TW202041217A - Polycyclic derivative modulator, preparation method and application thereof - Google Patents

Abstract

The present invention relates to a polycyclic derivative modulator, preparation method and application thereof. In particular, the present invention relates to compounds represented by the general formula (I), their preparation methods and pharmaceutical compositions containing the compounds, and their use as G protein-coupled receptor modulators in the treatment or prevention of central nervous system diseases and / or mental illnesses thereof. Each substituent in the general formula (I) is as defined in the specification.

Description

A polycyclic derivative regulator, its preparation method and application

The invention belongs to the field of drug synthesis, and specifically relates to a polycyclic derivative inhibitor and a preparation method and application thereof.

Dopamine D3 receptor is a member of the G protein-coupled receptor family. It is a subtype of dopamine receptors. It belongs to the same D2-like inhibitory receptor as dopamine D2 and D4 receptors. After binding to DA, it inhibits G-protein Reduce cAMP levels. D3 receptors are mainly distributed in the limbic system of the brain, especially the nucleus accumbens, olfactory nodules and calleja islands that are not related to motor function. Highly active D3 receptor modulators may have good anti-schizophrenia activity. D3 receptors are closely related to emotion, cognition, mentality, addiction, etc., and can better improve the negative symptoms of schizophrenia patients. D3 receptors may regulate cognition by regulating the release of acetylcholine and regulating glutamate receptors. Partial activation of D3 receptors can improve cognition.

The serotonin 2A receptor (5-HT2A) receptor is a member of the G protein-coupled receptor family. It is a major excitatory receptor subtype of the 5-HT receptor. It is distributed in the center and the periphery. , Emotions, learning and memory are closely related. Highly active 5-HT2A receptor inhibitors have significant anti-schizophrenia effects and can reduce the side effects of the extrapyramidal tract.

Schizophrenia is a kind of mental illness with the highest prevalence. It has a slow course and is prone to recurring, aggravating or worsening. It causes a serious burden of disease and adverse consequences for patients and their families. Psychiatric patients will have positive symptoms such as delusions, hallucinations, thought, language and behavior disorders, lack of emotion and expression, poor speech, lack of pleasure and other negative symptoms, as well as symptoms such as cognitive impairment. Although the research and development and clinical application of anti-schizophrenia drugs have been greatly developed in the past few decades, traditional antipsychotics (first generation) (haloperidol, droperidol, thioridazine, etc.) and Atypical antipsychotics (second generation) (clozapine, risperidone, olanzapine, aripiprazole, etc.) are all effective in treating positive symptoms, but are not ideal for improving negative symptoms and cognitive impairment, so There is an urgent need to develop anti-schizophrenia drugs that can improve not only positive symptoms, but also negative symptoms and cognitive impairment. Highly active dopamine D3 receptor modulators can improve the negative symptoms, positive symptoms and cognitive impairment of patients with schizophrenia, and have no side effects such as extrapyramidal and weight gain of the first and second generation antipsychotics.

D3 receptor antagonists or partial agonists have a good effect on improving the positive symptoms, negative symptoms and cognitive dysfunction of schizophrenia. International applications WO2007093540, WO2009013212A2, WO2010031735A1 and WO2012117001A1 have reported D3 receptor and 5HT _2A dual modulator compounds, but most of the compounds have binding activity Ki to D3 receptor and 5HT _2A above 10 nM; Jiangsu Hengyi patent WO2014086098A1 reported D3 selective inhibitor, but no study on the binding activity of 5HT _2A ; the D3 antagonist Cariprazine developed by Gedeon Richter was launched in 2015 and applied for international patent WO2005012266A1. Cariprazine has strong D3 receptor agonist activity , The treatment of schizophrenia has a significant advantage over existing drugs for negative symptoms, but Cariprazine has weak inhibitory activity on 5-HT2A receptors, resulting in more serious extrapyramidal (ESP) side effects, so it is urgent There is a need to develop highly active D3 receptor modulators, and at the same time have optimized 5HT _2A binding activity, to reduce the side effects of extrapyramidal tract and improve the effect of negative symptoms of schizophrenia and cognitive improvement.

The compound of the present invention not only has potent D3 receptor agonistic activity, but also has significantly better 5-HT2A inhibitory activity than Cariprazine. It is clinically expected to have good therapeutic effects such as negative symptoms of schizophrenia and can significantly reduce the risk of EPS side effects.

The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:

among them:

L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb (CH ₂ ) _n2 -;

Ring A is selected from aryl or heteroaryl,

Ring B is selected from cycloalkyl or heterocyclic group;

Ring C is selected from cycloalkyl or heterocyclyl;

R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O) (CH ₂ ) _n1 OR _aa , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)R _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)NR _aa R _bb ,- P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ;

R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O) (CH ₂ ) _n1 OR _aa , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)R _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)NR _aa R _bb ,- P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ;

Or, two R ₂ on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group, If necessary, it may be further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, oxy, sulfur Group, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or Unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _cc , -(CH ₂ ) _n1 OR _cc , -(CH ₂ ) _n1 SR _cc , -(CH ₂ ) _n1 C(O)R _cc , -(CH ₂ ) _n1 C(O)OR _cc , -(CH ₂ ) _n1 S(O) _m1 R _cc , -(CH ₂ ) _n1 NR _cc R _dd , -(CH ₂ ) _n1 C(O)NR _cc R _dd , -(CH ₂ ) _n1 C(O)NHR _cc , -(CH ₂ ) _n1 NR _cc C(O ) R _dd and -(CH ₂ ) _n1 NR _cc S(O) _m1 R _dd are substituted by one or more substituents;

R _{3 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , the alkyl group, Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amine, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxyheterocyclyl, thioheterocyclyl, aryl And heteroaryl groups, optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, Pendant oxy, thio, nitro, cyano, hydroxyl, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkane Oxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _cc , -(CH ₂ ) _n1 OR _cc , -(CH ₂ ) _n1 SR _cc , -(CH ₂ ) _n1 C(O)R _cc , -(CH ₂ ) _n1 C(O)OR _cc , -(CH ₂ ) _n1 S(O ) _m1 R _cc , -(CH ₂ ) _n1 NR _cc R _dd , -(CH ₂ ) _n1 C(O)NR _cc R _dd , -(C H ₂ ) _n1 C(O)NHR _cc , -(CH ₂ ) _n1 NR _cc C(O)R _dd and -(CH ₂ ) _n1 NR _cc S(O) _m1 R _dd replace;

R _aa , R _bb , R _cc and R _dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, Nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, pendant oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or Substituted by one or more substituents in unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, thio, nitro, cyano, hydroxyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted hetero One or more substituents in the cyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;

x is 0, 1, 2, 3 or 4;

y is 0, 1, 2, 3 or 4;

z is 0, 1, 2, 3 or 4;

m1 is 0, 1 or 2;

n1 is 0, 1, 2, 3, 4 or 5; and

n2 is 0, 1, 2, 3, 4, or 5.

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (II):

among them:

L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb (CH ₂ ) _n2 -;

Ring A is selected from aryl or heteroaryl;

Ring B is selected from cycloalkyl or heterocyclic group;

R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , the alkyl group, Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amine, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxyheterocyclyl, thioheterocyclyl, aryl And heteroaryl groups, optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, Pendant oxy, thio, nitro, cyano, hydroxyl, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkane Oxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _cc , -(CH ₂ ) _n1 OR _cc , -(CH ₂ ) _n1 SR _cc , -(CH ₂ ) _n1 C(O)R _cc , -(CH ₂ ) _n1 C(O)OR _cc , -(CH ₂ ) _n1 S(O ) _m1 R _cc , -(CH ₂ ) _n1 NR _cc R _dd , -(CH ₂ ) _n1 C(O)NR _cc R _dd ,-(C H ₂ ) _n1 C(O)NHR _cc , -(CH ₂ ) _n1 NR _cc C(O)R _dd and -(CH ₂ ) _n1 NR _cc S(O) _m1 R _dd replace;

R _aa , R _bb , R _cc and R _dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, Nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further selected from deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Substituted amino, pendant oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted Or substituted by one or more substituents in unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;

Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, thio, nitro, cyano, hydroxyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted hetero One or more substituents in a cyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

x is 0, 1, 2, 3 or 4;

y is 0, 1, 2, 3 or 4;

m1 is 0, 1 or 2;

n1 is 0, 1, 2, 3, 4 or 5; and

n2 is 0, 1, 2, 3, 4, or 5.

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (III):

among them:

L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb (CH ₂ ) _n2 -;

Ring A is selected from aryl or heteroaryl;

Ring C is selected from cycloalkyl or heterocyclyl;

R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

R _{3 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ,;

R _aa and R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Group, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, the deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy Group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from hydrogen, halogen, hydroxyl, cyano, pendant oxy, alkyl, haloalkyl And one or more substituents in the alkoxy group;

Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, thio, nitro, cyano, hydroxyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted hetero One or more substituents in a cyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

m is 0, 1, 2, 3 or 4;

x is 0, 1, 2, 3 or 4;

y is 0, 1, 2, 3 or 4;

z is 0, 1, 2, 3 or 4;

m1 is 0, 1 or 2;

n1 is 0, 1, 2, 3, 4 or 5; and

n2 is 0, 1, 2, 3, 4, or 5.

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (IV):

among them:

R _{5 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

Or, two R ₅ on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group, If necessary, further selected from deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amine, pendant oxy, thio, nitro, cyano, hydroxyl, ester, alkenyl, alkynyl, alkoxy Substituted by one or more substituents in the group, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl and heteroaryl;

t is 0, 1, 2 or 3;

L, ring B, ring C, R ₂ , R ₃ , y and z are as described in general formula (I).

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in general formula (V):

among them:

M is selected from -NR _aa -or -CR _aa R _bb -;

R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ;

n is 0, 1, 2 or 3;

Ring A, ring B, R ₁ , R ₂ , _Raa , R _bb , x and y are as described in the general formula (I).

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (VI):

among them:

L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb -;

R ₂ , R ₃ , m, y, and z are as described in general formula (V).

。 The present invention also provides a preferred solution. The compound, its stereoisomers or pharmaceutically acceptable salts thereof, ring C is

.

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (VII):

among them:

R _{6 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

p is 0, 1, 2, 3, 4 or 5;

Ring B, R ₂ , R ₅ , y and t are as described in general formula (IV).

