HK40047619B - Modifier of four-membered ring derivative, preparation method and application thereof - Google Patents

Description

Four-membered ring derivative modifiers, their preparation methods and applications

Technical Field

This invention belongs to the field of drug synthesis, specifically relating to a four-membered ring derivative inhibitor, its preparation method, and its application.

Background Technology

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

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

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

D3 receptor antagonists or partial agonists have shown good efficacy in improving positive and negative symptoms and cognitive impairment in schizophrenia. International applications WO2007093540, WO2009013212A2, WO2010031735A1, and WO2012117001A1 report compounds that act as dual regulators of D3 receptors and _5HT2A , but the binding activity Ki of most of these compounds for both D3 receptors and _5HT2A is above 10 nM. Jiangsu Hengyi's patent WO2014086098A1 reports a selective D3 inhibitor, but no studies on its binding activity with _5HT2A have been conducted. [The last sentence appears to be incomplete and possibly refers to a different topic: "by Gedeon..."] Richter's D3 antagonist, Cariprazine, was launched in 2015 and has been granted an international patent (WO2005012266A1). Cariprazine has strong D3 receptor agonist activity and offers significant advantages over existing drugs in treating negative symptoms of schizophrenia. However, Cariprazine has weak inhibitory activity against 5-HT2A receptors, resulting in severe extrapyramidal (ESP) side effects. Therefore, there is an urgent need to develop highly active D3 receptor modulators with optimized 5- _HT2A binding activity to reduce ESP side effects while improving efficacy in treating negative symptoms and improving cognition in schizophrenia.

Summary of the Invention

All contents relating to patent PCT/CN2020/073153 are incorporated herein by reference.

The object of this invention is to provide a compound of general formula (IX-A), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IX-A) has the following structure:

in:

R ₄ is selected from 5-6 N-containing heterocyclic groups, preferably oxazolidinone groups;

_Ra is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl;

_Rb is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C1-6 hydroxyalkyl, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl, or 5-12 heteroaryl, wherein the amino, C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl, and _5-12 heteroaryl groups may optionally be further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, deuterium, halogen, hydroxyl, cyano, hydroxyl ... It is substituted by one or more substituents selected from _1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl;

R ₅ is selected from hydrogen, deuterium, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, _C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl;

Preferably, it is hydrogen, cyano, halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, or _C3-6 cycloalkyl;

Hydrogen or chlorine are preferred;

Alternatively, any two adjacent R ₅ links can form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group;

Preferably, it is a 5-6 membered heteroaryl group containing 1-2 N, S or O heteroatoms; more preferably, it is a thiophene group;

r is 0, 1, or 2;

m is 0 or 1; and

t can be 0, 1, 2 or 3; 2 is preferred.

The present invention also provides a preferred embodiment in which, for compounds represented by general formula (IX-A), their stereoisomers, or pharmaceutically acceptable salts thereof, when m is 1, _R4 is not -NHC(O) _C₂H₅ , _-NHC (O)N( _CH₃ ) _₂ , -NHC(O) _NHCH₃ , -NHC( _O ) _{NC₂H₅CH₃} , _-NHC (O) _{NHC₂H₅ ,}

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, is shown in general formulas (X) and (X-A):

in:

R ₄ and m are defined as in general formula (IX-A).

In a further preferred embodiment of the present invention, _R4 is selected from a 5-6 member N-containing heterocyclic group, and the 5-6 member N-containing heterocyclic group is preferably an oxazolidinone group;

_Ra is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl;

Preferably, _Ra is selected from hydrogen, cyano, halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, or _C3-6 cycloalkyl;

More preferably, _Ra is selected from hydrogen or methyl;

_Rb is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C1-6 hydroxyalkyl, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl, or 5-12 heteroaryl, wherein the amino, C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl, and _5-12 heteroaryl groups may optionally be further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, deuterium, halogen, hydroxyl, cyano, hydroxyl ... It is substituted by one or more substituents selected from _1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl;

Preferably, _Rb is selected from amino, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 hydroxyalkyl, C3-6 cycloalkyl, _3-6 membered heterocyclic, _C6-10 aryl, or 5-10 heteroaryl, wherein the amino, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 hydroxyalkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclic, _C6-10 aryl, and 5-10 heteroaryl groups may optionally be further substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, _C1-3 alkyl, or _C1-3 alkoxy.

More preferably, _Rb is selected from amino, methyl, ethyl, methoxy, isopropyl hydroxy, cyclopropyl, aziridine, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolinyl, or benzoxazolyl, wherein the amino, methyl, ethyl, methoxy, isopropyl hydroxy, cyclopropyl, aziridine, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolinyl, or benzoxazolyl may optionally be further substituted by one or more substituents selected from hydrogen, fluorine, cyano, hydroxy, methyl, or methoxy; and

r can be 0, 1, or 2.

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof has the general formula (IX-A) as shown in general formula (XI):

in:

_R6 is selected from hydrogen, deuterium, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, _C2-6 alkenyl, C2-6 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclic, _C6-12 aryl, or _5-12 heteroaryl;

R ₇ is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-8 membered cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl, 5-12 membered heteroaryl, _Ree , -C(O)( _CH2 ) _{n2 Ree} , -( _CH2 ) _n2 C(O) _{NRee Reff} , -C(O) _{NRee Reff} , -( _CH2 ) _n2 C(O) _NRee C(O) _Rff , -( _CH2 ) _n2 S(O) _{m2 Ree} , -( _CH2 ) _{n2 NRee} S(O) _{m2 Rff} The following _{are listed} : -( _CH2 ) _n2S (O) _m2NReeRff , -( _CH2 ) _n1S (O) _m2NReeRff , -( _CH2 ) _n2ORee , _-C (O) _{NRee ( CH2} ) _n2Rff , _-C (O)( _CH2 ) _n2ORee , -( _{CH2)n2SRee ,} -( _CH2 ) _n2C (O) _ORee , _-P (O _{) ReeRff} , -( _CH2 ) _n2NReeC (O) _{Rff or -(CH2)n2NReeS(O)m2Rff , wherein the C1-6 alkyl , C1-6} deuterated _alkyl , _C1-6 haloalkyl, _{C1-6 alkoxy} , _C1-6 haloalkoxy, C The _2-6 -membered alkenyl, _C2-6 ynyl, _C3-8 -membered cycloalkyl, 3-8-membered heterocyclic, _C6-12 aryl, and 5-12-membered heteroaryl groups may optionally be further substituted with _{one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, C1-6 alkyl, C1-6 deuterated alkyl} , _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 ynyl, C3-8-membered cycloalkyl, 3-8-membered heterocyclic, _C6-12 aryl, and 5-12-membered heteroaryl groups; preferably 5-10-membered heteroaryl, _Ree , -C(O)( _CH2 ) _{n2 Ree} , -C(O) _{NRee Reff} , -C(O) _NRff ( _CH2 ) _{n2 Ree} , -S(O) _m2 R _ee or -S(O) _m2 NR _ee R _ff ;

_Ree and _Rff are each independently selected from hydrogen, amino, _C1-6 alkyl, C1-6 haloalkyl, _C1-6 alkoxy, _C3-8 cycloalkyl, _3-8 heterocyclic, _C6-14 aryl or 5-14 heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C3-8 cycloalkyl, _3-8 heterocyclic, _C6-14 aryl and 5-14 heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, oxo, _C1-6 alkyl, _C1-6 haloalkyl and _C1-6 alkoxy;

Preferably, _Ree and _Rff are each independently selected from amino, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclic group containing 1-2 nitrogen atoms, or 5-10 membered heteroaryl group containing 1-2 oxygen, nitrogen, and sulfur atoms. The amino, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclic group containing 1-2 nitrogen atoms, and 5-10 membered heteroaryl group containing 1-2 oxygen, nitrogen, and sulfur atoms are optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, oxo, _C1-6 alkyl, and _C1-6 alkoxy groups.

