Benzothiophene derivative regulators, their preparation and use

Abstract

Nitrogen-containing ring derivative regulators, their preparation and use thereof. In particular, the present invention relates to compounds represented by general formula (I), their preparation or pharmaceutical compositions containing the compounds, and their use as G protein-coupled receptor regulators in the treatment or prevention of central nervous system disorders and / or psychiatric disorders. TIFF2023501306000193.tif46170

Description

[Technical Field]

[0001] The present invention is in the field of pharmaceutical synthesis, and in particular relates to nitrogen-containing ring derivative regulators, 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 can have significant antipsychotic effects and 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 WO2007093540A, WO2009013212A2, WO2010031735A1, and WO2012117001A1 report D3 receptor and 5HT2A dual-modulating compounds, but the maximum binding activity Ki of the compounds to D3 receptor and 5HT2A is greater than 10nM.International Patent Application WO2014086098A1 filed by Jiangsu Hengyi Pharmaceutical Co., Ltd. reports D3 selective inhibitors, but does not report on the binding activity study to 5HT2A. Cariprazine, a D3 antagonist developed by Gedeon Richter Plc., was listed on the market in 2015, and WO 2005012266A1 has been filed for its marketing. Cariprazine has potent D3 receptor agonist activity, and its use in treating 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, there is an urgent need to develop highly active D3 receptor modulators with optimized 5HT2A binding activity to reduce side effects such as extrapyramidal symptoms and improve cognitive outcomes and the effectiveness of these modulators on negative symptoms in schizophrenia. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Patent Application No. WO2007093540A [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 object of the present invention is to provide a compound of formula (I) having the structure

[0008] [ka]

[0009] (In the formula,

[0010] [ka]

[0011] is selected from the group consisting of a single bond and a double bond; M is N and CR aa selected from the group consisting of: Ring A is selected from the group consisting of aryl and heteroaryl; R1 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -NR aa C(O)(CH2) n1 OR aa , -NR aa C(=S)(CH2) n1 OR bb , -(CH2) n1 SRaa , -(CH2) n1 C(O)R aa , -(CH2) n1 C(O)OR aa , -(CH2) n1 S(O) m1 R aa , -(CH2) n1 NR aa R bb , -(CH2) n1 C(O)NR aa R bb , -P(O)R aa R bb , -(CH2) n1 NR aa C(O)R bb and -(CH2) n1 NR aa S(O) m1 R bb selected from the group consisting of: R2 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -NR aa C(O)(CH2) n1 OR aa , -NR aa C(=S)(CH2) n1 OR bb , -(CH2) n1 SR aa , -(CH2) n1 C(O)R aa , -(CH2) n1 C(O)OR aa , -(CH2) n1 S(O) m1 R aa , -(CH2) n1 NR aa R bb , -(CH2) n1 C(O)NR aa R bb , -P(O)Raa R bb , -(CH2) n1 NR aa C(O)R bb and -(CH2) n1 NR aa S(O) m1 R bb or selected from the group consisting of; or two R2 on the same or different carbon atoms join to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, an ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R cc , -(CH2) n1 OR cc , -(CH2) n1 SR cc , -(CH2) n1 C(O)R cc , -(CH2) n1 C(O)OR cc , -(CH2) n1 S(O) m1 R cc , -(CH2) n1 NR cc R dd , -(CH2) n1 C(O)NR cc R dd , -(CH2) n1 C(O)NHR cc , -(CH2) n1 NR cc C(O)R dd and -(CH2) n1 NR cc S(O) m1 R ddand optionally further substituted by one or more substituents selected from the group consisting of: R3 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -NR aa C(O)(CH2) n1 OR aa , -NR aa C(=S)(CH2) n1 OR bb , -(CH2) n1 SR aa , -(CH2) n1 C(O)R aa , -(CH2) n1 C(O)OR aa , -(CH2) n1 S(O) m1 R aa , -(CH2) n1 NR aa R bb , -(CH2) n1 S(O)(=NR aa )R bb , -(CH2) n1 S(O) m1 NR aa R bb , -(CH2) n1 C(O)NR aa R bb , -P(O)R aa R bb , -(CH2) n1 NR aa C(O)R bb and -(CH2) n1 NR aa S(O) m1 R bb or selected from the group consisting of; or two R3 on the same or different carbon atoms join to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, an ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH2) n1 R cc , -(CH2) n1 OR cc , -(CH2) n1 SR cc , -(CH2) n1 C(O)R cc , -(CH2) n1 C(O)OR cc , -(CH2) n1 S(O) m1 R cc , -(CH2) n1 NR cc R dd , -(CH2) n1 C(O)NR cc R dd , -(CH2) n1 C(O)NHR cc , -(CH2) n1 NR cc C(O)R dd and -(CH2) n1 NR cc S(O) m1 R dd and optionally further substituted by one or more substituents selected from the group consisting of: R4 and R5 are hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH2) n1 Raa 、 -(CH2) n1 C(O)R aa 、 -C(O)(CH2) n1 R aa 、 -(CH2) n1 C(O)NR aa R bb 、 -(CH2) n1 S(O) m1 R aa 、 -(CH2) n1 S(O) m1 NR aa R bb 、 -(CH2) n1 OR aa 、 -C(O)NR aa (CH2) n1 R bb 、 -NR aa C(=S)(CH2) n1 OR bb 、 -(CH2) n1 SR aa 、 -(CH2) n1 C(O)OR aa 、 -(CH2) n1 S(O)(=NR aa )R bb 、 -P(O)R aa R bb 、 -(CH2) n1 NR aa C(O)R bb and -(CH2) n1 NR aa S(O) m1 R bbwherein alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, an ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH) n1 R cc , -(CH2) n1 OR cc , -(CH2) n1 SR cc , -(CH2) n1 C(O)R cc , -(CH2) n1 C(O)OR cc , -(CH2) n1 S(O) m1 R cc , -(CH2) n1 NR cc R dd , -(CH2) n1 C(O)NR cc R dd , -(CH2) n1 C(O)NHR cc , -(CH2) n1 NR cc C(O)R dd and -(CH2) n1 NR cc S(O) m1 R dd each optionally further substituted with one or more substituents selected from the group consisting of: or R and R are joined to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, an ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH) n1 R cc , -(CH2) n1 OR cc , -(CH2) n1 SR cc , -(CH2) n1 C(O)R cc , -(CH2) n1 C(O)OR cc , -(CH2) n1 S(O) m1 R cc , -(CH2) n1 NR cc R dd , -(CH2) n1 C(O)NR cc R dd , -(CH2) n1 C(O)NHR cc , -(CH2) n1 NR cc C(O)R dd and -(CH2) n1 NR cc S(O) m1 R dd and optionally further substituted by one or more substituents selected from the group consisting of: R aa , R bb , R cc and R ddare each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Or R aa and R bb are joined to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; m is 0, 1 or 2; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; n1 is 0, 1, 2, 3, 4 or 5); The compound of formula (I) is the compound

[0012] [ka]

[0013] Does not include The present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] In a preferred embodiment of the present invention, in the compound, its stereoisomer or its pharmaceutically acceptable salt, ring A is C 6~10 It is selected from the group consisting of aryl and 5- to 10-membered heteroaryl, preferably phenyl, 5- to 6-membered monocyclic heteroaryl, benzo-5- to 6-membered heteroaryl and benzo-3- to 6-membered heterocyclyl.

[0015] In a preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt comprises

[0016] [ka]

[0017] teeth,

[0018] [ka]

[0019] is selected from the group consisting of:

[0020] In a preferred embodiment of the present invention, in the compound, its stereoisomer or its pharmaceutically acceptable salt, R4 is selected from the group consisting of hydrogen and C 1~6 alkyl, preferably selected from the group consisting of hydrogen and methyl; R5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14Aryl, 5-14 membered heteroaryl, -(CH2) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)(CH2) n1 R aa , -C(O)NR aa (CH2) n1 R bb , -S(O)2R aa , -(CH2) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, cyano, halogen, C 1~6 Alkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; -R aa , -C(O)(CH2) n1 R aa , -C(O)NR aa (CH2) n1 R bb and -S(O)2R aa Preferably selected from the group consisting of: Or, R4 and R5 join to form a 3- to 8-membered heterocyclyl or a 5- to 14-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl or the 5- to 14-membered heteroaryl is selected from the group consisting of hydrogen, C 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy, C 3~8 Hydroxyalkyl, -C(O)R cc and -C(O)NR cc R dd and optionally further substituted by one or more substituents selected from the group consisting of: wherein heterocyclyl or heteroaryl is selected from the group consisting of heterocyclyl containing 1 to 2 nitrogen, oxygen or sulfur atoms, and heteroaryl containing 1 to 2 nitrogen, oxygen or sulfur atoms; R aa and R bb 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, wherein 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 are substituted with halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 each optionally further substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Preferably, R aa and R bb is hydrogen, amino, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein amino, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl are substituted with halogen, hydroxy, cyano, oxo, C 1~3 Alkyl, C 1~3 Haloalkyl, C1~3 Alkoxy, C 3~6 each optionally further substituted with one or more substituents selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; R cc and R dd 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, wherein 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 are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; n1 is 0, 1, 2 or 3.

[0021] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (IV) is a compound of formula (IV-A):

[0022] [ka]

[0023] (R2 is hydrogen, cyano, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 is selected from the group consisting of cycloalkyl; Or, two R2 on the same or different carbon atoms are bonded to form C 3~8Forms a cycloalkyl or a 3- to 8-membered heterocyclyl, wherein C 3~8 Cycloalkyl or 3- to 8-membered heterocyclyl is a deuterium atom, C 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy and C 3~8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R3 is hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, hydroxy, cyano, C 2~6 Alkenyl and C 2~6 alkynyl; R4 is hydrogen and C 1~6 selected from the group consisting of alkyl; R5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, -(CH2) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)(CH2) n1 R aa , -C(O)NR aa (CH2) n1 R bb , -S(O)2R aa , -(CH2) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are substituted with cyano, halogen, C 1~6Alkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; or R4 and R5 join to form a 3- to 8-membered heterocyclyl or a 5- to 14-membered heteroaryl, which is 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy, C 3~8 Hydroxyalkyl, -C(O)R cc and -C(O)NR cc R dd and optionally further substituted by one or more substituents selected from the group consisting of: R aa and R bb 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, wherein 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 are substituted with halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 each optionally further substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or R aa and R bb is joined together with the adjacent nitrogen atom to form a 4- to 10-membered heterocyclyl, which is substituted with halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6Haloalkyl, C 1~6 Alkoxy and C 1~6 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R cc and R dd 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, wherein 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 are substituted with halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; m is 1 or 2; n1 is 0, 1, 2 or 3) is.

[0024] In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, the compound of formula (IV-A) is a compound of formula (IX-B):

[0025] [ka]

[0026] (R2 is hydrogen, cyano, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; R3 is hydrogen, halogen, hydroxy, cyano, C 1~6Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 haloalkoxy; R4 is hydrogen and C 1~6 selected from the group consisting of alkyl; R5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, -(CH2) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)(CH2) n1 R aa , -C(O)NR aa (CH2) n1 R bb , -S(O)2R aa , -(CH2) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are substituted with cyano, halogen, C 1~6 Alkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; or R4 and R5 join to form a 3- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl, which is 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy and C 3~8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R aa and Rbb 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 5-10 membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, which are independently selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 each optionally further substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or R aa and R bb is joined together with the adjacent nitrogen atom to form a 4- to 6-membered heterocyclyl, which is substituted with halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 and optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl. is.

[0027] In another preferred embodiment of the present invention, in the compound of formula (IX-B), its stereoisomer or its pharmaceutically acceptable salt, R2 is hydrogen, cyano, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 cycloalkyl; R3 is hydrogen, halogen and C 1~3 selected from the group consisting of alkyl; R4 is hydrogen and C 1~3 selected from the group consisting of alkyl; R5 is -(CH2) n1 R aa , -C(O)Raa , -C(O)NR aa R bb , -S(O)2R aa and -S(O) m1 NR aa R bb selected from the group consisting of: R aa and R bb is hydrogen, amino, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 3~6 cycloalkyl, and 5-6 membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, which are independently selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 each optionally further substituted with one or more substituents selected from the group consisting of cycloalkyl; Or R aa and R bb are joined together with the adjacent nitrogen atom to form a 4- to 6-membered nitrogen-containing heterocyclyl, which is free of halogen, hydroxy, C 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 optionally further substituted with one or more substituents selected from the group consisting of alkoxy; When R2, R3 and R4 are hydrogen, R5 is not hydrogen or butyloxycarbonyl; When R2, R3 and R4 are methyl, R5 is not methyl.

