Modifiers for four-membered ring derivatives, preparation methods, and uses thereof

Abstract

To provide a compound represented by general formula (IX-A) as a G protein-coupled receptor modifier in the treatment or prevention of central nervous system disorders and / or mental disorders, a method for preparing the same, a pharmaceutical composition containing the compound, and its use. [Solution] The above problem is solved by a compound of general formula (IX-A), its stereoisomer, or a pharmaceutically acceptable salt thereof. [C1] JPEG2026048711000125.jpg34170

Description

[Technical Field]

[0001] The present invention belongs to the field of drug synthesis, and more particularly to four-membered ring derivative inhibitors, methods for preparing them, and their use. [Background technology]

[0002] The dopamine D3 receptor is a member of the G protein-coupled receptor family and a subtype of dopamine receptors. It belongs to the D2-like inhibitory receptor group, along with dopamine D2 and D4 receptors. When bound to DA, it reduces cAMP levels by inhibiting the G protein. D3 receptors are primarily distributed in the mesolimbic system, particularly in the nucleus accumbens, olfactory tubercle, and islets of Kaleja, which are not involved in motor function. Highly active D3 receptor modifiers may also possess excellent anti-schizophrenic 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 receptor modulation. Partial agonism of D3 receptors 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, and memory. Highly active 5-HT2A receptor inhibitors have significant anti-schizophrenic effects and can reduce extrapyramidal side effects.

[0004] Schizophrenia is the most common mental illness with a slow course, characterized by recurrent seizures, exacerbations, or worsening episodes, resulting in a serious burden and adverse consequences for patients and their families. Psychopaths may experience positive symptoms such as delusions, hallucinations, and disturbances of thought, language, and behavior, as well as negative symptoms such as lack of affect and expression, insufficient speech and lack of pleasure, and cognitive impairment. While research, development, and clinical use of anti-schizophrenic drugs have advanced significantly in recent decades, conventional antipsychotics (first generation) (haloperidol, droperidol, thioridazine, etc.) and atypical antipsychotics (second generation) (clozapine, risperidone, olanzapine, aripiprazole, etc.) are effective in treating positive symptoms but 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 modifiers 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 positive symptoms, negative symptoms, and cognitive impairments of schizophrenia. International patent applications WO2007093540, WO2009013212A2, WO2010031735A1, and WO2012117001A1 describe D3 receptors and 5HT 2A We have reported on double-modified compounds, but regarding D3 receptors and 5HT 2A The maximum binding activity Ki of the compound to 5HT exceeds 10 nM. International patent application WO2014086098A1 filed by Jiangsu Hengyi Pharmaceutical reports on a D3 selective inhibitor, but 5HT 2ANo studies have been reported on its binding activity to 5-HT2A receptors. Kaliprazine, a D3 antagonist developed by Gedeon Richter, became available in 2015, and an international patent application, WO2005012266A1, was filed. Kaliprazine possesses potent D3 receptor agonist activity, and its use in the treatment of negative symptoms of schizophrenia offers significant advantages over existing drugs. However, Kaliprazine exhibits weak inhibitory activity against 5-HT2A receptors, resulting in serious extrapyramidal symptoms (ESPs) as a side effect. Therefore, to reduce the side effects of extrapyramidal symptoms and improve the efficacy and cognitive improvement of negative symptoms in schizophrenia, a 5HT2A inhibitor is needed. 2A There is an urgent need to develop highly active D3 receptor modifiers with optimized binding activity. [Prior art documents] [Patent Documents]

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

[0007] All the content included in Patent Application No. PCT / CN2020 / 073153 is incorporated into the present invention by reference.

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

[0009]

Chemical formula

[0010] Wherein, R4 is selected from the group consisting of 5- to 6-membered N-containing heterocyclyl,

[0011]

Chemical formula

[0012] and the 5- to 6-membered N-containing heterocyclyl is preferably oxazolidinonyl; R a is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 alkyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkenyl, C 2~6 alkynyl, C 3~8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl; R b is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 alkyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 haloalkoxy, C 2~6Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Selected from the group consisting of aryls and 5-12 membered heteroaryls, amino, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Aryl and 5-12 member heteroaryls can optionally contain hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Further substituted with one or more substituents selected from the group consisting of aryls and 5- to 12-membered heteroaryls; R5 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Selected from the group consisting of aryls and 5- to 12-membered heteroaryls; Preferably, hydrogen, cyano, halogen, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 Selected from the group consisting of cycloalkyl groups; More preferably, selected from the group consisting of hydrogen and chlorine; Alternatively, any two adjacent R5 groups may combine to form a 5-6 member heterocycline or 5-6 member heteroaryl; Preferably, a 5-6 membered heteroaryl compound containing 1 to 2 N, S, or O heteroatoms, more preferably a thienyl compound; r is 0, 1, or 2; m is either 0 or 1; t is 0, 1, 2, or 3, preferably 2.

[0013] The present invention also,

[0014] [ka]

[0015] but

[0016] [ka]

[0017] The present invention also provides preferred embodiments relating to the compound of formula (IX-A), its stereoisomer or pharmaceutically acceptable salt thereof, where m is 1, and R4 is not less than or equal to the following.

[0018] [ka]

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

[0020] [ka]

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

[0022] [ka]

[0023] (In the formula, R4 and m are as defined in equation (IX-A). Preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof are also provided, as shown.

[0024] In another preferred embodiment of the present invention, R4 is a 5-6 member nitrogen-containing heterocycline,

[0025] [ka]

[0026] A heterocyclyl containing 5-6 memberned nitrogen is selected from the group consisting of the following, and is preferably oxazolidinonyl; R a These are hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Selected from the group consisting of aryls and 5- to 12-membered heteroaryls; Preferably, R a These are hydrogen, cyano, halogen, and C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 Selected from the group consisting of cycloalkyl groups; Comfortable, R a is selected from the group consisting of hydrogen and methyl; Rb is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 alkyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 haloalkoxy, C 2~6 alkenyl, C 2~6 alkynyl, C 3~8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6~12 selected from the group consisting of aryl and 5- to 12-membered heteroaryl, amino, C 1~6 alkyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkenyl, C 2~6 alkynyl, C 3~8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6~12 aryl and 5- to 12-membered heteroaryl are each optionally hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 alkyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, C 2~6 alkenyl, C 2~6 alkynyl, C 3~8 [[ID=5,5]]cycloalkyl, 3- to 8-membered heterocyclyl, C 6~12 further substituted by one or more substituents selected from the group consisting of aryl and 5- to 12-membered heteroaryl; preferably, R b is amino, C 1~3 alkyl, C 1~3 alkoxy, C 1~3 hydroxyalkyl, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6~10 selected from the group consisting of aryl and 5- to 10-membered heteroaryl, amino, C 1~3 [[ID=7,3]]alkyl, C1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl and 5-10 member heteroaryls can optionally contain hydrogen, halogen, hydroxyl, cyano, and C. 1~3 Alkyl and C 1~3 Further substituted with one or more substituents selected from the group consisting of alkoxys; Comfortable, R b is selected from the group consisting of amino, methyl, ethyl, methoxy, hydroxyisopropyl, cyclopropyl, azetidinyl, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolyl, and benzoxazolyl, and each of these is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, fluorine, cyano, hydroxy, methyl, and methoxy; r is 0, 1, or 2.

[0027] The present invention also relates that formula (IX-A) is equal to formula (XI)

[0028] [ka]

[0029] (In the formula, R6 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C6~12 Selected from the group consisting of aryls and 5- to 12-membered heteroaryls; R7 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Aryl, 5-12 member heteroaryl, R ee -C(O)(CH2) n2 R ee ,-(CH2) n2 C(O)NR ee R ff -C(O)NR ee R ff ,-(CH2) n2 C(O)NR ee C(O)R ff ,-(CH2) n2 S(O) m2 R ee ,-(CH2) n2 NR ee S(O) m2 R ff ,-(CH2) n2 S(O) m2 NR ee R ff ,-(CH2) n1 S(O) m2 NR ee R ff ,-(CH2) n2 Ure ee -C(O)NR ee (CH2) n2 R ff -C(O)(CH2) n2 Ure ee ,-(CH2) n2 SR ee ,-(CH2) n2 C(O)OR ee ,-P(O)R ee R ff ,-(CH2) n2NR ee C(O)R ff and -(CH2) n2 NR ee S(O) m2 R ff Selected from the group consisting of C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Aryl and 5-12 member heteroaryls can optionally contain deuterium, halogen, amino, nitro, hydroxy, cyano, or C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 It is further substituted with one or more substituents selected from the group consisting of aryls and 5-12 membered heteroaryls, preferably 5-10 membered heteroaryls, R ee -C(O)(CH2) n2 R ee -C(O)NR ee R ff -C(O)NR ff (CH2) n2 R ee , -S(O) m2 R ee and -S(O) m2 NR ee R ff Selected from the group consisting of; R ee and R ff These are hydrogen, amino acid, and C, respectively. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Independently selected from the group consisting of aryls and 5-14 member heteroaryls, 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 5-14 member heteroaryls can optionally contain hydrogen, halogen, hydroxyl, cyano, oxo, and C. 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 Further substituted with one or more substituents selected from the group consisting of alkoxys; Preferably, R ee and R ff These are amino acids and C, respectively. 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 Independently selected from the group consisting of cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclyls containing 1 to 2 nitrogen atoms, and 5-10 membered heteroaryls containing 1 to 2 oxygen, nitrogen, and sulfur atoms, amino, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 Cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclyls containing 1 to 2 nitrogen atoms, and 5-10 membered heteroaryls containing 1 to 2 oxygen, nitrogen, or sulfur atoms are each optionally a halogen, hydroxyl, cyano, oxo, or C 1~6 Alkyl and C 1~6 Substituted by one or more substituents selected from the group consisting of alkoxys; Comfortable, R ee and R ff Each of them is, (CH3)2N-, CH3NH-, CH3-, CH3CH2-, CH3CH2NH-, CH3CH2NCH3-, (CH3)2COH-, (CH3)2COHCH2-, CH3OCH2-,