M, R ₄ and n are as described in general formula (V).

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (VIII):

among them:

Ring A is selected from aryl or heteroaryl;

R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group;

Or, two R ₂ on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group, If necessary, it is further selected from hydrogen, deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amine, pendant oxy, thio, nitro, cyano, hydroxyl, ester, alkenyl, alkynyl, Substituted by one or more substituents in alkoxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl or heteroaryl;

R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ,;

R _aa and R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Group, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, the deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy , Amine, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, if necessary, further selected from hydrogen atom, halogen, hydroxyl, cyano, pendant oxy, alkyl, haloalkyl And one or more substituents in the alkoxy group;

Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, thio, nitro, cyano, hydroxyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted hetero One or more substituents in the cyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;

m is 0, 1, 2, 3 or 4;

x is 0, 1, 2, 3 or 4;

y is 0, 1, 2, 3 or 4;

m1 is 0, 1 or 2; and

n1 is 0, 1, 2, 3, 4, or 5.

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomers or pharmaceutically acceptable salts thereof is as shown in the general formula (VIII-A) and the general formula (VIII-B):

among them:

Ring A, R ₁ , R ₄ , m and x are as described in general formula (VIII).

The present invention also provides a preferred solution. The compound, its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (VIII-C) and general formula (VIII-D):

among them:

Ring A, R ₁ , R ₂ , R ₄ , m, x and y are as described in general formula (VIII).

The present invention also provides a preferred solution, the compound of general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

Ring A is selected from C _6-14 aryl or 5-14 membered heteroaryl, preferably phenyl or benzo 5-6 membered heteroaryl containing 1-2 N, S or O, more preferably phenyl, Benzothienyl, benzisoxazolyl or benzisothiazolyl;

R _{1 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen , Amine, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5 -14 heteroaryl, preferably hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl.

The present invention also provides a preferred solution, the compound of general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

選自如下基團： The present invention also provides a preferred solution. The compound of general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the

Selected from the following groups:

The present invention also provides a preferred solution. The compound of general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R _{2 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C _2-6 Alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5-14 heteroaryl,

Preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C ₁₃ alkoxy, C _1-3 haloalkoxy, halogen, amino, Nitro, hydroxy, cyano, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 5-6 heterocyclic group, C _6-14 aryl or 5-6 heteroaryl base.

The present invention also provides a preferred solution. The compound of general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R _{4 is} selected from -NHR _bb , -NHC(O)(CH ₂ ) _n1 R _bb , -NHC(O)NR _aa (CH ₂ ) _n1 R _bb or -NHS(O) ₂ R _bb ;

The R _aa and R _bb are each independently selected from hydrogen, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group, wherein the amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-14 aryl and 5-14 membered heteroaryl, optionally further selected from halogen, hydroxy, cyano, oxy, C _1-6 alkane Group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group Substituted by one or more substituents,

Preferably, the R _aa and R _bb are each independently selected from hydrogen, amino, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkane Group, 3-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group, wherein the amino group, C _1-3 alkyl group, C _1-3 haloalkyl group, C _1-3 alkoxy group, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, optionally further selected from halogen, hydroxy, cyano, oxy, C _1-3 alkyl, C _{1 -3} haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group substituted by one or more substituents ,

Alternatively, R _aa and R _{bb are} linked to form a 5-6 membered heterocyclic group or heteroaryl group, and the heterocyclic group or heteroaryl group may be further selected from halogen, hydroxyl, cyano, oxy, C _{1-3 if necessary} One or more of alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl Substituted by a substituent;

Wherein, the heterocyclic group or heteroaryl group contains 1-2 identical or different nitrogen, oxygen or sulfur atoms;

n1 is 0, 1, 2, or 3.

The present invention also provides a preferred solution. The compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and the specific structure of the compound represented by the general formula (IX), its stereo Isomer or its pharmaceutically acceptable salt:

among them:

R ₅ and t are as described in general formula (IV);

Ring B, R ₂ , R ₄ and y are as described in general formula (V).

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomer or its pharmaceutically acceptable salt is as shown in the general formula (IX-A):

among them:

R _{2 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen , Amine, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5 -14 heteroaryl, preferably hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl;

、

、

或

R _{4 is} selected from 5-6 membered N-containing heterocyclic groups,

,

,

or

R _{aa is} selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-12 aryl or 5 -12 heteroaryl;

R _{bb is} selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl or 5-12 heteroaryl, the amino group, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-12 aryl and 5-12 hetero Aryl group, if necessary, is further substituted by hydrogen, deuterium, halogen, amine, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl Group or 5-12 heteroaryl group, the C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl and 5-12 heteroaryl one or more Substituted by a substituent;

R _{5 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen , Amine, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5 -14 heteroaryl;

Or, two R ₅ on the same carbon atom or different carbon atoms are linked to form a C _3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C _6-14 aryl group or a 5-14 heteroaryl group. C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl and 5-14 heteroaryl, optionally further selected from hydrogen, deuterium, C _1-6 alkyl, C _{1- 6} Deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C _2-6 alkenyl , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-12 aryl and 5-12 heteroaryl substituted by one or more substituents;

r is 0, 1 or 2;

m is 1, 2 or 3;

y is 0, 1, 2 or 3; preferably 0 or 1; and

t is 0, 1, 2, or 3.

、 The present invention also provides a preferred solution. The compound of general formula (IX-A), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R _{4 is} selected from oxazolidinone,

,

R _{aa is} selected from hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl;

R _{bb is} selected from hydrogen, amino, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, C _{6 -10} aryl or 5-10 heteroaryl, the amino group, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-6 Membered heterocyclic group, C _6-10 aryl group and 5-10 heteroaryl group, optionally further selected from hydrogen, halogen, hydroxyl, cyano, C _1-3 alkyl or C _1-3 alkoxy Substituted by one or more substituents; and

r is 0, 1, or 2.

The present invention also provides a preferred solution. The compound of general formula (IX-A), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

R _{5 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen , Amine, nitro, hydroxy, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl or 5 -12 heteroaryl, preferably hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl;

Alternatively, any two adjacent R _{5 are} linked to form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, preferably a 5-6 membered heteroaryl group containing 1-2 N, S or O, More preferably, thienyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl.

The present invention also provides a preferred solution. The compound, its stereoisomers or pharmaceutically acceptable salts thereof, the general formula (IX-A) is further represented by (IX-B) and (IX-C):

The present invention also provides a preferred solution. The specific structure of the compound, its stereoisomer or its pharmaceutically acceptable salt is shown in general formula (X) and general formula (X-A):

among them:

R ₄ and m are as described in the general formula (VIII).

R ₅ and t are as described in general formula (IX).

The present invention also provides a preferred solution, any one of the compounds represented by the general formulae, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: ring A is selected from the following groups:

Ring B is selected from the following groups:

Ring C is selected from the following groups:

The present invention also provides a preferred solution, the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt,

R _{1 is} selected from hydrogen, cyano, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-6 cycloalkyl;

R _{2 is} selected from hydrogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl;

Or, two R ₂ on the same carbon atom or different carbon atoms are linked to form a C _3-8 cycloalkyl group and a 3-8 membered heterocyclic group. The cycloalkyl group and the heterocyclic group may be further selected from deuterium if necessary. , C _1-6 alkyl, halogen, amino, pendant oxy, thio, cyano, hydroxyl, C _3-8 alkoxy, C _3-8 haloalkoxy and C _3-8 hydroxyalkyl Substituted by one or more substituents;

R _{3 is} selected from 3-8 membered heterocyclic groups, -NR _aa R _bb , -C(O)R _aa , -C(O)NR _aa R _bb , -NHC(O)NR _aa R _bb , -NHC(O )NR _aa C(O)R _bb , -S(O) ₂ R _aa , -NR _aa S(O) ₂ R _bb , -NHS(O) _m1 NR _aa R _bb , -S(O)NR _aa R _bb , -S(O) ₂ NR _aa R _bb , -OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -C(O)OR _aa , -(CH ₂ ) _n1 (O=S =NR _aa )R _bb or -NR _aa C(O)R _bb ;

R _{aa is} selected from hydrogen, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _{6 -14} aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 3- 8-membered heterocyclic group, C _6-14 aryl group and 5-14 membered heteroaryl group may be further selected from hydrogen atom, halogen, hydroxyl, cyano, pendant oxy, C _1-6 alkyl, C _{1- 6} substituted by one or more substituents in haloalkyl and C _1-6 alkoxy;

R _{bb is} selected from hydrogen, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _{6 -14} aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 3- 8-membered heterocyclic group, C _6-14 aryl group, and 5-14 membered heteroaryl group, optionally further selected from hydrogen atom, halogen, hydroxyl, cyano, oxy, C _1-6 alkyl, C _1-6 Substituted by one or more substituents in haloalkyl and C _1-6 alkoxy;

Or, R _aa and R _{bb are} linked to form a heterocyclic group, which is optionally further selected from hydrogen, C _1-6 alkyl, halogen, amine, pendant oxy, thio, cyano, hydroxyl, C _3-8 alkoxy, C _3-8 haloalkoxy and C _3-8 hydroxyalkyl are substituted by one or more substituents.

The present invention also provides a preferred solution. Any one of the compounds represented by the general formulae, its stereoisomers or pharmaceutically acceptable salts thereof, is characterized by being selected from the following compounds:

The present invention also relates to a method for preparing a compound represented by general formula (VIII) or its stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

The general formula (VIII-1) reacts with the chlorine, amine, carboxylic acid or sulfonyl chloride represented by the general formula (VIII-2) to obtain the compound represented by the general formula (VIII) or its stereoisomer and its pharmacy Acceptable salt

The present invention also relates to a method for preparing the compound represented by general formula (IX-A) or its stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

The general formula (IX-A-1) is reacted with the general formula (VIII-2) to obtain the compound represented by the general formula (IX-A) or its stereoisomers and pharmaceutically acceptable salts thereof;

、

、

The general formula (VIII-2) is selected from R _bb -Br , R _bb -NH ₂ ,

,

,

The present invention also relates to a method for preparing the compound represented by intermediate (VIII-5) or its stereoisomer and pharmaceutically acceptable salt thereof, which comprises the following steps:

The general formula (VIII-3) is reacted with the general formula (VIII-4) to obtain the compound represented by the general formula (VIII-5) or its stereoisomers and pharmaceutically acceptable salts thereof;

among them:

Pg ₁ is a hydrogen or amino protecting group, selected from allyloxycarbonyl, trifluoroacetoxy, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, and methoxycarbonyl , P-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tertiary butoxycarbonyl, benzyl or p-methoxyphenyl; preferably tertiary butoxycarbonyl;

Pg ₂ is a hydrogen or hydroxyl protecting group, selected from methyl, tertiary butyl, triphenyl, methyl sulfide methyl ether, 2-methoxyethoxy methyl ether, methoxy methyl ether, p-methoxy Benzyl ether, p-pentanyl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzyl, or p-toluenesulfonyl Group; preferably p-toluenesulfonyl;

The definitions of ring A, R ₁ , R ₂ , x and y are as described in general formula (I).