More preferably, _Ree and _Rff are each independently selected from the following substituents:

(CH ₃ ) ₂ N-, CH ₃ NH-, CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ NH-, CH ₃ CH ₂ NCH ₃ -, (CH ₃ ) ₂ COH-, (CH ₃ ) ₂ COHCH ₂ -, CH ₃ OCH ₂ -,

n2 is selected from 0, 1, or 2;

m2 is selected from 0, 1, or 2 and

m is selected from 0, 1, or 2.

In a further preferred embodiment of the invention, _Ree and _Rff are each independently selected from hydrogen and the following substituents:

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof has the general formula (XI) as shown in formulas (XI-A) and (XI-B):

In a preferred embodiment of the present invention, _R6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, _C2-3 alkenyl or _C2-3 alkynyl; preferably hydrogen;

R ₇ is selected from R _ee , -C(O)(CH ₂ ) _n2 R _ee , -C(O)NR _ee R _ff , -C(O)NR _ff (CH ₂ ) _n2 R _ee , -S(O) _m2 R _ee or -S(O) _m2 NR _ee R _ff ;

_Ree is selected from hydrogen, amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C3-8 cycloalkyl, _3-8 heterocyclic, _C6-14 aryl or 5-14 heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C3-8 cycloalkyl, 3-8 heterocyclic, _C6-14 aryl and 5-14 heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano, oxo, _C1-6 alkyl, _C1-6 haloalkyl and _C1-6 alkoxy;

Preferably, _Ree is selected from amino, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclic group containing 1-2 oxygen, nitrogen, and sulfur heteroatoms, or 5-10 membered heteroaryl group containing 1-2 oxygen, nitrogen, and sulfur heteroatoms. The amino, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4-6 membered heterocyclic group containing 1-2 oxygen, nitrogen, and sulfur heteroatoms, and 5-10 membered heteroaryl group containing 1-2 oxygen, nitrogen, and sulfur heteroatoms may optionally be substituted by one or more substituents selected from halogen, hydroxyl, cyano, oxo, _C1-6 alkyl, and _C1-6 alkoxy groups.

More preferably, _Ree is selected from the following substituents: ( _CH3 ) _2N- , _CH3NH- , _CH3- , _CH3CH2- , _CH3CH2NH- , _CH3CH2NCH3- , ( _{CH3 ) 2C ( OH} )-, ( _CH3 ) _2C ( _OH ) _CH2- , _{CH3OCH2- ,}

R _ff is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl;

Preferably, R _{_ff} is selected from hydrogen, cyano, halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, or _C3-6 cycloalkyl;

More preferably, R _ff is selected from hydrogen or methyl;

n2 is selected from 0, 1, or 2; and

m2 is selected from 0, 1, or 2.

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is characterized by being selected from the following groups:

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof has the general formula (XI) as shown in general formula (XII):

in:

R ₈ is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, C6-8 alkyl, C6-12 ... The _6-12 aryl and 5-12 heteroaryl groups are optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl, or 5-12 heteroaryl groups;

Preferably, the amino group, _C1-3 alkyl group, _C1-3 hydroxyalkyl group, _C3-6 cycloalkyl group, 3-6 membered heterocyclic group, _C6-10 aryl group, or 5-10 heteroaryl group is used, wherein the amino group, _C1-3 alkyl group, _C1-3 hydroxyalkyl group, _C3-6 cycloalkyl group, 3-6 membered heterocyclic group, _C6-10 aryl group, and 5-10 heteroaryl group are optionally further substituted by one or more substituents selected from hydrogen, hydroxyl group, cyano group, _C1-3 alkyl group, and _C1-3 alkoxy group;

Further selected from the following groups:

_CH3O- , HOC( _CH3 ) _2- ,

and

v is 0 or 1.

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof has the general formula (XI) as shown in general formula (XII):

in:

R ₈ is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclic, C6-8 alkyl, C6-12 ... _{The 6-12} aryl and 5-12 heteroaryl groups are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclic, _C6-12 aryl, or 5-12 heteroaryl groups;

Preferably, the amino group, _C1-3 alkyl group, _C1-3 hydroxyalkyl group, _C3-6 cycloalkyl group, 3-6 membered heterocyclic group, _C6-10 aryl group, or 5-10 heteroaryl group is used, wherein the amino group, _C1-3 alkyl group, _C1-3 hydroxyalkyl group, _C3-6 cycloalkyl group, 3-6 membered heterocyclic group, _C6-10 aryl group, or 5-10 heteroaryl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano, _C1-3 alkyl, _C1-3 alkoxy, or _C3-6 cycloalkyl.

Further selected from the following groups:

_CH3O- , HOC( _CH3 ) _2- ,

and

v is 0 or 1.

The present invention also provides a preferred embodiment in which the compound represented by general formula (XII), its stereoisomers, or its pharmaceutically acceptable salts, when _v is 0, _R8 is not _-C₂H₅ , _-N ( _CH₃ ) _{₂ , -NHCH₃} , _{-NC₂H₅CH₃} , _{-NHC₂H₅ ,}

When v is 1, _R8 is not a phenyl group.

The present invention also provides a preferred embodiment, wherein the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, has the general formula (XII) as shown in general formulas (XII-A) and (XII-B):

The present invention also provides a preferred embodiment, wherein the compound of general formula (IX-A), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

R ₄ is selected from

_Rb is selected from _C3-6 cycloalkyl or containing 1-2 5-10 heteroaryl groups selected from nitrogen, oxygen or sulfur atoms, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy or _C1-3 haloalkoxy;

_R5 is selected from hydrogen, halogen, or _C1-3 alkyl;

m is 1;

t can be 1, 2, or 3.

The present invention also provides a preferred embodiment in which the compound of general formula (IX-A), its stereoisomer or pharmaceutically acceptable salt thereof, when r is 0 and _Rb is 0, _Rb is substituted by at least one substituent;

When r is 0 and _Rb is 0, _Rb is substituted by at least one substituent.

The present invention also provides a more preferred embodiment, wherein the compound of general formula (IX-A), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

_Rb is selected from _C3-6 cycloalkyl, 5-6 nitrogen- or oxygen-containing heteroaryl or 9-10 nitrogen-containing fused-ring heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 alkoxy or _C1-3 haloalkoxy;

_R5 is selected from hydrogen, halogen, methyl or ethyl.

The present invention also provides a more preferred embodiment, wherein the compound of general formula (IX-A), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

_Rb is selected from cyclopropyl, pyridinyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, or quinolinyl, and optionally further substituted by one or more substituents selected from halogen, _C1-3 alkyl, or _C1-3 haloalkyl.

The compound of this invention not only has potent D3 receptor agonist activity, but also exhibits significantly better 5-HT2A inhibitory activity than Cariprazine. Clinically, it demonstrates good therapeutic efficacy for treating negative symptoms of schizophrenia and can significantly reduce the risk of EPS side effects.

The present invention also relates to a method for processing compounds of general formula (XII) or their stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

The reaction of the acyl chloride or carboxylic acid represented by general formula (XII-1) with that represented by general formula (XII-2) yields the compound represented by general formula (XII) or its stereoisomer and its pharmaceutically acceptable salt.

This invention also relates to compounds of formula (XII-1), their stereoisomers, or pharmaceutically acceptable salts thereof.