[0030] [ka]

[0031] Independently selected from the group consisting of; n2 is selected from the group consisting of 0, 1, and 2; m2 is selected from the group consisting of 0, 1, and 2; m is selected from the group consisting of 0, 1, and 2. Preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof are also provided, as shown.

[0032] In another preferred embodiment of the present invention, R ee and R ff Each of these is independently selected from the group consisting of hydrogen and the following substituents.

[0033] [ka]

[0034] The present invention also provides preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein formula (XI) is as shown in formula (XI-A) or formula (XI-B).

[0035] [ka]

[0036] In preferred embodiments of the present invention, R6 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~3 Alkyl, C 1~3 Alkyl deuterated, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 2~3 Alkenyl and C 2~3 Selected from the group consisting of alkynyls, preferably hydrogen; R7 is R ee -C(O)(CH2) n2 R ee-C(O)NR ee R ff -C(O)NR ff (CH2) n2 R ee , -S(O) m2 R ee and -S(O) m2 NR ee R ff Selected from the group consisting of; R ee is hydrogen, amino acid, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~14 Selected from the group consisting of aryls and 5-14 member heteroaryls, 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 5-14 member heteroaryls can be optionally halogenated, hydroxylated, cyano, oxo, or C13. 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 Further substituted with one or more substituents selected from the group consisting of alkoxys; Preferably, R ee is amino, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 Selected from the group consisting of cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclyls containing 1 to 2 oxygen, nitrogen, and sulfur heteroatoms, and 5-10 membered heteroaryls containing 1 to 2 oxygen, nitrogen, and sulfur heteroatoms, and amino, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 3~6 Cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclyls containing 1-2 oxygen, nitrogen, or sulfur heteroatoms, and 5-10 membered heteroaryls containing 1-2 oxygen, nitrogen, or sulfur heteroatoms are each optionally halogenated, hydroxyl, cyano, oxo, or C.1~6 Alkyl and C 1~6 Substituted by one or more substituents selected from the group consisting of alkoxys; Comfortable, R ee teeth, (CH3)2N-, CH3NH-, CH3-, CH3CH2-, CH3CH2NH-, CH3CH2NCH3-, (CH3)2C(OH)-, (CH3)2C(OH)CH2-, CH3OCH2-,

[0037] [ka]

[0038] Selected from the group consisting of; R ff These are hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Selected from the group consisting of aryls and 5- to 12-membered heteroaryls; Preferably, R ff These are hydrogen, cyano, halogen, and C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 3~6 Selected from the group consisting of cycloalkyl groups; Comfortable, R ff is selected from the group consisting of hydrogen and methyl; n2 is selected from the group consisting of 0, 1, and 2; m2 is selected from the group consisting of 0, 1, and 2.

[0039] The present invention also,

[0040] [ka]

[0041] but,

[0042] [ka]

[0043] The present invention also provides preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, characterized by being selected from the group consisting of the following.

[0044] The present invention also states that formula (XI) is equal to formula (XII).

[0045] [ka]

[0046] (In the formula, R8 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Selected from the group consisting of aryls and 5-12 membered heteroaryls, amino, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12Aryl and 5-12 member heteroaryls can optionally contain hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Further substituted with one or more substituents selected from the group consisting of aryls and 5- to 12-membered heteroaryls; Preferably, amino, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Selected from the group consisting of aryls and 5-10 membered heteroaryls, amino, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl and 5-10 member heteroaryls can optionally contain hydrogen, hydroxyl, cyano, and C. 1~3 Alkyl and C 1~3 Further substituted with one or more substituents selected from the group consisting of alkoxys; CH3O-, HOC(CH3)2-,

[0047] [ka]

[0048] Further selected from the group consisting of; v is either 0 or 1. Preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof are also provided, as shown.

[0049] The present invention also states that formula (XI) is equal to formula (XII).

[0050] [ka]

[0051] (In the formula, R8 is hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Selected from the group consisting of aryls and 5-12 membered heteroaryls, amino, C 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Aryl and 5-12 member heteroaryls can optionally contain deuterium, halogen, amino, nitro, hydroxy, cyano, or C. 1~6 Alkyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~12 Further substituted with one or more substituents selected from the group consisting of aryls and 5- to 12-membered heteroaryls; Preferably, amino, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Selected from the group consisting of aryls and 5-10 membered heteroaryls, amino, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl and 5-10 member heteroaryls can be optionally hydroxy, cyano, or C. 1~3 Alkyl, C 1~3 Alkoxy and C 3~6 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups; CH3O-, HOC(CH3)2-,

[0052] [ka]

[0053] Further selected from the group consisting of; v is either 0 or 1. Preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof are also provided, as shown.

[0054] The present invention also states that when v is 0, R8 is -C2H5, -N(CH3)2, -NHCH3, -NC2H5CH3, -NHC2H5,

[0055] [ka]

[0056] Instead, When v is 1, R8 is not phenyl. Preferred embodiments also provide compounds of formula (XII), stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0057] The present invention also provides preferred embodiments, compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein formula (XII) is as shown in formula (XII-A) or formula (XII-B).

[0058] [ka]

[0059] The present invention also, R4

[0060] [ka]

[0061] and; R b However, deuterium, halogen, amino, hydroxy, C can be arbitrarily added. 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 1~3 C is further substituted by one or more substituents selected from the group consisting of haloalkoxys. 3~6 Selected from the group consisting of cycloalkyls and 5-10 membered heteroaryls containing one or two nitrogen, oxygen, and sulfur atoms; R5 is hydrogen, halogen and C 1~3 Selected from the group consisting of alkyl groups; m is 1; The present invention also provides preferred embodiments, compounds of formula (IX-A), stereoisomers thereof, or pharmaceutically acceptable salts thereof, where t is 1, 2, or 3.

[0062] This invention also includes cases where r is 0 and R b but

[0063] [ka]

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

[0065] [Chemical formula]

[0066] In the case where it is, R b is also provided with a preferred embodiment, a compound of formula (IX-A), its stereoisomer or its pharmaceutically acceptable salt, which is substituted by at least one substituent.

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

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

[0069] The compounds of the present invention not only possess potent D3 receptor agonist activity, but also exhibit significantly superior inhibitory activity against 5-HT2A compared to caliprazine, leading to favorable clinical efficacy in treating negative symptoms of schizophrenia and a substantial reduction in the risk of EPS side effects.

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

[0071] [ka]

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

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

[0074] [ka]

[0075] The present invention also relates to a method for preparing a compound of formula (XII-1), its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0076] [ka]

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

[0078] The present invention also relates to a method for preparing an intermediate compound of formula (XII - 3), its stereoisomer or its pharmaceutically acceptable salt,

[0079] [Chemical formula]

[0080] a step of reacting a compound of formula (XII - 4) with a compound of formula (XII - 5) to obtain a compound of formula (XII - 3), its stereoisomer or its pharmaceutically acceptable salt and in the formula, Pg2 is a hydroxy protecting group selected from the group consisting of methyl (-CH3), tert - butyl (-C(CH3)3), triphenyl (-CPh3), methylthiomethyl ether (MTM), 2 - methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p - methoxybenzyl ether (PMB), pivaloyl (Piv), benzyl ether group (-CH2Ph), methoxymethyl (-CH2OCH3), trimethylsilyl (-Si(CH3)3), tetrahydrofuranyl (-THP), tert - butyldisilyl (-SiMe2(t - Bu)), acetyl (-Ac), benzoyl (-COPh) and p - toluenesulfonyl (-SO2PhMe), and preferably is p - toluenesulfonyl, and relates to a method.

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

[0082] The present invention also relates to the use of compounds of the above general formula, specific compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of G protein-coupled receptor-modifying pharmaceuticals, particularly dopamine D3 receptor-modifying pharmaceuticals and 5-HT2A receptor-modifying pharmaceuticals.