The present invention also relates to a technical solution, a pharmaceutical composition, which includes a compound of general formula (I) shown in any one of the rights to a therapeutically effective dose and a compound of general formula shown in any one, and its stereoisomers or Its pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention also relates to a technical solution. Any one of the compound of the general formula (I) and the compound of the general formula shown in any one, and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition Preparation of G protein-coupled receptor modulators, in particular, application in dopamine D3 receptor modulators and 5-HT2A receptor modulator drugs.

The present invention further relates to a method for preparing the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of inflammatory diseases.

The present invention also relates to a method for treating and/or preventing central nervous system diseases and/or mental diseases or disorders, which comprises administering to a patient a therapeutically effective dose of the compound represented by the general formula (I), its stereoisomer or its pharmacy Above acceptable salt, or a pharmaceutical composition thereof.

The present invention also provides a method of using the compound or pharmaceutical composition of the present invention to treat disease conditions, including but not limited to conditions related to dopamine receptors and 5-HT receptor modulators.

The present invention also relates to a method for treating nervous system diseases and/or mental diseases in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, Solvate, hydrate or derivative.

In some embodiments, the method involves the treatment of conditions such as cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, and heart disease.

In some embodiments, the method involves the treatment and/or prevention of central nervous system diseases and/or mental diseases or disorders, selected from schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, Memory impairment and/or cognitive impairment, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus, depression, autism, Alzheimer's disease, Alzheimer's disease, seizures, neuralgia or detoxification symptoms, severe depression and mania and other diseases.

The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating a mammal including a neurological disease and/or psychiatric disease. The method includes administering to the mammal a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and the scope of patent application have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbons An alkyl group having 1 to 3 carbon atoms is most preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second 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-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 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-methyl Benzylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy, or carboxylate, the The preferred invention is methyl, ethyl, isopropyl, tertiary butyl, haloalkyl, deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means -CH ₂ -, "ethylene" means -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "Butylene" refers to -(CH ₂ ) ₄ -, etc. The term "alkenyl" refers to an alkyl group as defined above composed 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 may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxy, 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. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, and more preferably ring Propyl, cyclobutyl or cyclohexyl.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings with 5 to 20 members, which may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. For example, the number of spiro atoms shared between the ring and the ring divides the spirocycloalkyl into a single spirocycloalkyl, a dispirocycloalkyl or a polyspirocycloalkyl, preferably a single spirocycloalkyl and Bispirocycloalkyl. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

It also contains a spirocycloalkyl group in which a single spirocycloalkyl group and a heterocycloalkyl group share a spiro atom. Non-limiting examples include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. For example, the number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 4 members/4 members, 5 members/5 members or 5 members/6 members Member bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-member, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 members, and more preferably 7 to 100 members. For example, the number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is 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) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS- , The remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, oxetanyl, pyrrolidinyl, oxazolidin-2-onyl, azepyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophene Dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl or pyranyl, etc.; Preferably oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, oxazolidin-2-onyl, morpholinyl, piperazinyl or azepanyl; more preferably oxygen heterocycle Butyl, pyrrolidinyl, piperidinyl, piperazinyl, azetyl or oxazolidin-2-onyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups by single bonds, or Any two or more atoms on the ring are further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings with 3 to 20 members, in which one or more ring atoms are nitrogen, oxygen, boron, phosphorus, and 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) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. For example, the number of spiro atoms shared between the ring and the ring divides the spiro heterocyclic group into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 3 members/5 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiro heterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. 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 bond, but none of the rings have a fully conjugated π-electron system, where 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 rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. For example, the number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3 members/5 members, 4 members/5 members or 5 members/6 Member bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

或

等。

or

Wait.

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. For example, the number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, Heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy, or carboxylate.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

和

等。

with

Wait.

Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazole Pyridyl, pyridyl, pyrimidinyl, thiadiazole, isoxazole, oxadiazole or pyrazinyl, etc., preferably pyridyl, oxazolyl, isoxazole, oxadiazole, tetrazole, triazole , Thienyl, imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyridyl, thienyl, oxazolyl, isoxazolyl, indolyl, furan Pyranyl 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, non-limiting examples of which include:

Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate 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, cyclopentyloxy, or cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

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

"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

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

"Alkynyl" refers to (CH≡C-), where the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen , Mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl Or carboxylate group.

"Hydroxy" refers to the -OH group.

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

"Amino" refers to -NH ₂ .

"Cyano" refers to -CN.

"Nitro" refers to -NO ₂ .

"Carboxy" refers to -C(O)OH.

"THF" means tetrahydrofuran.

"EtOAc" means ethyl acetate.

"MeOH" means methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" means Otoharu.

"DMA" refers to N,N-dimethylacetamide.

"Et ₂ O" means diethyl ether.

"DCE" means 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(dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"N-BuLi" refers to n-butyl lithium.

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

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.

In the present invention, the hydrogen atom can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"As needed" or "as needed" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as required" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a 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 too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiological/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the medicinal composition is to promote the administration of the biological body, facilitate the absorption of the active ingredient and exert its biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has due biological activity.

The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

Example

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), the internal standard was four Methyl Silane (TMS).

The liquid mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm~0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.

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

Example 1

3-(6-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1,1-dimethylurea

The first step: (6-spiro[3.3]heptane-2-carboxaldehyde) tertiary butyl carbamate

Add 6-((third-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylic acid (500mg, 1.9mmol) and dry tetrahydrofuran (10mL) to a 50mL three-necked flask in sequence, and dry ice at -78℃ Acetone bath and nitrogen Under air protection, diisobutylaluminum hydride (3.2mL, 3.8mmol, 1.2M toluene solution) was slowly added dropwise. After the reaction solution was stirred at -78°C for 0.5 hours, saturated citric acid aqueous solution was quenched, the reaction solution was slowly raised to room temperature, extracted with dichloromethane (100mL) and washed with saturated brine (30mLx3), and the organic phase was treated with anhydrous sulfuric acid Dry with sodium, filter and spin dry. The crude product (6-spiro[3.3]heptane-2-carbaldehyde) tertiary butyl carbamate (150 mg) was obtained, which was used directly in the next step.

The second step: (6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)aminocarbamate

Add (6-spiro[3.3]heptane-2-carboxaldehyde) tert-butyl aminocarboxylate (100mg, 0.42mmol), 1-(2,3-dichlorophenyl)piperazine ( 96 mg, 0.42 mmol) and 1,2-dichloroethane (15 mL), sodium cyanoborohydride (79 mg, 1.25 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was extracted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3 ]Heptan-2-yl) tertiary butyl carbamate (130 mg, yield: 68%).

MS m/z(ESI): 454.2[M+H] ⁺ .

The third step: 6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride

Add (6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)aminoformic acid to the 25mL eggplant-shaped bottle one by one. Butyl ester (130mg, 0.29mmol) and ethyl acetate (1mL), Add hydrochloric acid ethyl acetate solution (6 mL, 4M) with stirring. After the reaction solution was stirred at room temperature for 0.5 hours, the solvent was removed by rotary evaporation to obtain crude 6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptane -2-amine hydrochloride (100 mg).

MS m/z(ESI): 354.1[M+H] ⁺ .

The fourth step: 3-(6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1,1-di Methylurea

Add 6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride (50mg, 0.11mmol ), triethylamine (65mg, 0.65mmol) and dichloromethane (1.5mL), dimethylaminomethyl chloride (23mg, 0.22mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1, 1-Dimethylurea (12 mg, yield: 26%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.23-7.11 (m, 2H), 7.03-6.90 (m, 1H), 4.38 (br, 1H), 4.24-4.07 (m, 1H), 3.56-3.01 (m, 5H), 3.00-2.42 (m, 13H), 2.42-2.23 (m, 2H), 2.21-2.03 (m, 1H), 1.90-1.71 (m, 4H).

MS m/z(ESI): 425.2[M+H] ⁺ .

Example 2

N-(6-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)pyridine-3-sulfonamide

The first step: N-(6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)pyridine-3-sulfonyl amine

Add 6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride (50mg, 0.11mmol ), triethylamine (65mg, 0.65mmol) and dichloromethane (1.5mL), pyridine-3-sulfonyl chloride (38mg, 0.22mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1, 1-Dimethylurea (13 mg, yield: 24%).

MS m/z(ESI): 495.1[M+H] ⁺ .

Example 3

3-(6-((4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1,1-dimethyl Urea

The first step: tertiary-butyl (6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl) Carbamate

Add (6-spiro[3.3]heptane-2-carboxaldehyde) tertiary butyl aminocarboxylate (100mg, 0.42mmol), 4-(1,2-benzisothiazol-3-yl) in a 50mL eggplant-shaped bottle in sequence )-1-piperazine (92mg, 0.42mmol) and 1,2-dichloroethane (15mL), sodium cyanoborohydride (79mg, 1.25mmol) was added with stirring. reaction After stirring the solution at room temperature for 12 hours, it was extracted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl ) Tert-butyl spiro[3.3]heptan-2-yl)carbamate (151 mg, yield: 82%).

MS m/z(ESI): 443.2[M+H] ⁺ .

The second step: 6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride

Add tert-butyl(6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptane-2 -Yl) carbamate (151 mg, 0.34 mmol) and ethyl acetate (1 mL), and add hydrochloric acid ethyl acetate solution (6 mL, 4M) with stirring. After the reaction solution was stirred at room temperature for 0.5 hours, it was spin-dried to remove the solvent to obtain crude 6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3 ] Heptane-2-amine hydrochloride (120 mg).

