Modulator of four-membered ring derivatives, preparation method and use thereof

Abstract

Modulators of four-membered ring derivatives, preparation methods, and uses thereof are provided. In particular, compounds represented by general formula (IX-A), preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof as G protein-coupled receptor modulators in the treatment or prevention of central nervous system disorders and / or psychiatric disorders are provided. The definitions of each substituent in general formula (IX-A) are the same as those defined herein. TIFF2022554130000151.tif53142

Description

[Technical Field]

[0001] The present invention is in the field of drug synthesis, and in particular relates to four-membered ring derivative inhibitors, methods for preparing same, and uses thereof. [Background technology]

[0002] The dopamine D3 receptor is a member of the G protein-coupled receptor family and a subtype of dopamine receptor. It belongs to the D2-like inhibitory receptor family, along with dopamine D2 and D4 receptors. Upon binding to DA, it inhibits G proteins, thereby reducing cAMP levels. D3 receptors are primarily distributed in the mesolimbic system, particularly in the nucleus accumbens, olfactory tubercle, and islet of Calleja, which are not involved in motor function. Highly active D3 receptor modulators may also have potent antipsychotic activity. D3 receptors are closely related to mood, cognition, temperament, and addiction, and can improve negative symptoms in schizophrenic patients. D3 receptors can play a regulatory role in cognition by regulating acetylcholine release and glutamate receptors. Partial agonism of the D3 receptor can improve cognition.

[0003] 5-hydroxytryptamine 2A (5-HT2A) receptors are members of the G protein-coupled receptor family and are the major excitatory receptor subtype of 5-HT receptors. They are distributed centrally and peripherally and are closely related to temperament, emotion, learning, memory, etc. Highly active 5-HT2A receptor inhibitors have significant anti-schizophrenic effects and can reduce extrapyramidal side effects.

[0004] Schizophrenia is the most prevalent mental illness with a slow course, prone to repeated attacks, exacerbations, or deteriorations, resulting in serious burdens and adverse consequences for patients and their families. Psychopaths may experience positive symptoms, such as delusions, hallucinations, and disorders of thought, language, and behavior, as well as negative symptoms, such as lack of affect and expression, insufficient speech, lack of pleasure, and other symptoms, including cognitive impairment. Although the research, development, and clinical use of anti-schizophrenic drugs have made significant progress in the past few decades, both conventional antipsychotics (first generation) (such as haloperidol, droperidol, and thioridazine) and atypical antipsychotics (second generation) (such as clozapine, risperidone, olanzapine, and aripiprazole) are effective in treating positive symptoms but are insufficient in improving negative symptoms and cognitive impairment. Therefore, there is an urgent need to develop anti-schizophrenic drugs that can improve not only positive symptoms but also negative symptoms and cognitive impairment. Highly active dopamine D3 receptor modulators can improve negative symptoms, positive symptoms and cognitive impairment in patients with schizophrenia without the side effects of first and second generation antipsychotics, such as extrapyramidal symptoms and weight gain.

[0005] D3 receptor antagonists or partial agonists have excellent efficacy in improving the positive symptoms, negative symptoms, and cognitive impairment of schizophrenia. International Patent Applications WO2007093540, WO2009013212A2, WO2010031735A1, and WO2012117001A1 disclose the D3 receptor and 5HT 2A reported a dual modulator compound, but it did not modulate the D3 receptor and 5HT 2A The maximum binding activity (Ki) of the compound to 5HT exceeds 10 nM. International patent application WO2014086098A1 filed by Jiangsu Hengyi Pharmaceutical Co., Ltd. reports a D3 selective inhibitor, but 2ANo studies on the binding activity to D3 receptors have been reported. Cariprazine, a D3 antagonist developed by Gedeon Richter, became available in 2015, and International Patent Application WO2005012266A1 was filed. Cariprazine has potent D3 receptor agonist activity, and its use in treating the negative symptoms of schizophrenia offers significant advantages over existing drugs. However, cariprazine has weak inhibitory activity against the 5-HT2A receptor, resulting in serious side effects such as extrapyramidal symptoms (ESP). Therefore, the development of 5HT2A inhibitors to reduce the side effects of extrapyramidal symptoms and improve the effects on negative symptoms and cognitive improvement in schizophrenia is being pursued. 2A There is an urgent need to develop highly active D3 receptor modulators with optimized binding activity. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Patent Application No. WO2007093540 [Patent Document 2] International Patent Application No. WO2009013212A2 [Patent Document 3] International Patent Application No. WO2010031735A1 [Patent Document 4] International Patent Application No. WO2012117001A1 [Patent Document 5] International Patent Application No. WO2014086098A1 [Patent Document 6] International Patent Application No. WO2005012266A1 [Patent Document 7] Patent application number PCT / CN2020 / 073153 Summary of the Invention [Means for solving the problem]

[0007] The entire contents of Patent Application No. PCT / CN2020 / 073153 are incorporated herein by reference.

[0008] The object of the present invention is to provide a compound of formula (IX-A), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (IX-A) is as follows:

[0009] [ka]

[0010] During the ceremony, R4 is a 5-6 membered N-containing heterocyclyl;

[0011] [ka]

[0012] wherein the 5-6 membered N-containing heterocyclyl is preferably oxazolidinonyl; R a is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R b is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkoxy, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 The aryl and 5- to 12-membered heteroaryl are each optionally selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R5 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, hydrogen, cyano, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 cycloalkyl; More preferably, selected from the group consisting of hydrogen and chlorine; or any two adjacent R5s combine to form a 5- or 6-membered heterocyclyl or a 5- or 6-membered heteroaryl; Preferably, it forms a 5-6 membered heteroaryl containing 1 to 2 N, S or O heteroatoms, more preferably thienyl; r is 0, 1 or 2; m is 0 or 1; t is 0, 1, 2 or 3, preferably 2.

[0013] The present invention also provides

[0014] [ka]

[0015] but

[0016] [ka]

[0017] and m is 1, then R4 is not:

[0018] [ka]

[0019] , -NHC(O)C2H5, -NHC(O)N(CH3)2, -NHC(O)NHCH3, -NHC(O)NC2H5CH3, -NHC(O)NHC2H5,

[0020] [ka]

[0021] The present invention also relates to a compound represented by formula (X) or formula (XA):

[0022] [ka]

[0023] (In the formula, R4 and m are as defined in formula (IX-A). Also provided are preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0024] In another preferred embodiment of the present invention, R4 is a 5-6 membered N-containing heterocyclyl,

[0025] [ka]

[0026] wherein the 5-6 membered N-containing heterocyclyl is preferably oxazolidinonyl; R a is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, R a is hydrogen, cyano, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 cycloalkyl; More preferably, R a is selected from the group consisting of hydrogen and methyl; Rb is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 The aryl and 5- to 12-membered heteroaryl are each optionally selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, R b is amino, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl; 1~3 Alkyl, C1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are each optionally selected from hydrogen, halogen, hydroxy, cyano, C 1~3 Alkyl and C 1~3 further substituted by one or more substituents selected from the group consisting of alkoxy; More preferably, R b is selected from the group consisting of amino, methyl, ethyl, methoxy, hydroxyisopropyl, cyclopropyl, azetidinyl, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolyl, and benzoxazolyl, wherein amino, methyl, ethyl, methoxy, hydroxyisopropyl, cyclopropyl, azetidinyl, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolyl, and benzoxazolyl are each optionally further substituted by one or more substituents selected from the group consisting of hydrogen, fluorine, cyano, hydroxy, methyl, and methoxy; r is 0, 1 or 2.

[0027] The present invention also relates to a compound represented by the formula (IX-A), wherein the compound represented by the formula (XI)

[0028] [ka]

[0029] (In the formula, R6 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R7 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, R ee , -C(O)(CH2) n2 R ee , -(CH2) n2 C(O)NR ee R ff , -C(O)NR ee R ff , -(CH2) n2 C(O)NR ee C(O)R ff , -(CH2) n2 S(O) m2 R ee , -(CH2) n2 NR ee S(O) m2 R ff , -(CH2) n2 S(O) m2 NR ee R ff , -(CH2) n1 S(O) m2 NR ee R ff , -(CH2) n2 OR ee , -C(O)NR ee (CH2) n2 R ff , -C(O)(CH2) n2 OR ee , -(CH2) n2 SR ee , -(CH2) n2 C(O)OR ee , -P(O)R ee R ff , -(CH2) n2NR ee C(O)R ff and -(CH2) n2 NR ee S(O) m2 R ff C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 The aryl and 5- to 12-membered heteroaryl are each optionally substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 R is further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl, preferably 5- to 10-membered heteroaryl, ee , -C(O)(CH2) n2 R ee , -C(O)NR ee R ff , -C(O)NR ff (CH2) n2 R ee , -S(O) m2 R ee and -S(O) m2 NR ee R ff selected from the group consisting of: R ee and R ff are hydrogen, amino, and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl; 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 The aryl and 5- to 14-membered heteroaryl are each optionally selected from hydrogen, halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 further substituted by one or more substituents selected from the group consisting of alkoxy; Preferably, R ee and R ff are amino and C, respectively. 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 independently selected from the group consisting of cycloalkyl, phenyl, naphthyl, biphenyl, 4- to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms, and 5- to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, or sulfur atoms; 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 Cycloalkyl, phenyl, naphthyl, biphenyl, 4- to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms, and 5- to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, or sulfur atoms each optionally include halogen, hydroxy, cyano, oxo, C 1~6 Alkyl and C 1~6 substituted by one or more substituents selected from the group consisting of alkoxy; More preferably, R ee and R ff are respectively, (CH3)2N-, CH3NH-, CH3-, CH3CH2-, CH3CH2NH-, CH3CH2NCH3-, (CH3)2COH-, (CH3)2COHCH2-, CH3OCH2-,

[0030] [ka]

[0031] independently selected from the group consisting of: n2 is selected from the group consisting of 0, 1 and 2; m2 is selected from the group consisting of 0, 1 and 2; m is selected from the group consisting of 0, 1 and 2. Also provided are preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0032] In another preferred embodiment of the present invention, R ee and R ff are each independently selected from the group consisting of hydrogen and the following substituents:

[0033] [ka]

[0034] The present invention also provides a preferred embodiment, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (XI) is as shown in formula (XI-A) or formula (XI-B):

[0035] [ka]

[0036] In a preferred embodiment of the present invention, R6 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 2~3 Alkenyl and C 2~3 alkynyl, preferably hydrogen; R7 is R ee , -C(O)(CH2) n2 R ee, -C(O)NR ee R ff , -C(O)NR ff (CH2) n2 R ee , -S(O) m2 R ee and -S(O) m2 NR ee R ff selected from the group consisting of: R ee is hydrogen, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl; 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 The aryl and 5- to 14-membered heteroaryl are each optionally selected from halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 further substituted by one or more substituents selected from the group consisting of alkoxy; Preferably, R ee is amino, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 cycloalkyl, phenyl, naphthyl, biphenyl, 4- to 6-membered heterocyclyl containing 1 to 2 oxygen, nitrogen, or sulfur heteroatoms, and 5- to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, or sulfur heteroatoms; 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 Cycloalkyl, phenyl, naphthyl, biphenyl, 4- to 6-membered heterocyclyl containing 1 to 2 oxygen, nitrogen, or sulfur heteroatoms, and 5- to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, or sulfur heteroatoms are each optionally selected from the group consisting of halogen, hydroxy, cyano, oxo, C1~6 Alkyl and C 1~6 substituted by one or more substituents selected from the group consisting of alkoxy; More preferably, R ee teeth, (CH3)2N-, CH3NH-, CH3-, CH3CH2-, CH3CH2NH-, CH3CH2NCH3-, (CH3)2C(OH)-, (CH3)2C(OH)CH2-, CH3OCH2-,

[0037] [ka]

[0038] selected from the group consisting of: R ff is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, R ff is hydrogen, cyano, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 cycloalkyl; More preferably, R ff is selected from the group consisting of hydrogen and methyl; n2 is selected from the group consisting of 0, 1 and 2; m2 is selected from the group consisting of 0, 1 and 2.