[0028] In another preferred embodiment of the present invention, in the compound of formula (IX-B), its stereoisomer or its pharmaceutically acceptable salt, R2 is selected from the group consisting of hydrogen, cyano, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoromethyl and cyclopropyl; R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl and ethyl; R4 is selected from the group consisting of hydrogen and methyl; R5 is -R aa , -C(O)R aa and -C(O)NR aa R bb selected from the group consisting of: R aa and R bb is hydrogen, C 1~3 Alkyl, C 1~3 Fluoroalkyl, C 1~3 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, furyl, oxazolyl, and isoxazolyl, each independently selected from the group consisting of halogen, hydroxy, cyano, C 1~3 Alkyl and C 1~3 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R aa and R bb is joined together with the adjacent nitrogen atom to form an azetidinyl, pyrrolidinyl, or piperidinyl, which is free of halogen, hydroxy, C 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 and optionally further substituted with one or more substituents selected from the group consisting of alkoxy.

[0029] In another preferred embodiment of the present invention, the compound, its stereoisomer, or its pharmaceutically acceptable salt has the specific structure of formula (XII):

[0030] [ka]

[0031] (In the formula, Ring B is C 3~8 selected from the group consisting of cycloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl; preferably selected from the group consisting of cyclopropyl, azetidinyl, pyrrolidonyl, furyl, oxazolyl, and isoxazolyl; R2 is hydrogen, cyano, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; hydrogen and C 1~6 Preferably selected from the group consisting of haloalkyl; more preferably selected from the group consisting of hydrogen and trifluoromethyl; R4 is hydrogen and C 1~6 alkyl; preferably selected from the group consisting of hydrogen and methyl; R6 is hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, hydroxy, cyano, C 2~6 Alkenyl and C 2~6 alkynyl; preferably selected from the group consisting of hydrogen and halogen; more preferably selected from the group consisting of hydrogen and fluorine; R 17 is hydrogen, halogen, amino, hydroxy, cyano, 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, wherein amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl and 5-10 membered heteroaryl are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy; hydrogen, amino, halogen, amino, hydroxy, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3alkoxy; each optionally further substituted with one or more substituents more preferably selected from the group consisting of hydrogen, fluorine, chlorine, hydroxy, cyano, methyl and methoxy; v is an integer from 0 to 5, preferably 0, 1, 2 or 3. This is shown in.

[0032] In another preferred embodiment of the present invention, in any one of the compounds, their stereoisomers or their pharmaceutically acceptable salts,

[0033] [ka]

[0034] teeth,

[0035] [ka]

[0036] [ka]

[0037] is selected from the group consisting of:

[0038] In another preferred embodiment of the present invention, in any one of the compounds, their stereoisomers, or their pharmaceutically acceptable salts, ring A is

[0039] [ka]

[0040] is.

[0041] In another preferred embodiment of the present invention, in any one of the compounds, their stereoisomers or their pharmaceutically acceptable salts, R1 is hydrogen, cyano, halogen, C1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 cycloalkyl; R2 is hydrogen, cyano, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 is selected from the group consisting of cycloalkyl; Or, two R2 on the same or different carbon atoms are bonded to form C 3~8 Forms a cycloalkyl or a 3- to 8-membered heterocyclyl, wherein C 3~8 Cycloalkyl or 3- to 8-membered heterocyclyl is a hydrogen, deuterium atom, C 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy and C 3~8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R3 is a hydrogen atom, halogen, hydroxy, or C 1~6 Alkyl and C 1~6 or selected from the group consisting of alkoxy; Or, two R3 on the same or different carbon atoms are bonded to form C 3~8 Forms a cycloalkyl or a 3- to 8-membered heterocyclyl, wherein C 3~8 Cycloalkyl or 3-8 membered heterocyclyl is hydrogen, deuterium, C 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy and C 3~8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R4 is hydrogen and C 1~6 selected from the group consisting of alkyl; R5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl, 5-14 membered heteroaryl, -(CH2)n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)(CH2) n1 R aa , -C(O)NR aa (CH2) n1 R bb , -S(O)2R aa , -(CH2) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, cyano, halogen, C 1~6 Alkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; or R4 and R5 join to form a 3- to 8-membered heterocyclyl or a 5- to 14-membered heteroaryl, which may be selected from the group consisting of hydrogen, C 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy, C 3~8 Hydroxyalkyl, -C(O)R cc and -C(O)NR cc R dd and optionally further substituted by one or more substituents selected from the group consisting of: R aa 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, wherein amino, C 1~6 Alkyl, C 1~6Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy and 5-14 membered heteroaryl; R bb 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, wherein 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 are selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an oxo group, a C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R aa and R bb are joined to form a heterocyclyl, where the heterocyclyl is a hydrogen atom, C 1~6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3~8 Alkoxy, C 3~8 Haloalkoxy and C 3~8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R cc and R dd is hydrogen, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein 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 are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy.

[0042] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising:

[0043] [ka]

[0044] deprotecting the compound of formula (IX-B3) to obtain a compound of formula (IX-B1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; reacting a compound of formula (IX-B1) with an acyl chloride, amine, carboxylic acid or sulfonyl chloride of formula (II-2) to obtain a compound of formula (VIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; The compound of formula (II-2) represents R5X, R5OH or R5NH2; X is a halogen, preferably fluorine, chlorine or bromine; The present invention provides a process for preparing a compound of formula (IX-B), its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that Pg is a hydrogen or amino protecting group selected from the group consisting of allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenylmethyloxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, t-butoxycarbonyl, benzyl, and p-methoxyphenyl, preferably t-butoxycarbonyl.

[0045] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of formula (I), any one of the compounds of the general formula, their stereoisomers or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0046] The present invention also relates to the use of any one of the compounds of formula (I), any one of the compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition in the preparation of modulators of G protein-coupled receptors, in particular modulators of dopamine D3 receptors and modulators of 5-HT2A receptors.

[0047] The present invention further relates to a method for treating inflammatory diseases with a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0048] The present invention also relates to a method for preventing and / or treating 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 (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0049] The present invention also provides methods for treating disease states by using compounds or pharmaceutical compositions according to the present invention, including, but not limited to, conditions associated with modulators of G protein-coupled receptors.

[0050] 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.

[0051] In some embodiments, the methods involve the treatment of conditions such as cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, respiratory diseases, and cardiac diseases.

[0052] In some embodiments, the methods include treatment and / or prevention of a central nervous system and / or psychiatric disease or disorder 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, dementia, Alzheimer's disease, seizures, neuralgia, drug withdrawal symptoms, major depressive disorder, and mania.

[0053] The treatment methods provided herein comprise administering a therapeutically effective amount of a compound of the present invention to a subject. In one embodiment, the present invention provides a method for treating a central nervous system disorder and / or a psychiatric disorder in a mammal. The method comprises administering a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof to the mammal.

[0054] The compound according to the present invention or a pharmaceutical composition thereof not only has potent D3 receptor agonist activity, but also has significantly better inhibitory activity against 5-HT2A than cariprazine, and is expected to have excellent clinical efficacy in treating the negative symptoms of schizophrenia and significantly reduce the risk of EPS side effects.

[0055] definition Unless otherwise specified, terms used in the specification and claims have the meanings set forth below.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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:

[0060] [ka]

[0061] and spirocycloalkyl, in which the cycloalkyl and heterocyclyl are bonded through a spiro atom, non-limiting examples of which include:

[0062] [ka]

[0063] 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:

[0064] [ka]

[0065] 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:

[0066] [ka]

[0067] 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.

[0068] 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 oxatanyl, oxatanyl, pyrrolidinyl, oxazolidin-2-one group, azepinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxatanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, oxazolidin-2-one group, morpholinyl, piperazinyl and azepinyl, more preferably oxatanyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl and oxazolidin-2-one group. Polycyclic heterocyclyls include heterocyclyls having spiro rings, fused rings 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.

[0069] 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 / 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:

[0070] [ka]

[0071] 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:

[0072] [ka]

[0073] 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:

[0074] [ka]

[0075] 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 include:

[0076] [ka]

[0077] 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.

[0078] 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:

[0079] [ka]

[0080] 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.

[0081] The term "heteroaryl" refers to a 5- to 14-membered heteroaromatic ring system having one to four heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl is preferably a 5- to 10-membered heteroaryl, more preferably a 5- or 6-membered heteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, etc., preferably pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, pyrimidinyl, and thiazolyl, more preferably pyrazolyl, furanyl, pyridyl, oxazolyl, isoxazole, furanyl, and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, and the ring attached to the parent structure is a heteroaryl ring. Non-limiting examples include the following:

[0082] [ka]

[0083] 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.

[0084] 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.

[0085] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above.

[0086] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is defined above.

[0087] "Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, where alkyl is as defined above.

[0088] "Alkenyl" refers to an olefin chain, also known as an alkene group. The alkenyl 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.

[0089] "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.

[0090] "Hydroxy" refers to the group --OH.

[0091] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0092] "Amino" refers to the group -NH2.

[0093] "Cyano" refers to the radical -CN.

[0094] "Nitro" refers to the -NO2 group.

[0095] "Carboxy" refers to the group --C(O)OH.

[0096] "THF" refers to tetrahydrofuran.

[0097] "EtOAc" refers to ethyl acetate.

[0098] "MeOH" refers to methanol.

[0099] "DMF" refers to N,N-dimethylformamide.

[0100] "DIPEA" refers to diisopropylethylamine.

[0101] "TFA" refers to trifluoroacetic acid.

[0102] "MeCN" refers to acetonitrile.

[0103] "DMA" refers to N,N-dimethylacetamide.

[0104] "Et2O" refers to diethyl ether.

[0105] "DCE" refers to 1,2-dichloroethane.

[0106] "DIPEA" refers to N,N-diisopropylethylamine.

[0107] "NBS" refers to N-bromosuccinimide.

[0108] "NIS" refers to N-iodosuccinimide.

[0109] "Cbz-Cl" refers to benzyl chloroformate.

[0110] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0111] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0112] "HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0113] "KHMDS" refers to potassium hexamethyldisilazide.

[0114] "LiHMDS" refers to lithium bis(trimethylsilyl)amide.

[0115] "MeLi" refers to methyllithium.

[0116] "n-BuLi" refers to n-butyllithium.

[0117] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0118] 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" have the same meaning, i.e., X may be any one or more of A, B, and C.

[0119] 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.

[0120] "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.

[0121] 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.

[0122] 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, 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.

[0123] "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

[0124] 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]

[0125] 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).

[0126] 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 column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18, 150 × 4.6 mm column).

[0127] Thin-layer silica gel chromatography (TLC) plates are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The size of the silica gel plates used for TLC is 0.15 mm to 0.2 mm, and the size of the silica gel plates used for product purification is 0.4 mm to 0.5 mm. Yantai Huanghai 200-300 mesh silica gel is generally used as the support for column chromatography.

[0128] The starting materials used in the examples of the present invention are known and commercially available or can be synthesized by or by following methods known in the art.

[0129] Unless otherwise specified, all reactions of this invention are conducted under a dry nitrogen or argon atmosphere with continuous magnetic stirring, solvents are anhydrous, and reaction temperatures are in degrees Celsius.

[0130] Example 1 N-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0131] [ka]

[0132] Step 1: tert-butyl (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate

[0133] [ka]

[0134] 1-(2,3-Dichlorophenyl)piperazine (460 mg, 2 mmol) was dissolved in 10 mL of acetonitrile in a 100 mL round-bottom flask. 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate (794 mg, 2 mmol) and potassium carbonate (834 mg, 6 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (550 mg, white solid, yield: 60.5%). MS m / z(ESI):456.2 [M+H] + .

[0135] Step 2: trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexan-1-amine

[0136] [ka]

[0137] tert-Butyl (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (550 mg, 1.2 mmol) was dissolved in 5 mL of dichloromethane in a 100 mL round-bottom flask, followed by the addition of a solution of hydrochloric acid in ethyl acetate (4 M, 1 mL, 4 mmol). The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness by rotary evaporation to give trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexan-1-amine (400 mg, white solid, yield: 91.3%). MS m / z(ESI):356.1 [M+H] + .

[0138] Step 3: N-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0139] [ka]

[0140] Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexan-1-amine (80 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (67 mg, 0.66 mmol) and N,N'-carbonyldiimidazole (43 mg, 0.27 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3,3-Difluoroazetidine hydrochloride (42 mg, 0.34 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL x 3). The organic phase was concentrated and purified by preparative HPLC to give the product N-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide (69 mg, white solid, yield: 64.6%). MS m / z (ESI): 475.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.19 - 7.11 (m, 2H), 7.00 - 6.94 (m, 1H), 4.24 (t, J = 12.1 Hz, 4H), 3.98 (d, J = 8.1 Hz, 1H), 3.63 - 3.50 (m, 1H), 3.24 - 3.03 (m, 4H), 2.85 - 2.61 (m, 4H), 2.56 -2.43 (m, 2H), 2.08 - 1.95 (m, 2H), 1.84 - 1.75 (m, 2H), 1.56 - 1.43 (m, 2H), 1.28 - 1.22 (m, 1H), 1.16 - 1.01 (m, 4H).