MS m/z(ESI): 343.2[M+H] ⁺ .

The third step: 3-(6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1, 1-Dimethylurea

Add 6-((4-(benzo(d)isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride (50mg , 0.11mmol), triethylamine (67mg, 0.66mmol) and dichloromethane (1.5mL), dimethylaminomethyl chloride (24mg, 0.22mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. Crude product Prepared for HPLC separation to obtain 3-(6-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1 , 1-Dimethylurea (16 mg, yield: 35%).

MS m/z(ESI): 414.2[M+H] ⁺ .

Example 4

3-(6-((4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1,1-dimethyl Urea

The first step: (6-((4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)aminocarbamate ester

Add (6-spiro[3.3]heptane-2-carboxaldehyde) tert-butyl aminoformate (100mg, 0.42mmol), 1-(benzo[B]thiophen-4-yl)piper in a 50mL eggplant-shaped flask in sequence Oxazine (91 mg, 0.42 mmol) and 1,2-dichloroethane (15 mL), sodium cyanoborohydride (79 mg, 1.25 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was extracted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (6-((4-(benzo[b]thiophen-4-yl)piperazin-1-yl)methyl) Tertiary butyl spiro[3.3]heptan-2-yl)carbamate (142 mg, yield: 77%).

MS m/z(ESI): 442.2[M+H] ⁺ .

The second step: 6-((4-(benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride

Add (6-((4-(benzo(b)thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)aminocarboxylic acid in a 25mL eggplant-shaped bottle Tertiary butyl ester (142 mg, 0.32 mmol) and ethyl acetate (1 mL), and ethyl acetate solution of hydrochloric acid (6 mL, 4M) was added with stirring. After the reaction solution was stirred at room temperature for 0.5 hours, it was spin-dried to remove the solvent to obtain crude 6-((4-(benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3] Heptane-2-amine hydrochloride (120 mg).

MS m/z(ESI): 342.2[M+H] ⁺ .

The third step: 3-(6-((4-(benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)-1,1 -Dimethylurea

6-((4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptane-2-amine hydrochloride (50mg, 0.11 mmol), triethylamine (67 mg, 0.66 mmol) and dichloromethane (1.5 mL), dimethylaminomethyl chloride (24 mg, 0.22 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(6-((4-(benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)- 1,1-Dimethylurea (9mg, yield: 20%).

MS m/z(ESI): 413.2[M+H] ⁺ .

Example 5

3-(5-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-yl)-1,1-dimethylurea

The first step: 5',5'-Dimethyltetrahydro-1H-spiro[pentene-2,2'-[1,3]dioxane]-5(3H)-one

Add tetrahydropentene-2,5-dione (10g, 72mmol), 2,2-dimethylpropane-1,3-diol (7.5g, 72mmol) and toluene (200mL) into a 250mL eggplant-shaped flask. ), p-toluenesulfonic acid monohydrate (688mg, 3.6mmol) was added. The reaction liquid was added to reflux, the water trap was removed, and the reaction was carried out for 5 hours. The reaction solution was cooled, washed with saturated sodium bicarbonate aqueous solution (50 mL×3), and the organic phase was dried and spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 6/1) and purified to obtain 5',5'-dimethyltetrahydro-1H-spiro[pentene-2,2'-[1, 3] Dioxane]-5(3H)-one (5.3 g, yield: 32%).

1H NMR(400MHz,CDCl ₃ ) δ : 3.50(s, 2H), 3.45(s, 2H), 2.80(m, 2H), 2.44(m, 2H), 2.27(m, 2H), 2.15(m, 2H) ), 1.80 (m, 2H), 0.96 (s, 6H).

The second step: 5',5'-dimethyl-5-methylenehexahydro-1H-spiro[pentene-2,2'-[1,3]dioxane]

Add methyltriphenylphosphonium bromide (8.4g, 23.6mmol) and toluene (150mL) in a 250mL three-necked flask, and add sodium hydrogen (898mg, 22.5mmol, 60%w/w) under the protection of nitrogen at 0℃ . The reaction solution was stirred at room temperature for 2 hours under the protection of nitrogen, and then 5',5'-dimethyltetrahydro-1H-spiro[pentadene-2,2'-[1,3]dioxane] was added. -5(3H)-ketone (5.3 g, 23.6 mmol). The reaction solution was heated to 110°C, reacted for 12 hours, and then cooled to room temperature. The reaction solution was concentrated, washed with saturated sodium bicarbonate aqueous solution (50mLx3), saturated brine (30mLx3), and the organic phase was dried over anhydrous sodium sulfate and filtered. Spin dry. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 9/1) and purified to obtain 5',5'-dimethyl-5-methylenehexahydro-1H-spiro[pentene-2, 2'-[1,3]dioxane] (4.5g, yield: 86%).

The third step: (5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[1,3]dioxane]-5-yl)methanol

Add 5',5'-dimethyl-5-methylenehexahydro-1H-spiro[pentene-2,2'-[1,3]dioxane] (4.5g, 20.2mmol) and tetrahydrofuran (50mL), add borane (20mL, 20.2mmol, 1M tetrahydrofuran solution) under the protection of nitrogen at 0°C. The reaction solution was stirred at room temperature for 2 hours under the protection of nitrogen, and then sodium hydroxide aqueous solution (10mL, 20.2mmol, 2M aqueous solution) and hydrogen peroxide (20mL, 30% aqueous solution) were slowly added, and then the reaction solution was stirred at room temperature for 0.5 hours. Wash with saturated sodium bicarbonate aqueous solution (50 mL×3), saturated brine (30 mL×3), and extract with ethyl acetate (30 mL×3). The organic phase is dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 3/1) and purified to obtain a racemic mixture (5',5'-dimethylhexahydro-1H-spiro[pentene-2,2' -[1,3]dioxane]-5-yl)methanol (2.7 g, yield: 56%).

The fourth step: (5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[1,3]dioxane]-5-yl)methyl 4-methyl Besylate

Add the racemic mixture (5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[1,3]dioxane]-5-yl) to a 100mL eggplant-shaped bottle in sequence Methanol (2.7g, 11.2mmol), triethylamine (3.4g, 33.7mmol) and dichloromethane (100mL), 4-toluenesulfonyl chloride (2.36g, 12.4mmol) was slowly added. The reaction solution was stirred overnight at room temperature, the reaction solution was added with dichloromethane (20 mL), washed with water (30 mL×3), the organic phase was dried, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 5/1) and purified to obtain (5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[1 ,3]Dioxane]-5-yl)methyl 4-methylbenzenesulfonate (3.6g, yield: 81%).

MS m/z(ESI): 395.2[M+H]+.

The fifth step: 1-(2,3-dichlorophenyl)-4-((5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[1,3 ]Dioxane)-5-yl)methyl)piperazine

Add (5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[1,3]dioxane]-5-yl)methyl 4 -Methylbenzenesulfonate (1.0g, 2.5mmol), potassium carbonate (1.05g, 7.6mmol) and acetonitrile (30mL), slowly add 1-(2,3-dichlorophenyl)piperazine (0.59g, 2.5mmol). The reaction solution was added to reflux overnight. The reaction solution was cooled, dichloromethane (50 mL) was added, washed with water (30 mL×3), the organic phase was dried and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain 1-(2,3-dichlorophenyl)-4-((5',5'-dimethylhexahydro- 1H-Spiro[pentene-2,2'-[1,3]dioxane]-5-yl)methyl)piperazine (630 mg, yield: 55%).

MS m/z(ESI): 453.2[M+H] ⁺ .

The sixth step: 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)hexahydropentene-2(1H)-one

Add 1-(2,3-dichlorophenyl)-4-((5',5'-dimethylhexahydro-1H-spiro[pentene-2,2'-[ 1,3]Dioxane]-5-yl)methyl)piperazine (630 mg, 1.39 mmol) and tetrahydrofuran (20 mL), and aqueous hydrochloric acid (10 mL, 2M) was added at 0°C. After the reaction solution was stirred at room temperature for 12 hours, it was diluted with ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×3), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)hexahydropentene-2(1H)-one (450mg) was obtained, and the crude product was directly used in the next step .

MS m/z(ESI): 367.1[M+H] ⁺ .

The seventh step: 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-ol

Add 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)hexahydropentene-2(1H)-one (450mg, 1.23mmol ) And methanol (20 mL), sodium borohydride (93 mg, 2.45 mmol) was slowly added at 0°C. After the reaction solution was stirred at room temperature for 2 hours, the solvent was spin-dried, ethyl acetate (30 mL) was added, and the organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 40/1) and purified to obtain 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentane Telen-2-ol (310 mg, yield: 69%).

MS m/z(ESI): 369.1[M+H] ⁺ .

The eighth step: 2-(5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-yl)isoindoline-1 ,3-diketone

Add 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-ol (310mg, 0.84mmol) and o-benzene to a 50mL three-necked flask. Dimethylimidine (185mg, 1.26), triphenylphosphine (330mg, 1.26mmol) and anhydrous tetrahydrofuran (15mL), at 0°C and under nitrogen protection, slowly add diisopropyl azodicarboxylate (255mg, 1.26 mmol). After the reaction solution was reacted at room temperature for 15 hours, the reaction solution was concentrated, dissolved in dichloromethane (100 mL) and washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) Purified to obtain 2-(5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-yl)isoindoline -1,3-dione (240 mg, yield: 57%).

MS m/z(ESI): 498.2[M+H] ⁺ .

Step 9: 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-amine

Add 2-(5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-yl)isoindoline into a 50mL eggplant-shaped bottle in sequence Dole-1,3-dione (240 mg, 0.48 mmol) and methanol (20 mL) were slowly added with hydrazine hydrate monohydrate (120 mg, 2.41 mmol) under stirring. After the reaction solution was stirred at 70°C for 2 hours, the solvent was spin-dried, ethyl acetate (30 mL) was added, and the organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 40/1) and purified to obtain 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentane Telen-2-amine (120 mg, yield: 68%).

MS m/z(ESI): 368.2[M+H] ⁺ .