The present invention also relates to a method for providing a compound of formula (XII-1) or its stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

Deprotection of general formula (XII-3) yields the compound of general formula (XII-1) or its stereoisomer and its pharmaceutically acceptable salt;

in:

Pg ₁ is an amino protecting group selected from allyloxycarbonyl (Alloc), trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, methoxycarbonyl (FMOC), p-toluenesulfonyl (Tos), formate, acetyl, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), benzyl (Bn) or p-methoxyphenyl (PMP); preferably tert-butyloxycarbonyl (Boc).

The present invention also relates to a method for preparing the compound shown in intermediate (XII-3) or its stereoisomer and pharmaceutically acceptable salt thereof, comprising the following steps:

The reaction of general formula (XII-4) with general formula (XII-5) yields the compound shown in general formula (XII-3) or its stereoisomer and its pharmaceutically acceptable salt;

in:

_Pg2 is a hydroxyl protecting group selected from methyl ( _-CH3 ), tert-butyl (-C( _CH3 ) ₃ ), triphenyl ( _-CPh3 ), methyl thiomethyl ether (MTM), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), piv, benzyl ether ( _-CH2Ph ), methoxymethyl ( _-CH2OCH3 ), trimethylsilyl (-Si( _CH3 ) _{3 )} , tetrahydrofuranyl (-THP), tert-butyldimethylsilyl ( _-SiMe2 (t-Bu)), acetyl (-Ac), benzoyl (-COPh), or p-toluenesulfonyl ( _-SO2PhMe ); preferably p-toluenesulfonyl.

The present invention also relates to a pharmaceutical composition comprising a compound of any of the general formulas shown and a specific compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients at a therapeutically effective dose.

The present invention also relates to a use of any of the general formula compounds and specific compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof, in the preparation of G protein-coupled receptor modulators, particularly in dopamine D3 receptor modulators and 5-HT2A receptor modulators.

The present invention further relates to compounds of general formula (IX-A), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in a method for preparing a treatment for inflammatory diseases.

The present invention also relates to a method for treating and/or preventing central nervous system diseases and/or mental illnesses or conditions, comprising administering to a patient a therapeutically effective dose of a compound of general formula (IX-A), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to dopamine receptors and 5-HT2A receptor modulators.

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

In some implementations, this method relates to the treatment of conditions such as cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, respiratory diseases, and heart diseases.

In some implementations, this method relates to the treatment and/or prevention of central nervous system diseases and/or mental illnesses or conditions selected from schizophrenia, depression, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and/or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, depression, autism, Alzheimer's disease, seizures, neuralgia or withdrawal symptoms, major depressive disorder, and bipolar disorder.

The treatment methods provided herein include 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 disorders and/or mental illnesses in mammals. The method includes 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 said mammal.

Detailed description of the invention

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

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

The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to _-CH₂- , "ethylene" refers to -( _CH₂ ) _₂- , "propylene" refers to -( _CH₂ ) _₃- , "butylene" refers to -( _CH₂ ) _₄- , etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl, more preferably cyclopropyl, cyclobutyl, or cyclohexyl.

The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile/6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 5-membered/5-membered, or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, S(O) _m (where m is an integer from 0 to 2) or P(O) _n (where n is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, it comprises 3 to 8 ring atoms; most preferably, it comprises 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxacyclobutyl, oxacyclobutyl, pyrrolyl, oxazolidinyl-2-one, acrylonitrile, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, or pyranyl; preferably oxacyclobutyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, piperazinyl, oxazolidinyl-2-one, morpholinyl, piperazinyl, or acrylonitrile; more preferably oxacyclobutyl, pyrrolyl, piperidinyl, piperazinyl, acrylonitrile, or oxazolidinyl-2-one. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved may optionally be connected to other groups by single bonds, or may be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 3 to 20 cyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms of nitrogen, oxygen, boron, phosphorus, S(O) _m (where m is an integer from 0 to 2) or P(O) _n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 cyclic, more preferably 7 to 10 cyclic. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3/5, 4/4, 4/5, 4/6, 5/5, or 5/6 monospirocyclic group. Non-limiting examples of spirocyclic groups include:

wait.

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/5-membered, 4-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

wait.

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

wait.

The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

wait.

The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5 to 10-membered, and even more preferably 5- or 6-membered, wherein the heteroatoms are preferably 1 to 2 selected from oxygen, sulfur, and nitrogen atoms. Examples include imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, isoxazolyl, oxadiazole, or pyrazinyl, preferably pyridyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole, tetrazolyl, triazolyl, thiophene, imidazolyl, pyridyl, pyrimidinyl, or thiazolyl; more preferably pyridyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, or pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

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

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

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

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

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

"Alkyne" refers to (CH≡C-), wherein the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine, or iodine.

"Amino" refers to _-NH2 .

“Cyano” refers to -CN.

"Nitro" refers to _-NO2 .

"Carboxyl group" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

“EtOAc” refers to ethyl acetate.

“MeOH” refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

“MeCN” refers to Yi Qing.

“DMA” stands for N,N-dimethylacetamide.

“Et ₂ O” refers to diethyl ether.

“DCE” refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

“NBS” refers to N-bromosuccinimide.

“NIS” refers to N-iodosuccinimide.

“Cbz-Cl” refers to benzyl chloroformate.

“Pd ₂ (dba) ₃ ” refers to tris(dibenzylacetone)palladium.

“Dppf” refers to 1,1’-bis(diphenylphosphine)ferrocene.

“HATU” refers to 2-(7-benzotriazole oxide)-N,N,N’,N’-tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilamide.

"LiHMDS" refers to lithium bis(trimethylsilyl)amine.

“MeLi” refers to methyl lithium.

“n-BuLi” refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

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

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

"Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

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

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

Generally, the compounds of formula (IX-A) or their pharmaceutically acceptable salts are administered via any acceptable method of administration with similar practicality. The therapeutically effective amount of the compounds disclosed herein can range from about 0.01 to about 500 mg per kg of patient body weight per day, and can be administered in single or multiple doses. Suitable dose levels can be from about 0.1 to about 250 mg/kg per day; or from about 0.5 to about 100 mg/kg per day. Suitable dose levels can be from about 0.01 to about 250 mg/kg per day, from about 0.05 to about 100 mg/kg per day, or from about 0.1 to about 50 mg/kg per day. Within this range, the dose can be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg/kg per day. When administered orally, the composition may be provided in tablet form 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, i.e., the active ingredient, disclosed herein depends on many factors, such as the severity of the disease to be treated, the patient's age and relative health condition, the potency of the compound used, the route and form of administration, and other factors.

"Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

Detailed Implementation

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

Example

The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO- _d6 ), deuterated methanol ( _CD3OD ), and deuterated chloroform ( _CDCl3 ) as solvents, and tetramethylsilane (TMS) as the internal standard.

LC-MS determinations were performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

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

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

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

Example 1

1-Benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

Step 1: 1-Benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

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), followed by the addition of CDI (29 mg, 0.178 mmol) and stirring at room temperature for 1 hour. Then, benzylamine (36 mg, 0.324 mmol) was added and stirring at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After preparative chromatography, a white solid 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea (10 mg, yield: 12%) was obtained.

¹ H NMR (400MHz, CDCl ₃ )δ7.36-7.27 (m, 5H), 7.18-7.04 (m, 2H), 6.97 (d, J=6.9Hz, 1H), 4.58 (s, 1H), 4.37 (d, J=5.7Hz, 2H), 4.1 7(d, J=7.5Hz, 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] ⁺ .