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

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

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

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

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

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

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

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

[0091] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms, preferably having 1 to 8 carbon atoms, more preferably having 1 to 6 carbon atoms, and most preferably having 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 Examples include -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 group having 1 to 6 carbon atoms, and 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, and the like. The alkyl group may or may not be substituted. If substituted, the substituent may be substituted at any available bond point. The substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0092] The term "alkylene" refers to alkyl groups in which hydrogen atoms are further substituted, for example, "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, and "butylene" refers to -(CH2)4-. The term "alkenyl" refers to alkyl groups defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. The alkenyl group may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0093] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents 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, and cyclooctyl. Polycyclic cycloalkyls include cycloalkyls having a spiro ring, a fused ring, or a crosslinking ring. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl, more preferably cyclopropyl, cyclobutyl, and cyclohexyl.

[0094] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having individual rings linked by a single shared carbon atom (called a spiro atom), where the rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Spirocycloalkyls are preferably 6- to 14-membered spirocycloalkyls, more preferably 7- to 10-membered spirocycloalkyls. Depending on the number of spiro atoms shared between the rings, spirocycloalkyls can be classified as mono-spirocycloalkyls, di-spirocycloalkyls, or poly-spirocycloalkyls, where spirocycloalkyls are preferably mono-spirocycloalkyls or di-spirocycloalkyls, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyls. Non-limiting examples of spirocycloalkyls include:

[0095] [ka]

[0096] Examples include spirocycloalkyls, in which cycloalkyls and heterocyclyls are linked via a single spiro atom, and non-limiting examples include the following:

[0097] [ka]

[0098] The term "condensed cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group, where each ring in the system shares one set of adjacent carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Condensed cycloalkyls are preferably 6-14 membered condensed cycloalkyls, more preferably 7-10 membered condensed cycloalkyls. Depending on the number of ring members, condensed cycloalkyls can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyls, and condensed cycloalkyls are preferably bicyclic or tricyclic condensed cycloalkyls, more preferably 4-membered / 4-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic condensed cycloalkyls. Non-limiting examples of condensed cycloalkyls include the following:

[0099] [ka]

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

[0101] [ka]

[0102] A cycloalkyl ring can be condensed with an aryl, heteroaryl, or heterocyclyl ring, and the ring bonded to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl. The cycloalkyl ring may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0103] The term "heterocyclyl" refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, where one or more ring atoms are nitrogen, oxygen, boron, phosphorus, or S(O). m (where m is an integer from 0 to 2) and P(O) nThe heteroatoms are selected from the group consisting of (where n is an integer from 0 to 2), excluding -OO-, -OS-, or -SS- in the ring, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, more preferably 3 to 8 ring atoms, most preferably 3 to 8 ring atoms, with 1 to 4 atoms being heteroatoms. Non-limiting examples of monocyclic heterocyclils include oxacyclobutyl, oxacyclobutyl, pyrrolidinyl, oxazolidine-2-one group, azepinyl, imidazolidinyl, tetrahydrofuranil, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranil, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinil, thiomorpholinil, homopiperazinyl, and pyranyl. Preferably, oxacyclobutyl, tetrahydrofuranil, pyrrolidinyl, pyrazolidine, piperazinyl, oxazolidine-2-one group, morpholinil, piperazinyl, and azepinyl are used. More preferably, oxacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, and oxazolidine-2-one group are used. Examples of polycyclic heterocyclils include heterocyclils having a spiro ring, a fused ring, or a crosslinking ring. Heterocyclyls having a spiro ring, fused ring, or bridging ring are optionally bonded to other groups via single bonds, or further bonded to other cycloalkyls, heterocyclyls, aryls, and heteroaryls via any two or more atoms on the ring.

[0104] The term "spiroheterocryl" refers to a 3- to 20-membered polycyclic heterocycline group having individual rings linked by a single covalent atom (called a spiro atom), where one or more ring atoms are nitrogen, oxygen, boron, phosphorus, or S(O). m (where m is an integer from 0 to 2) and P(O) nThe spiroheterocyclyl is a heteroatom selected from the group consisting of (where n is an integer from 0 to 2), and the remaining ring atoms are carbon atoms, which may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. The spiroheterocyclyl is preferably a 6-14 member spiroheterocyclyl, more preferably a 7-10 member spiroheterocyclyl. Depending on the number of spiroatoms shared between the rings, the spiroheterocyclyl can be divided into mono-spiroheterocyclyl, di-spiroheterocyclyl, or poly-spiroheterocyclyl, and the spiroheterocyclyl is preferably a mono-spiroheterocyclyl or di-spiroheterocyclyl, more preferably a 3-member / 5-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member mono-spiroheterocyclyl. Non-limiting examples of spiroheterocyclyls include the following:

[0105] [ka]

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

[0107] [ka]

[0108] The term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclyl group in which each of the two rings of the system shares two non-bonded atoms, and the rings may have one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more ring atoms are nitrogen, oxygen and S(O) m The cross-linked heterocyclyl is a heteroatom selected from the group consisting of (where m is an integer from 0 to 2), and the remaining ring atom is a carbon atom. The cross-linked heterocyclyl is preferably a 6- to 14-membered cross-linked heterocyclyl, more preferably a 7- to 10-membered cross-linked heterocyclyl. Depending on the number of ring members, the cross-linked heterocyclyl can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic cross-linked heterocyclyl, and the cross-linked heterocyclyl is preferably a bicyclic, tricyclic, or tetracyclic cross-linked heterocyclyl, more preferably a bicyclic or tricyclic cross-linked heterocyclyl. Non-limiting examples of cross-linked heterocyclyl include the following.

[0109] [ka]

[0110] A heterocyclyl ring can be condensed with an aryl, heteroaryl, or cycloalkyl ring, and the ring bonded to the parent structure is a heterocyclyl. Examples of non-limiting heterocyclyl rings include the following:

[0111] [ka]

[0112] The heterocyclyl may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

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

[0114] [ka]

[0115] The aryl group may or may not be substituted. If substituted, the substituent is 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 groups.

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

[0117] [ka]

[0118] The heteroaryl group may or may not be substituted. If substituted, the substituent is 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 groups.

[0119] The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

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

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

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

[0123] "Alkenyl" refers to a chain alkenyl, 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.

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

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

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

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

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

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

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

[0131] "THF" refers to tetrahydrofuran.

[0132] ",''" refers to ethyl acetate.

[0133] "MeOH" refers to methanol.

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

[0135] "DIPEA" refers to diisopropylethylamine.

[0136] "TFA" refers to trifluoroacetic acid.

[0137] "MeCN" refers to acetonitrile.

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

[0139] "Et2O" refers to diethyl ether.

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

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

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

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

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

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

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

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

[0148] "KHMDS" refers to potassium hexamethyldisilazide.

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

[0150] "MeLi" refers to methyllithium.

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

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

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

[0154] The hydrogen atoms in this invention may be substituted with their isotope, deuterium. Any hydrogen atoms in the example compounds of this invention may be substituted with a deuterium atom.

[0155] "Optional" or "optionally" means that the described event or environment may or may not subsequently occur, and such description includes the circumstances under which the event or environment occurs or does not occur. For example, "optionally alkyl-substituted heterocyclil" means that alkyl groups may or may not be present, and such description includes the circumstances under which the heterocyclil is alkyl-substituted and the circumstances under which the heterocyclil is not alkyl-substituted.

[0156] "Substituting" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are independently substituted by a corresponding number of substituents. It goes without saying that substituents are present only in possible chemical positions. Those skilled in the art can determine whether substitution is possible or impossible by experiment or theory without excessive effort. For example, combinations of amino or hydroxyl atoms with free hydrogens and carbon atoms with unsaturated bonds (such as olefins) can be unstable.

[0157] A "pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs, other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of compounds to living organisms, thereby aiding in the absorption of the active ingredient to exert its biological activity.

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

[0159] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention that is safe, effective, and possesses the desired biological activity in mammals. [Modes for carrying out the invention]

[0160] The present invention will be further described with reference to the following examples, but these examples should not be considered to limit the scope of the present invention. [Examples]

[0161] The structure of the compound of the present invention was determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR shift (δ) is shown in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 instrument. Deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) were used as solvents for measurement, and tetramethylsilane (TMS) was used as the internal standard.

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

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

[0164] The raw materials used in the embodiments of the present invention are known and commercially available, or can be synthesized by employing or following methods known in the art.

[0165] Unless otherwise specified, all reactions of the present invention were carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, the solvent was dehydrated, and the reaction temperature was in degrees Celsius.