[0039] The present invention also provides

[0040] [ka]

[0041] but,

[0042] [ka]

[0043] Also provided is a preferred embodiment, a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

[0044] The present invention also relates to a compound represented by the formula (XI) of the formula (XII)

[0045] [ka]

[0046] (In the formula, R8 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12The aryl and 5- to 12-membered heteroaryl are each optionally selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, amino, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl; 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are each optionally selected from hydrogen, hydroxy, cyano, C 1~3 Alkyl and C 1~3 further substituted by one or more substituents selected from the group consisting of alkoxy; CH3O-, HOC(CH3)2-,

[0047] [ka]

[0048] further selected from the group consisting of: v is 0 or 1) Also provided are preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0049] The present invention also relates to a compound represented by the formula (XI) of the formula (XII)

[0050] [ka]

[0051] (In the formula, R8 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 The aryl and 5- to 12-membered heteroaryl are each optionally substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Preferably, amino, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl; 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl are each optionally selected from hydroxy, cyano, C 1~3 Alkyl, C 1~3 Alkoxy and C 3~6 is further substituted by one or more substituents selected from the group consisting of cycloalkyl; CH3O-, HOC(CH3)2-,

[0052] [ka]

[0053] further selected from the group consisting of: v is 0 or 1) Also provided are preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0054] The present invention also relates to a group in which when v is 0, R8 is -C2H5, -N(CH3)2, -NHCH3, -NC2H5CH3, -NHC2H5,

[0055] [ka]

[0056] Instead, Also provided is a preferred embodiment, a compound of formula (XII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein when v is 1, R8 is not phenyl.

[0057] The present invention also provides a preferred embodiment, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (XII) is as shown in formula (XII-A) or formula (XII-B):

[0058] [ka]

[0059] The present invention also provides R4,

[0060] [ka]

[0061] and; R b optionally deuterium, halogen, amino, hydroxy, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 1~3 C further substituted by one or more substituents selected from the group consisting of haloalkoxy 3~6 selected from the group consisting of cycloalkyl and 5-10 membered heteroaryl containing 1 to 2 nitrogen, oxygen, or sulfur atoms; R5 is hydrogen, halogen and C 1~3 selected from the group consisting of alkyl; m is 1; Also provided are preferred embodiments, compounds of formula (IX-A), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein t is 1, 2, or 3.

[0062] The present invention also relates to a compound in which r is 0 and R b but

[0063] [ka]

[0064] If R bis substituted by at least one substituent; r is 0 and R b but

[0065] [ka]

[0066] If R b Also provided is a preferred embodiment, a compound of formula (IX-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: is substituted by at least one substituent.

[0067] The present invention also provides R b However, optionally deuterium, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 1~3 C further substituted by one or more substituents selected from the group consisting of haloalkoxy 3~6 selected from the group consisting of cycloalkyl, nitrogen- or oxygen-containing 5- to 10-membered heteroaryl, and nitrogen-containing 9- to 10-membered fused heteroaryl; Also provided is a further preferred embodiment, a compound of formula (IX-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of hydrogen, halogen, methyl, and ethyl.

[0068] The present invention also provides R b Optionally, halogen, C 1~3 Alkyl and C 1~3 Also provided is a further preferred embodiment, a compound of formula (IX-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of haloalkyl, cyclopropyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, and quinolyl, which is further substituted by one or more substituents selected from the group consisting of haloalkyl, cyclopropyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, and quinolyl.

[0069] The compounds of the present invention not only have potent D3 receptor agonist activity, but also have significantly better inhibitory activity against 5-HT2A than cariprazine, leading to better clinical efficacy in treating negative symptoms of schizophrenia and significantly reduced risk of EPS side effects.

[0070] The present invention also provides a process for preparing a compound of formula (XII), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0071] [ka]

[0072] The present invention relates to a process comprising the step of reacting a compound of formula (XII-1) with an acyl chloride or carboxylic acid of formula (XII-2) to obtain a compound of formula (XII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0073] The present invention also relates to a compound of formula (XII-1), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0074] [ka]

[0075] The present invention also provides a process for preparing a compound of formula (XII-1), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising:

[0076] [ka]

[0077] Deprotecting the compound of formula (XII-3) to obtain a compound of formula (XII-1), its stereoisomer or a pharmaceutically acceptable salt thereof. wherein Pg1 is an amino protecting group selected from the group consisting of allyloxycarbonyl (Alloc), trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenemethoxycarbonyl (FMOC), p-toluenesulfonyl (Tos), formate, acetyl, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), benzyl (Bn), and p-methoxyphenyl (PMP), preferably tert-butoxycarbonyl (Boc).

[0078] The present invention also provides a process for preparing an intermediate compound of formula (XII-3), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising:

[0079] [ka]

[0080] Reacting a compound of formula (XII-4) with a compound of formula (XII-5) to obtain a compound of formula (XII-3), its stereoisomer or a pharmaceutically acceptable salt thereof. wherein wherein Pg2 is a hydroxy protecting group selected from the group consisting of methyl (-CH3), tert-butyl (-C(CH3)3), triphenyl (-CPh3), methylthiomethyl ether (MTM), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), pivaloyl (Piv), benzyl ether group (-CH2Ph), methoxymethyl (-CHOCH3), trimethylsilyl (-Si(CH3)3), tetrahydrofuranyl (-THP), tert-butyldisilyl (-SiMe2(t-Bu)), acetyl (-Ac), benzoyl (-COPh), and p-toluenesulfonyl (-SO2PhMe), preferably p-toluenesulfonyl.

[0081] The present invention also relates to pharmaceutical compositions comprising a therapeutically effective dose of a compound of the above general formula, a specific compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0082] The present invention also relates to the use of a compound of the above general formula, a specific compound, a stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a G protein-coupled receptor modulating drug, in particular a dopamine D3 receptor modulating drug and a 5-HT2A receptor modulating drug.

[0083] The present invention further relates to a method for treating inflammatory diseases with a compound of formula (IX-A), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0084] The present invention also relates to a method for treating and / or preventing a central nervous system disease and / or a psychiatric disease or disorder, comprising the step of administering to a patient a therapeutically effective dose of a compound of formula (IX-A), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0085] The present invention also provides methods for treating disease conditions, including but not limited to conditions associated with dopamine receptor modulators and 5-HT2A receptor modulators, by using compounds or pharmaceutical compositions according to the present invention.

[0086] The present invention also relates to a method for treating a neurological and / or psychiatric disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0087] In some embodiments, the methods include treatment of conditions such as cancer, bone diseases, inflammatory diseases, immune diseases, neurological diseases, metabolic diseases, respiratory diseases, and cardiac diseases.

[0088] In some embodiments, the methods include treatment and / or prevention of a central nervous system disease and / or psychiatric disease or disorder selected from the group consisting of schizophrenia, depression, a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal symptoms, tinnitus, depression, autism, senile dementia, Alzheimer's disease, seizures, neuralgia, drug withdrawal symptomatic major depressive disorder, and mania.

[0089] The treatment methods provided herein comprise administering to a subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides a method for treating a neurological disease and / or a psychiatric disorder in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0090] definition Unless otherwise specified, terms used in the specification and claims have the meanings set forth below.

[0091] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing from 1 to 20 carbon atoms; preferably, alkyl has 1 to 8 carbon atoms, more preferably, alkyl has 1 to 6 carbon atoms, and most preferably, alkyl has 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3 n-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0092] The term "alkylene" refers to an alkyl further substituted with a hydrogen atom; for example, "methylene" refers to -CH-, "ethylene" refers to -(CH)-, "propylene" refers to -(CH)-, "butylene" refers to -(CH)-, etc. The term "alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0093] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyls include cycloalkyls having spirocyclic, fused, or bridged rings. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl, more preferably cyclopropyl, cyclobutyl, and cyclohexyl.

[0094] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having individual rings connected through one shared carbon atom (called a spiro atom); the rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Spirocycloalkyls are preferably 6- to 14-membered spirocycloalkyls, more preferably 7- to 10-membered spirocycloalkyls. According to the number of spiro atoms shared between the rings, spirocycloalkyls can be divided into mono-spirocycloalkyls, dis-spirocycloalkyls, or poly-spirocycloalkyls; spirocycloalkyls are preferably mono-spirocycloalkyls or dis-spirocycloalkyls, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyls. Non-limiting examples of spirocycloalkyls include:

[0095] [ka]

[0096] and spirocycloalkyl, in which the cycloalkyl and heterocyclyl are bonded through a spiro atom, non-limiting examples of which include:

[0097] [ka]

[0098] The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group, in which each ring of the system shares an adjacent pair of carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Fused cycloalkyls are preferably 6- to 14-membered fused cycloalkyls, more preferably 7- to 10-membered fused cycloalkyls. According to the number of ring members, fused cycloalkyls can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyls, and fused cycloalkyls are preferably bicyclic or tricyclic fused cycloalkyls, more preferably 4-membered / 4-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyls. Non-limiting examples of fused cycloalkyls include the following:

[0099] [ka]

[0100] The term "bridged cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group, in which each two rings of the system share two unbonded carbon atoms, and the rings may have one or more double bonds, but none of the rings has a completely conjugated π-electron system. Bridged cycloalkyls are preferably 6- to 14-membered bridged cycloalkyls, more preferably 7- to 10-membered bridged cycloalkyls. According to the number of ring members, bridged cycloalkyls can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyls, and bridged cycloalkyls are preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls include the following:

[0101] [ka]

[0102] A cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocyclyl ring, where the ring attached to the parent structure is a cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. A cycloalkyl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0103] The term "heterocyclyl" refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen, boron, phosphorus, S(O), m (m is an integer from 0 to 2) and P(O) n(wherein n is an integer from 0 to 2), excluding -OO-, -OS-, or -SS- in the ring, the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, more preferably 3 to 8 ring atoms, and most preferably 3 to 8 ring atoms, with 1 to 4 atoms being heteroatoms. Non-limiting examples of monocyclic heterocyclyls include oxacyclobutyl, oxacyclobutyl, pyrrolidinyl, oxazolidin-2-one, azepinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxacyclobutyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, oxazolidin-2-one, morpholinyl, piperazinyl and azepinyl, more preferably oxacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl and oxazolidin-2-one. Polycyclic heterocyclyls include heterocyclyls having spiro, fused or bridged rings. Heterocyclyls having spiro, fused, or bridged rings are optionally bonded to other groups through a single bond, or further bonded to other cycloalkyls, heterocyclyls, aryls, and heteroaryls through any two or more atoms on the ring.