The tenth step: 3-(5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-yl)-1,1-dimethyl Urea

Add 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-amine (50mg, 0.14mmol), triethyl Amine (27 mg, 0.27 mmol) and dichloromethane (2 mL), dimethylaminomethyl chloride (19 mg, 0.19 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(5-((4- (2,3-Dichlorophenyl)piperazin-1-yl)methyl)octahydropentene-2-yl)-1,1-dimethylurea (19mg, yield: 32%)

MS m/z(ESI): 439.2[M+H] ⁺ .

Example 6

5-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)-N,N-dimethylhexahydrocyclopenta[c]pyrrole-2(1H) -Formamide

The first step: 5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

Add ethyltriphenylphosphonium bromide (1.2g, 3.3mmol) and tetrahydrofuran (5mL) to a 100mL single-necked flask in turn. Cool the reaction solution to 0°C. Add potassium tert-butoxide (373mg, 3.3mmol). Stir at room temperature for 1 hour, add 5-carbonylhexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (0.5g, 2.2mmol) in tetrahydrofuran (5mL) to the above In the reaction solution, the reaction solution was reacted at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (15mLx2), washed with saturated brine (10mL), the organic phase was dried with anhydrous sodium sulfate, filtered, spin-dried, and separated by column chromatography (petroleum ether/ Ethyl acetate: 10/1) to obtain 5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (475mg, colorless oil, yield: 95.8% ).

¹ H NMR(400MHz, CDCl ₃ ) δ 4.91-4.86(m,2H), 3.53(dd, J =11.0,7.0Hz,2H), 3.11(dd, J =11.0,3.9Hz,2H), 2.67(s ,2H),2.56(dd, J =16.2,6.0Hz,2H),2.26-2.12(m,2H),1.45(s,9H).

The second step: 5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

(4-Vinylbicyclo[2.2.2]octane-1-yl) tertiary butyl carbamate (1.0g, 4.4mmol) was dissolved in dry tetrahydrofuran (10mL), borane tetrahydrofuran complex was added under ice bath The compound (13.4mL, 1M, 13.4mmol) was added and stirred for 2 hours. After the reaction is complete, sodium hydroxide (3M, 4.5mL) is slowly added dropwise, a large amount of gas is released, and then hydrogen peroxide (30%, 5mL) is slowly added dropwise. The reaction solution is stirred at room temperature for 1 hour. The reaction solution is ethyl acetate Ester extraction (25mLx2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (dichloromethane/methanol: 10/1) to obtain 5-(hydroxymethyl)hexahydrocyclopenta[ c] Pyrrole-2(1H)-tert-butyl carboxylate (1.0 g, colorless oil, yield: 92.5%).

¹ H NMR(400MHz, CDCl ₃ ) δ 3.64(t, J = 7.5Hz, 2H), 1.85-1.76(m, 7H), 1.53-1.47(m, 6H), 1.42(s, 9H), 1.39(s ,2H).

The third step: tertiary butyl 5-methanylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Add tertiary butyl 5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (350mg, 1.6mmol) in a 100mL single-necked flask and dissolve in dimethyl sulfoxide (4mL) ), add 2-iodobenzoic acid (609 mg, 2.2 mmol) at room temperature, and stir for 1 hour. After the reaction, it was diluted with 2 mL of water, extracted with ethyl acetate (15 mL×2), and washed with water and saturated brine (1:1, 10 mL×2). The organic phase Dry with anhydrous sodium sulfate and spin dry to obtain crude 5-methanylhexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (350 mg).

The fourth step: tertiary butyl 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)hexahydrocyclopenta[c]pyrrole-2(1H) -Carboxylate

Add 5-methanylhexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (350mg, 1.5mmol), 1-(2,3-dichlorobenzene) to a 100mL single-mouth bottle Di)piperazine (338 mg, 1.5 mmol) was dissolved in dichloromethane (4 mL), sodium cyanoborohydride (138 mg, 2.2 mmol) was added at room temperature, and the mixture was stirred for 12 hours. After the reaction, it was quenched by adding saturated ammonium chloride solution, and extracted with dichloromethane (15 mL×2). The organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by column chromatography (petroleum ether/ethyl acetate: 1/1) to obtain 5-((4-(2,3-dichlorophenyl)piperazine-1 -Yl)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl carboxylate (410 mg, white solid, yield 61.7%).

MS m/z (ESI): 454.2 [M+H] ⁺ .

Step 5: 5-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)octahydrocyclopenta[c]pyrrole

5-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester ( 410 mg, 0.90 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the addition was stirred for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydrocyclopenta[c]pyrrole trifluoroacetate ( 840mg).

MS m/z (ESI): 354.1 [M+H] ⁺ .

The sixth step: 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H )-Formamide

Same as Example 5, step ten.

MS m/z(ESI): 425.2[M+H] ⁺ .

Example 7

5-((4-(2,3-Dichlorophenyl)piperazin-1-yl)methyl)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)-methan amine

Add 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)octahydrocyclopenta[c]pyrrole trifluoroacetate (100mg, 0.22mmol), triethylamine (111mg, 1.1mmol) and dichloromethane (1.5mL), ethyl isocyanate (31mg, 0.44mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 5-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-ethylhexahydrocyclopenta[c]pyrrole- 2(1H)-Formamide (22mg, white solid, yield: 23.4%)

MS m/z (ESI): 425.2 [M+H] ⁺ .

Example 8

5-((4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)methyl)-N-ethylhexahydrocyclopenta[c]pyrrole-2(1H)- Formamide

The same as in Example 6, Example 7.

MS m/z(ESI): 413.2[M+H] ⁺

Example 9

3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-N-ethylazetidine-1-methamide

The first step: tertiary butyl 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)-2-carbonylethyl)azetidine-1-carboxylate

Add 2-(1-(third-butoxycarbonyl)azetidin-3-yl)acetic acid (500mg, 2.3mmol), 1-(2,3-dichlorophenyl)piperazine ( 536mg, 2.3mmol) was dissolved in dichloroethane (8 mL) was added at room temperature N, N- diisopropylethylamine (767 μ L, 4.7mmol, d = 0.782) and 2- (7-oxidation of benzene Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.3g, 3.5mmol), stirred for 12 hours. After the reaction, it was quenched by adding saturated sodium chloride solution, and extracted with dichloromethane (15 mL×2). The organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by column chromatography (petroleum ether/ethyl acetate: 1/1) to obtain 3-(2-(4-(2,3-dichlorophenyl)piperazine) -1-yl)-2-carbonylethyl) tert-butyl azetidine-1-carboxylate (920 mg, colorless oil, yield 86.4%).

MS m/z(ESI): 428.1[M+H] ⁺

The second step: tertiary butyl 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)azetidine-1-carboxylate

3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-2-carbonylethyl) azetidine-1-carboxylic acid tert-butyl ester (0.92g, 2.2mmol ) Was dissolved in dry tetrahydrofuran (10 mL), borane tetrahydrofuran complex (10.7 mL, 1M, 10.7 mmol) was added under ice bath, and the mixture was stirred at 70°C for 2 hours. After the reaction was completed, methanol was added to quench under ice bath, concentrated under reduced pressure, and separated by column chromatography (petroleum ether/ethyl acetate: 1/1) to obtain 3-(2-(4-(2,3-dichlorobenzene) (Yl)piperazin-1-yl)ethyl)tert-butyl azetidine-1-carboxylate (0.85 g, white solid, yield: 95.5%).

MS m/z(ESI): 414.12[M+H] ⁺ .

The third step: 1-(2-(azetidine-3-yl)ethyl)-4-(2,3-dichlorophenyl)piperazine

Tertiary butyl 3-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) azetidine-1-carboxylate (380mg, 0.97mmol) dissolved in two To methyl chloride (5 mL), trifluoroacetic acid (1 mL) was added at room temperature, and after the addition, the mixture was stirred for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 1-(2-(azetidin-3-yl)ethyl)-4-(2,3-dichlorophenyl)piperazine trifluoroacetate (420 mg).

MS m/z(ESI): 314.1[M+H] ⁺

The fourth step: 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-N-ethylazetidine-1-methanamide

Add 1-(2-(azetidin-3-yl)ethyl)-4-(2,3-dichlorophenyl)piperazine trifluoroacetate (80mg, 0.19mmol) in a 10mL reaction flask, three Ethylamine (98mg, 0.97mmol) and dichloromethane (1.5mL), ethyl isocyanate (27mg, 0.39mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-N-ethylazetidine-1-methanamide ( 15.1mg, yield: 20.1%).

MS m/z(ESI): 385.1[M+H] ⁺ .

¹ H NMR(400MHz, CDCl ₃ ) δ 7.24-7.15(m,2H), 7.03(d, J =7.6Hz,1H), 4.06(t, J =7.9Hz,2H), 3.69-3.52(m,4H) ), 3.43(s, 2H), 3.20(ddd, J = 39.3, 22.0, 9.6Hz, 8H), 2.91(t, J = 9.8Hz, 2H), 2.79-2.71(m, 2H), 2.54(s, 1H), 2.27-2.20 (m, 1H), 1.57 (s, 4H), 1.13 (t, J = 7.2Hz, 3H).

Example 10

3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-N,N-dimethylazetidine-1-carboxamide

Same as Example 5, step ten.

MS m/z(ESI): 385.2[M+H] ⁺ .

Example 11

3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-N-phenylazobutidine-1-carboxamide

The same as in Example 9.

MS m/z(ESI): 433.2[M+H] ⁺ .

Example 12

1-(2,3-Dichlorophenyl)-4-(2-(1-(pyridin-3-ylsulfonyl)azetidin-3-yl)ethyl)piperazine

Same as Example 5, step ten.

MS m/z(ESI): 455.1[M+H] ⁺ .

Example 13

3-(5-(4-(2,3-Dichlorophenyl)piperazin-1-yl)octahydropentene-2-yl)-1,1-dimethylurea

The first step: 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)hexahydropentene-2(1H)-one

Add tetrahydropentene-2,5-dione (750mg, 5.43mmol), 1-(2,3-dichlorophenyl)piperazine (1.25g, 5.43mmol) and 1, in a 100mL eggplant-shaped flask, 2-Dichloroethane (25 mL), sodium cyanoborohydride (682, 10.86 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was extracted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)hexahydropentene-2 (1H)-ketone (700 mg, yield: 36%).

MS m/z(ESI): 353.1[M+H] ⁺ .