Example 2

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

Step 1: tert-butyl (3-oxocyclobutyl) carbamate

3-O-cyclobutylcarboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol), and toluene (30 mL) were added sequentially to a 100 mL round-bottom flask. Diphenyl azidophosphate (4.0 g, 14.5 mmol) was then slowly added at -5 °C to 0 °C. The reaction mixture was stirred at 0 °C for 16 hours. The mixture was washed with saturated sodium bicarbonate aqueous solution (30 mL x 1) and saturated sodium chloride aqueous solution (30 mL x 1) at 0 °C, and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was then added to the organic phase, and the reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain tert-butyl (3-oxocyclobutyl)carbamate (500 mg, yield: 205%).

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

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

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

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

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

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

MS m/z (ESI): 244.2 [M+H] ⁺ .

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

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

MS m/z (ESI): 216.2 [M+H] ⁺ .

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

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

MS m/z (ESI): 370.2 [M+H] ⁺ .

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

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

MS m/z (ESI): 428.2 [M+H] ⁺ .

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

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

MS m/z (ESI): 328.1 [M+H] ⁺ .

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

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

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

MS m/z (ESI): 399.2 [M+H] ⁺ .

Example 2A

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

Step 1: trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (intermediate 2-1) and cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (intermediate 2-2)

The hydrochloride of 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine was resolved to yield trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (2-1) and cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (2-2).

Chiral preparation conditions:

instrument SFC-200 (Thar, Waters) Column AD 20*250mm, 10um (Daicel) Column pressure 100 bar mobile phase CO2/Methanol(0.2% Methanol Ammonia)＝70/30 Flow rate 130g/min Detection wavelength UV 254nm Column temperature 35℃

Intermediate 2-1: _tR = 1.285 min

¹ H NMR (400MHz, Chloroform-d) δ7.18-7.12(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] ⁺ .

Intermediate 2-2: _tR = 0.882 min

¹ H NMR (400MHz, Chloroform-d) δ7.18-7.11(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] ⁺ .

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

Starting with intermediate 2-1, 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea was obtained under the reaction conditions of step 8 in Example 2.

¹ H NMR (400MHz, Chloroform-d) δ7.23-7.07 (m, 2H), 7.07-6.91 (m, 1H), 4.49 (d, J=7.1Hz, 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] ⁺ .

Example 2B

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

Starting with intermediate 2-2, 3-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea was obtained under the reaction conditions of step 8 in Example 2.

¹ H NMR (400MHz, Chloroform-d) δ7.20-7.12 (m, 2H), 6.97 (dd, J=6.7, 2.8Hz, 1H), 4.41 (d, J=7.5Hz, 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, 7.0Hz, 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] ⁺ .

Example 3

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

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

3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50 mg, 0.11 mmol), diisopropylethylamine (88 mg, 0.69 mmol), and dichloromethane (10 mL) were added sequentially to a 10 mL reaction flask. Propionyl chloride (12.7 mg, 0.14 mmol) was then added with stirring. The reaction mixture was stirred at room temperature for 12 hours, washed with water, dried over an evaporative dryness to remove the solvent, and the crude product was obtained. The crude product was further separated by preparative HPLC to yield N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide (18 mg, yield: 41%).

MS m/z (ESI): 384.2 [M+H] ⁺ .

Example 4

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

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

¹ H NMR (400MHz, CDCl ₃ )δ7.20-7.12 (m, 2H), 6.97 (dd, J=7.0, 2.4Hz, 1H), 5.08 (dd, J=28.8, 7.3Hz, 1H), 4.64 (s, 1H), 4.43-4.09 (m, 1H), 3.14 (s, 4H), 2.73 (s, 4H), 2.56 (ddd, J=16.2, 7. 4, 2.8Hz, 2H), 2.43 (s, 3H), 2.05 (dddd, J=33.4, 24.1, 16.7, 8.5Hz, 4H), 1.83-1. 68 (m, 2H), 1.48 (dt, J=9.6, 6.0Hz, 2H), 0.76 (q, J=6.3Hz, 2H), 0.61-0.53 (m, 2H).

MS m/z (ESI): 411.2 [M+H] ⁺ .

Example 5

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

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

MS m/z (ESI): 471.2 [M+H] ⁺ .

Example 6

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

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

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

MS m/z (ESI): 416.2 [M+H] ⁺ .

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

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

MS m/z (ESI): 316.1 [M+H] ⁺ .

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

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

MS m/z (ESI): 387.2 [M+H] ⁺ .

Example 7

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

The operation is the same as in Example 2.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 8

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

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

MS m/z (ESI): 436.1 [M+H] ⁺ .

Example 9

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

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

MS m/z (ESI): 400.1 [M+H] ⁺ .

Example 10

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

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

The synthesis of Example 10 can also be obtained by referring to the synthesis method of Example 5.

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

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 11

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

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

The synthesis of Example 11 can also be obtained by referring to the synthesis method of Example 5.

MS m/z (ESI): 414.1 [M+H] ⁺ .

Example 12

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

Referring to Example 4, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyacridine-1-carboxamide (22 mg, white solid, yield: 23%) was obtained.

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

MS m/z (ESI): 441.1 [M+H] ⁺ .

Example 13

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

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

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

MS m/z (ESI): 412.1 [M+H] ⁺ .

Example 13A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide urea was obtained under the reaction conditions of Example 13.

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

MS m/z (ESI): 412.1 [M+H] ⁺ .

Example 13B

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

Starting with intermediate 2-2, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropane-1-carboxamide urea (13B) was obtained under the reaction conditions of Example 13.

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

MS m/z (ESI): 412.1 [M+H] ⁺ .

Example 14

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

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

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

MS m/z (ESI): 439.1 [M+H] ⁺ .

Example 14A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide (21 mg, white solid, yield: 32%) was obtained under the reaction conditions of Example 14.

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

MS m/z (ESI): 439.1 [M+H] ⁺ .

Example 15

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

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

The synthesis of Example 15 can also be obtained by referring to the synthesis method of Example 5.

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

MS m/z (ESI): 428.1 [M+H] ⁺ .

Example 16

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

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

The synthesis of Example 16 can also be obtained by referring to the synthesis method of Example 5.

MS m/z (ESI): 451.1 [M+H] ⁺ .

Example 17

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

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

The synthesis of Example 17 can also be obtained by referring to the synthesis method of Example 5.

MS m/z (ESI): 451.1 [M+H] ⁺ .

Example 18

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

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

¹ H NMR (400MHz, CDCl ₃ )δ7.20-7.10(m, 2H), 7.00-6.92(m, 1H), 4.75-4.60(m, 1H), 4.14-3.73(m, 1H), 3.09(s, 4H), 2.67(s, 4H), 2.62-2. 49 (m, 2H), 2.42-2.29 (m, 3H), 2.25-1.89 (m, 5H), 1.79-1.54 (m, 4H), 1.16 (d, J=4.8Hz, 2H), 0.99 (q, J=6.8Hz, 2H).

MS m/z(ESI): 432.0[M+H] ⁺ .

Example 19

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

Using 1-(benzo[b]thiophen-4-yl)piperazine as a raw material, 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea was obtained with reference to Example 6.

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

MS m/z (ESI): 401.2 [M+H] ⁺ .

Example 20

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

Referring to Example 3, the first step yielded N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (white solid, yield: 26%).

The synthesis of Example 20 was also performed using the following method:

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

¹ H NMR (400MHz, Chloroform-d) δ7.79 (d, J=1.9Hz, 1H), 7.24-7.14 (m, 4H), 6.98 (m, 2.0Hz, 1H), 4.68-4.59 (m, 0.3H), 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=7.0Hz, 2H), 2.07-1.99(m, 1H), 1.89-1.80(m, 2H), 1.75-1.67(m, 2H).