[0104] The term "spiroheterocyclyl" refers to a 3- to 20-membered polycyclic heterocyclyl group having individual rings joined through one common atom (called a spiroatom), where one or more of the ring atoms is nitrogen, oxygen, boron, phosphorus, S(O) m (m is an integer from 0 to 2) and P(O) n(n is an integer from 0 to 2), and the remaining ring atoms are carbon atoms, and may contain one or more double bonds, but neither ring has a completely conjugated π-electron system. Spiroheterocyclyl is preferably a 6- to 14-membered spiroheterocyclyl, more preferably a 7- to 10-membered spiroheterocyclyl. Depending on the number of spiro atoms shared between rings, spiroheterocyclyl can be divided into mono-spiroheterocyclyl, di-spiroheterocyclyl, or poly-spiroheterocyclyl. Spiroheterocyclyl is preferably a mono-spiroheterocyclyl or di-spiroheterocyclyl, more preferably a 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include the following:

[0105] [ka]

[0106] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms with another ring, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more ring atoms is selected from the group consisting of nitrogen, oxygen, and S(O). m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon atoms. The fused heterocyclyl is preferably a 6- to 14-membered fused heterocyclyl, more preferably a 7- to 10-membered fused heterocyclyl. According to the number of ring members, the fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, and is preferably a bicyclic or tricyclic fused heterocyclyl, more preferably a 3-membered / 5-membered, 4-membered / 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include the following:

[0107] [ka]

[0108] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclyl group in which each two rings of the system share two non-bonded atoms, the rings may have one or more double bonds, but neither ring has a completely conjugated pi-electron system, and one or more ring atoms are selected from the group consisting of nitrogen, oxygen, and S(O). m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon atoms. The bridged heterocyclyl is preferably a 6- to 14-membered bridged heterocyclyl, more preferably a 7- to 10-membered bridged heterocyclyl. According to the number of ring members, the bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and the bridged heterocyclyl is preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyls include the following:

[0109] [ka]

[0110] A heterocyclyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0111] [ka]

[0112] A heterocyclyl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0113] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring having a conjugated π-electron system (i.e., each ring of the system shares an adjacent pair of carbon atoms with another ring of the system), preferably a 6- to 10-membered aryl, such as phenyl and naphthyl. Aryl is more preferably phenyl. An aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring. Non-limiting examples include:

[0114] [ka]

[0115] Aryl may be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0116] The term "heteroaryl" refers to a 5- to 14-membered heteroaromatic ring system having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 12-membered heteroaryl, more preferably 5- to 10-membered heteroaryl, and even more preferably 5- or 6-membered heteroaryl, and the heteroatoms are 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, etc., preferably pyridyl, thiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, pyrimidinyl, and thiazolyl, more preferably pyridyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, and pyrimidinyl. A heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0117] [ka]

[0118] Heteroaryl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0119] The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0120] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above.

[0121] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is defined above.

[0122] "Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, where alkyl is as defined above.

[0123] "Alkenyl" refers to the chain alkenyl, also known as an alkene group, which may be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0124] "Alkynyl" refers to (CH≡C-). Alkynyl may be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0125] "Hydroxy" refers to the group --OH.

[0126] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0127] "Amino" refers to the group -NH2.

[0128] "Cyano" refers to the radical -CN.

[0129] "Nitro" refers to the -NO2 group.

[0130] "Carboxy" refers to the group --C(O)OH.

[0131] "THF" refers to tetrahydrofuran.

[0132] "EtOAc" refers to ethyl acetate.

[0133] "MeOH" refers to methanol.

[0134] "DMF" refers to N,N-dimethylformamide.

[0135] "DIPEA" refers to diisopropylethylamine.

[0136] "TFA" refers to trifluoroacetic acid.

[0137] "MeCN" refers to acetonitrile.

[0138] "DMA" refers to N,N-dimethylacetamide.

[0139] "Et2O" refers to diethyl ether.

[0140] "DCE" refers to 1,2-dichloroethane.

[0141] "DIPEA" refers to N,N-diisopropylethylamine.

[0142] "NBS" refers to N-bromosuccinimide.

[0143] "NIS" refers to N-iodosuccinimide.

[0144] "Cbz-Cl" refers to benzyl chloroformate.

[0145] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0146] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0147] "HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0148] "KHMDS" refers to potassium hexamethyldisilazide.

[0149] "LiHMDS" refers to lithium bis(trimethylsilyl)amide.

[0150] "MeLi" refers to methyllithium.

[0151] "n-BuLi" refers to n-butyllithium.

[0152] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0153] Different expressions such as "X is selected from the group consisting of A, B, or C," "X is selected from the group consisting of A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X may be any one or more of A, B, and C.

[0154] A hydrogen atom of the present invention may be replaced by its isotope, deuterium. Any hydrogen atom in the example compounds of the present invention may be replaced by a deuterium atom.

[0155] "Optional" or "optionally" means that the described event or circumstance may or may not occur thereafter, and such a description includes situations in which the event or circumstance occurs or does not occur. For example, "heterocyclyl optionally substituted by alkyl" means that the alkyl group may or may not be present, and such a description includes situations in which the heterocyclyl is substituted by alkyl and situations in which the heterocyclyl is not substituted by alkyl.

[0156] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3, being independently replaced with a corresponding number of substituents. It goes without saying that substituents are present only at possible chemical positions. Those skilled in the art can determine whether a substitution is possible or not by experiment or theory without undue effort. For example, the combination of an amino or hydroxyl group having free hydrogen with a carbon atom having an unsaturated bond (such as an olefin) may be unstable.

[0157] A "pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism, which aids in the absorption of the active ingredient so that it exerts its biological activity.

[0158] In general, the compound of formula (IX-A) or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount by any accepted mode of administration for drugs having similar uses. The therapeutically effective amount of a compound of the present disclosure may range from about 0.01 to about 500 mg / kg of patient body weight per day, which may be administered in a single dose or multiple doses. Suitable dosage levels may be from about 0.1 to about 250 mg / kg per day, from about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range, the dosage may be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg / kg per day. When administered orally, the composition may be provided in the form of a tablet containing from about 1.0 to about 1000 mg of the active ingredient, particularly about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7.5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient, preferably 0.1, 0.2, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7.5, 10, 15 and 20 mg of the active ingredient. The actual amount of compound of the present disclosure, i.e., the active ingredient, will depend on many factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound used, and the route and form of administration.

[0159] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective in mammals and possesses the desired biological activity. DETAILED DESCRIPTION OF THE INVENTION

[0160] The present invention will now be further described with reference to the following examples, which should not be construed as limiting the scope of the invention. [Example]

[0161] The structures of the compounds of the present invention were characterized by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 instrument. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0162] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. High-performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18, 150 × 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18, 150 × 4.6 mm chromatography column).

[0163] Thin-layer silica gel chromatography (TLC) plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The size of the silica gel plates used for TLC was 0.15 mm to 0.2 mm, and the size of the silica gel plates used for product purification was 0.4 mm to 0.5 mm. Yantai Huanghai 200-300 mesh silica gel was generally used as the support for column chromatography.

[0164] The starting materials used in the examples of the present invention are known and commercially available or can be synthesized by adapting or following methods known in the art.

[0165] Unless otherwise specified, all reactions of this invention were carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, solvents were anhydrous, and reaction temperatures were in degrees Celsius.

[0166] Example 1 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

[0167] [ka]

[0168] Step 1: 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

[0169] [ka]

[0170] Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexan-1-amine (60 mg, 0.162 mmol) and triethylamine (50 mg, 0.49 mmol) were added to DCM (3 mL). CDI (29 mg, 0.178 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. Benzylamine (36 mg, 0.324 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative chromatography to give 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea as a white solid (10 mg, yield: 12%). 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 5H), 7.18 - 7.04 (m, 2H), 6.97 (d, J = 6.9 Hz, 1H), 4.58 (s, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 7.5 Hz, 1H), 3.48 (s, 1H), 3.11-2.79 (m, 8H), 2.00 (s, 2H), 1.79-1.64 (m, 4H), 1.33 - 1.00 (m, 9H). MS m / z (ESI): 503.2 [M+H] + .

[0171] Example 2 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0172] [ka]

[0173] Step 1: tert-butyl (3-oxocyclobutyl)carbamate

[0174] [ka]

[0175] 3-Oxocyclobutane-1-carboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol), and toluene (30 mL) were added sequentially to a 100 mL eggplant-shaped flask. Diphenylphosphoryl azide (4.0 g, 14.5 mmol) was added slowly at -5 to 0 °C. The reaction solution was stirred at 0 °C for 16 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate (30 mL x 1) and saturated aqueous sodium chloride (30 mL x 1) at 0 °C, and the organic phase was dried over anhydrous sodium sulfate. tert-Butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100 °C and stirred for 16 hours. The reaction solution was concentrated to dryness by rotary evaporation to obtain the 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 (400 MHz, CDCl3) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50 - 3.33 (m, 2H), 3.11 - 2.97 (m, 2H), 1.46 (s, 9H).

[0176] Step 2: Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene)acetate

[0177] [ka]

[0178] tert-Butyl (3-oxocyclobutyl)carbamate (450 mg, 2.43 mmol) and toluene (20 mL) were added sequentially to a 50 mL eggplant-shaped flask, followed by the slow addition of methyl (triphenylphosphoranylidene)acetate (1.22 g, 3.64 mmol). The reaction solution was refluxed under a nitrogen atmosphere for 16 hours, cooled, and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 6 / 1) to obtain methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene)acetate (450 mg, yield: 76.8%). 1 H NMR (400 MHz, CDCl3) δ 5.76 - 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).

[0179] Step 3: Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)acetate

[0180] [ka]

[0181] Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene)acetate (450 mg, 1.9 mmol) and methanol (10 mL) were added sequentially to a 50 mL eggplant-shaped flask. Pd / C (45 mg, containing 10% palladium and 50% water) was added slowly under a nitrogen atmosphere. The reaction solution was stirred under a hydrogen atmosphere (1 atm) for 5 hours, filtered, concentrated to dryness by rotary evaporation, and the solvent was removed to give the crude product, 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] + .

[0182] Step 4: tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate

[0183] [ka]

[0184] Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)acetate (450 mg, 1.9 mmol) and anhydrous tetrahydrofuran (10 mL) were added sequentially to a 50 mL eggplant-shaped flask. Lithium aluminum hydride (210 mg, 5.6 mmol) was added slowly at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 2 hours and quenched with saturated aqueous sodium bicarbonate. The reaction solution was directly dried over anhydrous sodium sulfate and stirred for 15 minutes. The organic phase was filtered, concentrated by rotary evaporation, and dried to give crude product 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] + .

[0185] Step 5: 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate

[0186] [ka]

[0187] tert-Butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate (450 mg, 2.1 mmol), triethylamine (634 mg, 6.3 mmol), and dichloromethane (10 mL) were added successively to a 50 mL eggplant-shaped flask, followed by the slow addition of 4-tosyl chloride (438 mg, 2.3 mmol). The reaction solution was stirred overnight at room temperature, followed by the addition of dichloromethane (20 mL) and washing with water (30 mL × 1). The organic phase was dried and concentrated by rotary evaporation to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (710 mg, yield: 84%). MS m / z(ESI):370.2 [M+H] + .