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

[0167] [ka]

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

[0169] [ka]

[0170] Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexane-1-amine (60 mg, 0.162 mmol) and triethylamine (50 mg, 0.49 mmol) were added to DCM (3 mL). CDI (29 mg, 0.178 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. Benzylamine (36 mg, 0.324 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and then it was extracted with ethyl acetate (20 mL x 3). The organic phase was mixed, 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 obtain 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea as a white solid (10 mg, yield: 12%). 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 5H), 7.18 - 7.04 (m, 2H), 6.97 (d, J = 6.9 Hz, 1H), 4.58 (s, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 7.5 Hz, 1H), 3.48 (s, 1H), 3.11-2.79 (m, 8H), 2.00 (s, 2H), 1.79-1.64 (m, 4H), 1.33 - 1.00 (m, 9H). MS m / z (ESI): 503.2 [M+H] + .

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

[0172] [ka]

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

[0174] [ka]

[0175] 3-Oxocyclobutane-1-carboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol), and toluene (30 mL) were continuously added to a 100 mL round-bottom flask. Diphenyl phosphoryl azide (4.0 g, 14.5 mmol) was slowly added from -5°C to 0°C. The reaction solution was stirred at 0°C for 16 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (30 mL x 1) and saturated sodium chloride aqueous solution (30 mL x 1) at 0°C, and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was concentrated by rotary evaporation and dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain tert-butyl(3-oxocyclobutyl) carbamate (500 mg, yield: 20.5%). 1 H NMR (400 MHz, CDCl3) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50 - 3.33 (m, 2H), 3.11 - 2.97 (m, 2H), 1.46 (s, 9H).

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

[0177] [ka]

[0178] 450 mg, 2.43 mmol of tert-butyl(3-oxocyclobutyl)carbamate and 20 mL of toluene were successively added to a 50 mL round-bottom flask, followed by the slow addition of methyl(triphenylphosphoranylidene) acetate (1.22 g, 3.64 mmol). The reaction solution was refluxed under a nitrogen atmosphere for 16 hours, cooled, concentrated by rotary evaporation, and dried to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 6 / 1) to obtain methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene) acetate (450 mg, yield: 76.8%). 1 H NMR (400 MHz, CDCl3) δ 5.76 - 5.66 (m, 1H), 4.80 (br, 1H), 4.24 (s, 1H), 3.69 (s, 3H), 3.63 - 3.49 (m, 1H), 3.27 - 3.10 (m, 1H), 3.00 - 2.86 (m, 1H), 2.82 - 2.64 (m, 1H), 1.45 (s, 9H).

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

[0180] [ka]

[0181] Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene) acetate (450 mg, 1.9 mmol) and methanol (10 mL) were continuously added to a 50 mL round-bottom flask. Pd / C (45 mg, containing 10% palladium and 50% water) was slowly added under a nitrogen atmosphere. The reaction solution was stirred under a hydrogen atmosphere (1 atm) for 5 hours, filtered, concentrated by rotary evaporation, dried, and the solvent removed to obtain the crude product methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl) acetate (450 mg), which was used directly in the next step. MS m / z(ESI):244.2 [M+H] + .

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

[0183] [ka]

[0184] Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl) acetate (450 mg, 1.9 mmol) and anhydrous tetrahydrofuran (10 mL) were continuously added to a 50 mL round-bottom flask. Lithium aluminum hydride (210 mg, 5.6 mmol) was slowly added at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 0°C for 2 hours and the reaction was quenched with saturated sodium bicarbonate aqueous solution. The reaction solution was dried directly over anhydrous sodium sulfate and stirred for 15 minutes. The organic phase was filtered, concentrated by rotary evaporation, and dried to obtain the crude product tert-butyl (3-(2-hydroxyethyl)cyclobutyl) carbamate (450 mg), which was used directly in the next step. MS m / z(ESI):216.2 [M+H] + .

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

[0186] [ka]

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

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

[0189] [ka]

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

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

[0192] [ka]

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

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

[0195] [ka]

[0196] 3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.11 mmol), triethylamine (69 mg, 0.69 mmol), and dichloromethane (2 mL) were successively added to a 10 mL reaction flask, followed by the addition of dimethylcarbamoyl chloride (18.4 mg, 0.17 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, concentrated by rotary evaporation, dried, and the solvent removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain 3-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (11 mg, yield: 24%). 1 H NMR (400 MHz, CDCl3) δ 7.23 - 7.10 (m, 2H), 7.08 - 6.91 (m, 1H), 4.61 - 3.93 (m, 2H), 3.56 - 3.02 (m, 4H), 3.03 - 2.64 (m, 8H), 2.65 - 2.31 (m, 3H), 2.31 - 1.21 (m, 7H). MS m / z (ESI): 399.2[M+H] + .

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

[0198] [ka]

[0199] Step 1: Trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine (intermediate 2-1) and cis-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine (intermediate 2-2)

[0200] [ka]

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

[0202] [Table 1]

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

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

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

[0206] [ka]

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

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

[0209] [ka]

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

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

[0212] [ka]

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

[0214] [ka]

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

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

[0217] [ka]

[0218] 3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine hydrochloride (33 mg, 0.09 mmol), triethylamine (46 mg, 0.45 mmol), and N'N-carbonyldiimidazole (22 mg, 0.16 mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 2 hours until the starting materials disappeared. Cyclopropylamine (10 mg, 0.18 mmol) was added, and the reaction solution was stirred at 35°C for 48 hours. The reaction solution was concentrated by rotary evaporation and dried. The resulting crude product was purified by preparative HPLC to obtain 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)urea (12 mg, yield: 32.2%). 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 7.0, 2.4 Hz, 1H), 5.08 (dd, J = 28.8, 7.3 Hz, 1H), 4.64 (s, 1H), 4.43 - 4.09 (m, 1H), 3.14 (s, 4H), 2.73 (s, 4H), 2.56 (ddd, J = 16.2, 7.4, 2.8 Hz, 2H), 2.43 (s, 3H), 2.05 (dddd, J = 33.4, 24.1, 16.7, 8.5 Hz, 4H), 1.83 - 1.68 (m, 2H), 1.48 (dt, J = 9.6, 6.0 Hz, 2H), 0.76 (q, J = 6.3 Hz, 2H), 0.61 - 0.53 (m, 2H). MS m / z (ESI): 411.2[M+H] + .

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

[0220] [ka]

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

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

[0223] [ka]

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

[0225] [ka]

[0226] 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzene sulfonate (200 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol), and acetonitrile (10 mL) were successively added to a 50 mL round-bottom flask, followed by the slow addition of 1-(benzo[b]thiophen-4-yl)piperazine (118 mg, 0.54 mmol). The reaction solution was refluxed overnight. The reaction solution was cooled, followed by the addition of dichloromethane (20 mL), and washed with water (30 mL x 3). The organic phase was dried, concentrated by rotary evaporation, and dried to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol: 50 / 1) to obtain tert-butyl(3-(2-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)cyclobutyl)carbamate (120 mg, yield: 53%). MS m / z (ESI): 416.2 [M+H] + .

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

[0228] [ka]

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

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

[0231] [ka]

[0232] 3-(2-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.12 mmol), triethylamine (71 mg, 0.70 mmol), and dichloromethane (2 mL) were successively added to a 10 mL reaction flask, followed by the addition of dimethylcarbamoyl chloride (19 mg, 0.18 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, concentrated by rotary evaporation, dried, and the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (17 mg, yield: 37%). MS m / z(ESI):387.2 [M+H] + .

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

[0234] [ka]

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

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

[0237] [ka]

[0238] Following step 8 of Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carboxamide (23 mg, white solid, yield: 28.3%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.21 - 7.12 (m, 2H), 7.01 - 6.96 (m, 2H), 6.39 (dd, J = 34.1, 8.0 Hz, 1H), 6.11 - 6.06 (m, 1H), 4.52 (dq, J = 84.5, 8.0 Hz, 1H), 3.23 - 3.05 (m, 4H), 2.76 (s, 4H), 2.59 (td, J = 7.4, 6.8, 2.2 Hz, 1H), 2.48 - 2.46 (m, 1H), 2.35 (s, 3H), 2.24 - 2.13 (m, 2H), 2.04 - 1.97 (m, 1H), 1.84 - 1.75 (m, 2H), 1.62 (qd, J = 9.1, 2.8 Hz, 2H). MS m / z (ESI): 436.1 [M+H] + .

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

[0240] [ka]

[0241] Following step 8 of Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide (29 mg, white solid, yield: 33%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.19 - 7.12 (m, 2H), 6.97 (dd, J = 7.0, 2.5 Hz, 1H), 6.63 (dd, J = 42.2, 8.2 Hz, 1H), 4.42 (dq, J = 87.5, 7.9 Hz, 1H), 3.86 (d, J = 4.7 Hz, 2H), 3.42 (d, J = 2.5 Hz, 3H), 3.22 - 3.06 (m, 4H), 2.81 - 2.61 (m, 4H), 2.58 - 2.52 (m, 1H), 2.45 - 2.32 (m, 2H), 2.21 - 2.03 (m, 2H), 2.02 - 1.91 (m, 1H), 1.79 - 1.73 (m, 1H), 1.70 - 1.67 (m, 1H), 1.57 - 1.49 (m, 1H). MS m / z (ESI): 400.1 [M+H] + .