MS m/z (ESI): 423.1M+H] ⁺ .

Examples 20A and 20B

N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (20A)

N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (20B)

In Example 20, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (20A) and N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazol-2-carboxamide (20B) were prepared by resolution, with a mass ratio of 20A to 20B of approximately 1:2.

Chiral preparation conditions:

instrument SFC-80 (Thar, Waters) Column AD 20*250mm, 10um (Daicel) Column pressure 100 bar mobile phase <![CDATA[CO₂/EtOH(1% Methanol Ammonia)＝50/50]]> Flow rate 80g/min Detection wavelength UV214nm Column temperature 35℃

Example 20A: _tR = 2.473min

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

MS m/z (ESI): 423.1M+H] ⁺ .

Example 20B: _tR = 1.782 min

¹ H NMR (400MHz, Chloroform-d) δ7.79 (s, 1H), 7.22 (s, 1H), 7.19-7.10 (m, 3H), 6.97 (dd, J=7.0, 2.5Hz, 1H), 4.49-4.37 (m, 1H), 3.28-3.03(m, 4H), 2.84-2.67(m, 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] ⁺ .

Example 21

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

N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazol-5-carboxamide was obtained with reference to Example 5.

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

MS m/z (ESI): 437.1 [M+H] ⁺ .

Example 21A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide (21A) (21 mg, white solid, yield: 25%) was obtained under the reaction conditions of Example 5.

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

MS m/z (ESI): 437.1 [M+H] ⁺ .

Example 21B

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

Starting with intermediate 2-2, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisothiazolyl-5-carboxamide (21B) was obtained under the reaction conditions of Example 5.

MS m/z (ESI): 437.1 [M+H] ⁺ .

Example 22

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

Referring to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisothiazol-5-carboxamide (21 mg, white solid, yield: 32%) was obtained.

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

MS m/z (ESI): 437.0 [M+H] ⁺ .

Example 23

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

Referring to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-5-carboxamide (14 mg, white solid, yield: 22%) was obtained.

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

MS m/z (ESI): 423.0 [M+H] ⁺ .

Example 23A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-5-carboxamide (23A) (white solid) was obtained under the reaction conditions of Example 5.

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

MS m/z (ESI): 423.2 [M+H] ⁺ .

Example 24

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

N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-5-carboxamide was obtained with reference to Example 5.

¹ H NMR (400MHz, CDCl ₃ )δ7.55 (s, 1H), 7.16 (dd, J=7.2, 4.3Hz, 2H), 6.96 (dd, J=6.6, 2.8Hz, 1H), 6.28 (d, J=7.7Hz, 1H), 4.47-4.32 (m, 1H), 3.09 (s, 4H), 2.68-2.5 8 (m, 7H), 2.41-2.33 (m, 2H), 2.18 (td, J=20.3, 12.2Hz, 2H), 2.02 (dd, J=15.7, 8.3Hz, 1H), 1.78 (dd, J=15.3, 7.6Hz, 1H), 1.71-1.55 (m, 3H).

MS m/z (ESI): 437.1 [M+H] ⁺ .

Example 25

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

N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-3-carboxamide was obtained with reference to Example 5.

¹ H NMR (400MHz, CDCl ₃ )δ8.33 (d, J=1.7Hz, 1H), 7.19-7.14 (m, 2H), 7.02-6.93 (m, 1H), 6.91 (d, J=1.6Hz, 1H), 4.48-4.64 (m, 1H), 3.29 -3.11(m, 4H), 2.79-2.60(m, 4H), 2.45-2.39(m, 2H), 2.26-2.22(m, 2H), 2.05-2.01(m, 1H), 1.76-1.60(m, 4H).

MS m/z (ESI): 423.1 [M+H] ⁺ .

Example 25A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isothiazol-3-carboxamide was obtained under the reaction conditions of Example 5.

¹ H NMR (400MHz, CDCl ₃ )δ8.46 (d, J=1.4Hz, 1H), 7.22-7.17 (m, 2H), 7.00 (d, J=6.8Hz, 2H), 6.81 (d, J=1.4Hz, 1H), 4.64 (dd, J=15.1 , 7.5Hz, 1H), 3.29 (s, 4H), 2.79-2.77 (m, 4H), 2.36 (s, 2H), 2.24 (d, J=7.0Hz, 2H), 2.01 (s, 1H), 1.60 (s, 4H).

MS m/z (ESI): 423.1 [M+H] ⁺ .

Example 26

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

Referring to Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-4-carboxamide (white solid) was obtained.

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

MS m/z (ESI): 437.1M+H] ⁺ .

Example 26A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazol-4-carboxamide was obtained under the reaction conditions of Example 5.

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

MS m/z (ESI): 437.1M+H] ⁺ .

Example 27

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

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

MS m/z (ESI): 483.1M+H] ⁺ .

Example 27A

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

Starting with intermediate 2-1, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamide was obtained under the reaction conditions of Example 5.

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

MS m/z (ESI): 483.1M+H] ⁺ .

Example 28

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

Referring to Example 1, the first step yielded 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methylurea (43 mg, white solid, yield: 33%).

¹ H NMR (400MHz, Chloroform-d) δ7.22-7.11 (m, 2H), 7.03-6.92 (m, 1H), 5.32 (dd, J=36 .5, 7.6Hz, 1H), 4.45-4.10 (m, 1H), 3.25-3.02 (m, 4H), 2.88 (d, J=1.7Hz, 3H), 2.82- 2.57(m, 4H), 2.57-2.51(m, 1H), 2.47-2.32(m, 3H), 2.24-2.10(m, 1H), 2.08-1.90( m, 1H), 2.06-1.75 (m, 2H), 1.50-1.39 (m, 1H), 0.880.78 (m, 2H), 0.75-0.67 (m, 2H).

MS m/z (ESI): 425.1 [M+H] ⁺ .

Example 29

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

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

MS m/z (ESI): 421.1M+H] ⁺ .

Example 30

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

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

Using 1-bromo-2,3-dichlorobenzene and (R)-3-methylpiperazine-1-carboxylic acid tert-butyl ester as raw materials, tert-butyl(R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylic acid ester (600 mg, yellow solid, yield: 32.6%) was obtained in the first step of Example 2.

¹ H NMR (400MHz, Chloroform-d) δ 7.26-7.21 (m, 1H), 7.21-7.11 (m, 1H), 7.11-6.94 (m, 1H), 3.99-3.00 (m, 7H), 1.49 (s, 9H), 0.91 (d, J=6.3Hz, 3H).

MS m/z (ESI): 345.1 [M+H] ⁺ .

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

Using (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylic acid tertiary ester as the starting material, (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%) was obtained in step 2 of Example 2.

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

MS m/z (ESI): 245.1 [M+H] ⁺ .

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

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

MS m/z (ESI): 342.1 [M+H] ⁺ .

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

(R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpropionamide (18 mg) was obtained with reference to Example 5.

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

MS m/z (ESI): 428.1 [M+H] ⁺ .

Biological testing evaluation

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

I. Radioligand-receptor binding experiment

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

1. Experimental objective:

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

2.1 Experimental Apparatus:

Vortex mixer (IKA; MS3 basic)

Electric thermostatic incubator (Shanghai Yiheng; DHP-9032)

Microplate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer; NTX)

Universal Harvester (PerkinElmer; UNIFILTER-96).