[0188] Step 6: tert-butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate

[0189] [ka]

[0190] 2-(3-((tert-Butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (350 mg, 0.95 mmol), potassium carbonate (392 mg, 2.84 mmol), and acetonitrile (10 mL) were added successively to a 50 mL eggplant-shaped flask, followed by the slow addition of 1-(2,3-dichlorophenyl)piperazine (219 mg, 0.95 mmol). The reaction solution was refluxed overnight. The reaction solution was cooled, followed by the addition of dichloromethane (20 mL) and washing with water (30 mL x 3). The organic phase was dried and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 50 / 1) to give tert-butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (310 mg, yield: 76%). MS m / z(ESI):428.2 [M+H] + .

[0191] Step 7: 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride

[0192] [ka]

[0193] tert-Butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (310 mg, 0.72 mmol) and ethyl acetate (2 mL) were added sequentially to a 25 mL recovery flask, followed by the addition of hydrochloric acid (10 mL, 4 M) in ethyl acetate at 0° C. The reaction solution was stirred at room temperature for 1 hour, concentrated to dryness by rotary evaporation, and the solvent was removed to give the crude product, 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (310 mg), which was used directly in the next step. MS m / z(ESI):328.1 [M+H] + .

[0194] Step 8: 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0195] [ka]

[0196] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.11 mmol), triethylamine (69 mg, 0.69 mmol), and dichloromethane (2 mL) were added sequentially to a 10 mL reaction flask, followed by the addition of dimethylcarbamoyl chloride (18.4 mg, 0.17 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, concentrated to dryness by rotary evaporation, and the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (11 mg, yield: 24%). 1 H NMR (400 MHz, CDCl3) δ 7.23 - 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] + .

[0197] Example 2A 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0198] [ka]

[0199] Step 1: trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (Intermediate 2-1) and cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (Intermediate 2-2)

[0200] [ka]

[0201] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride was separated to give trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (2-1) and cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (2-2).

[0202] [Table 1]

[0203] Intermediate 2-1:t R =1.285 minutes 1 H NMR (400 MHz, chloroform-d) δ 7.18 - 7.12 (m, 2H), 6.99 - 6.93 (m, 1H), 3.63 - 3.53 (m, 1H), 3.16 - 3.02 (m, 4H), 2.74 - 2.54 (m, 4H), 2.39 - 2.30 (m, 2H), 2.26 - 2.13 (m, 1H), 2.06 - 1.99 (m, 2H), 1.99 - 1.93 (m, 2H), 1.91 - 1.84 (m, 2H), 1.72 - 1.64 (m, 2H). MS m / z (ESI): 328.1 [M+H] + .

[0204] Intermediate 2-2:t R =0.882 minutes 1 H NMR (400 MHz, chloroform-d) δ 7.18 - 7.11 (m, 2H), 7.00 - 6.93 (m, 1H), 3.33 - 3.22 (m, 1H), 3.13 - 3.00 (m, 4H), 2.71 - 2.56 (m, 4H), 2.51 - 2.43 (m, 2H), 2.37 - 2.30 (m, 2H), 2.07 - 1.97 (m, 2H), 1.89 - 1.75 (m, 1H), 1.67 - 1.58 (m, 2H), 1.39 - 1.28 (m, 2H). MS m / z (ESI): 328.1 [M+H] + .

[0205] Step 2: 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0206] [ka]

[0207] According to the reaction conditions of step 8 of example 2, intermediate 2-1 was used as the starting material, and 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea was obtained accordingly. 1H NMR (400 MHz, chloroform-d) δ 7.23 - 7.07 (m, 2H), 7.07 - 6.91 (m, 1H), 4.49 (d, J = 7.1 Hz, 1H), 4.44 - 4.28 (m, 1H), 3.53 - 3.03 (m, 5H), 2.90 (s, 6H), 2.82 - 2.61 (m, 3H), 2.51 - 2.35 (m, 2H), 2.27 - 2.10 (m, 3H), 2.08 - 1.95 (m, 2H), 1.88 - 1.72 (m, 2H). MS m / z (ESI): 399.1[M+H] + .

[0208] Example 2B 3-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0209] [ka]

[0210] According to the reaction conditions of step 8 of example 2, intermediate 2-2 was used as the starting material, and 3-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea was obtained accordingly. 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 6.7, 2.8 Hz, 1H), 4.41 (d, J = 7.5 Hz, 1H), 4.21 - 4.08 (m, 1H), 3.21 - 3.04 (m, 4H), 2.89 (s, 6H), 2.81 - 2.59 (m, 4H), 2.53 (dd, J = 9.6, 7.0 Hz, 2H), 2.45 - 2.32 (m, 2H), 1.99 - 1.88 (m, 1H), 1.70 - 1.65 (m, 2H), 1.47 - 1.39 (m, 2H). MS m / z (ESI): 399.1[M+H] + .

[0211] Example 3 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide

[0212] [ka]

[0213] Step 1: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide

[0214] [ka]

[0215] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.11 mmol), diisopropylethylamine (88 mg, 0.69 mmol), and dichloromethane (10 mL) were added successively to a 10 mL reaction flask, followed by the addition of propionyl chloride (12.7 mg, 0.14 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours and washed with water. The organic phase was dried and concentrated by rotary evaporation to dryness, and the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide (18 mg, yield: 41%). MS m / z(ESI): 384.2[M+H] + .

[0216] Example 4 1-Cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea

[0217] [ka]

[0218] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (33 mg, 0.09 mmol), triethylamine (46 mg, 0.45 mmol), and N′N-carbonyldiimidazole (22 mg, 0.16 mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 2 hours, and the raw material disappeared. Cyclopropylamine (10 mg, 0.18 mmol) was added, and the reaction solution was stirred at 35° C. for 48 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the obtained crude product was purified 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 (400 MHz, CDCl3) δ 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 7.0, 2.4 Hz, 1H), 5.08 (dd, J = 28.8, 7.3 Hz, 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, 2.8 Hz, 2H), 2.43 (s, 3H), 2.05 (dddd, J = 33.4, 24.1, 16.7, 8.5 Hz, 4H), 1.83 - 1.68 (m, 2H), 1.48 (dt, J = 9.6, 6.0 Hz, 2H), 0.76 (q, J = 6.3 Hz, 2H), 0.61 - 0.53 (m, 2H). MS m / z (ESI): 411.2[M+H] + .

[0219] Example 5 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxamide

[0220] [ka]

[0221] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 1H-indole-2-carboxylic acid (30 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred overnight at room temperature and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high-performance liquid chromatography to give N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxamide. MS m / z(ESI): 471.2[M+H] + .

[0222] Example 6 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0223] [ka]

[0224] Step 1: tert-butyl (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)carbamate

[0225] [ka]

[0226] 2-(3-((tert-Butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (200 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol), and acetonitrile (10 mL) were added successively to a 50 mL eggplant-shaped flask, followed by the slow addition of 1-(benzo[b]thiophen-4-yl)piperazine (118 mg, 0.54 mmol). The reaction solution was refluxed overnight. The reaction solution was cooled, followed by the addition of dichloromethane (20 mL) and washing with water (30 mL × 3). The organic phase was dried and concentrated to dryness by rotary evaporation to obtain 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)cyclobutyl)carbamate (120 mg, yield: 53%). MS m / z(ESI):416.2 [M+H] + .

[0227] Step 2: 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride

[0228] [ka]

[0229] tert-Butyl (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (120 mg, 0.29 mmol) and ethyl acetate (1 mL) were added sequentially to a 25 mL recovery flask, followed by the addition of hydrochloric acid (6 mL, 4 M) in ethyl acetate at 0° C. The reaction solution was stirred at room temperature for 1 h, concentrated to dryness by rotary evaporation, and the solvent was removed to give the crude hydrochloride salt (110 mg), which was used directly in the next step. MS m / z(ESI):316.1 [M+H] + .

[0230] Step 3: 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

[0231] [ka]

[0232] 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.12 mmol), triethylamine (71 mg, 0.70 mmol), and dichloromethane (2 mL) were added sequentially to a 10 mL reaction flask, followed by the addition of dimethylcarbamoyl chloride (19 mg, 0.18 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, concentrated to dryness by rotary evaporation, and the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain 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] + .

[0233] Example 7 N-(3-(2-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)ethyl)cyclobutyl)furan-2-carboxamide

[0234] [ka]

[0235] The process was the same as in Example 2. MS m / z(ESI): 436.2[M+H] + .

[0236] Example 8 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carboxamide

[0237] [ka]

[0238] Following Step 8 of Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carboxamide (23 mg, white solid, yield: 28.3%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.21 - 7.12 (m, 2H), 7.01 - 6.96 (m, 2H), 6.39 (dd, J = 34.1, 8.0 Hz, 1H), 6.11 - 6.06 (m, 1H), 4.52 (dq, J = 84.5, 8.0 Hz, 1H), 3.23 - 3.05 (m, 4H), 2.76 (s, 4H), 2.59 (td, J = 7.4, 6.8, 2.2 Hz, 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, 2.8 Hz, 2H). MS m / z (ESI): 436.1 [M+H] + .

[0239] Example 9 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide

[0240] [ka]

[0241] Following Step 8 of Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide (29 mg, white solid, yield: 33%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.19 - 7.12 (m, 2H), 6.97 (dd, J = 7.0, 2.5 Hz, 1H), 6.63 (dd, J = 42.2, 8.2 Hz, 1H), 4.42 (dq, J = 87.5, 7.9 Hz, 1H), 3.86 (d, J = 4.7 Hz, 2H), 3.42 (d, J = 2.5 Hz, 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] + .

[0242] Example 10 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)nicotinamide

[0243] [ka]

[0244] According to Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)nicotinamide (25 mg, white solid, yield: 29%) was obtained.

[0245] The compound of Example 10 can also be obtained according to the synthesis method of Example 5. 1H NMR (400 MHz, chloroform-d) δ 8.97 (d, J = 2.2 Hz, 1H), 8.72 (dd, J = 4.8, 1.8 Hz, 1H), 8.12 (dq, J = 8.0, 2.0 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.19 - 7.12 (m, 2H), 6.97 (dt, J = 7.0, 2.7 Hz, 1H), 6.41 (dd, J = 14.4, 7.5 Hz, 1H), 4.85 - 4.34 (m, 1H), 3.12 (t, J = 5.0 Hz, 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] + .

[0246] Example 11 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropanamide

[0247] [ka]

[0248] According to Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropanamide (32 mg, white solid, yield: 30%) was obtained.

[0249] The compound of Example 11 can also be obtained according to the synthesis method of Example 5. MS m / z(ESI): 414.1 [M+H] + .

[0250] Example 12 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-carboxamide

[0251] [ka]

[0252] According to Example 4, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-carboxamide (22 mg, white solid, yield: 23%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.18 - 7.12 (m, 2H), 6.96 (dd, J = 7.1, 2.6 Hz, 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, 7.8 Hz, 2H), 1.44 (td, J = 9.2, 2.9 Hz, 1H). MS m / z (ESI): 441.1 [M+H] + .