[0141] Example 2 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0142] [ka]

[0143] Step 1: tert-butyl (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate

[0144] [ka]

[0145] 1-(Benzo[b]thiophen-4-yl)piperazine (440 mg, 2 mmol) was dissolved in 10 mL of acetonitrile in a 100 mL round-bottom flask. 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate (794 mg, 2 mmol) and potassium carbonate (834 mg, 6 mmol) were added to the reaction mixture. The reaction mixture was stirred at 80°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (500 mg, white solid, yield: 55.9%). MS m / z (ESI): 444.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.30 - 7.25 (m, 2H), 6.90 (d, J = 7.6 Hz, 1H), 4.44 - 4.24 (m, 1H), 3.46 - 3.31 (m, 1H), 3.29 - 3.19 (m, 4H), 2.95 - 2.63 (m, 4H), 2.61 - 2.42 (m, 2H), 2.09 - 1.94 (m, 2H), 1.87 - 1.72 (m, 2H), 1.58 - 1.49 (m, 2H), 1.44 (s, 9H), 1.30 - 1.20 (m, 1H), 1.16 - 0.98 (m, 4H).

[0146] Step 2: trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine

[0147] [ka]

[0148] tert-Butyl (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (500 mg, 1.13 mmol) was dissolved in 5 mL of dichloromethane in a 100 mL round-bottom flask, followed by the addition of a solution of hydrochloric acid in ethyl acetate (4 M, 1 mL, 4 mmol). The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness by rotary evaporation to give trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (350 mg, white solid, yield: 90.4%). MS m / z(ESI):344.2 [M+H] + .

[0149] Step 3: N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0150] [ka]

[0151] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol) and N,N'-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3,3-Difluoroazetidine hydrochloride (28 mg, 0.22 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed three times with water (2 mL x 3). The organic phase was concentrated and purified by preparative HPLC to give the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide (22 mg, white solid, yield: 32.1%). MS m / z (ESI): 463.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.56 (d, J = 8.0 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.31 - 7.26 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.24 (t, J = 12.1 Hz, 4H), 3.99 (d, J = 8.1 Hz, 1H), 3.64 - 3.51 (m, 1H), 3.37 - 3.14 (m, 4H), 2.94 - 2.67 (m, 4H), 2.64 - 2.51 (m, 2H), 2.08 - 1.96 (m, 2H), 1.89 - 1.76 (m, 2H), 1.59 - 1.48 (m, 2H), 1.29 - 1.23 (m, 1H), 1.19 - 1.04 (m, 4H).

[0152] Example 3 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylazetidine-1-carboxamide

[0153] [ka]

[0154] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol) and N,N'-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3-Methylazetidin-3-ol hydrochloride (27 mg, 0.22 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed three times with water (2 mL × 3). The organic phase was concentrated and purified by preparative HPLC to give the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylazetidine-1-carboxamide (23.5 mg, white solid, yield: 35.3%). MS m / z (ESI): 457.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.32 - 7.26 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.93 - 3.76 (m, 5H), 3.63 - 3.49 (m, 1H), 3.32 - 3.13 (m, 4H), 3.00 - 2.87 (m, 1H), 2.83 - 2.64 (m, 4H), 2.57 - 2.44 (m, 2H), 2.05 - 1.93 (m, 3H), 1.87 - 1.73 (m, 2H), 1.53 (s, 3H), 1.52 - 1.43 (m, 2H), 1.16 - 1.00 (m, 4H).

[0155] Example 4 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methoxy-3-methylazetidine-1-carboxamide

[0156] [ka]

[0157] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol) and N,N'-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3-Methoxy-3-methylazetidine hydrochloride (30 mg, 0.22 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed three times with water (2 mL x 3). The organic phase was concentrated and purified by preparative HPLC to give the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methoxy-3-methylazetidine-1-carboxamide (22 mg, white solid, yield: 32.1%). MS m / z (ESI): 471.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.29 - 7.23 (m, 1H), 6.90 (d, J = 7.4 Hz, 1H), 3.88 (dd, J = 11.6, 8.0 Hz, 3H), 3.65 (d, J = 8.0 Hz, 2H), 3.61 - 3.51 (m, 1H), 3.33 - 3.13 (m, 7H), 2.86 - 2.63 (m, 4H), 2.55 - 2.42 (m, 2H), 2.07 - 1.94 (m, 2H), 1.85 - 1.75 (m, 2H), 1.56 - 1.42 (m, 5H), 1.30 - 1.19 (m, 1H), 1.19 - 0.99 (m, 4H).

[0158] Example 5 3-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0159] [ka]

[0160] Step 1: tert-butyl bis(fluoromethyl)carbamate

[0161] [ka]

[0162] Tert-Butyl carbamate (500 mg, 4.3 mmol) was dissolved in 10 mL of DMF. NaH (427 mg, 10.7 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Fluoroiodomethane (1.7 g, 3.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl bis(fluoromethyl)carbamate (150 mg, colorless liquid, yield: 19%).

[0163] Step 2: Bis(fluoromethyl)amine hydrochloride

[0164] [ka]

[0165] tert-Butyl bis(fluoromethyl)carbamate (150 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL) and stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation to dryness to give the crude product, bis(fluoromethyl)amine hydrochloride (97 mg, 99%).

[0166] Step 3: 3-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0167] [ka]

[0168] The product, 3-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea, was obtained according to Example 1. MS m / z(ESI):452.2 [M+H] + .

[0169] Example 6 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-(fluoromethyl)-1-methylurea

[0170] [ka]

[0171] Step 1: tert-butyl(fluoromethyl)(methyl)carbamate

[0172] [ka]

[0173] Tert-butyl methylcarbamate (500 mg, 3.8 mmol) was dissolved in 10 mL of DMF. NaH (228 mg, 5.7 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Fluoroiodomethane (610 mg, 3.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl(fluoromethyl)(methyl)carbamate (50 mg, colorless liquid, yield: 8.1%).

[0174] Step 2: 1-Fluoro-N-methylmethanamine hydrochloride

[0175] [ka]

[0176] tert-Butyl(fluoromethyl)(methyl)carbamate (50 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL) and stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation to dryness to give the crude product 1-fluoro-N-methylmethanamine hydrochloride (30 mg, 99%).

[0177] Step 3: 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-(fluoromethyl)-1-methylurea

[0178] [ka]

[0179] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol) and N,N'-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 1-Fluoro-N-methylmethanamine hydrochloride (30 mg, 0.3 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL × 3). The organic phase was concentrated and purified by preparative HPLC to give the product 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-(fluoromethyl)-1-methylurea (12 mg, white solid, yield: 18.5%). MS m / z(ESI):433.2 [M+H] + .

[0180] Example 7 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0181] [ka]

[0182] Step 1: tert-butyl bis(fluoromethyl)carbamate

[0183] [ka]

[0184] Tert-Butyl carbamate (500 mg, 4.3 mmol) was dissolved in 10 mL of DMF. NaH (427 mg, 10.7 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Fluoroiodomethane (1.7 g, 3.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl bis(fluoromethyl)carbamate (150 mg, colorless liquid, yield: 19%).

[0185] Step 2: Bis(fluoromethyl)amine hydrochloride

[0186] [ka]

[0187] tert-Butyl bis(fluoromethyl)carbamate (150 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL) and stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation to dryness to give the crude product, bis(fluoromethyl)amine hydrochloride (97 mg, 99%).

[0188] Step 3: 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0189] [ka]

[0190] According to Example 5, 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea was obtained. MS m / z(ESI):451.2 [M+H] + .

[0191] Example 8 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(trifluoromethyl)urea

[0192] [ka]

[0193] Step 1: tert-Butyl methyl(trifluoromethyl)carbamate

[0194] [ka]

[0195] Tert-butyl methylcarbamate (500 mg, 3.8 mmol) was dissolved in 10 mL of DMF. NaH (228 mg, 5.7 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Trifluoroiodomethane (2.98 g, 3.8 mmol, 25% in DMF) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl methyl(trifluoromethyl)carbamate (40 mg, colorless liquid, yield: 5.3%).

[0196] Step 2: 1,1,1-trifluoro-N-methylmethanamine hydrochloride

[0197] [ka]

[0198] tert-Butyl methyl(trifluoromethyl)carbamate (40 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL) and stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation to dryness to give the crude product 1,1,1-trifluoro-N-methylmethanamine hydrochloride (25 mg, 99%).

[0199] Step 3: 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(trifluoromethyl)urea

[0200] [ka]

[0201] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol) and N,N'-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 1,1,1-Trifluoro-N-methylmethanamine hydrochloride (25 mg, 0.18 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed three times with water (2 mL × 3). The organic phase was concentrated and purified by preparative HPLC to give the product 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(trifluoromethyl)urea (8 mg, white solid, yield: 11.3%). MS m / z(ESI):469.2 [M+H] + .

[0202] Example 8 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide

[0203] [ka]

[0204] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine and triethylamine were dissolved in dichloromethane. Dimethylsulfamoyl chloride was added dropwise, and the reaction solution was stirred at room temperature for 16 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative chromatography to obtain N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide as a white solid. Same as Example 10, MS m / z(ESI): 451.2 [M+H] + .

[0205] Example 10 N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide

[0206] [ka]

[0207] Step 1: N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide

[0208] [ka]

[0209] Trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (60 mg, 0.17 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in dichloromethane (3 mL). Dimethylsulfamoyl chloride (49 mg, 0.34 mmol) was added dropwise, 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 N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide as a white solid (33 mg, yield: 43%). MS m / z (ESI): 452.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 3.97 (d, J = 8.0 Hz, 1H), 3.59 (s, 4H), 3.19-3.09 (m, 1H), 2.79 (s, 6H), 2.69 (s, 4H), 2.52 - 2.39 (m, 2H), 2.10-2.01 (m, 2H), 1.82 (d, J = 12.3 Hz, 2H), 1.50-1.44 (m, 2H), 1.34 - 0.97 (m, 4H).

[0210] Example 11 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)pyridine-3-sulfonamide

[0211] [ka]

[0212] According to Example 10, N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)pyridine-3-sulfonamide was obtained. MS m / z(ESI): 485.2 [M+H] + .

[0213] Example 12 3-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0214] [ka]

[0215] Step 1: Preparation of tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate

[0216] [ka]

[0217] tert-Butyl (4-oxocyclohexyl)carbamate (18.0 g, 84.40 mmol) was dissolved in anhydrous THF (400 mL). Allylmagnesium bromide (254 mL, 254 mmol, 1 M in THF) was added dropwise slowly at -70°C. After the addition was complete, the reaction solution was stirred for 1 hour. Water (100 mL) was added dropwise slowly to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (500 mL x 2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 55 / 45) to give tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, yield: 25%). MS m / z (ESI): 256.2 [M+H] + .

[0218] Step 2: Preparation of tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate

[0219] [ka]

[0220] tert-Butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, 21.15 mmol) was dissolved in THF (100 mL), followed by the addition of water (100 mL). KOsO·2H O (779 mg, 2.11 mmol) and NaIO (18.09 g, 84.59 mmol) were added to the reaction solution, respectively. The reaction solution was stirred overnight at room temperature. Saturated aqueous NaSO (50 mL) was added to the reaction solution, followed by the addition of ethyl acetate (400 mL) and stirring for 5 minutes. The organic phase was collected, dried, and concentrated to give tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, 88% yield). MS m / z (ESI): 258.1 [M+H] + .

[0221] Step 3: Preparation of tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate

[0222] [ka]

[0223] tert-Butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, 18.65 mmol) was dissolved in anhydrous THF (100 mL), and NaBH4 (1.41 g, 37.31 mmol) was added in batches. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was slowly added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate (200 mL × 2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (ethyl acetate / MeOH = 95 / 5) to give tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, yield: 66%). MS m / z(ESI): 260.2[M+H] + .

[0224] Step 4: Preparation of 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate

[0225] [ka]

[0226] tert-Butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, 12.34 mmol) was dissolved in anhydrous dichloromethane (50 mL), followed by the addition of DMAP (151 mg, 1.23 mmol) and DIPEA (3.19 g, 24.68 mmol). The reaction solution was cooled to 0° C., and TsCl (2.82 g, 14.81 mmol) was added thereto. The reaction solution was warmed to 30° C. and stirred overnight. The reaction solution was partitioned between water (50 mL) and dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate=1 / 2) to obtain 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2.0 g, yield: 39%). MS m / z(ESI): 414.1[M+H] + .