2.2 Experimental reagents and consumables:

[ ³ H]-methylspiperone (PerkinElmer; NET856250UC)

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

GR 103691(Sigma;162408-66-4)

ULTIMA GOLD (Perkin Elmer; 77-16061)

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

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

Polyethyleneimine

branched(Sigma; 408727)

Centrifuge tubes (BD, 352096; 352070)

Loading slot(JET BIOFIL；LTT001050)

Tray (JET BIOFIL; LTT001050)

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

Magnesium chloride (Sigma, 7786-30-3)

Tris-base (Sigma, 77-86-1).

3. Experimental methods:

Add 0.5–5 μL of the test compound (0.005 nM–100 nM, 10 concentrations in total) and 100 μL of buffer to each 96-well plate. Add 0.5 μL of cell membrane and 300 μL of buffer to each well. Add [ ^3H ]-methylspiperone to the buffer and incubate at 27 °C for 30 min. Wash the UNIFILTER-96 GF/B filter plate, which has been pre-incubated with 0.5% PEI for 1 h, twice with 1 mL/well buffer. Add the cell membrane suspension to the UNIFILTER-96 GF/B filter plate and wash four times. Incubate at 55 °C for 10 min. Add 40 μL of ULTIMA GOLD to each well and perform liquid scintillation counting.

4. Experimental data processing methods:

CPM (Counts per minute) values were read using TopCount. Percentage inhibition of [ ^3H ]-methylspiperone binding was calculated from the readings of the High control (DMSO control) and Low control (100 nM positive compound) experimental groups: {% inhibition rate = (CPM _sample - CPM _{low control} ) / (CPM _{high control} - CPM _{low control} ) × 100}. The compound concentrations were 10 from 100 nM to 0.005 nM after a 3-fold dilution of the reaction system. The _IC50 values of the compounds were calculated using a non-linear logic formula fitted to the percentage inhibition rate and the ten-point concentration data using GraphPad prism.

5. Experimental Results:

The binding activity of the compounds to D3 in this invention was determined by the above experiments, and the measured _IC50 values are shown in Table 1.

Table 1. _IC50 of the compounds in this invention for binding to D3

6. Experimental Conclusion:

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

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

1. Experimental objective:

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

2.1 Experimental Apparatus:

Vortex mixer (IKA; MS3 basic)

Electric thermostatic incubator (Shanghai Yiheng; DHP-9032)

Microplate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer; NTX)

Universal Harvester (PerkinElmer; UNIFILTER-96).

2.2 Experimental reagents and consumables:

[ ^3H ]-Ketanserin(PerkinElmer NET791)

Human Dopamine 5-HT2A Receptor membrane(PerkinElmer)

GR 103691(Sigma;162408-66-4)

ULTIMA GOID (Perkin Elmer; 77-16061)

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

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

Polyethyleneimine, branched (Sigma; 408727)

Centrifuge tubes (BD, 352096; 352070)

Loading slot(JET BIOFIL；LTT001050)

Tray (JET BIOFIL; LTT001050)

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

Magnesium chloride (Sigma, 7786-30-3)

Tris-base (Sigma, 77-86-1).

3. Experimental methods:

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

4. Experimental data processing methods:

The CPM (Counts per minute) value was read using TopCount. The percentage inhibition rate of [ ^3H ]-Ketanserin was calculated based on the readings of the High control (DMSO control) and Low control (100 nM positive compound) experimental groups. The data were {% inhibition rate = (CPM _sample - CPM _{low control} ) / (CPM _{high control} - CPM _{low control} ) × 100}. The concentrations of the compound were 10 from 100 nM to 0.005 nM after the reaction system was diluted 3 times. The _IC50 value of the compound was calculated by fitting the percentage inhibition rate and the ten concentration data to the parameter nonlinear logic formula using GraphPad prism.

5. Experimental Results:

The binding activity of the compound to 5-HT2A in this invention was determined by the above experiments, and the measured _IC50 values are shown in Table 2.

Table 2 _IC50 values of the binding ability of the compounds in this invention to 5-HT2A

6. Experimental Conclusion:

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

II. Cell Function Experiments

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

1. Experimental objective:

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

2.1 Experimental Apparatus:

384-well test plate (Perkin Elmer; 6007680)

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

Pipettes (Axygen)

EnVision (Perkin Elmer).

2.2 Experimental Reagents:

Fetal Bovine Serum (Gibco, 10999141)

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

Penicillin-Streptomycin, Liquid (Gibco; 15140122)

G418 (invitrogen; 0131-027)

Forskolin (Selleck, S2449)

BSA stabilizer (Perkin Elmer; CR84-100)

cAMP kit (Cisbio; 62AM4PEC)

IBMX (Sigma; 15879)

HEPES (Gibco; 15630080).

3. Experimental methods:

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

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

2. The CHO-D3 cell line was cultured in complete medium at 37°C and 5% _CO2 . After TrypLE digestion, the cells were resuspended in experimental buffer and seeded into 384 cell culture plates at a seeding density of 8000 cells per well.

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

4. Experimental data processing methods:

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

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

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

4) S/B = Single/Background;

5) Calculate compound _EC50 using GraphPad nonlinear fitting formula:

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

X: Log value of compound concentration; Y: Activation%

5. Experimental Results:

Table 3. _EC50 values of compounds on cAMP levels in cells stably expressing the D3 receptor.

6. Experimental Conclusion:

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

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.

1. Experimental objective:

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

2. Experimental instruments and reagents:

2.1 Experimental Apparatus:

384-well test plate (Corning; 3712)

Pipettes (Axygen)

FLIPR (Molecular Devices)

2.2 Experimental Reagents:

DMEM (Invitrogen; 11965)

Fetal bovine serum (Biowest; S1810-500)

Dialysis serum (S-FBS-AU-065; Serana)

Penicillin and streptomycin (Biowest; L0022-100)

Hygromycin B (CABI℃HEM, 400052)

Matrigel (BD; 354230)

DMSO (Sigma; D2650)

HBSS (Invitrogen; 14065)

HEPES (Invitrogen; 15630080)

Probenecid (Sigma; P8761)

BSA (renview; FA016)

TrypLE (ThermoFisher; 12604021).

3. Experimental methods:

1) Buffer preparation: 1 x HBSS, 20 mM HEPES, 2.5 mM probenecid (probenecid is 400 mM st℃ kin 1M NaOH), 0.1% BSA. Probenecid and BSA should be added fresh on the day of the experiment. Experimental buffers include dye buffers and compound dilution buffers, etc.

2) Cell culture medium: Ham's F-12K + 10% fetal bovine serum + 600ug/ml hygromycin B + 1* penicillin and streptomycin; Inoculation medium: Ham's F-12K + 10% dialysis serum; Assay buffer: 1 x HBSS + 20mM HEPES; Cell line: Flp-In-CHO-5HT2A stable pool.

3) Cell lines were cultured in complete medium at 37°C and 5% _CO2 until 70%-90% confluence. After digestion with TrypLE trypsin, cells were seeded at a density of 1× ^10⁴ cells/well in 384-well plates and incubated for 16-24 hours (at least overnight).

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

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

6) Discard the culture medium and add 20 μL of dye. Incubate at 37°C in the dark for 60 min and read the calcium signal.

7) Preparation of antagonists before the experiment: Prepare the working solution (6X) of the test compound using DMSO. Remove the cell culture plate and let it stand at room temperature for 10 minutes. Add 10 μL/well of the 6X test compound to a 384-well test plate and incubate at room temperature in the dark for 35 minutes. Transfer the test plate to a FLIPR and add 10 μL of diluted 5HT to each well, followed by 5 μL/well of the 6X agonist compound. Use the FLIPR to read and save the data. The total test volume is 30 μL, including 20 μL/well of dye buffer, 5 μL/well of the 5X test compound, and 5 μL/well of the 6X agonist compound.