[0253] Example 13 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0254] [ka]

[0255] 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 1-hydroxycyclopropane-1-carboxylic acid (18 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred overnight at room temperature and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high-performance liquid chromatography to give N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide (13 mg, white solid, yield: 21%). 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.12 (m, 2H), 7.07 (dd, J = 28.3, 8.0 Hz, 1H), 6.96 (dd, J = 7.1, 2.5 Hz, 1H), 4.38 (dq, J = 87.6, 7.9 Hz, 1H), 3.20 - 3.05 (m, 4H), 2.72 (s, 4H), 2.56 (dd, J = 8.9, 2.9 Hz, 1H), 2.41 (dd, J = 9.5, 6.3 Hz, 2H), 2.25 (d, J = 8.4 Hz, 1H), 2.19 - 2.06 (m, 2H), 1.99 (dd, J = 14.2, 6.4 Hz, 1H), 1.82 - 1.69 (m, 2H), 1.55 (dd, J = 9.1, 2.9 Hz, 1H), 1.35 - 1.30 (m, 2H), 1.01 (q, J = 4.6 Hz, 2H). MS m / z (ESI): 412.1 [M+H] + .

[0256] Example 13A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0257] [ka]

[0258] According to the reaction conditions of Example 13, intermediate 2-1 was used as the starting material, and N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide was obtained accordingly. 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.13 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.97 (dd, J = 7.0, 2.6 Hz, 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] + .

[0259] Example 13B N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide

[0260] [ka]

[0261] According to the reaction conditions of Example 13, intermediate 2-2 was used as the starting material, and N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide (13B) was obtained accordingly. 1 H NMR (400 MHz, chloroform-d) δ 7.24 - 7.15 (m, 2H), 7.09 (d, J = 7.8 Hz, 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). MS m / z (ESI): 412.1 [M+H] + .

[0262] Example 14 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide

[0263] [ka]

[0264] 3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of thiazole-2-carboxylic acid (23 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred overnight at room temperature and concentrated to dryness by rotary evaporation. The resulting crude product was purified 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 (400 MHz, chloroform-d) δ 7.86 (dd, J = 3.1, 1.5 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 42.4, 8.2 Hz, 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] + .

[0265] Example 14A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide

[0266] [ka]

[0267] According to the reaction conditions of Example 14, intermediate 2-1 was used as the starting material, and N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide (21 mg, white solid, yield: 32%) was obtained accordingly. 1 H NMR (400 MHz, chloroform-d) δ 7.86 (d, J = 3.1 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.45 (d, J = 8.0 Hz, 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] + .

[0268] Example 15 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-hydroxy-3-methylbutanamide

[0269] [ka]

[0270] According to Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-hydroxy-3-methylbutanamide (21 mg, white solid, yield: 20%) was obtained.

[0271] The compound of Example 15 can also be obtained according to the synthesis method of Example 5. 1H NMR (400 MHz, chloroform-d) δ 7.21 - 7.13 (m, 2H), 6.96 (dd, J = 7.0, 2.7 Hz, 1H), 6.08 (dd, J = 21.6, 7.5 Hz, 1H), 4.51 - 4.19 (m, 2H), 3.10 (d, J = 6.2 Hz, 4H), 2.76 - 2.62 (m, 4H), 2.56 (ddd, J = 8.9, 5.9, 2.7 Hz, 1H), 2.42 - 2.36 (m, 2H), 2.29 (d, J = 6.4 Hz, 2H), 2.05 - 1.96 (m, 3H), 1.72 (dq, J = 28.0, 7.6 Hz, 2H), 1.51 (td, J = 9.1, 2.8 Hz, 1H), 1.27 (d, J = 2.2 Hz, 6H). MS m / z (ESI): 428.1 [M+H] + .

[0272] Example 16 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(5-methyloxazol-2-yl)acetamide

[0273] [ka]

[0274] According to Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(5-methyloxazol-2-yl)acetamide (15 mg, white solid, yield: 16%) was obtained.

[0275] The compound of Example 16 can also be obtained according to the synthesis method of Example 5. MS m / z(ESI): 451.1 [M+H] + .

[0276] Example 17 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(3-methylisoxazol-5-yl)acetamide

[0277] [ka]

[0278] According to Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(3-methylisoxazol-5-yl)acetamide (26 mg, white solid, yield: 28%) was obtained.

[0279] The compound of Example 17 can also be obtained according to the synthesis method of Example 5. MS m / z(ESI): 451.1 [M+H] + .

[0280] Example 18 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide

[0281] [ka]

[0282] 3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (40 mg, 0.11 mmol), triethylamine (44 mg, 0.44 mmol), and cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 12 hours, concentrated to dryness by rotary evaporation, and the solvent was removed. The resulting crude product was purified 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 (400 MHz, CDCl3) δ 7.20 - 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 = 4.8 Hz, 2H), 0.99 (q, J = 6.8 Hz, 2H). MS m / z (ESI): 432.0 [M+H] + .

[0283] Example 19 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea

[0284] [ka]

[0285] According to Example 6, 1-(benzo[b]thiophen-4-yl)piperazine was used as the starting material, and 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea was obtained accordingly. 1H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 3.7 Hz, 2H), 7.31 - 7.26 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.54 - 4.09 (m, 2H), 3.41 - 3.15 (m, 6H), 2.85 (d, J = 4.0 Hz, 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] + .

[0286] Example 20 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide

[0287] [ka]

[0288] Following Step 1 of Example 3, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (white solid, yield: 26%) was obtained.

[0289] The compound of Example 20 can also be obtained by the following method.

[0290] [ka]

[0291] 3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature, followed by the addition of oxazole-2-carboxylic acid (20 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred overnight at room temperature and concentrated to dryness by rotary evaporation. The resulting crude product was purified 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 (400 MHz, chloroform-d) δ 7.79 (d, J = 1.9 Hz, 1H), 7.24 - 7.14 (m, 4H), 6.98 (m, 2.0 Hz, 1H), 4.68 - 4.59 (m, 0.3H), 4.48 - 4.38 (m, 0.7H), 3.26 - 3.15 (m, 4H), 2.98 - 2.81 (m, 4H), 2.64 - 2.56 (m, 2H), 2.22 (t, J = 7.0 Hz, 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] + .

[0292] (Example 20A and Example 20B) N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (20A)

[0293] N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (20B)

[0294] [ka]

[0295] The compound of Example 20 was separated to give N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (20A) and N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (20B). The mass ratio of 20A to 20B was approximately 1:2.

[0296] [Table 2]

[0297] Example 20A:t R =2.473 minutes 1 H NMR (400 MHz, chloroform-d) δ 7.79 (s, 1H), 7.24 - 7.20 (m, 2H), 7.17 - 7.11 (m, 2H), 6.97 (dd, J = 6.4, 3.1 Hz, 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] + .

[0298] Example 20B:t R =1.782 minutes 1H NMR (400 MHz, chloroform-d) δ 7.79 (s, 1H), 7.22 (s, 1H), 7.19 - 7.10 (m, 3H), 6.97 (dd, J = 7.0, 2.5 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.28 - 3.03 (m, 4H), 2.84 - 2.67 (m, 4H), 2.67 - 2.54 (m, 2H), 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] + .

[0299] Example 21 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide

[0300] [ka]

[0301] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.16 (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] + .

[0302] Example 21A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide

[0303] [ka]

[0304] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material, and accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide (21A) (21 mg, white solid, yield: 25%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 7.22 - 7.09 (m, 2H), 7.02 - 6.90 (m, 1H), 6.71 (d, J = 7.5 Hz, 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] + .

[0305] Example 21B N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide

[0306] [ka]

[0307] According to the reaction conditions of Example 5, intermediate 2-2 was used as the starting material, and N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide (21B) was obtained accordingly. MS m / z(ESI): 437.1[M+H] + .

[0308] Example 22 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisoxazole-5-carboxamide

[0309] [ka]

[0310] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisoxazole-5-carboxamide (21 mg, white solid, yield: 32%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.21 - 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] + .

[0311] Example 23 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamide

[0312] [ka]

[0313] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamide (14 mg, white solid, yield: 22%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.46 (d, J = 1.6 Hz, 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] + .

[0314] Example 23A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamide

[0315] [ka]

[0316] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material, and N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamide (23A) (white solid) was obtained accordingly. 1H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 1.8 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.98 (dd, J = 6.7, 2.9 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.78 (d, J = 7.6 Hz, 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] + .

[0317] Example 24 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-5-carboxamide

[0318] [ka]

[0319] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-5-carboxamide was obtained. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.16 (dd, J = 7.2, 4.3 Hz, 2H), 6.96 (dd, J = 6.6, 2.8 Hz, 1H), 6.28 (d, J = 7.7 Hz, 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, 12.2 Hz, 2H), 2.02 (dd, J = 15.7, 8.3 Hz, 1H), 1.78 (dd, J = 15.3, 7.6 Hz, 1H), 1.71 - 1.55 (m, 3H). MS m / z (ESI): 437.1 [M+H] + .

[0320] Example 25 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxamide

[0321] [ka]

[0322] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxamide was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.7 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.02 - 6.93 (m, 1H), 6.91 (d, J = 1.6 Hz, 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] + .

[0323] Example 25A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxamide

[0324] [ka]

[0325] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material to obtain N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxamide accordingly. 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 1.4 Hz, 1H), 7.22-7.17(m, 2H), 7.00 (d, J = 6.8 Hz, 2H), 6.81 (d, J = 1.4 Hz, 1H), 4.64 (dd, J = 15.1, 7.5 Hz, 1H), 3.29 (s, 4H), 2.79-2.77 (m, 4H), 2.36 (s, 2H), 2.24 (d, J = 7.0 Hz, 2H), 2.01 (s, 1H), 1.60 (s, 4H). MS m / z (ESI): 423.1 [M+H] + .

[0326] Example 26 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-carboxamide

[0327] [ka]

[0328] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-carboxamide (white solid) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 1.6 Hz, 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] + .

[0329] Example 26A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-carboxamide

[0330] [ka]

[0331] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material to obtain N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-carboxamide accordingly. 1H NMR (400 MHz, chloroform-d) δ 8.06 (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] + .

[0332] Example 27 N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide

[0333] [ka]

[0334] Step 1 of Example 5 was followed to give N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide (35 mg, white solid). 1 H NMR (400 MHz, chloroform-d) δ 8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.76 (d, J = 8.7 Hz, 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, 2.0 Hz, 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] + .

[0335] Example 27A N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide

[0336] [ka]

[0337] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material to obtain N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide accordingly. 1 H NMR (400 MHz, chloroform-d) δ 8.96 (dd, J = 4.3, 1.7 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.25 - 8.14 (m, 1H), 7.69 (d, J = 5.0 Hz, 2H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.98 (dd, J = 7.2, 2.4 Hz, 1H), 6.29 (d, J = 7.5 Hz, 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] + .

[0338] Example 28 1-Cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methylurea

[0339] [ka]

[0340] Following Step 1 of Example 1, 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methylurea (43 mg, white solid, yield: 33%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.22 - 7.11 (m, 2H), 7.03 - 6.92 (m, 1H), 5.32 (dd, J = 36.5, 7.6 Hz, 1H), 4.45 - 4.10 (m, 1H), 3.25 - 3.02 (m, 4H), 2.88 (d, J = 1.7 Hz, 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] + .

[0341] Example 29 1-cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide

[0342] [ka]

[0343] Step 1 of Example 5 was followed to give 1-cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide (31 mg, white solid). 1 H NMR (400 MHz, chloroform-d) δ 7.19 - 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] + .

