., 22.3 + -0.2 deg., 18.1 + -0.2 deg., 16.5 + -0.2 deg., and 26.7 + -0.2 deg.,

or at 7.1 + -0.2 deg., 25.8 + -0.2 deg., 24.3 + -0.2 deg., 20.0 + -0.2 deg., 23.5 + -0.2 deg., 15.6 + -0.2 deg., 13.6 + -0.2 deg., 15.1 + -0.2 deg., 22.3 + -0.2 deg., 18.1 + -0.2 deg., 16.5 + -0.2 deg. and 26.7 + -0.2 deg.,

or 25.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.1 +/-0.2 degrees, 22.3 +/-0.2 degrees, 18.1 +/-0.2 degrees, 21.2 +/-0.2 degrees, 10.4 +/-0.2 degrees and 11.1 +/-0.2 degrees;

most preferably, form a has an X-ray powder diffraction pattern substantially as shown in figure 1 or a DSC pattern substantially as shown in figure 2;

the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at 11.3 +/-0.2 degrees; or a diffraction peak at 18.7 ± 0.2 °; or a diffraction peak at 22.5 ± 0.2 °; or a diffraction peak at 19.3 ± 0.2 °; or a diffraction peak at 13.9 ± 0.2 °; or a diffraction peak at 28.2 ± 0.2 °; or a diffraction peak at 24.5 ± 0.2 °; or a diffraction peak at 13.5 ± 0.2 °; or a diffraction peak at 21.1 ± 0.2 °; or a diffraction peak at 17.4 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

at 18.7 +/-0.2 degrees and 22.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees and 18.7 +/-0.2 degrees,

or 11.3 +/-0.2 degrees and 13.9 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 18.7 +/-0.2 degrees and 22.5 +/-0.2 degrees,

or 11.3 +/-0.2 degrees, 22.5 +/-0.2 degrees and 19.3 +/-0.2 degrees,

or at 18.7 +/-0.2 degrees, 22.5 +/-0.2 degrees and 19.3 +/-0.2 degrees,

more preferably, the X-ray powder diffraction pattern of form B optionally further comprises one or more diffraction peaks at 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 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2,3, 4, 5, 6, 7,

further preferably, the X-ray powder diffraction pattern of form B comprises diffraction peaks at one or more 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 ° of 2 Θ; preferably, the compound contains diffraction peaks at 4, 5, 6, 8 and 10,

or at 18.7 + -0.2 deg., 22.5 + -0.2 deg., 19.3 + -0.2 deg., 13.9 + -0.2 deg., 28.2 + -0.2 deg., 24.5 + -0.2 deg., 13.5 + -0.2 deg., 21.1 + -0.2 deg., 17.4 + -0.2 deg. and 24.2 + -0.2 deg.;

most preferably, form B has an X-ray powder diffraction pattern substantially as shown in figure 3, or a DSC pattern substantially as shown in figure 4, or a TGA pattern substantially as shown in figure 5;

the X-ray powder diffraction pattern of the crystal form C has a diffraction peak at 19.0 +/-0.2 degrees; or a diffraction peak at 23.7 ± 0.2 °; or a diffraction peak at 24.2 ± 0.2 °; or a diffraction peak at 12.1 ± 0.2 °; or a diffraction peak at 14.3 ± 0.2 °; or a diffraction peak at 27.2 ± 0.2 °; or a diffraction peak at 20.0 ± 0.2 °; or a diffraction peak at 26.8 ± 0.2 °; or a diffraction peak at 11.8 ± 0.2 °; or a diffraction peak at 17.4 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

at 19.0 +/-0.2 degrees and 23.7 +/-0.2 degrees,

or 12.1 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or, at 14.3 + -0.2 deg. and 20.0 + -0.2 deg.,

or at 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees and 27.2 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg. and 20.0 + -0.2 deg.,

or at 24.2 +/-0.2 degrees, 12.1 +/-0.2 degrees and 11.8 +/-0.2 degrees,

or at 23.7 + -0.2 deg., 24.2 + -0.2 deg., 12.1 + -0.2 deg. and 20.0 + -0.2 deg.,

further preferably, the X-ray powder diffraction pattern of form C comprises diffraction peaks at one or more 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 ° of 2 Θ; preferably, the compound contains diffraction peaks at 4, 5, 6, 8 and 10,