4. Experimental data processing methods:

Calcium signal values were read using FLIPR. The calculated output at each sampling time point was the ratio of the 340/510nm to the 380/510nm wavelength signals. The maximum value minus the minimum value was derived from the ratio signal curve. The _IC50 value of the compound was calculated using a non-linear logic formula fitted with the percentage inhibition rate and ten concentration data points using GraphPad Prism.

5. Experimental Results:

Table 4: _IC50 values of the compounds on calcium ion mobility in cells stably expressing 5-HT2A receptors

6. Experimental Conclusion:

As can be seen from the data in the table, the compounds in the embodiments of the present invention showed good inhibitory activity in the functional calcium flow assay of cells stably expressing 5-HT2A.

III. Pharmacokinetic Determination in Balb/C Mice

1. Research Objective:

Using Balb/C mice as test animals, the pharmacokinetic behavior of the compounds of the present invention, when orally administered at a dose of 5 mg/kg, was studied in mice (plasma and brain tissue).

2. Experimental Design:

2.1 Experimental reagents:

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

2.2 Laboratory animals:

Balb/C Mouse, 12 males per group, Shanghai Jiesijie Laboratory Animal Co., Ltd., Animal Production License No. (SCXK(沪)2013-0006 N0.311620400001794).

2.3 Formulation:

Dissolve 0.5% CMC-Na (1% Tween 80) by sonication to prepare a clear solution or a homogeneous suspension.

2.4 Administration:

Each group of Balb/C mice consisted of 12 males; after fasting overnight, they were administered p.o. at a dose of 5 mg/kg and a volume of 10 mL/kg.

2.5 Sample Collection:

Mice were sacrificed with _CO2 at 1, 2, 4, 8 and 24 hours before and after drug administration. 0.2 mL of blood was collected from the heart and placed in an EDTA- _K2 test tube. The plasma was separated by centrifugation at 6000 rpm for 6 min at 4 °C and stored at -80 °C. The whole brain tissue was removed, weighed and placed in a 2 mL centrifuge tube and stored at -80 °C.

2.6 Sample preparation:

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

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

3) Take 70 μL of the supernatant solution after treatment and add 70 μL of water. Vortex mix for 10 minutes, then take 20 μL for LC/MS/MS analysis to determine the concentration of the analyte. LC/MS/MS analyzer: AB Sciex API 4000 Qtrap.

2.7 Liquid Chromatography Analysis:

●Liquid phase conditions: Shimadzu LC-20AD pump

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

● Flow rate: 0.4 mL/min

●Eluting time: 0-4.0 minutes, eluent as follows:

3. Experimental Results and Analysis:

The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiments are shown in Table 5 below:

Table 5: Results of Pharmacokinetic Experiments in Mice

4. Experimental conclusions:

As can be seen from the results of the mouse pharmacokinetics experiment in the table, the compounds in the embodiments of the present invention exhibit good metabolic properties, and the exposure AUC and maximum plasma concentration _Cmax are both good.

IV. In vitro liver microsomal stability test

1. Experimental objective:

The metabolic stability of the compounds of this invention in in vitro on liver microsomes was evaluated.

2. Experimental apparatus:

2.1 Instruments:

2.2 Reagents:

3. Experimental steps:

3.1. Preparation of compound working solution

Preparation of working solution for the compound: Add 2 μL of the compound stock solution to 998 μL of phosphate buffer to achieve a final concentration of 20 μM.

Preparation of working solution for control compound (7-hydroxycoumarin): The preparation process was the same as that for the control compound.

3.2. Preparation of liver microsomal working solution

78.1 μL of 20 mg/mL microsomes was diluted to 2.5 mL with 100 mM phosphate buffer, mixed well, and the final concentration was 0.625 mg/mL.

3.3. Prepare NADPH and UDPGA

Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.

3.4. Prepare the drilling agent (Alamethicin)

Weigh 1 mg of Alamethicin and add it to 200 μL of DMSO to prepare a solution of 5 mg/mL. Then take 10 μL of this solution and add it to 990 μL of phosphate buffer (pH 7.4) to obtain a final concentration of 50 μg/mL.

3.5. Preparation of the reaction termination solution

Termination solution: Cold acetonitrile containing 100 ng/mL labetalol hydrochloride and 400 ng/mL tolbutamide as internal standards, stored in a refrigerator at 2-8°C.

3.6. Incubation Process

400 μL of prepared liver microsomes, 25 μL of the compound working solution (10 μM), and 25 μL of Lamethicin (50 μg/mL) were added sequentially to a 96-well plate, and the mixture was pre-incubated at 37 °C for 10 min. Then, 50 μL of prepared NADPH/UDPGA was added to initiate the reaction, and the mixture was incubated at 37 °C. The total volume of the reaction system was 500 μL. The final concentrations of each component are as follows:

50 μL samples were taken at time points of 0 min, 5 min, 10 min, 20 min, 30 min and 60 min respectively, and 200 μL of cold stop solution containing internal standard was added to terminate the sample reaction. The samples were centrifuged at 4000g for 10 min, and the supernatant was taken for LC-MS/MS analysis.

4. Experimental Results:

Table 6. In vitro liver microsomal stability

Remark:

5. Experimental Conclusion:

The data above show that the compounds of the present invention are moderately metabolized in human, rat, and canine liver microsomes in vitro.

V. Rat Active Escape Experimental Pharmacodynamic Model

1. Experimental objective:

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

2. Experimental instruments and reagents:

2.1 Instruments:

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

2.2 Reagents:

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

2.3 Test Compounds:

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

3. Laboratory animals:

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

4. Preparation of solvents and compounds:

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

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

4.2 Compound preparation:

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

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

5. Experimental Procedure:

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

5.1 Establishment of the pharmacodynamic model:

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

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

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

5.1.4 If the animal does not dodge within 10 seconds of the electric shock, the electric shock is stopped, and it is recorded as an escape failure, thus ending the training session.

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

5.2 Baseline Testing and Grouping

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

5.3 Compound Screening Test

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

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

6. Data Processing:

The software collects the following data for data analysis:

The number of times an animal actively avoids something;

The number of times an animal fails to escape;

The escape latency of animals in passive escape;

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

7. Experimental Results:

Table 7

8. Experimental Conclusion:

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

Claims (28)