[0344] Example 30 (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropanamide

[0345] [ka]

[0346] Step 1: tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate

[0347] [ka]

[0348] According to step 1 of Example 2, 1-bromo-2,3-dichlorobenzene and tert-butyl (R)-3-methylpiperazine-1-carboxylate were used as starting materials, and accordingly tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate (600 mg, yellow solid, yield: 32.6%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.26–7.21 (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 = 6.3 Hz, 3H). MS m / z (ESI): 345.1 [M+H] + .

[0349] Step 2: (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine

[0350] [ka]

[0351] According to step 2 of example 2, tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate was used as the starting material, and accordingly (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%) was obtained. 1 H NMR (400 MHz, methanol-d4) δ 7.36–7.29 (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 = 6.3 Hz, 3H). MS m / z (ESI): 245.1 [M+H] + .

[0352] Step 3: (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutan-1-amine

[0353] [ka]

[0354] Steps 6 and 7 of Example 2 were followed to give (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutan-1-amine (280 mg). MS m / z(ESI): 342.1 [M+H] + .

[0355] Step 4: (R)—N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropanamide

[0356] [ka]

[0357] According to Example 5, (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropanamide (18 mg) was obtained. 1H NMR (400 MHz, chloroform-d) δ 7.25 - 7.20 (m, 1H), 7.16 (t, J = 7.9 Hz, 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 = 2.4 Hz, 6H), 0.90 (d, J = 6.2 Hz, 3H). MS m / z (ESI): 428.1 [M+H] + .

[0358] Biological Assays and Evaluation The invention is further described below in conjunction with the following test examples, which are not intended to limit the scope of the invention.

[0359] I. Radioligand-receptor binding assay Test Example 1. Determination of the binding ability of compounds of the present invention to dopamine D3 receptors

[0360] 1. Experimental Objective: The purpose of this test example is to determine the affinity of compounds for the dopamine D3 receptor.

[0361] 2.1 Experimental equipment: Vortex mixer (IKA; MS3 Basic) Electrically heated constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd.; DHP-9032) Microplate shaker (VWR; 12620-928) TopCount (PerkinElmer; NTX) Universal Harvester (PerkinElmer; UNIFILTER-96).

[0362] 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) 96 round deep-well plates, 1.1 mL (Perkin Elmer; P-DW-11-C) UNIFILTER-96GF / B filter plate (PerkinElmer; 6005174) Polyethyleneimine, branched (Sigma; 408727) Centrifuge tubes (BD, 352096; 352070) Loading slot (JET BIOFIL; LTT001050) Tray (JET BIOFIL; LTT001050) Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS) Magnesium chloride (Sigma, 7786-30-3) Tris base (Sigma, 77-86-1)

[0363] 3. Experimental Method: 0.5 to 5 μL of test compound (0.005 nM to 100 nM, a total of 10 concentrations) and 100 μL of buffer were added to a 96-well assay plate. 0.5 μL of cell membranes and 300 μL of buffer were added to each well. 3[H]-methylspiperone was added to the buffer and the plate was incubated at 27°C for 30 minutes. UNIFILTER-96GF / B filter plates preincubated with 0.5% PEI for 1 hour were washed twice with buffer (1 mL / well). The cell membrane suspension was added to the UNIFILTER-96GF / B filter plate, washed four times, and incubated at 55°C for 10 minutes. 40 μL of ULTIMA GOLD was added to each well and liquid scintillation counting was performed.

[0364] 4. Experimental data processing method: CPM (counts per minute) values ​​were measured by TopCount. 3 The percent inhibition of [H]-methylspiperone binding was calculated from the values ​​of the high control (DMSO control) experimental group and the low control (100 nM positive compound) experimental group {Inhibition % = (CPM サンプル -CPM 低対照 ) / (CPM 高対照 -CPM 低対照 ) × 100}. Ten concentrations of compound ranged from 100 nM to 0.005 nM after 3-fold dilution of the reaction system. Percent inhibition and 10-point concentration data were fit to a parametric nonlinear logistic equation by using GraphPad Prism to obtain the IC of the compound. 50 The value was calculated.

[0365] 5. Experimental results: The binding activity of the compounds of the present invention to D3 was determined by the above assay, and the obtained IC 50 The values ​​are shown in Table 1.

[0366] [Table 3]

[0367] 6. Experimental Conclusion: The compounds of the present invention have good affinity for the dopamine receptor D3.

[0368] Test Example 2. Determination of the binding ability of compounds of the present invention to 5-HT2A receptors 1. Experimental Objective: The purpose of this test example is to determine the affinity of compounds for the 5-HT2A receptor.

[0369] 2.1 Experimental equipment: Vortex mixer (IKA; MS3 Basic) Electrically heated constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd.; DHP-9032) Microplate shaker (VWR; 12620-928) TopCount (PerkinElmer; NTX) Universal Harvester (PerkinElmer; UNIFILTER-96).

[0370] 2.2 Experimental Reagents and Consumables: [ 3 H]-Ketanserin (PerkinElmer NET791) Human dopamine 5-HT2A receptor membrane (PerkinElmer) GR 103691 (Sigma; 162408-66-4) ULTIMA GOLD (Perkin Elmer; 77-16061) 96 round deep-well plates, 1.1 mL (Perkin Elmer; P-DW-11-C) UNIFILTER-96GF / B filter plate (PerkinElmer; 6005174) Polyethyleneimine, branched (Sigma; 408727) Centrifuge tubes (BD, 352096; 352070) Loading slot (JET BIOFIL; LTT001050) Tray (JET BIOFIL; LTT001050) Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS) Magnesium chloride (Sigma, 7786-30-3) Tris base (Sigma, 77-86-1)

[0371] 3. Experimental Method: 0.5 to 5 μL of test compound (0.005 nM to 100 nM, a total of 10 concentrations) and 100 μL of buffer were added to a 96-well assay plate. 0.5 μL of cell membranes and 300 μL of buffer were added to each well. 3 [H]-ketanserin was added to the buffer and the plate was incubated at 27°C for 30 minutes. UNIFILTER-96GF / B filter plates preincubated with 0.5% PEI for 1 hour were washed twice with buffer (1 mL / well). The cell membrane suspension was added to the UNIFILTER-96GF / B filter plate, washed four times, and incubated at 55°C for 10 minutes. 40 μL of ULTIMA GOLD was added to each well and liquid scintillation counting was performed.

[0372] 4. Experimental data processing method: CPM (counts per minute) values ​​were measured by TopCount. 3 The percent inhibition of [H]-ketanserin binding was calculated from the values ​​of the high control (DMSO control) experimental group and the low control (100 nM positive compound) experimental group {% inhibition = (CPM サンプル -CPM 低対照 ) / (CPM 高対照 -CPM 低対照 ) × 100}. Ten concentrations of compound ranged from 100 nM to 0.005 nM after 3-fold dilution of the reaction system. Percent inhibition and 10-point concentration data were fit to a parametric nonlinear logistic equation by using GraphPad Prism to obtain the IC of the compound. 50 The value was calculated.

[0373] 5. Experimental results: The binding activity of the compounds of the present invention to 5-HT2A was determined by the above assay, and the resulting IC 50 The values ​​are shown in Table 2.

[0374] [Table 4]

[0375] 6. Experimental Conclusion: The above data show that the compounds of the present invention have good affinity for 5-HT2A.

[0376] II. Cellular Function Assays Test Example 1. Determination of the effect of compounds of the present invention on cAMP content in cells stably expressing D3 receptors

[0377] 1. Experimental Objective: To determine the activating effect of the compounds on D3 receptors.

[0378] 2.1 Experimental equipment: 384-well assay plate (Perkin Elmer; 6007680) 96-well V-bottom PP plate, natural, RNASE / DNase-free (ThermoFisher; 249944) Pipette (Axygen) EnVision (Perkin Elmer).

[0379] 2.2 Experimental reagents: 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).

[0380] 3. Experimental Method: 1. Prepare buffer: 1x HBSS + 20mM HEPES + 0.1% BSA + 500µM IBMX. Complete medium: Ham's F12K + 10% fetal bovine serum + 1x penicillin-streptomycin + 400 μg / mL G418. 2. CHO-D3 cells were cultured in complete medium at 37° C., 5% CO 2. After TrypLE digestion, cells were resuspended in experimental buffer and seeded into 384-well cell culture plates at an inoculation density of 8000 cells per well. 3. Experimental buffer (1x HBSS, 0.1% BSA, 20mM HEPES and 500µM IBMX) was prepared. Compounds were diluted in the buffer. 2.5µL of compound solution was added to each well and the plate was incubated at 37°C for 10 minutes. Forskolin was diluted to 8µM (8x) in experimental buffer. 2.5µL of 8-fold diluted forskolin was added and the plate was incubated at 37°C for 30 minutes. cAMP-d2 and anti-cAMP-Eu 3+ was thawed and diluted 20-fold with lysis buffer. 10 μL of cAMP-d2 was added to experimental wells, followed by 10 μL of anti-cAMP-Eu 3+ The reaction plate was centrifuged at 200 g for 30 seconds at room temperature and then left at 25° C. for 1 hour. Data was collected using Envision.

[0381] 4. Experimental data processing method: 1) Z' value = 1-3 × (SDMax + SDMin) / (MeanMax - MeanMin); 2)CVMax=(SDMax / Average Max)×100%; 3)CVMin=(SDMin / Average Min)×100%; 4)S / B=signal / background; 5) EC of the compound 50 was calculated using the GraphPad nonlinear fitting equation: Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X) × Hill gradient) X: logarithm of compound concentration, Y: activation %

[0382] 5. Experimental results:

[0383] [Table 5]

[0384] 6. Experimental Conclusion: The data in the table show that the compounds of the examples of the present invention exhibit good agonist activity in the cAMP content effect assay in cells stably expressing the D3 receptor.

[0385] Test Example 2. Determination of the effects of compounds of the present invention on calcium ion mobility in cells stably expressing 5-HT2A receptors

[0386] 1. Experimental Objective: To determine the inhibitory effect of compounds on the 5-HT2A receptor.

[0387] 2. Laboratory equipment and reagents: 2.1 Experimental equipment: 384-well assay plate (Corning; 3712) Pipette (Axygen) FLIPR (Molecular Devices)

[0388] 2.2 Experimental reagents: DMEM (Invitrogen; 11965) Fetal bovine serum (Biowest; S1810-500) Dialysis serum (S-FBS-AU-065; Serana) Penicillin-streptomycin (Biowest; L0022-100) Hygromycin B (CABIOCHEM, 400052) Matrigel (BD; 354230) DMSO (Sigma; D2650) HBSS (Invitrogen; 14065) HEPES (Invitrogen; 15630080) Probenecid (Sigma; P8761) BSA (Genview; FA016) TrypLE (ThermoFisher; 12604021).