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

[0243] [ka]

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

[0245] The compound of Example 10 can also be obtained by following the synthesis method of Example 5. 1H NMR (400 MHz, chloroform-d) δ 8.97 (d, J = 2.2 Hz, 1H), 8.72 (dd, J = 4.8, 1.8 Hz, 1H), 8.12 (dq, J = 8.0, 2.0 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.19 - 7.12 (m, 2H), 6.97 (dt, J = 7.0, 2.7 Hz, 1H), 6.41 (dd, J = 14.4, 7.5 Hz, 1H), 4.85 - 4.34 (m, 1H), 3.12 (t, J = 5.0 Hz, 4H), 2.78 - 2.66 (m, 4H), 2.46 - 2.39 (m, 2H), 2.27 - 2.16 (m, 2H), 2.13 - 2.02 (m, 1H), 1.87 - 1.79 (m, 1H), 1.79 - 1.57 (m, 3H). MS m / z (ESI): 433.1 [M+H] + .

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

[0247] [ka]

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

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

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

[0251] [ka]

[0252] According to Example 4, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-carboxamide (22 mg, white solid, yield: 23%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.18 - 7.12 (m, 2H), 6.96 (dd, J = 7.1, 2.6 Hz, 1H), 4.41 - 4.22 (m, 1H), 4.21 - 4.15 (m, 2H), 4.11 - 4.06 (m, 2H), 3.85 - 3.78 (m, 2H), 3.29 (s, 3H), 3.16 - 3.08 (m, 4H), 2.69 (s, 4H), 2.55 - 2.49 (m, 1H), 2.42 - 2.35 (m, 2H), 2.11 (ddd, J = 11.5, 7.3, 2.9 Hz, 1H), 2.04 - 1.85 (m, 2H), 1.71 (dq, J = 32.8, 7.8 Hz, 2H), 1.44 (td, J = 9.2, 2.9 Hz, 1H). MS m / z (ESI): 441.1 [M+H] + .

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

[0254] [ka]

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

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

[0257] [ka]

[0258] According to the reaction conditions of Example 13, intermediate 2-1 was used as the starting material, and N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide was obtained accordingly. 1 H NMR (400 MHz, chloroform-d) δ 7.20 - 7.13 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.97 (dd, J = 7.0, 2.6 Hz, 1H), 4.56 - 4.44 (m, 1H), 3.22 - 3.07 (m, 4H), 2.86 - 2.66 (m, 4H), 2.50 - 2.41 (m, 2H), 2.32 - 2.24 (m, 1H), 2.20 - 2.05 (m, 5H), 1.84 - 1.76 (m, 2H), 1.38 - 1.32 (m, 2H), 1.06 - 1.00 (m, 2H). MS m / z (ESI): 412.1 [M+H] + .

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

[0260] [ka]

[0261] According to the reaction conditions of Example 13, intermediate 2-2 was used as the starting material, and accordingly, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide (13B) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.24 - 7.15 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 7.02 - 6.98 (m, 1H), 4.36 - 4.25 (m, 1H), 3.33 (s, 4H), 3.18 - 2.95 (m, 3H), 2.73 - 2.65 (m, 2H), 2.63 - 2.54 (m, 2H), 2.05 - 1.89 (m, 4H), 1.71 - 1.59 (m, 3H), 1.36 - 1.30 (m, 2H), 1.06 - 1.00 (m, 2H). MS m / z (ESI): 412.1 [M+H] + .

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

[0263] [ka]

[0264] 3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of thiazole-2-carboxylic acid (23 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred overnight at room temperature, concentrated by rotary evaporation, and dried. The resulting crude product was purified by high-performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide (21 mg, white solid, yield: 32%). 1 H NMR (400 MHz, chloroform-d) δ 7.86 (dd, J = 3.1, 1.5 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 42.4, 8.2 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.01 - 6.93 (m, 1H), 4.73 - 4.28 (m, 1H), 3.18 - 3.03 (m, 4H), 2.78 - 2.54 (m, 6H), 2.44 - 2.35 (m, 2H), 2.24 - 2.19 (m, 1H), 2.10 - 1.98 (m, 1H), 1.81 - 1.75 (m, 1H), 1.71 - 1.65 (m, 2H). MS m / z (ESI): 439.1 [M+H] + .

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

[0266] [ka]

[0267] According to the reaction conditions of Example 14, intermediate 2-1 was used as the starting material to obtain N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide (21 mg, white solid, yield: 32%). 1 H NMR (400 MHz, chloroform-d) δ 7.86 (d, J = 3.1 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.00 - 6.95 (m, 1H), 4.74 - 4.59 (m, 1H), 3.18 - 3.02 (m, 4H), 2.79 - 2.58 (m, 4H), 2.47 - 2.38 (m, 2H), 2.35 - 2.27 (m, 1H), 2.25 - 2.18 (m, 4H), 1.87 - 1.77 (m, 2H). MS m / z (ESI): 439.1 [M+H] + .

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

[0269] [ka]

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

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

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

[0273] [ka]

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

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

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

[0277] [ka]

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

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

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

[0281] [ka]

[0282] 3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine hydrochloride (40 mg, 0.11 mmol), triethylamine (44 mg, 0.44 mmol), and cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 12 hours, concentrated by rotary evaporation, dried, and the solvent was removed. The resulting crude product was purified by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide (15 mg, yield: 31.6%). 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.10 (m, 2H), 7.00 - 6.92 (m, 1H), 4.75 - 4.60 (m, 1H), 4.14 - 3.73 (m, 1H), 3.09 (s, 4H), 2.67 (s, 4H), 2.62 - 2.49 (m, 2H), 2.42 - 2.29 (m, 3H), 2.25 - 1.89 (m, 5H), 1.79 - 1.54 (m, 4H), 1.16 (d, J = 4.8 Hz, 2H), 0.99 (q, J = 6.8 Hz, 2H). MS m / z (ESI): 432.0 [M+H] + .

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

[0284] [ka]

[0285] According to Example 6, 1-(benzo[b]thiophene-4-yl)piperazine was used as a starting material, and accordingly, 3-(3-(2-(4-(benzo[b]thiophene-4-yl)piperazine-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea was obtained. 1H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 3.7 Hz, 2H), 7.31 - 7.26 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.54 - 4.09 (m, 2H), 3.41 - 3.15 (m, 6H), 2.85 (d, J = 4.0 Hz, 3H), 2.82 - 2.63 (m, 4H), 2.59 - 2.51 (m, 1H), 2.48 - 2.35 (m, 2H), 2.28 - 2.07 (m, 1H), 2.07 - 1.87 (m, 2H), 1.85 - 1.62 (m, 2H), 1.53 - 1.40 (m, 1H), 1.22 - 1.02 (m, 3H). MS m / z (ESI): 401.2 [M+H] + .

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

[0287] [ka]

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

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

[0290] [ka]

[0291] 3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature, followed by the addition of oxazole-2-carboxylic acid (20 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol), and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred overnight at room temperature, concentrated by rotary evaporation, and dried. The resulting crude product was purified by high-performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (13 mg, white solid, yield: 21%). 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 1.9 Hz, 1H), 7.24 - 7.14 (m, 4H), 6.98 (m, 2.0 Hz, 1H), 4.68 - 4.59 (m, 0.3H), 4.48 - 4.38 (m, 0.7H), 3.26 - 3.15 (m, 4H), 2.98 - 2.81 (m, 4H), 2.64 - 2.56 (m, 2H), 2.22 (t, J = 7.0 Hz, 2H), 2.07 - 1.99 (m, 1H), 1.89 - 1.80 (m, 2H), 1.75 - 1.67 (m, 2H). MS m / z (ESI): 423.1M+H] + .

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

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

[0294] [ka]

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

[0296] [Table 2]

[0297] Example 20A:t R =2.473 minutes 1 H NMR (400 MHz, chloroform-d) δ 7.79 (s, 1H), 7.24 - 7.20 (m, 2H), 7.17 - 7.11 (m, 2H), 6.97 (dd, J = 6.4, 3.1 Hz, 1H), 4.69 - 4.58 (m, 1H), 3.16 - 3.02 (m, 4H), 2.76 - 2.58 (m, 4H), 2.41 - 2.36 (m, 2H), 2.36 - 2.28 (m, 1H), 2.24 - 2.17 (m, 4H), 1.82 - 1.73 (m, 2H). MS m / z (ESI): 423.1M+H] + .