1. Compounds of general formula (IX-A), their stereoisomers, or their pharmaceutically acceptable salts, in: R ₄ is selected from _Ra is selected from hydrogen, halogen, hydroxyl, cyano, _C1-6 alkyl or _C3-8 cycloalkyl; _Rb is selected from hydrogen, amino, hydroxyl, cyano, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, C3-8 cycloalkyl, _3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 alkoxy, _C3-8 cycloalkyl, 3-8 membered heterocyclic, _C6-12 aryl or 5-12 heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano, _C1-6 alkyl or _C1-6 alkoxy; _R5 is selected from hydrogen, _C1-3 alkyl, _C1-3 alkoxy, halogen, amino, nitro, hydroxy, cyano or _C3-6 cycloalkyl; Alternatively, any two adjacent _R5 groups can be linked to form a 5-6 membered heteroaryl group containing 1-2 N, S, or O heteroatoms; r is 0, 1, or 2; m is 0 or 1; and t can be 0, 1, 2, or 3; When m is 1 R ₄ is not -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 , 2. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R ₄ is selected from _Ra is selected from hydrogen, halogen, hydroxyl, or _C1-6 alkyl; _Rb is selected from hydrogen, amino, hydroxyl, cyano, _C1-6 alkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclic or 5-12 heteroaryl, wherein the amino, _C1-6 alkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclic or 5-12 heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano or _C1-6 alkyl; _R5 is selected from hydrogen, _C1-3 alkyl, halogen, amino, nitro, hydroxy, or cyano; Alternatively, any two adjacent _R5 groups can be linked to form a 5-6 membered heteroaryl group containing 1-2 N, S, or O heteroatoms; r is 0, 1, or 2; m is 0 or 1; and t can be 0, 1, 2 or 3. 3. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, _R5 is selected from hydrogen or chlorine; Alternatively, any two adjacent _R5 links can form a thiophene group; r is 0 or 1; m is 0 or 1; and t is 2. 4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that the compound further represents general formula (X) and general formula (X-A): 5. Compounds of general formula (XI), their stereoisomers, or their pharmaceutically acceptable salts, in: _R6 is selected from hydrogen, _C1-6 alkyl, hydroxyl, cyano, or _C3-8 cycloalkyl; _R7 is selected from -C(O)( _CH2 ) _n2Ree , -( _CH2 ) _n2S (O) _{m2Ree , or} -C(O) _NRee ( _CH2 ) _{n2Reff ; Ree} is selected from hydrogen, amino, _C1-6 alkyl, _C3-6 cycloalkyl, 3-8 heterocyclic or 5-12 heteroaryl, wherein the amino, _C1-6 alkyl, _C3-6 cycloalkyl, 3-8 heterocyclic or 5-12 heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano, _C1-6 alkyl and _C1-6 alkoxy; R _ff is selected from hydrogen, amino, _C1-6 alkyl, _C3-6 cycloalkyl, 3-8 heterocyclic or 5-12 heteroaryl; n2 is selected from 0, 1, or 2; m2 is selected from 0, 1, or 2; and m is selected from 0 or 1. 6. The compound according to claim 5, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that _Ree is selected from the following substituents: ( _CH3 ) _2N- , _{CH3NH- , CH3-} , _CH3CH2- , _CH3CH2NH- , _CH3CH2NCH3- , _{( CH3} ) _{2C (OH)-, (CH3)2C ( OH ) CH2- , CH3OCH2-} , R _ff is selected from the following substituents: _CH3- , _{CH3CH2- ,} 7. The compound according to claim 5, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, _Ree is selected from hydrogen and the following substituents: R _ff is selected from hydrogen and the following substituents: 8. The compound according to claim 5, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, _R6 is hydrogen; _R7 is selected _{from -C(O)(CH2)n2Ree , -C} (O) _NRff ( _CH2 ) _{n2Ree or} -S(O) _{m2Ree ; Ree} is selected from hydrogen, amino, _C1-3 alkyl, _C3-6 cycloalkyl, 3-8 heterocyclic or 5-12 heteroaryl, wherein the amino, _C1-3 alkyl, _C3-6 cycloalkyl, 3-8 heterocyclic or 5-12 heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano, _C1-3 alkyl or _C1-3 alkoxy; R _{_ff} is selected from hydrogen, _C1-3 alkyl, or _C3-6 cycloalkyl; n2 is 0; and m2 is selected from 0, 1, or 2. 9. The compound according to claim 8, its stereoisomers, or a pharmaceutically acceptable salt thereof, characterized in that _Ree is selected from the following substituents: CH ₃ CH ₂ -, (CH ₃ ) ₂ C(OH)CH ₂ -, (CH ₃ ) ₂ C(OH), -CH ₃ OCH ₂ -, R _ff is selected from hydrogen or methyl. 10. The compound according to claim 5, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that the compound further comprises the following general formulas (XI-A) and (XI-B): 11. The compound according to claim 5 or 10, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that it comprises a group selected from: 12. The compound according to claim 5 or 10, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that it comprises a group selected from the following: 13. The compound according to claim 5, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that the compound further represents the general formula (XII): in: _R8 is selected from hydrogen, amino, _C1-3 alkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl, wherein the amino, _C1-3 alkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclic or 5-10 heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano, _C1-3 alkyl or _C1-3 alkoxy; v is 0 or 1; When _v is 0, _R8 is _{not -C₂H₅} , -N( _CH₃ ) _₂ , _-NHCH₃ , _{-NC₂H₅CH₃} , _{or -NHC₂H₅ .} 14. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that _R8 is further selected from the following groups: HOC( _CH3 ) _2- 15. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that general formula (XII) further represents general formula (XII-A) or (XII-B): 16. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R ₄ is selected from _Rb is selected from _C3-6 cycloalkyl or containing 1-2 5-10 heteroaryl groups selected from nitrogen, oxygen or sulfur atoms, optionally further substituted by one or more substituents selected from halogen, hydroxyl, _C1-3 alkyl or _C1-3 alkoxy; _R5 is selected from hydrogen, halogen, or _C1-3 alkyl; m is 1; t is 1, 2, or 3; When r is 0 and _Rb is 0, _Rb is substituted by at least one substituent; When r is 0 and _Rb is 0, _Rb is substituted by at least one substituent. 17. The compound of claim 16, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that _Rb is selected from _C3-6 cycloalkyl, 5-6 nitrogen- or oxygen-containing heteroaryl or 9-10 nitrogen-containing fused-ring heteroaryl, optionally further substituted by one or more substituents selected from halogen, _C1-3 alkyl or _C1-3 alkoxy. 18. The compound of claim 17, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _Rb is selected from cyclopropyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl or quinolinyl, optionally further substituted by one or more substituents selected from halogens or _C1-3 alkyl groups. 19. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that the specific structure of said compound is as follows: 20. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following compound: 21. A method for preparing the compound of general formula (XII) according to claim 13, or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps: The reaction of the acyl chloride or carboxylic acid represented by general formula (XII-1) with that represented by general formula (XII-2) yields the compound represented by general formula (XII) or its stereoisomer and its pharmaceutically acceptable salt; in: R ₈ and v are as described in claim 13. 22. The compound represented by formula (XII-1), its stereoisomers, or its pharmaceutically acceptable salts, 23. A method for preparing the compound of formula (XII-1) according to claim 22, or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps: Deprotection of general formula (XII-3) yields the compound of general formula (XII-1) or its stereoisomer and its pharmaceutically acceptable salt; in: Pg ₁ is an amino protecting group selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, methoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl. Optionally, the reaction of general formula (XII-4) with general formula (XII-5) yields the compound shown in general formula (XII-3) or its stereoisomer and its pharmaceutically acceptable salt; Pg ₂ is a hydroxyl protecting group selected from methyl, tert-butyl, triphenyl, methyl thiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, p-valeryl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzoyl, or p-toluenesulfonyl. 24. The method according to claim 23, characterized in that, Pg ₁ is tert-butyloxycarbonyl; Pg ₂ is p-toluenesulfonyl. 25. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1 to 20, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 26. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, or the pharmaceutical composition of claim 25, in the preparation of dopamine D3 receptor and 5-HT2A receptor modulators. 27. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, or the pharmaceutical composition of claim 25, in the preparation of a medicament for the treatment or prevention of neurological and/or mental disorders, wherein the neurological and/or mental disorders are selected from schizophrenia spectrum disorder, autism spectrum disorder, depression, Alzheimer's disease, epileptic seizures, and mania. 28. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, or the pharmaceutical composition of claim 25, in the preparation of a medicament for the treatment or prevention of neurological and/or mental disorders, wherein the neurological and/or mental disorders are selected from schizophrenia or autism.