Step 2: 5-(4-(2,3-Dichlorophenyl)piperazin-1-yl)octahydropentene-2-ol

Add 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)hexahydropentene-2(1H)-one (700mg, 1.98mmol) and methanol ( 20 mL), sodium borohydride (150 mg, 3.96 mmol) was slowly added at 0°C. After the reaction solution was stirred at room temperature for 2 hours, the solvent was spin-dried, ethyl acetate (30 mL) was added, and the organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 40/1) and purified to obtain 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2 -Alcohol (510 mg, yield: 72%).

MS m/z(ESI): 355.1[M+H] ⁺

The third step: 2-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2-yl)isoindoline-1,3-di ketone

Add 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2-ol (510mg, 1.44mmol) and phthalic acid in a 50mL three-necked flask. Amine (317 mg, 2.15 mmol), triphenylphosphine (565 mg, 2.15 mmol) and anhydrous tetrahydrofuran (25 mL) were slowly added diisopropyl azodicarboxylate (435 mg, 2.15 mmol) at 0°C under nitrogen protection. After the reaction solution was reacted at room temperature for 15 hours, the reaction solution was concentrated, dissolved in dichloromethane (100 mL) and washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain 2-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentane En-2-yl)isoindole-1,3-dione (340 mg, yield: 49%).

MS m/z(ESI): 484.2[M+H] ⁺ .

The fourth step: 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2-amine

Add 2-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2-yl)isoindoline-1 to a 50mL eggplant-shaped bottle in sequence, 3-Diketone (340 mg, 0.70 mmol) and methanol (20 mL), hydrazine hydrate monohydrate (176 mg, 3.51 mmol) was slowly added with stirring. After the reaction solution was stirred at 70°C for 2 hours, the solvent was spin-dried, ethyl acetate (30 mL) was added, and the organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product is separated by column chromatography (dichloro Methane/methanol: 40/1) Purified to obtain 5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2-amine (120mg, yield: 48%) .

MS m/z(ESI): 354.1[M+H] ⁺ .

The fifth step: 3-(5-(4-(2,3-dichlorophenyl)piperazin-1-yl)octahydropentene-2-yl)-1,1-dimethylurea

A 10 mL reaction flask was sequentially added (50 mg, 0.14 mmol), triethylamine (27 mg, 0.27 mmol) and dichloromethane (2 mL), and dimethylaminomethyl chloride (19 mg, 0.19 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain (9mg, yield: 15%)

MS m/z(ESI): 425.2[M+H] ⁺ .

Example 14

1-(trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)- 3-ethylurea

The first step: tertiary-butyl 6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

The 1-bromo-2,3-dichlorobenzene (1.0g, 4.4mmol), 2-Boc-2,6-diazaspiro(3,3) hemioxalate (1.3g, 5.7mmol) , Tris(dibenzylideneacetone)dipalladium (200mg, 0.22mmol), The mixture of (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (150mg, 0.22mmol) and dioxane (20mL) was stirred at 100°C under nitrogen protection 16 After hours, water (50mL) was added to the reaction solution, extracted with ethyl acetate (50mLx3), the combined organic phase was washed with saturated brine (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and passed through a column Chromatography (petroleum ether/ethyl acetate=10:1) was separated and purified to obtain white solid tert-butyl 6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptane Alkyl-2-carboxylate (1g, yield: 67%)

MS m/z(ESI): 343.1[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ ) δ 7.05(t, J =8.1Hz,1H), 6.93(dd, J =7.9,1.2Hz,1H), 6.41(dd, J =8.2,1.1Hz,1H), 4.17(s,4H), 4.10(s,4H), 1.45(s,9H).

The second step: 2-(2,3-Dichlorophenyl)-2,6-diazaspiro[3.3]heptane

6-(2,3-Dichlorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1g, 2.91mmol) was dissolved in anhydrous dichloromethane (12mL ), then add trifluoroacetic acid (3mL) and stir at room temperature for 1 hour, add saturated sodium carbonate solution to the reaction solution to adjust pH=10, extract with ethyl acetate (50mLx3), combine the organic phases with saturated brine (50mL ) Was washed, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptane ( 560mg, crude product)

MS m/z(ESI): 243.1[M+H] ⁺ .

The third step: (trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexylamine Tert-butyl carboxylate

The 2-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptane (400mg, 1.65mmol), 2-(trans-4-((third-butoxy A mixture of carbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate (980mg, 2.5mmol), potassium carbonate (683mg, 4.95mmol) and acetonitrile (10mL) was stirred at 80°C for 16 hours under the protection of nitrogen. Water (50mL) was added to the reaction solution, extracted with ethyl acetate (30mLx3), the combined organic phase was washed with saturated brine (50mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and passed through column chromatography After separation, a white solid (trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]hept-2-yl)ethyl)cyclohexyl was obtained Tertiary butyl carbamate (500 mg, yield: 65%).

MS m/z(ESI): 468.2[M+H] ⁺ .

The fourth step: trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexane -1-amine

The tertiary butyl trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexylamine Tertiary butyl carboxylate (500mg, 1.07mmol) was dissolved in anhydrous dichloromethane (12mL), then trifluoroacetic acid (3mL) was added and stirred at room temperature for 1 hour, and saturated sodium carbonate solution was added to the reaction solution to adjust the pH= 10. Extract with ethyl acetate (20mLx3), the combined organic phases were washed with saturated brine (30mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oily trans- 4-(2 -(6-(2,3-Dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexane-1-amine (400 mg, crude).

MS m/z(ESI): 368.2[M+H] ⁺ .

The fifth step: 1-trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl) ring Hexyl)-3-ethylurea

The trans-4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexane-1- Amine (50mg, 0.14mmol) and triethylamine (42mg, 0.42mmol) were dissolved in anhydrous dichloromethane (3mL), then ethylamine isocyanate (20mg, 0.28mmol) was added dropwise and stirred at room temperature for 1 hour. Water (20mL) was added to the mixture, extracted with ethyl acetate (20mLx3), the combined organic phase was washed with saturated brine (30mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by preparative chromatography to obtain a white solid 1-( trans- 4-(2-(6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)- 3-Ethylurea (13 mg, yield: 21%).

¹ H NMR(400MHz,CDCl ₃ ) δ 7.04(t, J =8.1Hz,1H), 6.92(d, J =7.9Hz,1H), 6.40(d, J =8.2Hz,1H), 4.17(s, 4H),4.08(d, J =8.0Hz,1H)3.51(m,4H),3.22-3.17(m,2H),2.57(s,2H),2.02-1.99(m,2H),1.75-1.73( m, 2H), 1.39-1.21 (m, 4H), 1.15-1.03 (m, 6H).

MS m/z(ESI): 439.2[M+H] ⁺ .

Example 15

3-(trans-4-(2-(6-(benzo[b]thiophen-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl )-1,1-Dimethylurea

Same as Example 14, MS m/z(ESI): 427.2.[M+H] ⁺ .

Example 16

1,1-Dimethyl-3-(trans-4-(2-(6-(thieno[3,2-c]pyridin-4-yl)-2,6-diazaspiro[3.3] Heptan-2-yl)ethyl)cyclohexyl)urea

Same as Example 14, MS m/z(ESI): 428.2.[M+H] ⁺ .

Example 17

3-(trans-4-(2-(6-(benzo[d]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl) ring Hexyl)-1,1-dimethylurea

Same as Example 14, MS m/z(ESI): 428.2.[M+H] ⁺ .

Example 18

3-(trans-4-(2-(7-(2,3-dichlorophenyl)-2,7-diazaspiro[4.4]nonane-2-yl)ethyl)cyclohexyl)- 1,1-dimethylurea

Same as Example 14, MS m/z(ESI): 467.2[M+H] ⁺ .

Example 19

3-(trans-4-(2-(2-(2,3-dichlorophenyl)-2,6-diazaspiro[3.4]octane-6-yl)ethyl)cyclohexyl)- 1,1-dimethylurea

Same as Example 14, MS m/z(ESI): 453.2[M+H] ⁺ .

Example 20

3-(trans-4-((6-(2,3-dichlorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexyl)-1, 1-Dimethylurea

Same as Example 14, MS m/z(ESI): 425.2[M+H] ⁺ .

Example 36

(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -Sulfanone

The first step: preparation of 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl methanesulfonate.

In a 100 mL round bottom flask, 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexane-1-ol (1g, 2.8mmol) was dissolved in two Triethylamine (560 mg, 5.6 mmol) and methyl sulfonate chloride (320 mg, 2.8 mmol) were added to methyl chloride (10 mL). The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, and the reaction was quenched with water. The organic phase was washed with water and saturated brine, and dried with anhydrous sodium sulfate. Filter, spin dry, and separate the crude product by column chromatography (petroleum ether/ethyl acetate=2/1 rinse) to obtain 4-(2-(4-(2,3-dichlorophenyl)piperazine-1- (Yl)ethyl)cyclohexyl methanesulfonate (800 mg, yield: 65.6%).

MS m/z(ESI): 435.1[M+H] ⁺ .

Step 2: Preparation of 1-(2,3-dichlorophenyl)-4-(2-(4-(methylthio)cyclohexyl)ethyl)piperazine

In a 100mL round bottom flask, 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl methanesulfonate (800mg, 1.8mmol) was dissolved in N, Sodium potassium mercaptan (126 mg, 1.8 mmol) was added to N-dimethylformamide (10 mL) and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried with anhydrous sodium sulfate. Filter, spin dry, and separate the crude product by column chromatography (petroleum ether/ethyl acetate=1/1 rinse) to obtain 1-(2,3-dichlorophenyl)-4-(2-(4-(formaldehyde) Sulfo)cyclohexyl)ethyl)piperazine (600 mg, yield: 84.2%).

MS m/z(ESI): 387.1[M+H] ⁺ .

The third step: (4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -sulfur Preparation of alkanone

1-(2,3-Dichlorophenyl)-4-(2-(4-(methylthio)cyclohexyl)ethyl)piperazine is first treated with m-chloroperoxybenzoic acid and then treated with amino formic acid Treated with ammonium and iodobenzene diacetate to obtain the product (4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl) -λ ⁶ -sulfanone.

MS m/z(ESI): 418.1[M+H] ⁺ .