[0298] Example 20B:t R =1.782 minutes 1H NMR (400 MHz, chloroform-d) δ 7.79 (s, 1H), 7.22 (s, 1H), 7.19 - 7.10 (m, 3H), 6.97 (dd, J = 7.0, 2.5 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.28 - 3.03 (m, 4H), 2.84 - 2.67 (m, 4H), 2.67 - 2.54 (m, 2H), 2.53 - 2.35 (m, 2H), 2.15 - 2.02 (m, 1H), 1.75 - 1.63 (m, 4H). MS m / z (ESI): 423.1M+H] + .

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

[0300] [ka]

[0301] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.16 (s, 1H), 7.23 - 7.09 (m, 2H), 7.05 - 6.91 (m, 1H), 6.75 - 6.51 (m, 1H), 4.70 - 4.33 (m, 1H), 3.41 - 3.00 (m, 4H), 2.90 - 2.54 (m, 4H), 2.54 - 2.40 (m, 2H), 2.34 (s, 3H), 2.26 - 2.02 (m, 3H), 1.91 - 1.58 (m, 4H). MS m / z (ESI): 437.1[M+H] + .

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

[0303] [ka]

[0304] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material to obtain N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide (21A) (21 mg, white solid, yield: 25%). 1 H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 7.22 - 7.09 (m, 2H), 7.02 - 6.90 (m, 1H), 6.71 (d, J = 7.5 Hz, 1H), 4.69 - 4.54 (m, 1H), 3.30 - 3.00 (m, 4H), 2.86 - 2.58 (m, 4H), 2.53 - 2.39 (m, 2H), 2.34 (s, 3H), 2.33 - 2.27 (m, 1H), 2.26 - 2.12 (m, 4H), 1.91 - 1.72 (m, 2H). MS m / z (ESI): 437.1[M+H] + .

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

[0306] [ka]

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

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

[0309] [ka]

[0310] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisoxazole-5-carboxamide (21 mg, white solid, yield: 32%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.21 - 7.11 (m, 2H), 7.02 - 6.93 (m, 1H), 6.77 - 6.57 (m, 2H), 4.69 - 4.33 (m, 1H), 3.30 - 3.01 (m, 4H), 2.89 - 2.56 (m, 5H), 2.49 - 2.38 (m, 2H), 2.36 (s, 3H), 2.27 - 2.15 (m, 1H), 2.10 - 1.99 (m, 1H), 1.87 - 1.57 (m, 4H). MS m / z (ESI): 437.0 [M+H] + .

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

[0312] [ka]

[0313] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamide (14 mg, white solid, yield: 22%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.46 (d, J = 1.6 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.06 - 6.87 (m, 2H), 6.84 - 6.77 (m, 1H), 4.70 - 4.34 (m, 1H), 3.24 - 3.01 (m, 4H), 2.76 - 2.57 (m, 5H), 2.46 - 2.35 (m, 2H), 2.34 - 2.14 (m, 2H), 2.11 - 1.99 (m, 1H), 1.83 - 1.59 (m, 3H). MS m / z (ESI): 423.0 [M+H] + .

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

[0315] [ka]

[0316] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material, and accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamide (23A) (white solid) was obtained. 1H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 1.8 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.98 (dd, J = 6.7, 2.9 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 4.70 - 4.57 (m, 1H), 3.28 - 3.02 (m, 4H), 2.86 - 2.56 (m, 4H), 2.50 - 2.39 (m, 2H), 2.39 - 2.30 (m, 1H), 2.28 - 2.14 (m, 4H), 1.88 - 1.76 (m, 2H). MS m / z (ESI): 423.2 [M+H] + .

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

[0318] [ka]

[0319] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-2-methyloxazole-5-carboxamide was obtained. 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.16 (dd, J = 7.2, 4.3 Hz, 2H), 6.96 (dd, J = 6.6, 2.8 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 4.47 - 4.32 (m, 1H), 3.09 (s, 4H), 2.68 - 2.58 (m, 7H), 2.41 - 2.33 (m, 2H), 2.18 (td, J = 20.3, 12.2 Hz, 2H), 2.02 (dd, J = 15.7, 8.3 Hz, 1H), 1.78 (dd, J = 15.3, 7.6 Hz, 1H), 1.71 - 1.55 (m, 3H). MS m / z (ESI): 437.1 [M+H] + .

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

[0321] [ka]

[0322] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxamide was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.7 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.02 - 6.93 (m, 1H), 6.91 (d, J = 1.6 Hz, 1H), 4.48-4.64 (m, 1H), 3.29-3.11 (m, 4H), 2.79 - 2.60 (m, 4H), 2.45 - 2.39 (m, 2H), 2.26-2.22 (m, 2H), 2.05-2.01(m, 1H), 1.76-1.60 (m, 4H). MS m / z (ESI): 423.1 [M+H] + .

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

[0324] [ka]

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

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

[0327] [ka]

[0328] According to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-carboxamide (white solid) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 1.6 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.05 - 6.90 (m, 2H), 4.66 - 4.36 (m, 1H), 3.19 - 3.05 (m, 4H), 2.74 - 2.63 (m, 3H), 2.64 - 2.53 (m, 2H), 2.50 - 2.46 (m, 3H), 2.42 - 2.34 (m, 2H), 2.21 - 2.13 (m, 1H), 2.08 - 1.94 (m, 1H), 1.68 - 1.60 (m, 4H). MS m / z (ESI): 437.1M+H] + .

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

[0330] [ka]

[0331] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material, and N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-carboxamide was obtained accordingly. 1H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.20 - 7.11 (m, 2H), 7.05 - 6.92 (m, 2H), 4.67 - 4.54 (m, 1H), 3.19 - 3.06 (m, 4H), 2.76 - 2.63 (m, 4H), 2.48 (s, 3H), 2.44 - 2.41 (m, 2H), 2.21 - 2.11 (m, 5H), 1.84 - 1.75 (m, 2H). MS m / z (ESI): 437.1M+H] + .

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

[0333] [ka]

[0334] Following Step 1 of Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide (35 mg, white solid) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.96 (dd, J = 4.2, 1.7 Hz, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.25 - 8.16 (m, 1H), 7.75 - 7.67 (m, 2H), 7.51 - 7.45 (m, 1H), 7.16 (dd, J = 7.0, 2.0 Hz, 2H), 7.03 - 6.95 (m, 1H), 6.29 - 6.15 (m, 1H), 4.84 - 4.52 (m, 1H), 3.23 - 3.05 (m, 4H), 2.80 - 2.67 (m, 4H), 2.52 - 2.41 (m, 2H), 2.35 - 2.04 (m, 3H), 1.70 - 1.57 (m, 4H). MS m / z (ESI): 483.1M+H] + .

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

[0336] [ka]

[0337] According to the reaction conditions of Example 5, intermediate 2-1 was used as the starting material, and accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide was obtained. 1 H NMR (400 MHz, chloroform-d) δ 8.96 (dd, J = 4.3, 1.7 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.25 - 8.14 (m, 1H), 7.69 (d, J = 5.0 Hz, 2H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.98 (dd, J = 7.2, 2.4 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 4.84 - 4.71 (m, 1H), 3.22 - 3.14 (m, 4H), 2.94 - 2.88 (m, 1H), 2.86 - 2.74 (m, 4H), 2.56 - 2.50 (m, 2H), 2.32 - 2.26 (m, 2H), 2.25 - 2.18 (m, 2H), 1.93 - 1.84 (m, 2H). MS m / z (ESI): 483.1M+H] + .

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

[0339] [ka]

[0340] Following Step 1 of Example 1, 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazine-1-yl)ethyl)cyclobutyl)-1-methylurea (43 mg, white solid, yield: 33%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.22 - 7.11 (m, 2H), 7.03 - 6.92 (m, 1H), 5.32 (dd, J = 36.5, 7.6 Hz, 1H), 4.45 - 4.10 (m, 1H), 3.25 - 3.02 (m, 4H), 2.88 (d, J = 1.7 Hz, 3H), 2.82 - 2.57 (m, 4H), 2.57 - 2.51 (m, 1H), 2.47 - 2.32 (m, 3H), 2.24 - 2.10 (m, 1H), 2.08 - 1.90 (m, 1H),2.06 - 1.75 (m, 2H), 1.50 - 1.39 (m, 1H), 0.88 - 0.78 (m, 2H), 0.75 - 0.67 (m, 2H). MS m / z (ESI): 425.1 [M+H] + .

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

[0342] [ka]

[0343] Following Step 1 of Example 5, 1-cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide (31 mg, white solid) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.19 - 7.12 (m, 2H), 7.00 - 6.94 (m, 1H), 6.56 - 6.36 (m, 1H), 4.54 - 4.17 (m, 1H), 3.21 - 3.02 (m, 4H), 2.79 - 2.60 (m, 4H), 2.57 - 2.53 (m, 1H), 2.43 - 2.36 (m, 2H), 2.18 - 2.12 (m, 1H), 2.06 - 1.95 (m, 1H), 1.68 - 1.65 (m, 3H), 1.63 - 1.56 (m, 3H), 1.51 - 1.45 (m, 2H). MS m / z (ESI): 421.1M+H] + .