[0227] Step 5: Preparation of 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate

[0228] [ka]

[0229] 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2 g, 4.84 mmol) was dissolved in anhydrous dichloromethane (50 mL), and DAST (4.68 g, 29.02 mmol) was added dropwise slowly at −70° C. After the addition was complete, the reaction solution was stirred at −70° C. for 2 hours. Water (10 mL) was added dropwise slowly to quench the reaction, and saturated NaHCO3 solution (10 mL) was added to adjust the pH to slightly alkaline. The combined solution was extracted with dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate=3 / 2) to give 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate (630 mg, yield: 31%) and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate (600 mg, yield: 31%). 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate: MS m / z (ESI): 416.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.39 (s, 1H), 4.21 - 4.12 (m, 2H), 3.45 - 3.30 (m, 1H), 2.45 (s, 3H), 2.06 - 1.75 (m, 7H), 1.52 - 1.46 (m, 1H), 1.44 (s, 9H), 1.41 - 1.31 (m, 2H). 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate: MS m / z (ESI): 396.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.32 (s, 1H), 4.49 (s, 1H), 4.13 - 4.00 (m, 2H), 3.75 - 3.61 (m, 1H), 2.45 (s, 3H), 2.30 - 2.27 (m, 2H), 1.99 - 1.94 (m, 1H), 1.85 - 1.76 (m, 2H), 1.70 - 1.64 (m, 1H), 1.56 - 1.50 (m, 1H), 1.45 (s, 9H).

[0230] Step 6: Preparation of tert-butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0231] [ka]

[0232] 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate (390 mg, 0.94 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 1-(2,3-dichlorophenyl)piperazine (260 mg, 1.13 mmol) and potassium carbonate (389 mg, 2.82 mmol). The reaction solution was stirred at 90° C. overnight. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate=1 / 9) to give tert-butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (210 mg, yield: 47%). MS m / z(ESI): 474.2[M+H] + .

[0233] Step 7: Preparation of cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0234] [ka]

[0235] tert-Butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (210 mg, 0.442 mmol) was dissolved in 25% TFA / dichloromethane (10 mL). The reaction solution was stirred at room temperature for 2 hours, concentrated, and dried to give cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (210 mg, as the TFA salt). MS m / z (ESI): 374.2 [M+H] + .

[0236] Step 8: Preparation of 3-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0237] [ka]

[0238] Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (210 mg, approximately 0.147 mmol as the TFA salt) was dissolved in anhydrous dichloromethane (5 mL), followed by the addition of DIPEA (0.1 mL) and dimethylcarbamic chloride (1 drop). The reaction solution was stirred overnight at room temperature. Water (5 mL) was added to the reaction solution, which was then extracted with dichloromethane (10 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by preparative HPLC to give 3-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea (21.1 mg, yield: 32%). MS m / z (ESI): 445.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 7.1, 2.3 Hz, 1H), 4.18 (d, J = 7.7 Hz, 1H), 3.75 - 3.60 (m, 1H), 3.27 - 3.03 (m, 4H), 2.89 (s, 6H), 2.86 - 2.51 (m, 6H), 2.04 - 1.81 (m, 6H), 1.64 - 1.53 (m, 1H), 1.52 - 1.40 (m, 3H).

[0239] Example 13 N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1H-indole-2-carboxamide

[0240] [ka]

[0241] Step 1: Preparation of N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1H-indole-2-carboxamide

[0242] [ka]

[0243] Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (100 mg, approximately 0.21 mmol as the TFA salt) was dissolved in anhydrous DMF (3 mL), and 1H-indole-2-carboxylic acid (52 mg, 0.32 mmol), HATU (160 mg, 0.42 mmol), and DIEA (0.2 mL) were added. The reaction solution was stirred at room temperature overnight. The reaction solution was filtered and purified by preparative HPLC to give N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1H-indole-2-carboxamide (25 mg, yield: 23%). MS m / z (ESI): 517.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.22 - 7.10 (m, 3H), 7.02 (t, J = 7.4 Hz, 1H), 3.95 - 3.79 (m, 1H), 3.08 - 2.92 (m, 4H), 2.67 - 2.51 (m, 6H), 1.99 - 1.87 (m, 2H), 1.86 - 1.51 (m, 8H).

[0244] Example 14 N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0245] [ka]

[0246] Step 1: Preparation of N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0247] [ka]

[0248] Using cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and furan-2-carboxylic acid as starting materials and following Step 1 of Example 13, N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide (off-white solid, yield: 36%) was obtained. MS m / z (ESI): 468.2[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 3.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.60 (dd, J = 3.5, 1.7 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.55 - 3.38 (m, 4H), 2.98 - 2.55 (m, 6H), 2.06 - 1.92 (m, 2H), 1.92 - 1.72 (m, 4H), 1.72 - 1.62 (m, 4H), 1.58 - 1.48 (m, 1H).

[0249] Example 15 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0250] [ka]

[0251] Step 1: Preparation of tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate

[0252] [ka]

[0253] tert-Butyl (4-oxocyclohexyl)carbamate (18.0 g, 84.40 mmol) was dissolved in anhydrous THF (400 mL). Allylmagnesium bromide (254 mL, 254 mmol, 1 M in THF) was added dropwise slowly at -70°C. After the addition was complete, the reaction solution was stirred for 1 hour. Water (100 mL) was added dropwise slowly to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (500 mL x 2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 55 / 45) to give tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, yield: 25%). MS m / z (ESI): 256.2 [M+H] + .

[0254] Step 2: Preparation of tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate

[0255] [ka]

[0256] tert-Butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, 21.15 mmol) was dissolved in THF (100 mL), followed by the addition of water (100 mL). KOsO·2H O (779 mg, 2.11 mmol) and NaIO (18.09 g, 84.59 mmol) were added to the reaction solution, respectively. The reaction solution was stirred overnight at room temperature. Saturated aqueous NaSO (50 mL) was added to the reaction solution, followed by the addition of ethyl acetate (400 mL) and stirring for 5 minutes. The organic phase was collected, dried, and concentrated to give tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, 88% yield). MS m / z (ESI): 258.1 [M+H] + .

[0257] Step 3: Preparation of tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate

[0258] [ka]

[0259] tert-Butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, 18.65 mmol) was dissolved in anhydrous THF (100 mL), and NaBH4 (1.41 g, 37.31 mmol) was added in batches. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was slowly added to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (200 mL × 2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (ethyl acetate / MeOH = 95 / 5) to give tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, yield: 66%). MS m / z(ESI): 260.2[M+H] + .

[0260] Step 4: Preparation of 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate

[0261] [ka]

[0262] tert-Butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, 12.34 mmol) was dissolved in anhydrous dichloromethane (50 mL), followed by the addition of DMAP (151 mg, 1.23 mmol) and DIPEA (3.19 g, 24.68 mmol). The reaction solution was cooled to 0° C., and TsCl (2.82 g, 14.81 mmol) was added thereto. The reaction solution was warmed to 30° C. and stirred overnight. The reaction solution was partitioned between water (50 mL) and dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate=1 / 2) to obtain 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2.0 g, yield: 39%). MS m / z(ESI): 414.1[M+H] + .

[0263] Step 5: Preparation of 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate

[0264] [ka]

[0265] 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2 g, 4.84 mmol) was dissolved in anhydrous dichloromethane (50 mL), and DAST (4.68 g, 29.02 mmol) was added dropwise slowly at −70° C. After the addition was complete, the reaction solution was stirred at −70° C. for 2 hours. Water (10 mL) was added dropwise slowly to quench the reaction, and saturated NaHCO3 solution (10 mL) was added to adjust the pH to slightly alkaline. The combined solution was extracted with dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate=3 / 2) to give 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate (630 mg, yield: 31%) and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate (600 mg, yield: 31%). 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate: MS m / z (ESI): 416.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.39 (s, 1H), 4.21 - 4.12 (m, 2H), 3.45 - 3.30 (m, 1H), 2.45 (s, 3H), 2.06 - 1.75 (m, 7H), 1.52 - 1.46 (m, 1H), 1.44 (s, 9H), 1.41 - 1.31 (m, 2H). 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate: MS m / z (ESI): 396.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.32 (s, 1H), 4.49 (s, 1H), 4.13 - 4.00 (m, 2H), 3.75 - 3.61 (m, 1H), 2.45 (s, 3H), 2.30 - 2.27 (m, 2H), 1.99 - 1.94 (m, 1H), 1.85 - 1.76 (m, 2H), 1.70 - 1.64 (m, 1H), 1.56 - 1.50 (m, 1H), 1.45 (s, 9H).

[0266] Step 6: Preparation of tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0267] [ka]

[0268] 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate was dissolved in acetonitrile (20 mL), followed by the addition of 1-(benzo[b]thiophen-4-yl)piperazine and potassium carbonate (389 mg, 2.82 mmol). The reaction solution was stirred at 90° C. overnight. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate=1 / 9) to give tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (180 mg, yield: 70%). MS m / z(ESI): 462.2[M+H] + .

[0269] Step 7: Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0270] [ka]

[0271] tert-Butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate was dissolved in 25% TFA / dichloromethane (10 mL). The reaction solution was stirred at room temperature for 2 hours, concentrated to dryness, and dried to give cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (180 mg, as the TFA salt). MS m / z(ESI): 362.1[M+H] + .

[0272] Step 8: Preparation of 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0273] [ka]

[0274] Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine was dissolved in anhydrous dichloromethane, followed by the addition of DIPEA and dimethylcarbamic chloride. The reaction solution was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by preparative HPLC to give 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea (18.0 mg, yield: 32%). MS m / z (ESI): 433.2[M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.96 (d, J = 7.9 Hz, 1H), 3.52 - 3.38 (m, 1H), 3.16 - 2.98 (m, 4H), 2.76 (s, 6H), 2.70 - 2.56 (m, 4H), 2.49 - 2.44 (m, 2H), 1.94 - 1.72 (m, 4H), 1.67 - 1.60 (m, 2H), 1.60 - 1.43 (m, 4H).

[0275] Example 16 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-ethylurea

[0276] [ka]

[0277] Step 1: Preparation of 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-ethylurea

[0278] [ka]

[0279] Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and triethylamine were dissolved in anhydrous dichloromethane. Isocyanatoethane was added dropwise, and the reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative chromatography to obtain 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-ethylurea (37.2 mg, yield: 66%). MS m / z (ESI): 433.2[M+H] + . 1H NMR (400 MHz, DMSO) δ 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.94 - 6.87 (m, 1H), 5.74 (d, J = 7.9 Hz, 1H), 5.62 (t, J = 5.5 Hz, 1H), 3.44 - 3.34 (m, 1H), 3.14 - 3.03 (m, 4H), 3.03 - 2.94 (m, 2H), 2.71 - 2.55 (m, 4H), 2.46 (s, 2H), 1.88 - 1.73 (m, 4H), 1.71 - 1.61 (m, 2H), 1.61 - 1.43 (m, 2H), 1.40 - 1.26 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

[0280] Example 17 N-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)pyrrolidine-1-carboxamide

[0281] [ka]

[0282] Using cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and pyrrole hydrochloride as starting materials and according to Step 3 of Example 8, N-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)pyrrolidine-1-carboxamide was obtained. MS m / z(ESI): 459.2[M+H] + .

[0283] Example 18 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-cyclopropylurea

[0284] [ka]

[0285] Using cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and cyclopropanamine hydrochloride as starting materials, and according to Step 3 of Example 8, 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-cyclopropylurea was obtained. MS m / z(ESI): 445.2[M+H] + .

[0286] Example 19 3-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea

[0287] [ka]

[0288] Step 1: Preparation of ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate

[0289] [ka]

[0290] Ethyl (1r,4r)-4-aminocyclohexane-1-carboxylate (5 g, 29 mmol) was dissolved in toluene (200 mL). Triethylamine (8.8 g, 88 mmol) and isobenzofuran-1,3-dione (5.2 g, 35 mmol) were added, and the reaction solution was stirred at 140° C. for 8 hours. The reaction solution was cooled to room temperature and concentrated to dryness by rotary evaporation. Water (50 mL) was added, and the solution was stirred for 30 minutes. The solid was precipitated and filtered. The solid was collected and concentrated to dryness by rotary evaporation to give ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g). MS m / z(ESI): 302.2 [M+H] + .

[0291] Step 2: Preparation of ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate

[0292] [ka]

[0293] Ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −78° C. Lithium diisopropylamide (11 mL, 11 mmol) was added, and the reaction solution was stirred at −78° C. for 30 minutes. Iodomethane (1.7 g, 12 mmol) was added, and the reaction solution was slowly warmed to room temperature and stirred overnight. An aqueous solution of ammonium chloride (50 mL) was added, and the solution was stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3.0 g, yield: 100%, crude).

[0294] Step 3: Preparation of 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0295] [ka]

[0296] Ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 °C. Lithium aluminum hydride (0.43 g, 11 mmol) was added, and the reaction solution was stirred at 0 °C for 2 hours. An aqueous solution of sodium hydroxide (3 M, 5 mL) was added to quench the reaction, followed by water (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, yield: 100%, crude).