[0389] 3. Experimental Method: 1) Buffer preparation: 1x HBSS, 20mM HEPES, 2.5mM probenecid (probenecid was made into a 400mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh on the day of the experiment. Experimental buffers include dye buffer and compound dilution buffer. 2) Cell culture medium: Ham's F-12K + 10% fetal bovine serum + 600 μg / ml hygromycin B + 1x penicillin-streptomycin. Inoculation medium: Ham's F-12K + 10% dialyzed serum. Assay buffer: 1x HBSS + 20 mM HEPES. Cell line: Flp-In-CHO-5HT2A stable pool. 3) Cells were cultured in complete medium at 37°C, 5% CO2 to a confluency of 70%-90%. Cells were digested with TrypLE trypsin and plated at 1 x 10 cells per well in a 384-well assay plate. 4 Cells were plated at a density of 1000 cells / well and incubated for 16 to 24 hours (at least overnight). 4) 20X Component A was thawed to room temperature, diluted with assay buffer to 2X working concentration (containing 5mM probenecid), and placed at room temperature for later use. 5) The cell culture plate was removed and allowed to stand at room temperature for 10 minutes. FBS was diluted to a concentration of 0.03% with apricot and assay buffer, and 20 μL of the solution was finally left in the 3764 culture plate. 20 μL of 2X Component A (containing 5 mM probenecid) was added to each experimental well, centrifuged at 200 g and room temperature for 3 to 5 seconds, and incubated at 37°C for 2 hours. 6) The medium was discarded and 20 μL of dye was added. The plate was incubated at 37°C in the dark for 60 minutes, and calcium signals were measured. 7) Antagonists were prepared before the experiment: Working solutions of test compounds (6x) were prepared with DMSO. The cell culture plates were removed and left at room temperature for 10 minutes. 6x test compounds were added to a 384-well assay plate (10 μL / well), which was then incubated at room temperature in the dark for 35 minutes. The assay plate was transferred to a FLIPR. 10 μL of diluted 5HT was added to each experimental well, followed by the addition of 6x agonist compounds (5 μL / well). Values ​​were measured by the FLIPR and stored. The total assay volume was 30 μL, containing 20 μL / well of dye buffer, 5 μL / well of 5x test compounds, and 5 μL / well of 6x agonist compounds.

[0390] 4. Experimental data processing method: Calcium signal values ​​were measured by FLIPR. The calculated power for each sampling time point in the experiment was the ratio of the 340 / 510 nm wavelength signal to the 380 / 510 nm wavelength signal. Maximum-minimum calculations were derived from the ratio signal curve. Percent inhibition and 10-point concentration data were fit to a parametric nonlinear logistic equation using GraphPad Prism to calculate compound IC values. 50 The value was calculated.

[0391] 5. Experimental results:

[0392] [Table 6]

[0393] 6. Experimental Conclusion: The data in the table show that the compounds of the examples of the present invention exhibit good inhibitory activity in calcium ion mobilization assays in cells stably expressing the 5-HT2A receptor.

[0394] III. Pharmacokinetic assay in Balb / c mice 1. Research purpose: Balb / c mice were used as test animals, and the pharmacokinetic behavior of the compounds of the examples of the present invention orally administered at a dose of 5 mg / kg in the mouse body (plasma and brain tissue) was investigated.

[0395] 2. Experimental Protocol: 2.1 Test Compounds: Examples of compounds of the present invention prepared by the applicant.

[0396] 2.2 Test animals: Male Balb / c mice (12 mice per group) were purchased from Shanghai Jiesijie Laboratory Animal Co., Ltd. with certificate number: SCXK(Shanghai)2013-0006 N0.311620400001794.

[0397] 2.3 Preparation of the preparation: Test compounds were dissolved in 0.5% CMC-Na (1% Tween 80) by sonication to prepare a clear solution or homogenous suspension.

[0398] 2.4 Administration: After an overnight fast, male Balb / c mice (12 mice per group) were administered test compounds po at a dose of 5 mg / kg and a dose volume of 10 mL / kg.

[0399] 2.5 Sample Collection: Before administration and 1, 2, 4, 8, and 24 hours after administration, 0.2 mL of blood was collected from the heart of the mice, and the mice were sacrificed with CO2. Samples were stored in EDTA-K2 tubes and centrifuged at 6000 rpm for 6 minutes at 4°C to separate the plasma. Plasma samples were stored at -80°C. Whole brain tissue was removed, weighed, placed in a 2 mL centrifuge tube, and stored at -80°C.

[0400] 2.6 Sample processing: 1) 160 μL of acetonitrile was added to 40 μL of plasma sample for precipitation, and then the mixture was centrifuged at 3500×g for 5 to 20 minutes. 2) 90 μL of acetonitrile containing an internal standard (100 ng / mL) was added to 30 μL of plasma and brain homogenate samples for precipitation, and then the mixture was centrifuged at 13,000 rpm for 8 minutes. 3) 70 μL of water was added to 70 μL of the treated supernatant and mixed by vortexing for 10 minutes. 20 μL of the supernatant was taken and analyzed for the concentration of the test compound by LC / MS / MS. LC / MS / MS analysis equipment: AB Sciex API 4000 Qtrap.

[0401] 2.7 Liquid Chromatography Analysis: Liquid chromatography conditions: Shimadzu LC-20AD pump Chromatography column: Agilent ZORBAX XDB-C18 (50 x 2.1 mm, 3.5 μm); mobile phase: eluent A was 0.1% formic acid in water, eluent B was acetonitrile. ●Flow rate: 0.4mL / min Elution time: 0 to 4.0 minutes, eluent:

[0402] [Table 7]

[0403] 3. Experimental results and analysis: The main pharmacokinetic parameters were calculated by WinNonlin 6.1. The results of the pharmacokinetic study in mice are shown in Table 5 below.

[0404] [Table 8A]

[0405] [Table 8B]

[0406] 4. Experimental Conclusion: From the experimental results of the pharmacokinetic assay in mice shown in the table, the compounds of the examples of the present invention exhibited good pharmacokinetic properties, and the exposure AUC and maximum plasma concentration C max It can be seen that both were good.

[0407] IV. In vitro liver microsome stability assay 1. Experimental Objective: To evaluate the metabolic stability of compounds of the present invention in liver microsomes in vitro.

[0408] 2. Experimental equipment: 2.1 Equipment:

[0409] [Table 9]

[0410] 2.2 Reagents:

[0411] [Table 10]

[0412] 3. Experimental process: 3.1. Preparation of compound working solutions Preparation of compound working solutions: 2 μL of compound stock solution was added to 998 μL of phosphate buffer for a final concentration of 20 μM.

[0413] Preparation of working solution of control compound (7-hydroxycoumarin): The preparation was consistent with that of the compound.

[0414] 3.2. Preparation of liver microsome working solution 78.1 μL of 20 mg / mL microsomes was diluted to 2.5 mL with 100 mM phosphate buffer and mixed thoroughly for a final concentration of 0.625 mg / mL.

[0415] 3.3. Preparation of NADPH and UDPGA 33.3 mg of NADPH and 25.8 mg of UDPGA were weighed out, followed by the addition of 2 mL of 100 mM phosphate buffer, resulting in a final concentration of 20 mM.

[0416] 3.4. Preparation of channel-forming reagent (alamethicin) 1 mg of alamethicin was weighed out and 200 μL of DMSO was added to it to obtain a 5 mg / mL solution. 10 μL of this solution was added to 990 μL of phosphate buffer (pH 7.4) for a final concentration of 50 μg / mL.

[0417] 3.5. Preparation of reaction stop solution Stop solution: cold acetonitrile containing 100 ng / mL labetalol hydrochloride and 400 ng / mL tolbutamide as internal standards stored in a refrigerator at 2 to 8°C.

[0418] 3.6. Incubation Procedure 400 μL of prepared liver microsomes, 25 μL of compound working solution (10 μM), and 25 μL of alamethicin (50 μg / mL) were added sequentially to a 96-well plate, which was then pre-incubated at 37°C for 10 minutes. 50 μL of prepared NADPH / UDPGA was added to initiate the reaction, and the plate was incubated at 37°C. The total volume of the reaction system was 500 μL. The final contents of the components were as follows:

[0419] [Table 11]

[0420] 50 μL samples were taken at 0, 5, 10, 20, 30, and 60 min, respectively, and then 200 μL of cold stop solution containing an internal standard was added to stop the reaction in the samples. The obtained samples were centrifuged at 4000 g for 10 min, and the supernatant was collected for LC-MS / MS analysis.

[0421] 4. Experimental results:

[0422] [Table 12]

[0423] Note:

[0424] [Table 13]

[0425] 5. Experimental Conclusion: The above data demonstrate that the compounds of the examples of the present invention are metabolized to a moderate extent in human, rat and dog liver microsomes in vitro.

[0426] V. Pharmacodynamic Model of Active Avoidance Test in Rats 1. Experimental Objective: To evaluate the antischizophrenic effects of compounds using a pharmacodynamic model of active avoidance in rats.

[0427] 2. Laboratory equipment and reagents: 2.1 Equipment:

[0428] [Table 14]

[0429] 2.2 Reagents:

[0430] [Table 15]

[0431] 2.3 Test Compounds: Examples of compounds of the present invention prepared by the applicant.

[0432] 3. Test animals:

[0433] [Table 16]

[0434] 4. Vehicle and Compound Formulation: 4.1 Vehicle (0.5% CMC-Na + 1% Tween 80) A certain amount (e.g., 1.0 g) of CMC-Na was weighed into a glass bottle, a certain volume (e.g., 200 mL) of purified water was added, and the resulting mixture was stirred to disperse it evenly. 1% (v / v) Tween 80 was added according to the solution volume, and the resulting mixture was stirred overnight to obtain a homogeneous, clear solution, which was then stored at 2 to 8°C for later use.

[0435] 4.2 Compound Preparation: A defined amount of compound was weighed out, followed by the addition of a defined volume of 0.5% CMC-Na + 1% Tween 80 solution. Compound solutions were prepared prior to administration, stored at 2-8°C, and used within 4 days.

[0436] The actual sample volume needs to be calculated during compound solution preparation and administration. The calculation equation is: Actual sample volume of compound = Theoretical metered sample volume x Purity / Salt factor.

[0437] 5. Experimental Procedure: After arrival at the experimental facility, animals were allowed to acclimate for 1 week before the start of the experiment.

[0438] 5.1 Establishment of the pharmacodynamic model: 5.1.1 Animals were placed in the shuttle box and allowed to acclimate for 5 seconds, followed by 10 seconds of sound and light stimulation.

[0439] 5.1.2 If the animal moved to the other side during the 10-second sound and light stimulation, no electric shock was administered, which was recorded as an avoidance and the training session was terminated.

[0440] 5.1.3 If the animal failed to move to the other side after 10 seconds of sound and light stimulation, it was given an electric shock, with a current strength of 0.6 mA and a duration of 10 seconds. If the animal moved to the other side during the 10 seconds of electric shock, the electric shock was stopped, which was recorded as an avoidance, and one training session was terminated.

[0441] 5.1.4 If the animal failed to avoid the 10-second electric shock, the electric shock was stopped, this was recorded as an avoidance failure, and the training session was terminated.

[0442] 5.1.5 Each animal was trained 30 times per day for a total of 6 days, and returned to its cage after training.

[0443] 5.2 Baseline Test and Grouping A baseline test was conducted on the day before the compound screening test. The test process was the same as in 5.1.1 to 5.1.3, and the number of baseline tests was 20. The animals that reached 16 escape attempts (80%) were divided into groups with 10 animals per group according to the number of escape attempts. The first group was orally administered with a vehicle, and the other groups were administered with the corresponding test compounds according to the experimental design.

[0444] 5.3 Compound screening test Compounds were administered orally (5 mL / kg) 1 hour before testing.

[0445] The test process was the same as in 5.1.1 to 5.1.4, and the number of tests was 20.