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

[0345] [ka]

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

[0347] [ka]

[0348] According to Step 1 of Example 2, 1-bromo-2,3-dichlorobenzene and tert-butyl(R)-3-methylpiperazine-1-carboxylate were used as starting materials to obtain tert-butyl(R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate (600 mg, yellow solid, yield: 32.6%). 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.26 - 7.21 (m, 1H), 7.21 - 7.11 (m, 1H), 7.11 - 6.94 (m, 1H), 3.99 - 3.00 (m, 7H), 1.49 (s, 9H), 0.91 (d, J = 6.3 Hz, 3H). MS m / z (ESI): 345.1 [M+H] + .

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

[0350] [ka]

[0351] According to step 2 of Example 2, tert-butyl(R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate was used as the starting material to obtain (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%). 1 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). MS m / z (ESI): 245.1 [M+H] + .

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

[0353] [ka]

[0354] (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazine-1-yl)ethyl)cyclobutan-1-amine (280 mg) was obtained according to steps 6 and 7 of Example 2. MS m / z (ESI): 342.1 [M+H] + .

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

[0356] [ka]

[0357] According to Example 5, (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazine-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropanamide (18 mg) was obtained. 1¹H NMR (400 MHz, chloroform-d) δ 7.25 - 7.20 (m, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.91 - 6.75 (m, 1H), 4.49 - 4.14 (m, 1H), 3.47 - 3.34 (m, 1H), 3.21 - 3.13 (m, 1H), 2.91 - 2.82 (m, 1H), 2.83 - 2.68 (m, 2H), 2.59 - 2.48 (m, 2H), 2.38 - 2.31 (m, 2H), 2.24 - 2.12 (m, 2H), 2.11 - 1.93 (m, 2H), 1.82 - 1.73 (m, 1H), 1.70 - 1.65 (m, 1H), 1.56 - 1.46 (m, 2H), 1.44 (d, J = 2.4 Hz, 6H), 0.90 (d, J = 6.2 Hz, 3H). MS m / z (ESI): 428.1 [M+H] + .

[0358] Biological assays and evaluations The present invention is further described below, along with the following test examples, which are not intended to limit the scope of the invention.

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

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

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

[0362] 2.2 Experimental reagents and consumables: [ 3 [H]-Methylpiperone (PerkinElmer; NET856250UC) Human dopamine D3 receptor membrane (PerkinElmer; ES-173-M400UA) GR 103691 (Sigma Corporation; 162408-66-4) ULTIMA GOLD (Perkin Elmer; 77-16061) 96-round deep-well plate, 1.1 mL (Perkin Elmer; P-DW-11-C) UNIFILTER-96GF / B filter plate (PerkinElmer; 6005174) Polyethyleneimine, branched (Sigma; 408727) Centrifuge tubes (BD Company, 352096; 352070) Loading slot (JET BIOFIL; LTT001050) Tray (JET BIOFIL; LTT001050) Pipette tips (Axygen; T-300-RS, T-200-YRS, T-1000-BRS) Magnesium chloride (Sigma, 7786-30-3) Tris base (Sigma, 77-86-1)

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

[0364] 4. Experimental data processing method: The CPM (counts per minute) value was measured using TopCount. 3 The inhibition rate percentage of [H]-methylpiperone binding was calculated from the values ​​of the high control (DMSO control) experimental group and the low control (100nM positive compound) experimental group {inhibition rate % = (CPM サンプル -CPM 低対照 ) / (CPM 高対照 -CPM 低対照 ) × 100}. The concentrations of the compound at 10 were 100 nM to 0.005 nM after 3-fold dilution of the reaction system. The inhibition rate percentage and 10-point concentration data were fitted to a parameter nonlinear logistic equation using GraphPad prism to determine the IC of the compound. 50 The value was calculated.

[0365] 5. Experimental results: The binding activity of the compound of the present invention to D3 was determined by the above assay, and the obtained IC 50 The values ​​are shown in Table 1 (Table 3).

[0366] [Table 3]

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

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

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

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

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

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

[0373] 5. Experimental results: The binding activity of the compound of the present invention to 5-HT2A was determined by the above assay, and the resulting IC was obtained. 50 The values ​​are shown in Table 2 (Table 4).

[0374] [Table 4]

[0375] 6. Conclusion of the experiment: The above data demonstrates that the compound of the present invention has good affinity for 5-HT2A.

[0376] II. Cell Function Assays Test Example 1. Determination of the effect of the compound of the present invention on the cAMP content in cells that stably express the D3 receptor.

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

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

[0379] 2.2 Experimental Reagents: Fetal bovine serum (Gibco, 10999141) Ham's F-12K (Kaighn's) culture medium (Hyclone Corporation; SH30526.01) Penicillin / Streptomycin, liquid (Gibco; 15140122) G418 (Invitrogen; 0131-027) Holskolin (Selleck, S2449) BSA stabilizer (Perkin Elmer; CR84-100) cAMP kit (Cisbio; 62AM4PEC) IBMX (Sigma Corporation; I5879) HEPES (Gibco; 15630080).

[0380] 3. Experimental method: 1. Buffer preparation: 1 × HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX. Complete culture 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 and 5% CO2. After TrypLE digestion, the cells were resuspended in experimental buffer and seeded into a 384-well cell culture plate at an inoculation density of 8000 cells per well. 3. Experimental buffer (1×HBSS, 0.1% BSA, 20 mM HEPES, and 500 μM IBMX) was prepared. The compounds were diluted in the buffer. 2.5 μL of the compound solution was added to each well, and the plate was incubated at 37°C for 10 minutes. Forskolin was diluted to 8 μM (8×) in the experimental buffer. 2.5 μL 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+ The cAMP-d2 was thawed and diluted 20-fold with lysis buffer. 10 μL of cAMP-d2 was added to the experimental well, followed by 10 μL of anti-cAMP-Eu. 3+ The substance was added. The reaction plate was centrifuged at 200g at room temperature for 30 seconds and allowed to stand at 25°C for 1 hour. Data was collected using Envision.

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

[0382] 5. Experimental results:

[0383] [Table 5]

[0384] 6. Conclusion of the experiment: The data in the table shows that the compounds of the examples of the present invention exhibit good agonist activity in a cAMP content efficacy assay in cells that stably express the D3 receptor.

[0385] Test Example 2. Determination of the effect of the compound of the present invention on calcium ion mobility in cells stably expressing the 5-HT2A receptor.

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

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

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

[0389] 3. Experimental method: 1) Buffer preparation: 1×HBSS, 20mM HEPES, 2.5mM probenecid (probenecid was prepared as a 400mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh on the day of the experiment. The experimental buffer included dye buffer and compound dilution buffer. 2) Cell culture medium: Ham's F-12K + 10% fetal bovine serum + 600 μg / ml hygromycin B + 1 × penicillin streptomycin. Inoculum: Ham's F-12K + 10% dialyzed serum. Assay buffer: 1 × HBSS + 20 mM HEPES. Cell line: Flp-In-CHO-5HT2A stable pool. 3) Cells were cultured in complete medium at 37°C and 5% CO2 to a culture density of 70% to 90%. Cells were digested with TrypLE trypsin and 1 × 10⁶ cells were placed in a 384-well assay plate. 4 Seed cells at a density of [number] cells / well and incubated for 16 to 24 hours (at least overnight). 4) Thaw 20X Component A at room temperature, dilute it with assay buffer to the 2× concentration (containing 5 mM probenecid), and leave it at room temperature for later use. 5) Remove the cell culture plate and allow it to stand at room temperature for 10 minutes. Dilute FBS to a concentration of 0.03% with Apricot and assay buffer, and 20 μL of the solution remained at the end of the 3764 culture plate. Add 20 μL of 2X Component A (containing 5 mM probenecid) to each experimental well, centrifuge at 200 g and room temperature for 3 to 5 seconds, and incubate at 37°C for 2 hours. 6) Discard the culture medium and add 20 μL of dye. Incubate the plate at 37°C in the dark for 60 minutes and measure the calcium signal. 7) Antagonist preparation before the experiment: The working solution of the test compound (6×) was prepared with DMSO. The cell culture plate was removed and allowed to stand at room temperature for 10 minutes. The 6× test compound was added to a 384-well assay plate (10 μL / well), and then incubated at room temperature in the dark for 35 minutes. The assay plate was transferred to FLIPR. 10 μL of diluted 5HT was added to each experimental well, followed by the addition of the 6× concentration agonist compound (5 μL / well). The values ​​were measured and stored using FLIPR. The total assay volume was 30 μL, containing 20 μL / well of dye buffer, 5 μL / well of the 5× concentration test compound, and 5 μL / well of the 6× concentration agonist compound.

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

[0391] 5. Experimental results:

[0392] [Table 6]

[0393] 6. Conclusion of the experiment: The data in the table shows that the compounds of the examples of the present invention exhibit good inhibitory activity in calcium ion mobility assays in cells that stably express the 5-HT2A receptor.