[0297] Step 4: Preparation of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde

[0298] [ka]

[0299] 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, 9.5 mmol) was dissolved in dichloromethane (30 mL). PCC (4.1 g, 19 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g). MS m / z(ESI): 272.2 [M+H] + .

[0300] Step 5: Preparation of 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione

[0301] [ka]

[0302] Methyltriphenylphosphonium bromide (2.9 g, 8.3 mmol) was dissolved in tetrahydrofuran (50 mL). The solution was purged with N2 and cooled to 0 °C. Potassium tert-butoxide (1.1 g, 10 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0 °C, followed by the addition of a solution of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g, 5.5 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at room temperature for 2 hours and then at 50 °C overnight. Water (100 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g). MS m / z(ESI): 270.2 [M+H] + .

[0303] Step 6: Preparation of 2-(4-(2-hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0304] [ka]

[0305] 2-(4-Methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The solution was cooled to 0 °C, and BH3 / THF (13.5 mL, 13.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to 0 °C, and 3 M aqueous NaOH (4 mL) was slowly added, followed by water (3 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was complete. Ethyl acetate (50 mL) was added, and the solution was washed with a saturated aqueous solution of Na2S2O3 (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (1.2 g, yield: 100%, crude), which was used directly in the next step. MS m / z(ESI): 288.2 [M+H] + .

[0306] Step 7: Preparation of 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate

[0307] [ka]

[0308] 2-(4-(2-hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.4 g, 13.4 mmol) and p-toluenesulfonyl chloride (1.0 g, 5.4 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g). MS m / z(ESI): 442.2 [M+H] +.

[0309] Step 8: Preparation of 2-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0310] [ka]

[0311] 2-(4-(1,3-Dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g, 3.4 mmol), 1-(2,3-dichlorophenyl)piperazine (0.79 g, 3.4 mmol), and potassium carbonate (1.4 g, 10.2 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was stirred at 80 °C overnight. The reaction solution was filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 2-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g). MS m / z(ESI): 500.2 [M+H] + .

[0312] Step 9: Preparation of 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine

[0313] [ka]

[0314] 2-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g, 2.8 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (0.35 mL, 7.0 mmol) was added, and the reaction solution was stirred at 80° C. overnight. The reaction solution was concentrated to dryness by rotary evaporation, followed by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (0.6 g). MS m / z(ESI): 370.2 [M+H] + .

[0315] Step 10: Preparation of 3-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea

[0316] [ka]

[0317] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (71 mg, 0.7 mmol) and dimethylcarbamic chloride (299 mg, 2.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography to give 3-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea (10.0 mg). MS m / z(ESI): 441.2 [M+H] + .

[0318] Example 20 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea

[0319] [ka]

[0320] Step 1: Preparation of ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate

[0321] [ka]

[0322] Ethyl (1r,4r)-4-aminocyclohexane-1-carboxylate (5 g, 29 mmol) was dissolved in toluene (200 mL). Triethylamine (8.8 g, 88 mmol) and isobenzofuran-1,3-dione (5.2 g, 35 mmol) were added, and the reaction solution was stirred at 140° C. for 8 hours. The reaction solution was cooled to room temperature and concentrated to dryness by rotary evaporation. Water (50 mL) was added, and the solution was stirred for 30 minutes. The solid was allowed to precipitate, and the solution was filtered. The solid was collected and concentrated to dryness by rotary evaporation to give ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g). MS m / z(ESI): 302.2 [M+H] + .

[0323] Step 2: Preparation of ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate

[0324] [ka]

[0325] Ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −78° C. Lithium diisopropylamide (11 mL, 11 mmol) was added, and the reaction solution was stirred at −78° C. for 30 minutes. Iodomethane (1.7 g, 12 mmol) was added, and the reaction solution was slowly warmed to room temperature and stirred overnight. An aqueous solution of ammonium chloride (50 mL) was added, and the solution was stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3.0 g, yield: 100%, crude).

[0326] Step 3: Preparation of 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0327] [ka]

[0328] Ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 °C. Lithium aluminum hydride (0.43 g, 11 mmol) was added, and the reaction solution was stirred at 0 °C for 2 hours. An aqueous solution of sodium hydroxide (3 M, 5 mL) was added to quench the reaction, followed by water (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, yield: 100%, crude).

[0329] Step 4: Preparation of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde

[0330] [ka]

[0331] 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, 9.5 mmol) was dissolved in dichloromethane (30 mL). PCC (4.1 g, 19 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g). MS m / z(ESI): 272.2 [M+H] + .

[0332] Step 5: Preparation of 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione

[0333] [ka]

[0334] Methyltriphenylphosphonium bromide (2.9 g, 8.3 mmol) was dissolved in tetrahydrofuran (50 mL). The solution was purged with N2 and cooled to 0 °C. Potassium tert-butoxide (1.1 g, 10 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0 °C, followed by the addition of a solution of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g, 5.5 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at room temperature for 2 hours and then at 50 °C overnight. Water (100 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g). MS m / z(ESI): 270.2 [M+H] + .

[0335] Step 6: Preparation of 2-(4-(2-hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0336] [ka]

[0337] 2-(4-Methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The solution was cooled to 0 °C, and BH3 / THF (13.5 mL, 13.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to 0 °C, and an aqueous solution of NaOH (3 M, 4 mL) was slowly added, followed by water (3 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was complete. Ethyl acetate (50 mL) was added, and the solution was washed with a saturated aqueous solution of Na2S2O3 (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (1.2 g, yield: 100%, crude), which was used directly in the next step. MS m / z(ESI): 288.2 [M+H] + .

[0338] Step 7: Preparation of 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate

[0339] [ka]

[0340] 2-(4-(2-hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.4 g, 13.4 mmol) and p-toluenesulfonyl chloride (1.0 g, 5.4 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g). MS m / z(ESI): 442.2 [M+H] +.

[0341] Step 8: Preparation of 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0342] [ka]

[0343] 2-(4-(1,3-Dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g, 3.4 mmol), 1-(benzo[b]thiophen-4-yl)piperazine (0.79 g, 3.4 mmol), and potassium carbonate (1.4 g, 10.2 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was stirred at 80 °C overnight. The reaction solution was filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 1 / 1) to give 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g). MS m / z(ESI): 500.2 [M+H] + .

[0344] Step 9: 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine

[0345] [ka]

[0346] 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g, 2.8 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (0.35 mL, 7.0 mmol) was added, and the reaction solution was stirred at 80° C. overnight. The reaction solution was concentrated to dryness by rotary evaporation, followed by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (0.6 g). MS m / z(ESI): 370.2 [M+H] + .

[0347] Step 10: 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea

[0348] [ka]

[0349] 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (71 mg, 0.7 mmol) and dimethylcarbamic chloride (299 mg, 2.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography by referring to Example 19 to give 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea (20.0 mg). MS m / z(ESI): 429.2 [M+H] + .

[0350] Example 21 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-1,1-dimethylurea

[0351] [ka]

[0352] Step 1: Preparation of tert-butyl (4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)carbamate

[0353] [ka]

[0354] Using 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate and 1-(benzo[b]thiophen-4-yl)piperazine as starting materials and following Step 6 of Example 12, tert-butyl (4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)carbamate (400 mg, yield: 72%) was obtained. MS m / z(ESI): 442.2[M+H] + .

[0355] Step 2: Preparation of 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine

[0356] [ka]

[0357] Using tert-butyl (4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)carbamate as a starting material and referring to Step 7 of Example 12, 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine (280 mg, yield: 91%) was obtained. MS m / z(ESI): 342.1[M+H] + .

[0358] Step 3: Preparation of 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-1,1-dimethylurea

[0359] [ka]

[0360] Using 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine as the starting material and following Step 8 of Example 12, 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-1,1-dimethylurea was obtained. MS m / z(ESI): 413.2[M+H] + .

[0361] Example 22 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-3-propylurea

[0362] [ka]

[0363] Step 1: Preparation of 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-3-propylurea

[0364] [ka]

[0365] Using 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine and isocyanatopropane as starting materials, 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-3-propylurea was obtained according to Step 8 of Example 12 or Example 16. MS m / z(ESI): 427.2[M+H] + .

[0366] Example 23 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-1,1-dimethylurea

[0367] [ka]

[0368] Using 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexan-1-amine and dimethylcarbamic chloride as starting materials and following Step 8 of Example 12, 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-1,1-dimethylurea was obtained. MS m / z(ESI): [M+H] + .433.2

[0369] Example 24 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-3-ethylurea

[0370] [ka]

[0371] Using 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexan-1-amine and isocyanatoethane as starting materials, and following Step 8 of Example 12 or Example 16, 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-3-ethylurea was obtained. MS m / z(ESI): [M+H] + .433.2

[0372] Example 25 1-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea

[0373] [ka]

[0374] Step 1: Preparation of 1-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea

[0375] [ka]

[0376] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl-1-amine (60 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (48.5 mg, 0.48 mmol) was added, and the reaction solution was stirred at room temperature for 5 minutes. Isocyanatoethane (17.3 mg, 0.24 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography to give 1-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea (11.9 mg, yield: 17%). MS m / z (ESI): 441.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.21 - 7.11 (m, 2H), 7.01 - 6.95 (m, 1H), 4.25 - 4.00 (m, 2H), 3.26 - 3.13 (m, 5H), 2.91 - 2.52 (m, 6H), 2.19 - 2.11 (m, 1H), 1.94 - 1.86 (m, 1H), 1.69 - 1.55 (m, 5H), 1.37 - 1.10 (m, 11H).

[0377] Example 26 N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-5-fluoropyrimidin-2-amine

[0378] [ka]

[0379] Step 1: Preparation of N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-5-fluoropyrimidin-2-amine

[0380] [ka]

[0381] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3 mL). Potassium carbonate (41 mg, 0.4 mmol) and 2-chloro-5-fluoropyrimidine (40 mg, 0.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography to give N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-5-fluoropyrimidin-2-amine. MS m / z(ESI): 466.1 [M+H] + .

[0382] Example 27 N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1H-indole-2-carboxamide

[0383] [ka]

[0384] Step 1: Preparation of N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1H-indole-2-carboxamide

[0385] [ka]

[0386] 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3 mL). 1H-Indole-2-carboxylic acid (27 mg, 0.17 mmol), HATU (74 mg, 0.2 mmol), and diisopropylethylamine (39 mg, 0.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography to give N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1H-indole-2-carboxamide. MS m / z(ESI): 513.2 [M+H] + .

[0387] Example 28 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1-dimethylurea

[0388] [ka]

[0389] Step 1: Preparation of 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1-dimethylurea

[0390] [ka]

[0391] 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1-amine was dissolved in N,N-dimethylformamide. Dimethylcarbamic acid, HATU, and diisopropylethylamine were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography by referring to Example 27 to obtain 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1-dimethylurea. MS m / z(ESI): 429.2 [M+H] + .

[0392] Example 29 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea

[0393] [ka]

[0394] According to Example 25, 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea was obtained. MS m / z(ESI): 429.2 [M+H] + .

[0395] Example 30 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0396] [ka]

[0397] Step 1: tert-butyl (R)-4-(2,3-dichlorophenyl)-2-methylpiperazine-1-carboxylate

[0398] [ka]

[0399] 1-Bromo-2,3-dichlorobenzene (1.35 g, 6 mmol), tert-butyl (R)-2-methylpiperazine-1-carboxylate (836 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium (228 mg, 0.25 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (289 mg, 0.5 mmol), and sodium tert-butoxide (1.44 g, 15 mmol) were dissolved in 20 mL of toluene in a 50 mL round-bottom flask and the reaction solution was purged with nitrogen. The reaction solution was stirred at 80 °C under a nitrogen atmosphere for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether / ethyl acetate = 4 / 1) to give tert-butyl (R)-4-(2,3-dichlorophenyl)-2-methylpiperazine-1-carboxylate (1.0 g, yellow solid, yield: 48.3%). MS m / z(ESI):345.1 [M+H] + .

[0400] Step 2: (R)-1-(2,3-dichlorophenyl)-3-methylpiperazine

[0401] [ka]

[0402] tert-Butyl (R)-4-(2,3-dichlorophenyl)-2-methylpiperazine-1-carboxylate (1 g, 2.89 mmol) was dissolved in 10 mL of dichloromethane in a 50 mL round-bottom flask, followed by the addition of trifluoroacetic acid (4 mL). The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness by rotary evaporation to give (R)-1-(2,3-dichlorophenyl)-3-methylpiperazine (600 mg, white solid, yield: 84.7%). MS m / z(ESI):245.1 [M+H] + .

[0403] Step 3: tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamate

[0404] [ka]

[0405] Using (R)-1-(2,3-dichlorophenyl)-3-methylpiperazine and 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate as starting materials and according to Step 1 of Example 2, tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamate (100 mg, yellow solid, yield: 26.0%) was obtained. MS m / z(ESI):470.1 [M+H] + .