[0446] 6. Data Processing: The following data were collected by the software for data analysis: Number of animal evasions Number of animal evasion failures Animal avoidance latency

[0447] All measurement data were expressed as the mean ± standard error (mean ± SEM) and analyzed by Graphpad 6 statistical software. Differences were considered significant when p<0.05.

[0448] 7. Experimental results:

[0449] [Table 17]

[0450] 8. Experimental Conclusion: From the above data, it can be seen that the compounds of the examples of the present invention have excellent effects in the pharmacodynamic model of active avoidance experiment in rats, which indicates that they have anti-schizophrenic effects.

Claims

1. A compound of formula (IX-A), its stereoisomer or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, R 4 is a 5- to 6-membered N-containing heterocyclyl, 【Chemistry 2】 selected from the group consisting of: R a is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R b is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Hydroxyalkyl, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl, wherein said amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 The aryl and 5- to 12-membered heteroaryl are each optionally substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R 5 are hydrogen, deuterium, and C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; Or, any two adjacent R 5 are joined to form a 5- to 6-membered heteroaryl; r is 0, 1 or 2; m is 0, 1 or 2; t is 0, 1, 2 or 3; 【Transformation 3】 but 【Chemistry 4】 and m is 1, then R 4 teeth, 【Transformation 5】 、-NHC(O)C 2 H 5 、-NHC(O)N(CH 3 ) 2 、-NHC(O)NHCH 3 、-NHC(O)N(C 2 H 5 )CH 3 、-NHC(O)NHC 2 H 5 、 【Transformation 6】 rather than; When m is 2, R 4 is -NHC(O)N(CH 3 ) 2 isn't it).

2. 5-6 membered N-containing heterocyclyl is oxazolidinonyl; R 5 is hydrogen, cyano, halogen, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; or any two adjacent R 5 joins to form a 5-6 membered heteroaryl containing 1 to 2 N, S, or O heteroatoms; t is 2, 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

3. R 5 are selected from the group consisting of hydrogen and chlorine; or any two adjacent R 5 combines to form thienyl, 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

4. Formula (X) or Formula (XA): 【Transformation 7】 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, further characterized in that:

5. R 4 5-6 membered N-containing heterocyclyl, 【Transformation 8】 selected from the group consisting of: R a But hydrogen, cyano, halogen, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 3～6 cycloalkyl; R b optionally halogen, hydroxy, cyano, C 1～3 Alkyl and C 1～3 amino, C, which is further substituted by one or more substituents selected from the group consisting of alkoxy 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Hydroxyalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl; 5. The compound according to claim 1 or 4, wherein r is 0, 1 or 2, or a stereoisomer or a pharmaceutically acceptable salt thereof.

6. 5-6 membered N-containing heterocyclyl is oxazolidinonyl; R a is selected from the group consisting of hydrogen and methyl; R b is selected from the group consisting of amino, methyl, ethyl, methoxy, hydroxyisopropyl, cyclopropyl, azetidinyl, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolyl and benzoxazolyl, optionally further substituted by one or more substituents selected from the group consisting of fluorine, cyano, hydroxy, methyl and methoxy, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. Formula (XI) 【Chemistry 9】 (In the formula, R 6 are hydrogen, deuterium, and C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R 7 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, R ee , -C(O)(CH 2 ) n2 R ee , -S(O) 2R ee , and -C(O)NR ee (CH 2 ) n2 Rff, 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 The aryl and 5- to 12-membered heteroaryl are each optionally substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; R ee and R ff are hydrogen, amino, and C, respectively. 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl and 5- to 12-membered heteroaryl are each optionally selected from halogen, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 further substituted by one or more substituents selected from the group consisting of alkoxy; n2 is selected from the group consisting of 0, 1 and 2; m is selected from the group consisting of 0, 1 and 2. A compound, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:

8. R ee and R ff are each optionally selected from halogen, hydroxy, cyano, C 1～6 Alkyl and C 1～6 amino, C, which is further substituted by one or more substituents selected from the group consisting of alkoxy 1～6 Alkyl, C 3～6 The compound according to claim 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each of the 4 to 6-membered heterocyclyls containing 1 to 2 nitrogen atoms is independently selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4 to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms, and 5 to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, or sulfur atoms.

9. R ee and R ff are respectively, (CH 3 ) 2 N-, CH 3 NH-, CH 3 -CH 3 CH 2 -CH 3 CH 2 NH-, CH 3 CH 2 NCH 3 -、(CH 3 ) 2 C(OH)-、(CH 3 ) 2 C(OH)CH 2 -CH 3 OCH 2 - 【Chemistry 10】 8. The compound of claim 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of:

10. R ee and R ff 8. The compound according to claim 7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein: are each independently selected from the group consisting of hydrogen and the following substituents: 【Chemistry 11】

11. R 6 However, hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy, C 1～3 Haloalkoxy, C 2～3 Alkenyl and C 2～3 alkynyl; R ee But hydrogen, amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl and 5- to 12-membered heteroaryl are each optionally selected from halogen, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 further substituted by one or more substituents selected from the group consisting of alkoxy; R ff But hydrogen, amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl; 8. The compound according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein n2 is selected from the group consisting of 0, 1 and 2.

12. R 6 is hydrogen; R ee optionally halogen, hydroxy, cyano, C 1～6 Alkyl and C 1～6 substituted by one or more substituents selected from the group consisting of alkoxy, amino, C 1～6 Alkyl, C 3～6 selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 6-membered heterocyclyl containing 1 to 2 oxygen, nitrogen, or sulfur heteroatoms, and 5- to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, or sulfur heteroatoms; R ff But hydrogen, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 3～6 8. The compound of claim 7, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of cycloalkyl.

13. R ee が、(CH 3 ) 2 N-、CH 3 NH-、CH 3 -、CH 3 CH 2 -、CH 3 CH 2 NH-、CH 3 CH 2 NCH 3 -、(CH 3 ) 2 C(OH)-、(CH 3 ) 2 C(OH)CH 2 -、CH 3 OH 2 -、 【Chemistry 12】 selected from the group consisting of: R ff 8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 7, wherein is selected from the group consisting of hydrogen and methyl.

14. Formula (XI-A) or Formula (XI-B) 【Chemistry 13】 8. The compound according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, further characterized in that:

15. If m is 0, 【Chemistry 14】 but, 【Chemistry 15】 selected from the group consisting of: If m is 1, 【Chemistry 16】 but, 【Chemistry 17】 selected from the group consisting of: If m is 2, [Chemistry 18] but, 【Chemistry 19】 15. The compound according to claim 7 or 14, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: 【Request Item 16】 【Chemistry 20】 but, 【Chemistry 21】 15. The compound according to claim 7 or 14, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

17. Formula (XII) 【Chemistry 22】 (In the formula, R 8 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl, wherein said amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 The aryl and 5- to 12-membered heteroaryl are each optionally substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; v is 0 or 1; If v is 0, R 8 -C 2 H 5 , -N(CH 3 ) 2 , -NHCH 3 , -NC 2 H 5 CH 3 , -NHC 2 H 5 , 【Chemistry 23】 rather than; If v is 1, R 8 is not phenyl) A compound, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:

18. R 8 is amino, C 1～3 Alkyl, C 1～3 Hydroxyalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 aryl and 5- to 10-membered heteroaryl, wherein said amino, C 1～3 Alkyl, C 1～3 Hydroxyalkyl, C 3～6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6～10 The aryl and 5- to 10-membered heteroaryl are each optionally selected from hydroxy, cyano, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 18. The compound of claim 17, its stereoisomer, or a pharmaceutically acceptable salt thereof, further substituted by one or more substituents selected from the group consisting of cycloalkyl.

19. R 8 is CH 3 O-, HOC(CH 3 ) 2 -, 【Chemistry 24】 18. The compound of claim 17, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

20. The compound of claim 17, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula (XII) is further represented by formula (XII-A) or formula (XII-B): 【Chemistry 25】

21. R 4 but, 【Chemistry 26】 and; R b optionally deuterium, halogen, amino, hydroxy, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 1～3 C further substituted by one or more substituents selected from the group consisting of haloalkoxy 3～6 selected from the group consisting of cycloalkyl and 5-10 membered heteroaryl containing 1 to 2 nitrogen, oxygen, or sulfur atoms; R 5 However, hydrogen, halogens and C 1～3 selected from the group consisting of alkyl; m is 1; t is 1, 2 or 3; r is 0 and R b but 【Chemistry 27】 If R b is substituted by at least one substituent; r is 0 and R b but 【Chemistry 28】 If R b The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: is substituted by at least one substituent.

22. R b However, optionally deuterium, halogen, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 1～3 C further substituted by one or more substituents selected from the group consisting of haloalkoxy 3～6 The compound according to claim 21, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of cycloalkyl, nitrogen- or oxygen-containing 5- to 6-membered heteroaryl and nitrogen-containing 9- to 10-membered fused heteroaryl.

23. R b Optionally, halogen, C 1～3 Alkyl and C 1～3 22. The compound according to claim 21, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of cyclopropyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl and quinolyl, further substituted by one or more substituents selected from the group consisting of haloalkyl.

24. A compound, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the specific structure of the compound is as follows: 【Chemistry 29A】 【Chemical 29B】 【Chemical 29C】

25. 18. A process for preparing a compound of formula (XII) according to claim 17, its stereoisomer or a pharmaceutically acceptable salt thereof, comprising: 【Transformation 30】 Reacting a compound of formula (XII-1) with an acyl chloride or carboxylic acid of formula (XII-2) to obtain the compound of formula (XII), its stereoisomer, or its pharmaceutically acceptable salt. A method comprising:

26. A compound of formula (XII-1), its stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 31】

27. A process for preparing a compound of formula (XII-1) according to claim 26, its stereoisomer or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 32】 deprotecting the compound of formula (XII-3) to obtain the compound of formula (XII-1), its stereoisomer, or its pharmaceutically acceptable salt; Optionally, reacting the compound of formula (XII-4) with a compound of formula (XII-5) to obtain the compound of formula (XII-3), its stereoisomer or its pharmaceutically acceptable salt. The invention is characterized in that it comprises 【Transformation 33】 During the ceremony, Pg 1 is an amino protecting group selected from the group consisting of allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenemethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, and p-methoxyphenyl; Pg 2 is a hydroxy protecting group selected from the group consisting of methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether group, methoxymethyl, trimethylsilyl, tetrahydrofuryl, tert-butyldisilyl, acetyl, benzoyl, and p-toluenesulfonyl.

28. Pg 1 is tert-butoxycarbonyl, and Pg 2 28. The method of claim 27, wherein is p-toluenesulfonyl.

29. 25. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 24, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

30. 30. The pharmaceutical composition of claim 29, wherein the therapeutically effective dose is 0.1 to 500 mg.

31. 30. Use of a compound according to any one of claims 1 to 24, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29 in the preparation of a G protein-coupled receptor modulating medicament.

32. The use according to claim 31, wherein the G protein-coupled receptor modulating drug is a dopamine D3 receptor modulating drug or a 5-HT2A receptor modulating drug.

33. 30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or according to claim 29, for treating or preventing a central nervous system disease and / or a psychiatric disease or disorder.

34. 34. The pharmaceutical composition of claim 33, wherein the nervous system disease and / or psychiatric disease is selected from the group consisting of schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal symptoms, tinnitus, depression, autism, senile dementia, Alzheimer's disease, seizures, neuralgia, detoxification symptomatic major depressive disorder, and mania.

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