[0394] 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 in mice (plasma and brain tissue) after oral administration at a dose of 5 mg / kg was investigated.

[0395] 2. Experimental protocol: 2.1 Test compound: Compounds of the present invention prepared by the applicant.

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

[0397] 2.3 Preparation of the preparation: The test compound was dissolved in 0.5% CMC-Na (1% Tween 80) by sonication to prepare a clear solution or a homogeneous suspension.

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

[0399] 2.5 Sample collection: 0.2 mL of blood was collected from the hearts of mice before administration and 1, 2, 4, 8, and 24 hours after administration, and the mice were sacrificed with CO2. The samples were stored in EDTA-K2 tubes and separated from the plasma by centrifugation at 4°C and 6000 rpm for 6 minutes. The plasma samples were stored at -80°C. Whole brain tissue was removed, weighed, placed in a 2 mL centrifuge tube, and stored at -80°C.

[0400] 2.6 Sample Processing: 1) 160 μL of acetonitrile was added to a 40 μL plasma sample for precipitation, and the mixture was then 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 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 vortex for 10 minutes. 20 μL of the supernatant was taken and the concentration of the test compound was analyzed by LC / MS / MS. LC / MS / MS analyzer: AB Sciex API 4000 Qtrap.

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

[0402] [Table 7]

[0403] 3. Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the pharmacokinetic studies in mice are shown in Table 5 (Table 8) below.

[0404] [Table 8A]

[0405] [Table 8B]

[0406] 4. Conclusion of the experiment: The experimental results of pharmacokinetic assays in mice shown in the table indicate that the compounds of the present invention exhibit good pharmacokinetic properties, with high exposure AUC and high maximum plasma concentration C. max It appears that both were in good condition.

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

[0408] 2. Experimental equipment: 2.1 Equipment:

[0409] [Table 9]

[0410] 2.2 Reagents:

[0411] [Table 10]

[0412] 3. Experimental process: 3.1 Preparation of the compound's solution Preparation of the compound solution: 2 μL of the compound stock solution was added to 998 μL of phosphate buffer, resulting in a final concentration of 20 μM.

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

[0414] 3.2 Preparation of the Liver Microsome Solution 78.1 μL of 20 mg / mL microsomes were diluted to 2.5 mL with 100 mM phosphate buffer and thoroughly mixed, resulting in a final concentration of 0.625 mg / mL.

[0415] 3.3. Preparation of NADPH and UDPGA 33.3 mg of NADPH and 25.8 mg of UDPGA were weighed out, and then 2 mL of 100 mM phosphate buffer was added. The final concentration was 20 mM.

[0416] 3.4. Preparation of channel-forming reagent (aramethicine) 1 mg of aramethicine was weighed, 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), and the final concentration was 50 μg / mL.

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

[0418] 3.6. Incubation Procedure 400 μL of prepared liver microsomes, 25 μL of compound solution (10 μM), and 25 μL of aramethicine (50 μg / mL) were sequentially added to a 96-well plate, and 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 component content was as follows:

[0419] [Table 11]

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

[0421] 4. Experimental results:

[0422] [Table 12]

[0423] Note:

[0424] [Table 13]

[0425] 5. Conclusion of the experiment: The above data demonstrates that the compounds of the examples of the present invention are moderately metabolized in human, rat, and canine liver microsomes in vitro.

[0426] V. Pharmacodynamic model of active avoidance experiment in rats 1. Experimental Objective: To evaluate the anti-schizophrenic effects of compounds using a pharmacodynamic model of active avoidance experiments in rats.

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

[0428] [Table 14]

[0429] 2.2 Reagents:

[0430] [Table 15]

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

[0432] 3. Test animals:

[0433] [Table 16]

[0434] 4. Preparation of vehicles and compounds: 4.1 Vehicle (0.5% CMC-Na + 1% Tween80) A fixed amount (e.g., 1.0 g) of CMC-Na was weighed and placed in a glass bottle. A fixed volume (e.g., 200 mL) of purified water was added, and the resulting mixture was stirred to ensure even dispersion. 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 stored at 2 to 8°C for later use.

[0435] 4.2 Compound preparation: The prescribed amount of compound was weighed, followed by the addition of a prescribed volume of 0.5% CMC-Na + 1% Tween 80 solution. The compound solution was prepared immediately before administration, stored at 2 to 8°C, and used within 4 days.

[0436] The actual sample volume needs to be calculated during the preparation and administration of the compound solution. The calculation formula is as follows: Actual sample volume of compound = Theoretical measured sample volume × Purity / Salt coefficient.

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

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

[0439] 5.1.2 If the animal moved to the other side during a 10-second period of auditory and light stimulation, no electric shock was administered, this was recorded as avoidance, and the training session was completed.

[0440] 5.1.3 If an animal is unable to move to the other side after 10 seconds of auditory and light stimulation, an electric shock is administered with a current intensity of 0.6 mA for a duration of 10 seconds. If the animal moves to the other side during the 10 seconds of electric shock, the electric shock is stopped, this is recorded as avoidance, and the training session is completed.

[0441] 5.1.4 If the animal fails to dodge the electric shock within 10 seconds, the electric shock is stopped, this is recorded as a dodge failure, and the training session is terminated.

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

[0443] 5.2 Baseline Study and Grouping A baseline study was conducted the day before the compound screening study. The study process was the same as in sections 5.1.1 to 5.1.3, with 20 baseline studies. Animals that had avoided the test 16 times (80%) were divided into groups of 10 animals each, based on the number of avoidances. The first group received oral administration of the vehicle, while the other groups received the corresponding test compound according to the experimental design.

[0444] 5.3 Compound Screening Test The compound was administered orally (5 mL / kg) one hour before the test.

[0445] The testing process was the same as in sections 5.1.1 to 5.1.4, with 20 tests conducted.

[0446] 6. Data processing: The following data was collected using software for data analysis. Number of times animals avoided the animal Number of times the animal failed to avoid the obstacle Animal avoidance latency

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

[0448] 7. Experimental results:

[0449] [Table 17]

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

Claims

[Claim 1] Compounds of formula (IX-A), their stereoisomers, or pharmaceutically acceptable salts thereof 【Chemistry 1】 (In the formula, R 4 This is a 5-6 member nitrogen-containing heterocycline. 【Chemistry 2】 Selected from the group consisting of; The aforementioned 5-6 membered N-containing heterocyclyl is preferably oxazolidinonyl; R a is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1～6 alkyl, C 1～6 deuterated alkyl, C 1～6 haloalkyl, C 1～6 alkoxy, C 1～6 haloalkoxy, C 2～6 alkenyl, C 2～6 alkynyl, C 3～8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl; R b These are hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, and C. 1～6 Alkyl, C 1～6 Alkyl deuterated, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Hydroxyalkyl, C 1～6 Haloalkoxy, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～8 Cycloalkyl, 3-8 membered heterocyclyl, C 6～12 Selected from the group consisting of aryls and 5- to 12-membered heteroaryls, the amino, C 1～6 Alkyl, C 1～6 Alkyl deuterated, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～8 Cycloalkyl, 3-8 membered heterocyclyl, C 6～12 Aryl and 5- to 12-membered heteroaryls can optionally contain deuterium, halogen, amino, nitro, hydroxy, cyano, or C. 1～6 Alkyl, C 1～6 Alkyl deuterated, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～8 Cycloalkyl, 3-8 membered heterocyclyl, C 6～12 Further substituted with one or more substituents selected from the group consisting of aryls and 5- to 12-membered heteroaryls; R 5 is hydrogen, deuterium, C 1～6 Alkyl, C 1～6 Alkyl deuterated, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2～6 Alkenil, C 2～6 Alkinyl, C 3～8 Cycloalkyl, 3-8 membered heterocyclyl, C 6～12 Selected from the group consisting of aryls and 5- to 12-membered heteroaryls; Preferably, R 5 These are hydrogen, cyano, halogen, and C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy and C 3～6 Selected from the group consisting of cycloalkyl, more preferably selected from the group consisting of hydrogen and chlorine; Alternatively, any two adjacent R 5 These combine to form a 5-6 membered heterocycline or 5-6 membered heteroaryl, preferably a 5-6 membered heteroaryl containing 1 to 2 N, S, or O heteroatoms, more preferably a thienyl; r is 0, 1, or 2; m is either 0 or 1; t is 0, 1, 2, or 3, preferably 2; 【Transformation 3】 but 【Chemistry 4】 And if m is 1, then R 4 teeth, 【Transformation 5】 、-NHC(O)C 2 H 5 、-NHC(O)N(CH 3 ) 2 、-NHC(O)NHCH 3 、-NHC(O)N(C 2 H 5 )CH 3 、-NHC(O)NHC 2 H 5 、 【Transformation 6】 Not; If m is 2, then R 4 is -NHC(O)N(CH 3 ) 2 isn't it).

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