[0406] Step 4: trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0407] [ka]

[0408] Using tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamate as the starting material and following Step 2 of Example 2, trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine (75 mg, yellow solid, yield: 95.2%) was obtained. MS m / z(ESI):370.1 [M+H] + .

[0409] Step 5: 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0410] [ka]

[0411] Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine (60 mg, 0.16 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (50 mg, 0.5 mmol) and dimethylcarbamic chloride (35 mg, 0.32 mmol) were added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL × 3). The organic phase was concentrated and purified by preparative HPLC to obtain the product 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (8.3 mg, white solid, yield: 13.9%). MS m / z (ESI): 441.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.39 - 7.17 (m, 2H), 7.13 - 7.01 (m, 1H), 3.59 - 3.45 (m, 2H), 3.28 - 3.15 (m, 2H), 3.08 - 2.93 (m, 2H), 2.89 (s, 6H), 2.78 - 2.57 (m, 3H), 2.52 - 2.41 (m, 1H), 1.97 - 1.77 (m, 4H), 1.55 - 1.39 (m, 2H), 1.37 - 1.21 (m, 3H), 1.17 (d, J = 6.0 Hz, 3H), 1.13 - 1.03 (m, 2H).

[0412] Example 31 3-(trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-cyclopropylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0413] [ka]

[0414] Using 4-bromobenzo[b]thiophene and tert-butyl (R)-3-cyclopropylpiperazine-1-carboxylate as starting materials, 3-(trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-cyclopropylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained according to Example 30. MS m / z(ESI):455.2 [M+H] + .

[0415] Example 32 Preparation of 3-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-cyanopiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0416] [ka]

[0417] According to Example 30, 3-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-cyanopiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained. MS m / z(ESI):440.2[M+H] + .

[0418] Example 33 3-(trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0419] [ka]

[0420] Using 4-bromobenzo[b]thiophene and tert-butyl (R)-3-methylpiperazine-1-carboxylate as starting materials, the product 3-(trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained according to Example 30. MS m / z(ESI):429.2 [M+H] + .

[0421] Example 34 3-(trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0422] [ka]

[0423] Step 1: 2-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane

[0424] [ka]

[0425] Using 4-bromobenzo[b]thiophene and 2,5-diazabicyclo[4.2.0]octane as starting materials and following Step 1 of Example 30, 2-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane (290 mg, white solid, yield: 48%) was obtained. MS m / z(ESI): 245.1 [M+H] + .

[0426] Step 2: tert-butyl (trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)carbamate

[0427] [ka]

[0428] Using 2-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane as the starting material and following Step 3 of Example 30, tert-butyl (trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)carbamate (301 mg, white solid, yield: 54%) was obtained. MS m / z(ESI): 470.3 [M+H] + .

[0429] Step 3: trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexan-1-amine

[0430] [ka]

[0431] Using tert-butyl (trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)carbamate as a starting material and following Step 7 of Example 12, trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexan-1-amine triflate (299 mg, yield: 99%) was obtained. MS m / z(ESI): 370.2 [M+H] + .

[0432] Step 4: 3-(trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0433] [ka]

[0434] Using trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexan-1-amine as the starting material and following Step 8 of Example 12, 3-(trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)-1,1-dimethylurea (23 mg, white solid, yield: 35%) was obtained. MS m / z(ESI):441.3 [M+H] + .

[0435] Example 35 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0436] [ka]

[0437] Step 1: tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate

[0438] [ka]

[0439] Using 1-bromo-2,3-dichlorobenzene and tert-butyl (R)-3-methylpiperazine-1-carboxylate as starting materials, and following Step 1 of Example 30, tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate (600 mg, yellow solid, yield: 32.6%) was obtained. MS m / z (ESI): 345.1 [M+H] + . 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).

[0440] Step 2: (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine

[0441] [ka]

[0442] Using tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate as the starting material, and following Step 2 of Example 30, (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%) was obtained. MS m / z (ESI): 245.1 [M+H] + . 1H 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).

[0443] Step 3: tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamate

[0444] [ka]

[0445] Using (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine and 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate as starting materials and according to Step 1 of Example 2, tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamate (100 mg, yellow solid, yield: 26.0%) was obtained. MS m / z(ESI):470.1 [M+H] + .

[0446] Step 4: trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0447] [ka]

[0448] Using tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamate as the starting material and following Step 2 of Example 2, trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine (75 mg, yellow solid, yield: 95.2%) was obtained. MS m / z(ESI):370.1 [M+H] + .

[0449] Step 5: 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0450] [ka]

[0451] Using trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material and following Step 5 of Example 30, 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (25 mg, white solid, yield: 35.0%) was obtained. MS m / z (ESI): 441.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.38 - 7.15 (m, 3H), 3.56 - 3.44 (m, 1H), 3.36 (s, 2H), 3.12 (d, J = 11.6 Hz, 1H), 2.93 (s, 1H), 2.87 (s, 6H), 2.77 - 2.67 (m, 1H), 2.52 - 2.34 (m, 3H), 2.17 - 2.02 (m, 1H), 1.96 - 1.75 (m, 4H), 1.57 - 1.42 (m, 2H), 1.37 - 1.21 (m, 3H), 1.15 - 0.99 (m, 2H), 0.87 (d, J = 6.1 Hz, 3H).

[0452] Example 36 3-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0453] [ka]

[0454] Using trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material and following Step 5 of Example 30, 3-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained. MS m / z(ESI):483.2 [M+H] + .

[0455] Example 37 N-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide

[0456] [ka]

[0457] Using trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material and following Step 5 of Example 30, N-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide was obtained. MS m / z(ESI):507.2 [M+H] + .

[0458] Example 38 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0459] [ka]

[0460] Using 1-(benzo[b]thiophen-4-yl)-1,4-diazepane as the starting material and following steps 1 to 3 of Example 2, N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide was obtained. MS m / z(ESI):477.2 [M+H] + .

[0461] Example 39 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0462] [ka]

[0463] Step 1: Preparation of tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0464] [ka]

[0465] Using 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 1-(benzo[b]thiophen-4-yl)-1,4-diazepane as starting materials and following Step 6 of Example 12, tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)carbamate was obtained. MS m / z(ESI): 476.2[M+H] + .

[0466] Step 2: Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0467] [ka]

[0468] Using tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)carbamate as the starting material and following Step 7 of Example 12, cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexan-1-amine was obtained. MS m / z(ESI): 376.2[M+H] + .

[0469] Step 3: Preparation of 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0470] [ka]

[0471] Using cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexan-1-amine as the starting material and following Step 8 of Example 12, 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea was obtained. MS m / z (ESI): 447.2[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.96 (d, J = 7.9 Hz, 1H), 3.55 - 3.37 (m, 5H), 2.90 - 2.78 (m, 2H), 2.75 (s, 6H), 2.71 - 2.51 (m, 4H), 2.58 (s, 4H), 2.05 - 1.90 (m, 2H), 1.89 - 1.71 (m, 4H), 1.66 - 1.58 (m, 2H), 1.58 - 1.40 (m, 4H).

[0472] Example 40 N-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0473] [ka]

[0474] Step 1: Preparation of tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0475] [ka]

[0476] Using 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 1-(benzo[b]thiophen-4-yl)piperazine as starting materials and following Step 6 of Example 12, tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (180 mg, yield: 70%) was obtained. MS m / z(ESI): 462.2[M+H] + .

[0477] Step 2: Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0478] [ka]

[0479] Using tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate as the starting material, and following Step 7 of Example 12, cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (180 mg, as the TFA salt) was obtained. MS m / z(ESI): 362.2[M+H] + .

[0480] Step 3: Preparation of N-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0481] [ka]

[0482] Using cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and furan-2-carbonyl chloride as starting materials and according to Step 8 of Example 12, N-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide (33.3 mg, yield: 56%) was obtained. MS m / z (ESI): 456.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.20 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 3.3 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.66 - 6.57 (m, 1H), 3.86 - 3.72 (m, 1H), 3.15 - 2.97 (m, 4H), 2.74 - 2.57 (m, 4H), 2.50 - 2.43 (m, 2H), 1.98 - 1.75 (m, 4H), 1.72 - 1.48 (m, 6H).

[0483] Example 41 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-hydroxy-2-methylpropanamide

[0484] [ka]

[0485] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine and 2-hydroxy-2-methylpropionic acid as starting materials, N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-hydroxy-2-methylpropanamide was obtained according to Example 27. MS m / z(ESI):430.2 [M+H] + .

[0486] Example 42 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide

[0487] [ka]

[0488] Step 1: N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide

[0489] [ka]

[0490] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (100 mg, 0.291 mmol) was dissolved in anhydrous DMF (5 mL), and 1-hydroxycyclopropane-1-carboxylic acid (59 mg, 0.582 mmol), DIEA (301 mg, 2.328 mmol), and HATU (221 mg, 0.582 mmol) were added, respectively. The reaction solution was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by preparative HPLC to give N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide (38.4 mg, 31% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 5.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.21 (s, 1H), 3.61 - 3.47 (m, 1H), 3.16 - 2.96 (m, 4H), 2.73 - 2.53 (m, 4H), 2.39 (t, J = 7.5 Hz, 2H), 1.85 - 1.67 (m, 4H), 1.45 - 1.35 (m, 2H), 1.35 - 1.19 (m, 3H), 1.07 - 0.90 (m, 4H), 0.84 - 0.74 (m, 2H). MS m / z (ESI): 428.2 [M+H] + .

[0491] Example 43 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide

[0492] [ka]

[0493] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine and oxazole-2-carboxylic acid as starting materials, N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide was obtained according to Example 27. MS m / z (ESI): 439.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 5.5 Hz, 1H), 7.33 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 3.90 - 3.75 (m, 1H), 3.25 - 3.05 (m, 4H), 2.89 - 2.65 (m, 4H), 2.59 - 2.45 (m, 2H), 2.07 - 1.94 (m, 2H), 1.94 - 1.84 (m, 2H), 1.55 - 1.29 (m, 6H), 1.23 - 1.08 (m, 1H).

[0494] Example 44 2-((trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)amino)pyrimidine-5-carbonitrile

[0495] [ka]

[0496] Step 1: trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0497] [ka]

[0498] Using 4-bromobenzo[b]thiophene as the starting material and following steps 1 to 3 of Example 35, trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine was obtained. MS m / z(ESI): 358.2[M+H] + .

[0499] Step 2: (R)-4-(2-(4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0500] [ka]

[0501] trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine was dissolved in N,N-dimethylformamide. Potassium carbonate and 2-chloropyrimidine-5-carbonitrile were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high-performance liquid chromatography according to Example 26 to give 2-((trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)amino)pyrimidine-5-carbonitrile. MS m / z (ESI): 461.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.43 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.40 (dd, J = 11.2, 5.5 Hz, 2H), 7.29-7.26 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 5.59 (d, J = 8.0 Hz, 1H), 3.86 - 3.83 (m, 1H), 3.37-3.30 (m, 2H), 3.06-3.04 (m, 2H), 2.88-2.80 (m, 3H), 2.65 (s, 1H), 2.48 (s, 1H), 2.11 (d, J = 11.1 Hz, 2H), 1.88 (s, 2H), 1.51 (d, J = 6.4 Hz, 2H), 1.30-1.13(m, 8H).

[0502] Example 45 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide

[0503] [ka]

[0504] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material, the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide was obtained according to Example 27. MS m / z (ESI): 438.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.64 (dd, J = 1.8, 0.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 5.5 Hz, 1H), 7.42 (dd, J = 5.6, 0.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.09 (dd, J = 3.5, 0.8 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.56 (dd, J = 3.5, 1.8 Hz, 1H), 3.89 - 3.74 (m, 1H), 3.26 - 3.08 (m, 4H), 2.90 - 2.67 (m, 4H), 2.61 - 2.49 (m, 2H), 2.02 - 1.81 (m, 4H), 1.58 - 1.48 (m, 2H), 1.47 - 1.26 (m, 4H), 1.23 - 1.06 (m, 2H).

[0505] Example 46 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuran-2-carboxamide

[0506] [ka]

[0507] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material, the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuran-2-carboxamide was obtained according to Example 27. MS m / z (ESI): 452.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.62 - 7.47 (m, 2H), 7.42 (dd, J = 5.6, 0.8 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.06 - 6.88 (m, 2H), 6.17 (dd, J = 3.3, 1.1 Hz, 1H), 3.91 - 3.70 (m, 1H), 3.26 - 3.07 (m, 4H), 2.90 - 2.65 (m, 4H), 2.62 - 2.47 (m, 2H), 2.36 (s, 3H), 2.00 - 1.79 (m, 4H), 1.67 - 1.49 (m, 2H), 1.47 - 1.25 (m, 4H), 1.23 - 1.05 (m, 2H).