Example 37

(4-(2-(4-(2,3-Dichlorophenyl)-1,4-diazoheptan-1-yl)ethyl)cyclohexyl)(imino)(methyl)- λ ⁶ -Sulfanone

Take 1-(2,3-dichlorophenyl)-4-(2-(4-(methylthio)cyclohexyl)ethyl)-1,4-diazoheptyl ring as raw material to obtain with reference to Example 36 Product (4-(2-(4-(2,3-dichlorophenyl)-1,4-diazoheptan-1-yl)ethyl)cyclohexyl)(imino)(methyl) -λ ⁶ -sulfanone.

MS m/z(ESI): 432.1[M+H] ⁺ .

Example 38

4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -Sulfanone

With 1-(benzo[b]thiophen-4-yl)-4-(2-(4-(methylthio)cyclohexyl)ethyl)piperazine as raw material, refer to Example 36 to obtain the product 4-(2- (4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -sulfanone.

MS m/z(ESI): 406.1[M+H] ⁺ .

Example 39

4-(2-(4-(6-Fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -Sulfanone

Using 6-fluoro-3-(4-(2-(4-(methylthio)cyclohexyl)ethyl)piperazin-1-yl)benzo[d]isothiazole as raw material, refer to Example 36 to obtain product 4 -(2-(4-(6-Fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -sulfur Alkanone.

MS m/z(ESI): 409.2[M+H] ⁺ .

Example 40

(4-(2-(4-(Benzo(d)isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -Sulfanone

With 3-(4-(2-(4-(methylthio)cyclohexyl)ethyl)piperazin-1-yl)benzo[d]isothiazole as raw material, refer to Example 36 to obtain the product (4-(2 -(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(methyl)-λ ⁶ -sulfanone.

MS m/z(ESI): 407.2[M+H] ⁺ .

Example 41

(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(pyridin-3-yl)-λ ⁶ -Sulfanone

With 1-(2,3-dichlorophenyl)-4-(2-(4-(pyridin-3-ylthio)cyclohexyl)ethyl)piperazine as raw material, refer to Example 36 to obtain the product (4- (2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)(imino)(pyridin-3-yl)-λ ⁶ -sulfanone.

MS m/z(ESI): 481.2[M+H] ⁺ .

Example 42

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

The first step: 1-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)-3-ethylurea

Combine trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexane-1-amine (60mg, 0.162mmol) and triethylamine ( 50mg, 0.49mmol) was added to DCM (3mL), then CDI (29mg, 0.178mmol) was added and stirred at room temperature for 1 hour, then ethylamine hydrochloride (27mg, 0.324mmol) was added and stirred at room temperature for 16 hours. Water (20mL) was added to the solution, extracted with ethyl acetate (20mLx3), the combined organic phases were washed with saturated brine (30mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by preparative chromatography to obtain white Solid 1-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)-3-ethylurea (15mg, yield: twenty one%)

¹ H NMR (400MHz, CDCl ₃ ) δ 7.20-7.11 (m, 2H), 6.98 (d, J = 6.7Hz, 1H), 4.23-4.04 (m, 2H), 3.47 (s, 1H), 3.23-3.12 (m, 5H), 2.79 (s, 4H), 2.01 (s, 2H), 1.80-1.78 (m, 2H), 1.31-1.28 (m, 4H), 1.15-1.05 (m, 10H).

MS m/z(ESI): 441.2[M+H] ⁺ .

Example 43

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

The first step: (trans-4-(2-(methoxy(methyl)amino)-2-oxyethyl)cyclohexyl) amino acid tertiary butyl ester

Dissolve 2-(trans-4-((third-butoxycarbonyl)amino)cyclohexyl)acetic acid (5g, 19.46mmol) in dichloromethane (50mL), then add triethylamine (4.9g , 48.6mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea (9.6g, 25.29mmol) were stirred at room temperature for 10 minutes, Then add dimethylhydroxylamine hydrochloride (2.28g, 23.35mmol) and stir at room temperature for 16 hours, add water (50mL) to the reaction solution, extract with ethyl acetate (50mLx3), combine the organic phases with saturated brine (30mL) After washing, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and was separated and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain a white solid (trans-4-(2-( Methoxy(methyl)amino)-2-oxyethyl)cyclohexyl)carbamic acid tert-butyl ester (5g, yield: 86%)

¹ H NMR (400MHz, CDCl ₃ ) δ 3.67 (s, 3H), 3.18 (s, 3H), 2.31 (d, J = 6.3 Hz, 2H), 2.01-1.92 (m, 2H), 1.86-1.71 (m ,3H),1.44(s,9H),1.21-0.99(m,4H).

MS m/z(ESI): 301.2[M+H] ⁺ .

The second step: (trans-4-(2-oxopropyl)cyclohexyl) amino acid tertiary butyl ester

((Trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl) tertiary butyl carbamate (2g, 6.67mmol) was dissolved in tetrahydrofuran (20mL), then Add methylmagnesium bromide (7mL, 21mmol, 3M) dropwise at 0 degrees Celsius, then stir at 0 degrees Celsius for 1 hour, quench the reaction solution with saturated ammonium chloride (40mL), extract with ethyl acetate (50mLx3), and combine The organic phase was washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain a white solid ( Tertiary butyl trans-4-(2-oxopropyl)cyclohexyl)carbamate (1g, yield: 59%)

¹ H NMR(400MHz, CDCl ₃ ) δ 4.37(s,1H), 3.35(s,1H), 2.31(d, J =6.4Hz,2H), 2.12(s,3H),1.98(dd, J =12.2 , 2.7Hz, 2H), 1.78-1.68 (m, 3H), 1.44 (s, 9H), 1.21-0.92 (m, 4H).

The third step: (trans-4-(2-hydroxypropyl)cyclohexyl) amino acid tertiary butyl ester

Dissolve (trans-4-(2-oxopropyl)cyclohexyl) aminocarboxylate (530mg, 2.08mmol) in anhydrous methanol (50mL), then add sodium borohydride (164mg, 4.15 mmol) was stirred at room temperature for half an hour, water (50mL) was added to the reaction solution, extracted with ethyl acetate (50mLx3), the combined organic phase was washed with saturated brine (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure gave a white solid (trans-4-(2-hydroxypropyl)cyclohexyl) tertiary butyl ester (500 mg, crude product).

MS m/z(ESI): 258.2[M+H] ⁺ .

The fourth step: 1-(trans-4-((third-butoxycarbonyl)amino)cyclohexyl)propane-2-yl methanesulfonate

(Trans-4-(2-hydroxypropyl)cyclohexyl) amino acid tert-butyl ester (500mg, 1.95mmol) and triethylamine (400mg, 3.9mmol) were dissolved in DCM (10mL), and then Add methanesulfonyl chloride (266mg, 2.33mmol) dropwise at 0 degrees Celsius, then stir at 0 degrees Celsius for 1 hour, add water (40mL) to the reaction solution, extract with ethyl acetate (50mLx3), combine the organic phases with saturated brine (50mL ) Was washed, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and used directly in the next step without purification to obtain a colorless oily substance 1-(trans-4-((third-butoxycarbonyl)) Amino)cyclohexyl)propane-2-yl methanesulfonate (600 mg, crude).

The fifth step: (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)aminocarbamate

Combine 1-(2,3-dichlorophenyl)piperazine (610mg, 1.81mmol) and 1-(trans-4-((third-butoxycarbonyl)amino)cyclohexyl)propane-2- Methanesulfonate (380mg, 1.65mmol) was dissolved in acetonitrile (50mL), then potassium carbonate (683mg, 4.95mmol) was added and stirred at 80 degrees Celsius for 16 hours. Water (30mL) was added to the reaction solution and extracted with ethyl acetate. (30mLx3), the combined organic phase was washed with saturated brine (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate=1/1) , A white solid (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)aminocarboxylate (400mg, product Rate: 47%).

MS m/z(ESI): 470.2[M+H] ⁺ .

The sixth step: trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexane-1-amine

Dissolve (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)aminocarbamate (400mg, 0.85mmol) In dichloromethane (9mL), add trifluoroacetic acid (3mL) and stir at room temperature for 1 hour, add saturated sodium carbonate solution to adjust pH=10, extract with ethyl acetate (50mLx3), combine the organic phases with saturated brine (30mL) was washed, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain trans-4-(2-(4-(2,3-dichlorophenyl)piperazine-1) as a colorless oil -Yl)propyl)cyclohexane-1-amine (200 mg, crude product).

MS m/z(ESI): [M+H] ⁺ .370.2

The seventh step: 3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)-1,1-dimethylurea

Combine trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexane-1-amine (60mg, 0.162mmol) and triethylamine ( 35mg, 0.324mmol) was dissolved in DCM (3mL), then dimethylaminomethyl chloride (35mg, 0.324mmol) was added dropwise, and then stirred at room temperature for 16 hours, water (20mL) was added to the reaction solution, and acetic acid Ethyl extraction (20mLx3), the combined organic phase was washed with saturated brine (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by preparative chromatography to obtain a white solid 3-(trans-4- (2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)-1,1-dimethylurea (15 mg, yield: 21%).

¹ H NMR(400MHz, CDCl ₃ ) δ 7.19-7.09(m,2H), 6.97(dd, J =6.6,2.8Hz,1H), 4.12(d, J =7.6Hz,1H), 3.59(d, J =3.5Hz, 1H), 3.07 (m, 4H), 2.88 (s, 6H), 2.74 (m, 4H), 2.02 (s, 2H), 1.79-1.61 (m, 4H), 1.33-1.04 (m, 8H).

MS m/z(ESI): 441.2[M+H] ⁺ .

Example 44

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

The first step: 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

Combine trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexane-1-amine (60mg, 0.162mmol) and triethylamine ( 50mg, 0.49mmol) was added to DCM (3mL), then CDI (29mg, 0.178mmol) was added and stirred at room temperature for 1 hour, then benzylamine (36mg, 0.324mmol) was added and stirred at room temperature for 16 hours, and water was added to the reaction solution (20mL), extracted with ethyl acetate (20mLx3), the combined organic phase was washed with saturated brine (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by preparative chromatography to obtain a white solid 1- Benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea (10mg, yield: 12% ).

¹ H NMR(400MHz, CDCl ₃ ) δ 7.36-7.27(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),4.17(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 45

N-((trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)aminomethan)furan-2-methanamide

MS m/z(ESI): [M+H] ⁺ .464.2.