or 19.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 27.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 26.8 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 29.1 +/-0.2 degrees and 22.9 +/-0.2 degrees;

most preferably, form C has an X-ray powder diffraction pattern substantially as shown in figure 6, or a DSC pattern substantially as shown in figure 7, or a TGA pattern substantially as shown in figure 8;

the X-ray powder diffraction pattern of the crystal form D has a diffraction peak at 20.8 +/-0.2 degrees; or a diffraction peak at 16.9 ± 0.2 °; or a diffraction peak at 22.7 ± 0.2 °; or a diffraction peak at 14.5 ± 0.2 °; or a diffraction peak at 13.6 ± 0.2 °; or a diffraction peak at 15.8 ± 0.2 °; or a diffraction peak at 22.3 ± 0.2 °; or a diffraction peak at 16.2 ± 0.2 °; or a diffraction peak at 17.9 ± 0.2 °; or a diffraction peak at 29.4 ± 0.2 °; preferably any 2-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably any 6, 7 or 8 thereof;

16.9 +/-0.2 degrees and 22.7 +/-0.2 degrees,

or 20.8 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or, at 14.5 + -0.2 deg. and 15.8 + -0.2 deg.,

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees and 13.6 +/-0.2 degrees,

or 20.8 +/-0.2 degrees, 22.7 +/-0.2 degrees and 15.8 +/-0.2 degrees,

or at 14.5 +/-0.2 degrees, 22.3 +/-0.2 degrees and 16.2 +/-0.2 degrees,

further preferably, the X-ray powder diffraction pattern of form D comprises diffraction peaks at one or more 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 ° of 2 Θ; preferably, the compound contains diffraction peaks at 4, 5, 6, 8 and 10,

or 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 °;

or 16.9 +/-0.2 degrees, 22.7 +/-0.2 degrees, 14.5 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.8 +/-0.2 degrees, 22.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.9 +/-0.2 degrees, 29.4 +/-0.2 degrees, 31.1 +/-0.2 degrees, 21.8 +/-0.2 degrees and 23.4 +/-0.2 degrees;

most preferably, form D has an X-ray powder diffraction pattern substantially as shown in figure 9.

11. A crystalline form according to any one of claims 1 to 10, characterised in that the crystalline form is a solvent-containing or solvent-free form in which the solvent is selected from one or more of water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, 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.

12. A crystalline form according to any one of claims 1 to 11, characterised in that the number of solvents is from 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.

13. A process for preparing the crystalline form of any one of claims 1 to 12, comprising in particular the steps of:

1) Weighing a proper amount of compound, suspending the compound by using a poor solvent, and shaking the mixture;

2) Quickly centrifuging the suspension, removing supernatant, and drying to obtain a target product;

preferably:

the poor 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-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-propanol, ethyl formate, isopropyl acetate, tert-butanol, 2-butanone or 3-pentanone,

preferably one or more of ethyl formate, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dichloromethane, isopropyl acetate or isopropanol;

or, the method specifically comprises the following steps:

1) Weighing a proper amount of free alkali, dissolving the free alkali in a good solvent,

2) Adding an anti-solvent into the obtained solution, stirring until solid is separated out,

3) Quickly centrifuging the suspension, removing supernatant, and drying to obtain a target product;

preferably:

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

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,

14. A pharmaceutical composition comprising a therapeutically effective dose of the crystalline form of any one of claims 1 to 12, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. Use of the crystalline form according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 14, for the preparation of a G protein-coupled receptor modulator, in particular for the preparation of a dopamine D3 receptor and 5-HT2A receptor modulator medicament.

16. Use of a crystalline form according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the treatment or prevention of a central nervous system disease and/or a psychiatric disease or disorder; the nervous system disease and/or mental disease is preferably diseases such as schizophrenia, sleep disorder, mood disorder, schizophrenia spectrum disorder, spastic disorder, memory disorder and/or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus, depression, autism, senile dementia, alzheimer's disease, epileptic seizure, neuralgia or drug withdrawal symptom major depression and mania.