[0508] Example 47 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-methoxyacetamide

[0509] [ka]

[0510] Step 8 of Example 12 was followed to give N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-methoxyacetamide (21 mg). MS m / z (ESI): 416.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.56 (d, J = 8.0 Hz, 1H), 7.33 - 7.24 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 8.6 Hz, 1H), 3.87 (s, 2H), 3.83 - 3.72 (m, 1H), 3.41 (s, 3H), 3.35 - 3.18 (m, 4H), 2.91 - 2.67 (m, 4H), 2.66 - 2.51 (m, 2H), 2.00 (d, J = 10.9 Hz, 2H), 1.82 (d, J = 11.8 Hz, 2H), 1.61 - 1.50 (m, 2H), 1.35 - 1.23 (m, 2H), 1.20 - 1.12 (m, 3H).

[0511] Example 48 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylbutanamide

[0512] [ka]

[0513] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material, the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylbutanamide was obtained according to Example 27. MS m / z (ESI): 444.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.55 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 5.5 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.71 - 3.54 (m, 1H), 3.24 - 3.06 (m, 4H), 2.86 - 2.64 (m, 4H), 2.57 - 2.46 (m, 2H), 2.30 (s, 2H), 1.99 - 1.80 (m, 4H), 1.55 - 1.45 (m, 2H), 1.39 - 1.18 (m, 10H), 1.17 - 1.03 (m, 2H).

[0514] Example 49 N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-fluoropyrimidin-2-amine

[0515] [ka]

[0516] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material, the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-fluoropyrimidin-2-amine was obtained according to Example 26. MS m / z (ESI): 440.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 2H), 7.59 - 7.48 (m, 2H), 7.42 (d, J = 5.6 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.23 - 3.15 (m, 4H), 2.84 - 2.70 (m, 4H), 2.59 - 2.50 (m, 2H), 2.22 - 2.16 (m, 1H), 2.10 - 1.98 (m, 3H), 1.91 - 1.82 (m, 2H), 1.65 - 1.49 (m, 3H), 1.21 - 1.10 (m, 2H).

[0517] Example 50 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methoxy-1-methylurea

[0518] [ka]

[0519] Using trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material and following Step 3 of Example 1, the product 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methoxy-1-methylurea was obtained. MS m / z (ESI): 431.2 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.62 - 7.48 (m, 2H), 7.42 (dd, J = 5.6, 0.8 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 7.7, 0.8 Hz, 1H), 3.63 (s, 3H), 3.57 - 3.41 (m, 1H), 3.26 - 3.10 (m, 4H), 3.03 (s, 3H), 2.86 - 2.65 (m, 4H), 2.60 - 2.46 (m, 2H), 1.97 - 1.80 (m, 4H), 1.56 - 1.42 (m, 2H), 1.40 - 1.25 (m, 4H), 1.20 - 1.02 (m, 2H).

[0520] Example 51 N-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)furan-2-carboxamide

[0521] [ka]

[0522] Using 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexan-1-amine and furan-2-carboxylic acid as starting materials and according to Step 1 of Example 14, N-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)furan-2-carboxamide was obtained. MS m / z (ESI): 456.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.46-7.42(m, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.14-7.09 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.65 - 6.54 (m, 1H), 6.50 (d, J = 5.1 Hz, 1H), 6.33-6.16 (m, 1H), 4.93-4.73 (m, 1H), 4.38 - 3.96 (m, 1H), 3.24 (s, 4H), 2.78 (s, 4H), 2.13 - 1.95 (m, 2H), 1.88-1.83 (m, 2H), 1.75 - 1.54 (m, 4H), 1.34 - 1.12 (m, 3H).

[0523] Biological Assays and Evaluation The invention is further illustrated below in conjunction with the following test examples which are not intended to limit the scope of the invention.

[0524] I. Radioligand-receptor binding assay Test Example 1. Determination of the binding ability of compounds of the present invention to dopamine D3 receptors

[0525] 1. Experimental Objective: The purpose of this test example is to determine the affinity of compounds for the dopamine D3 receptor.

[0526] 2. Laboratory equipment and reagents: 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).

[0527] 2.2 Experimental reagents and materials: [ 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) Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS) Magnesium chloride (Sigma, 7786-30-3) Tris base (Sigma, 77-86-1) HCl (Beijing XingJing Precision Chemical Technology CO.,LTD).

[0528] 3. Experimental Method: Assay buffer: 50 mM Tris-HCl pH 7.4, 10 mM MgCl2; Wash solution: 50 mM Tris-HCl pH 7.4, stored at 4°C; 0.5% PEI solution: 0.5 g PEI dissolved in 100 mL ddH2O, reserve solution stored at 4°C.

[0529] 5 μL of test compound (0.005 nM to 100 nM, 10 concentrations in total) and 100 μL of buffer were added to a 96-well assay plate. 1 μL of cell membrane and 300 μL of buffer were added to each well, and the plate was shaken at 600 rpm for 5 minutes. 3 100 μL of a mixture of [H]-methylspiperone (final concentration was 0.5 nM) was added to each well. The plate was shaken at 600 rpm for 5 minutes and 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.

[0530] 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.

[0531] 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.

[0532] [Table 1]

[0533] 6. Experimental Conclusion: The compounds of the present invention have good affinity for the dopamine receptor D3.

[0534] 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.

[0535] 2. Laboratory equipment and reagents: 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).

[0536] 2.2 Experimental reagents and materials: [ 3 H]-Ketanserin (PerkinElmer NET791) Human dopamine 5-HT2A receptor membrane (PerkinElmer) 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) Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS) calcium chloride (Sigma); Tris base (Sigma, 77-86-1); HCl (Beijing XingJing Precision Chemical Technology CO.,LTD); L-ascorbic acid (Tianjin Guangfu Co., Ltd.).

[0537] 3. Experimental Method: Assay buffer: 50 mM Tris-HCl pH 7.4, 4 mM CaCl2; Wash solution: 50 mM Tris-HCl pH 7.4, stored at 4°C; 0.5% PEI solution: 0.5 g PEI dissolved in 100 mL ddH2O, reserve solution stored at 4°C.

[0538] 5 μL of test compound (0.005 nM to 100 nM, 10 concentrations in total) and 100 μL of buffer were added to a 96-well assay plate. 1.5 μL of cell membranes and 300 μL of buffer were added to each well. The plate was shaken at 600 rpm for 5 minutes. Buffer and [ 3 A 100 μL mixture of [H]-ketanserin (final concentration was 2 nM) was added to each well. The plate was shaken at 600 rpm for 5 minutes and 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.

[0539] 4. Experimental data processing method: CPM (counts per minute) values ​​were measured by TopCount. 3The 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.

[0540] 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.

[0541] [Table 2]

[0542] 6. Experimental Conclusion: The compounds of the present invention have good affinity for 5-HT2A.

[0543] 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 1. Experimental Objective: To determine the activating effect of the compounds on D3 receptors.

[0544] 2. Laboratory equipment and reagents: 2.1 Experimental equipment: 384-well assay plate (Perkin Elmer; 6007680) 96-well V-bottom PP plate, natural, RNASE / DNase-free (ThermoFisher; 249944) EnVision (Perkin Elmer).

[0545] 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) HBSS (Gibco; 14025076); TrypLE (ThermoFisher; 12604021).

[0546] 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.

[0547] 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 %

[0548] 5. Experimental results:

[0549] [Table 3]

[0550] 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 effect assay in cells stably expressing the D3 receptor.

[0551] Test Example 2. Determination of the effects of compounds of the present invention on calcium ion mobility in cells stably expressing 5-HT2A receptors

[0552] 1. Experimental Objective: To determine the inhibitory effect of compounds on the 5-HT2A receptor.

[0553] 2. Laboratory equipment and reagents: 2.1 Experimental equipment: 384-well assay plate (Corning; 3712) Pipette (Axygen) FLIPR (Molecular Devices)

[0554] 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).

[0555] 3. Experimental Method: 1) Buffer preparation: 1x HBSS, 20mM HEPES, 2.5mM probenecid (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 assay well, and the plate was centrifuged at 200 g and room temperature for 3 to 5 seconds and then 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 obtained 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 (10 μL / well) to the 384-well assay plate, which was then incubated at room temperature in the dark for 35 minutes. 8) 5HT was diluted to 6 nM (6x) using assay buffer. 50 μL of the solution was transferred to a 384-well plate (Corning, 3657) and placed at room temperature for further use. The assay plate was transferred to a FLIPR, followed by the addition of agonist compounds at 6x concentrations (5 μL / well). 10 μL of diluted 5HT was added to each experimental well using the FLIPR, and values ​​were determined and stored. The total assay volume was 30 μL, containing 20 μL / well of dye buffer, 5 μL / well of 5x concentration of test compound, and 5 μL / well of 6x concentration of agonist compound.

[0556] 4. Experimental data processing method: Calcium signal values ​​were determined by FLIPR. The ratio of the 340 / 510 nm wavelength signal to the 380 / 510 nm wavelength signal was used as the calculated result for each sampling time point in the experiment. 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 determine the IC values ​​of compounds. 50 The value was calculated.

[0557] 5. Experimental results:

[0558] [Table 4]

[0559] 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.

[0560] III. Pharmacokinetic assay in Balb / c mice 1. Research purpose: Balb / c mice were used as test animals. The pharmacokinetic behavior of the compounds of the present invention was studied in mice (plasma and brain tissue) orally administered at a dose of 5 mg / kg.

[0561] 2. Experimental Protocol: 2.1 Test Compounds: Examples of compounds of the present invention prepared by the applicant.

[0562] 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.

[0563] 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.

[0564] 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 volume of 10 mL / kg.

[0565] 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.

[0566] 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 solution 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.

[0567] 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:

[0568] [Table 5]

[0569] 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.

[0570] [Table 6]

[0571] 4. Experimental Conclusion: From the results of the pharmacokinetic test 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 is clear that both are good.

[0572] 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.

[0573] 2. Laboratory equipment and reagents: 2.1 Equipment:

[0574] [Table 7]

[0575] 2.2 Reagents:

[0576] [Table 8]

[0577] 3. Experimental Procedure: 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.

[0578] Preparation of working solution of control compound (7-hydroxycoumarin): The preparation was consistent with that of the compound.

[0579] 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.

[0580] 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.

[0581] 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.

[0582] 3.5. Preparation of reaction stop solution Stop solution: cold acetonitrile containing 100 ng / mL labetalol hydrochloride and 400 ng / mL tolbutamide was used as an internal standard and stored in a refrigerator at 2 to 8°C.

[0583] 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:

[0584] [Table 9]

[0585] 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.

[0586] 4. Experimental results:

[0587] [Table 10]

[0588] Note:

[0589] [Table 11]

[0590] 5. Experimental Conclusion: The above data demonstrate that the compounds of the examples of the present invention are metabolized to a moderate extent in mouse liver microsomes.

[0591] 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.

[0592] 2. Laboratory equipment and reagents: 2.1 Equipment:

[0593] [Table 12]

[0594] 2.2 Reagents:

[0595] [Table 13]

[0596] 2.3 Test Compounds: Examples of compounds of the present invention prepared by the applicant.

[0597] 3. Test animals:

[0598] [Table 14]

[0599] 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.

[0600] 4.2 Compound Preparation: The formula weight of compound was weighed out, followed by the addition of the formula 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.

[0601] 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.

[0602] 5. Experimental Protocol: After arrival at the experimental facility, animals were allowed to acclimate for 1 week before the start of the experiment.

[0603] 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.

[0604] 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.

[0605] 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.

[0606] 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.

[0607] 5.1.5 Each animal was trained 30 times per day for a total of 6 days, and returned to its cage after training.

[0608] 5.2 Baseline Test and Grouping A baseline test was conducted on the day before the compound screening test. The test procedures were the same as those 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 the vehicle, and the other groups were administered with the corresponding test compounds according to the experimental design.

[0609] 5.3 Compound screening test Compounds were administered orally (5 mL / kg) 1 hour before testing.

[0610] The test procedure was the same as in 5.1.1 to 5.1.4, and the number of tests was 20.

[0611] 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

[0612] 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.

[0613] 7. Experimental results:

[0614] [Table 15]

[0615] 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.

[0616] VI. 14-day repeated intragastric administration toxicity study in SD rats 6.1 Experimental Objectives The aim of this study was to investigate the toxicity potential of the compound after repeated intragastric administration for 14 days in SD rats.

[0617] 6.2 Experimental materials and equipment: 6.2.1 Test compound Test compound 1: The compound of Example 42.

[0618] 6.2.2 Vehicle: Name: 0.5%CMC-Na(1%tween80) aqueous solution

[0619] 6.2.3 Animal information: Species and strain: Sprague-Dawley (SD) rats Animal grade: SPF grade Number and sex of animals: 60, half male and half female

[0620] 6.3 Experimental Method: Sixty rats (30 rats / sex) were divided into 20 groups according to their sex and weight. Forty rats were used for toxicity studies (groups 1 to 4, 5 rats / sex / group), and 24 rats were used for toxicokinetic studies (groups 5 to 8, 3 rats / sex / group). Animals in groups 1 and 5 were intragastrically administered with 0.5% CMC-Na (1% Tween 80) aqueous solution as a vehicle control. Animals in groups 2 and 6, 3 and 7, and 4 and 8 were intragastrically administered with the compound of Example 42 at doses of 2, 10, and 30 mg / kg, respectively. The animals were administered once daily for 14 consecutive days. The administration volume was 10 mL / kg. During the experiment, clinical observations, body weight, food intake, body temperature, clinical pathological indicators (blood counts, coagulation function, blood biochemistry), and toxicokinetics were monitored. All animals were euthanized on D15. During the experiment, gross anatomical observations were made on animals in groups 1 to 4. Histopathological examinations were performed on abnormal tissues and on the brain, kidneys, adrenal glands, lungs and bronchi, prostate, testes and epididymis.

[0621] 6.4 Test Data List 6.4.1 Dying / Death No mortality / moribundity was observed in any group of animals during the experiment.

[0622] 6.4.2 Toxicokinetics The mean systemic exposure (AUC) of female animals to male animals in each dose group of the compound of Example 42 for D1 and D14 last The ratios (AUC ) were between 0.83 and 2.52, indicating that the exposure of the compound of Example 42 in female animals was generally higher than that in male animals. Two-tailed and one-tailed t-tests were used to compare the mean systemic exposure (AUC ) of female and male animals in each dose group at D1 and D14. last The results showed that there was no statistical significance between female and male animals (P>0.05).

[0623] At D1 and D14, the mean exposure of the compound of Example 42 in both female and male animals increased with increasing dose, and the magnitude of increase in mean exposure was greater than that of dose.

[0624] Average AUC of the compound of Example 42 in female and male animals in each dose group at the last dose (D14) 14 days after intragastric administration at doses of 2, 10 or 30 mg / kg, respectively. last The ratio of 1.03 to 2.12 at the first dose (D1) was between 1.03 and 2.12, and no accumulation was observed.

[0625] 6.5 Experimental Conclusions: In this experiment, the compound of Example 42 was intragastrically administered to SD rats at a dose of 2, 10 or 30 mg / kg for 2 weeks (once a day). The main toxic responses were a decrease in body weight, food intake and body temperature; a decrease in blood cell counts, such as WBC, Lymph, Retic and PLT; a decrease in coagulation function, such as FIBw and shortened APTT; and the main target organs for toxicity were the lungs and adrenal glands. Under these experimental conditions, the maximum tolerated dose (MTD) of the compound of Example 42 was 30 mg / kg.

Claims

1. Compound of formula (IV-A): 【Chemistry 1】 (In the formula, 【Chemistry 2】 is selected from the group consisting of a single bond and a double bond; R 2 is hydrogen, cyano, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl and C 3～6 is selected from the group consisting of cycloalkyl; Or, two R on the same or different carbon atoms 2 is combined to C 3～8 forms a cycloalkyl or a 3- to 8-membered heterocyclyl, where C 3～8 Cycloalkyl or 3- to 8-membered heterocyclyl may be substituted with deuterium, C 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy and C 3～8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 3 is hydrogen, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, hydroxy, cyano, C 2～6 Alkenyl and C 2～6 alkynyl; R 4 is hydrogen and C 1～6 selected from the group consisting of alkyl; R 5 is hydrogen, C 1～6 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl, 5- to 14-membered heteroaryl, -(CH 2 ) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)(CH 2 ) n1 R aa , -C(O)NR aa (CH 2 ) n1 R bb , -S(O) 2 R aa , -(CH 2 ) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1～6 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are exemplified by cyano, halogen, C 1～6 Alkyl and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R 4 and R 5 are joined to form a 3- to 8-membered heterocyclyl or a 5- to 14-membered heteroaryl, which is 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy, C 3～8 Hydroxyalkyl, -C(O)R cc and -C(O)NR cc R dd and optionally further substituted by one or more substituents selected from the group consisting of: R aa and R bb is hydrogen, amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are substituted with halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 each optionally further substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or R aa and R bb are joined together with the adjacent nitrogen atom to form a 4- to 10-membered heterocyclyl, which is substituted with halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 1～6 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R cc and R dd is hydrogen, amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are substituted with halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; m is 1 or 2; n1 is 0, 1, 2 or 3, y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; The compound of formula (IV-A) is 【Transformation 3】 A compound, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it does not contain

2. The compound has formula (IX-B): 【Chemistry 4】 (R 2 is hydrogen, cyano, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl and C 3～6 cycloalkyl; R 3 is hydrogen, halogen, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 1～6 haloalkoxy; R 4 is hydrogen and C 1～6 selected from the group consisting of alkyl; R 5 is hydrogen, C 1～6 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl, 5- to 14-membered heteroaryl, -(CH 2 ) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)(CH 2 ) n1 R aa , -C(O)NR aa (CH 2 ) n1 R bb , -S(O) 2 R aa , -(CH 2 ) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1～6 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are exemplified by cyano, halogen, C 1～6 Alkyl and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R 4 and R 5 are joined to form a 3- to 8-membered heterocyclyl or a 5- to 10-membered heteroaryl, which is 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy and C 3～8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R aa and R bb is hydrogen, amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 aryl, and 5-10 membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of N, O and S, which are independently selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 each optionally further substituted with one or more substituents selected from the group consisting of aryl and 5- to 14-membered heteroaryl; Or R aa and R bb are joined together with the adjacent nitrogen atom to form a 4- to 6-membered heterocyclyl, which is substituted with halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 1～6 and optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl.

2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, further characterized in that:

3. R 2 But hydrogen, cyano, halogen, C 1～3 Alkyl, C 1～3 Haloalkyl and C 3～6 cycloalkyl; R 3 However, hydrogen, halogens and C 1～3 selected from the group consisting of alkyl; R 4 But hydrogen and C 1～3 selected from the group consisting of alkyl; R 5 But -(CH 2 ) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -S(O) 2 R aa and -S(O) m1 NR aa R bb selected from the group consisting of: R aa and R bb But hydrogen, amino, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy, C 3～6 cycloalkyl, and 5-6 membered heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, which are each independently selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 3～6 each optionally further substituted with one or more substituents selected from the group consisting of cycloalkyl; Or R aa and R bb are joined together with the adjacent nitrogen atom to form a 4- to 6-membered nitrogen-containing heterocyclyl, which is not subject to halogen, hydroxy, C 1～3 Alkyl, C 1～3 Haloalkyl and C 1～3 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, optionally further substituted with one or more substituents selected from the group consisting of alkoxy.

4. R 2 is selected from the group consisting of hydrogen, cyano, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoromethyl and cyclopropyl; R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, and ethyl; R 4 is selected from the group consisting of hydrogen and methyl; R 5 But -R aa , -C(O)R aa and -C(O)NR aa R bb selected from the group consisting of: R aa and R bb But hydrogen, C 1～3 Alkyl, C 1～3 Fluoroalkyl, C 1～3 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, furyl, oxazolyl, and isoxazolyl, each independently selected from the group consisting of halogen, hydroxy, cyano, C 1～3 Alkyl and C 1～3 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R aa and R bb are joined together with the adjacent nitrogen atom to form an azetidinyl, pyrrolidinyl or piperidinyl, which is free of halogen, hydroxy, C 1～3 Alkyl, C 1～3 Haloalkyl and C 1～3 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, optionally further substituted with one or more substituents selected from the group consisting of alkoxy. 【Request Item 5】 【Chemistry 5】 but, 【Transformation 6】 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

6. R 2 But hydrogen, cyano, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl and C 3～6 is selected from the group consisting of cycloalkyl; Or, two R on the same or different carbon atoms 2 combine to form C 3～8 forms a cycloalkyl or a 3- to 8-membered heterocyclyl, where C 3～8 Cycloalkyl or 3- to 8-membered heterocyclyl is a hydrogen, deuterium atom, C 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy and C 3～8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 3 However, hydrogen atoms, halogens, hydroxyl, C 1～6 Alkyl and C 1～6 or selected from the group consisting of alkoxy; Or, two R on the same or different carbon atoms 3 combine to form C 3～8 forms a cycloalkyl or a 3- to 8-membered heterocyclyl, where C 3～8 Cycloalkyl or 3- to 8-membered heterocyclyl is hydrogen, deuterium, C 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy and C 3～8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R 4 But hydrogen and C 1～6 selected from the group consisting of alkyl; R 5 But hydrogen, C 1～6 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl, 5- to 14-membered heteroaryl, -(CH 2 ) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -C(O)NR aa (CH 2 ) n1 R bb , -S(O) 2 R aa , -(CH 2 ) n1 S(O)(=NR aa )R bb , -S(O) m1 NR aa R bb and -C(O)OR aa wherein C 1～6 Alkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, cyano, halogen, C 1～6 Alkyl and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R 4 and R 5 are joined to form a heterocyclyl, where heterocyclyl is selected from the group consisting of hydrogen, C 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy and C 3～8 optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl; R aa 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 6～14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; R bb 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 6～14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an oxo group, a C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; Or R aa and R bb are joined to form a heterocyclyl, where the heterocyclyl is a hydrogen atom, C 1～6 Alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3～8 Alkoxy, C 3～8 Haloalkoxy and C 3～8 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, optionally further substituted with one or more substituents selected from the group consisting of hydroxyalkyl.

7. R 2 is hydrogen, halogen, and C 1～6 selected from the group consisting of alkyl; R 3 is hydrogen, halogen, and C 1～6 selected from the group consisting of alkyl; R 4 is hydrogen and C 1～6 selected from the group consisting of alkyl; R 5 -R aa or -C(O)R aa Selected from; R aa is C 3～6 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 aryl and 5- to 6-membered heteroaryl, wherein C 3～6 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Aryl and 5- to 6-membered heteroaryl are substituted with halogen, hydroxy, cyano, C 1～6 Alkyl, and C 1～6 each optionally further substituted with one or more substituents selected from the group consisting of alkoxy; 7. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof.

8. The compound has the formula (XII): 【Transformation 7】 (In the formula, Ring B is C 3～8 selected from the group consisting of cycloalkyl, 3- to 8-membered heterocyclyl, and 5- to 10-membered heteroaryl; R 2 is hydrogen, cyano, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl and C 3～6 cycloalkyl; R 4 is hydrogen and C 1～6 selected from the group consisting of alkyl; R 6 is hydrogen, halogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, hydroxy, cyano, C 2～6 Alkenyl and C 2～6 alkynyl; R 17 is hydrogen, halogen, amino, hydroxy, cyano, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 aryl and 5- to 14-membered heteroaryl, wherein amino, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～14 Aryl and 5- to 14-membered heteroaryl are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 selected from the group consisting of alkoxy; v is an integer from 0 to 5) 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, further characterized in that:

9. Ring B is selected from the group consisting of cyclopropyl, azetidinyl, pyrrolidonyl, furyl, oxazolyl, and isoxazolyl; R 2 is hydrogen or C 1～6 haloalkyl; R 4 is selected from hydrogen or methyl; R 6 is selected from hydrogen or halogen; R 17 is hydrogen, amino, halogen, amino, hydroxy, cyano, C 1～3 Alkyl, C 1～3 Haloalkyl and C 1～3 selected from the group consisting of alkoxy; v is an integer of 0, 1, 2, or 3 9. The compound according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof.

10. The specific structure of the compound is: 【Chemical Engineering 8A】 【Chemical 8B】 A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: 【Request Item 11】 【Chemistry 9】 deprotecting the compound of formula (IX-B3) to obtain a compound of formula (IX-B1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; reacting a compound of formula (IX-B1) with an acyl chloride, amine, carboxylic acid or sulfonyl chloride of formula (II-2) to obtain a compound of formula (IX-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; The compound of formula (II-2) is R 5 X, R 5 OH or R 5 NH 2 represents; X is a halogen; 3. A process for preparing a compound of formula (IX-B), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 2, characterized in that Pg is an amino-protecting group selected from the group consisting of allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenylmethyloxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, t-butoxycarbonyl, benzyl, and p-methoxyphenyl.

12. 11. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

13. 13. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 in the preparation of a modulator of a G protein-coupled receptor.

14. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 in the preparation of a modulator of a dopamine D3 receptor and a modulator of a 5-HT2A receptor.

15. 13. Use of a compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing a central nervous system disease and / or a psychiatric disorder, wherein the nervous system disease and / or psychiatric disorder is selected from the group consisting of schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic 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 syndromes, tinnitus, depression, autism, dementia, Alzheimer's disease, epileptic seizures, neuralgia, drug withdrawal symptoms, major depressive disorder, and mania.

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