Example 46

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

The first step: tertiary butyl (3-oxocyclobutyl) carbamate

Add 3-oxocyclobutanyl carboxylic acid (1.5g, 13.2mmol), triethylamine (2.0mL, 14.5mmol) and toluene (30mL) into a 100mL eggplant-shaped flask in sequence, at -5℃~0℃ , Slowly add diphenyl azide phosphate (4.0 g, 14.5 mmol). The reaction solution was stirred at 0°C for 16 hours. At 0°C, wash with saturated aqueous sodium bicarbonate solution (30 mL×1), and wash with saturated aqueous sodium chloride solution (30 mL×1), the organic phase was dried over anhydrous sodium sulfate. Then tertiary butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100° C. and stirred for 16 hours. The reaction solution was spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 5/1) and purified to obtain (3-oxocyclobutyl) carbamate (500 mg, yield: 20.5%).

¹ H NMR (400MHz, CDCl ₃ ) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50-3.33 (m, 2H), 3.11-2.97 (m, 2H), 1.46 (s, 9H).

Step 2: Methyl 2-(3-((Third-Butoxycarbonyl)amino)cyclobutylene)acetate

Add (3-oxocyclobutyl) tert-butyl carbamate (450mg, 2.43mmol) and toluene (20mL) in a 50mL eggplant-shaped flask, and slowly add methoxymethylmethylenetriphenylphosphine (1.22g, 3.64mmol). The reaction solution was refluxed for 16 hours under the protection of nitrogen. The reaction solution was cooled and spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 6/1) and purified to obtain methyl 2-(3-((third-butoxycarbonyl)amino)cyclobutylene) acetate (450mg, Yield: 76.8%).

¹ H NMR (400MHz, CDCl ₃ ) δ 5.76-5.66 (m, 1H), 4.80 (br, 1H), 4.24 (s, 1H), 3.69 (s, 3H), 3.63-3.49 (m, 1H), 3.27 -3.10(m,1H), 3.00-2.86(m,1H), 2.82-2.64(m,1H), 1.45(s,9H).

The third step: 2-(3-((3rd-butoxycarbonyl)amino)cyclobutyl)methyl acetate

Add 2-(3-((third-butoxycarbonyl)amino)cyclobutylene)acetate (450mg, 1.9mmol) and methanol (10mL) to a 50mL eggplant-shaped flask in sequence, slowly under nitrogen protection Add palladium on carbon (45ma, 10% palladium, 50% water). The reaction solution was stirred under hydrogen (1atm) for 5 hours, and the reaction The liquid was filtered to remove the solvent and spin-dried to obtain crude methyl 2-(3-((third-butoxycarbonyl)amino)cyclobutyl)acetate (450 mg), which was used directly in the next step.

MS m/z(ESI): 244.2[M+H] ⁺ .

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

Add methyl 2-(3-((third-butoxycarbonyl)amino)cyclobutyl)acetate (450mg, 1.9mmol) and dry tetrahydrofuran (10mL) to a 50mL eggplant-shaped flask in sequence, at 0℃ and nitrogen Under protection, lithium tetrahydroaluminum (210mg, 5.6mmol) was slowly added. After the reaction solution was stirred at 0°C for 2 hours, it was quenched with a saturated sodium bicarbonate aqueous solution, directly added with anhydrous sodium sulfate to dry, and stirred for 15 minutes. The organic phase was filtered and spin-dried to obtain crude tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate (450 mg), which was directly used in the next step.

MS m/z(ESI): 216.2[M+H] ⁺ .

Step 5: 2-(3-((Third-Butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonic acid

Add tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate (450mg, 2.1mmol), triethylamine (634mg, 6.3mmol) and dichloromethane (10mL ), 4-toluenesulfonyl chloride (438mg, 2.3mmol) was slowly added. The reaction solution was stirred at room temperature overnight, the reaction solution was added with dichloromethane (20 mL), washed with water (30 mL×1), the organic phase was dried, and spin-dried to obtain a crude product. The crude product was separated by column chromatography (petroleum ether/ethyl acetate: 5/1) and purified to obtain 4-methylbenzenesulfonic acid 2-(3-((third-butoxycarbonyl)amino)cyclobutyl ) Ethyl ester (710 mg, yield: 84%).

MS m/z(ESI): 370.2[M+H] ⁺ .

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

Add 2-(3-((third-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonic acid (350mg, 0.95mmol), potassium carbonate (392mg, 2.84 mmol) and acetonitrile (10 mL), slowly add 1-(2,3-dichlorophenyl)piperazine (219 mg, 0.95 mmol). The reaction solution was added to reflux overnight. The reaction solution was cooled, dichloromethane (20 mL) was added, washed with water (30 mL×3), the organic phase was dried and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl) Tertiary butyl cyclobutyl)carbamate (310 mg, yield: 76%).

MS m/z(ESI): 428.2[M+H] ⁺ .

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

Add (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)amino acid tert-butyl ester (310mg, 0.72mmol) and ethyl acetate (2mL), add hydrochloric acid ethyl acetate solution (10mL, 4M) at 0°C. After the reaction solution was stirred at room temperature for 1 hour, it was spin-dried to remove the solvent to obtain crude 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane- 1-amine hydrochloride (310mg), the crude product was used directly in the next step.

MS m/z(ESI): 328.1[M+H] ⁺ .

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

Add 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.11mmol) to a 10mL reaction flask successively , Triethylamine (69mg, 0.69mmol) and dichloromethane (2mL), dimethylaminomethyl chloride (18.4mg, 0.17mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a 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-dimethyl Urea (11 mg, yield: 24%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.23-7.10 (m, 2H), 7.08-6.91 (m, 1H), 4.61-3.93 (m, 2H), 3.56-3.02 (m, 4H), 3.03-2.64 ( m, 8H), 2.65-2.31 (m, 3H), 2.31-1.21 (m, 7H).

MS m/z(ESI): 399.2[M+H] ⁺ .

Example 46A

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

The first step: trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (Intermediate 46-1 ) and Cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (Intermediate 46-2 )

The 3-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride was resolved to obtain trans-3-(2- (4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine ( 46-1 ) and cis-3-(2-(4-(2, 3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine ( 46-2 ).

Chiral preparation conditions:

Intermediate 46-1: t _R =1.285min

¹ H NMR (400MHz, Chloroform- d ) δ 7.18-7.12 (m, 2H), 6.99-6.93 (m, 1H), 3.63-3.53 (m, 1H), 3.16-3.02 (m, 4H), 2.74-2.54 (m,4H),2.39-2.30(m,2H),2.26-2.13(m,1H),2.06-1.99(m,2H),1.99-1.93(m,2H),1.91-1.84(m,2H) ,1.72-1.64(m,2H).

MS m/z(ESI): 328.1[M+H] ⁺ .

Intermediate 46-2: t _R =0.882min

¹ H NMR (400MHz, Chloroform- d ) δ 7.18-7.11 (m, 2H), 7.00-6.93 (m, 1H), 3.33-3.22 (m, 1H), 3.13-3.00 (m, 4H), 2.71-2.56 (m,4H),2.51-2.43(m,2H), 2.37-2.30(m,2H),2.07-1.97(m,2H),1.89-1.75(m,1H),1.67-1.58(m,2H) ,1.39-1.28(m,2H).

MS m/z(ESI): 328.1[M+H] ⁺ .

The second step: 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethyl Urea

Using Intermediate 46-1 as the starting material and referring to the reaction conditions in the eighth step of Example 46 to obtain 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazine-1- (Yl)ethyl)cyclobutyl)-1,1-dimethylurea.

¹ H NMR (400MHz, Chloroform- d ) δ 7.23-7.07 (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 46B

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

Using Intermediate 46-2 as the starting material and referring to the reaction conditions in the eighth step of Example 46 to obtain 3-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazine-1- (Yl)ethyl)cyclobutyl)-1,1-dimethylurea.

¹ H NMR (400MHz, Chloroform- d ) δ 7.20-7.12 (m, 2H), 6.97 (dd, J = 6.7, 2.8 Hz, 1H), 4.41 (d, J = 7.5 Hz, 1H), 4.21-4.08 ( m,1H),3.21-3.04(m,4H),2.89(s,6H),2.81-2.59(m,4H),2.53(dd, J =9.6,7.0Hz,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 47

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

Reference Example 44 obtained 1-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylurea in the first step.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.23-7.09 (m, 2H), 7.03-6.90 (m, 1H), 4.98-4.64 (m, 1H), 4.62-4.31 (m, 1H), 4.31-3.99 ( m, 1H), 3.42-3.08 (m, 4H), 3.06-2.65 (m, 7H), 2.63-2.38 (m, 4H), 2.32-1.62 (m, 4H), 1.58-1.37 (m, 1H). MS m/z(ESI): 385.2[M+H] ⁺ .

Example 48

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

The first step: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propanamide

Add 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.11mmol) to a 10mL reaction flask successively , Diisopropylethylamine (88mg, 0.69mmol), and dichloromethane (10mL), add propyl chloride (12.7mg, 0.14mmol) under stirring. After the reaction solution was stirred at room temperature for 12 hours, it was washed with water, the organic phase was dried, and the solvent was removed by rotary drying to obtain a crude product. The crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propanamide (18mg, yield : 41%).

MS m/z(ESI): 384.2[M+H] ⁺ .

Example 49

1-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-ethylurea

The first step: 1-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-ethylurea

Add 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.11mmol) to a 10mL reaction flask successively , Triethylamine (58mg, 0.57mmol) and dichloromethane (2mL), ethyl isocyanate (16mg, 0.23mmol) was added with stirring. After the reaction solution was stirred at room temperature for 1 hour, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 1-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-ethylurea (24mg , Yield: 53%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.21-7.10 (m, 2H), 7.01-6.92 (m, 1H), 4.73 (br, 2H), 4.27-3.91 (m, 1H), 3.26-3.01 (m, 6H), 2.89-2.60 (m, 4H), 2.60-2.31 (m, 3H), 2.30-1.85 (m, 2H), 1.85-1.36 (m, 4H), 1.19-1.04 (m, 3H).

MS m/z(ESI): 399.2[M+H] ⁺ .

Example 50

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

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

¹ H NMR(400MHz, CDCl ₃ ) δ 7.20-7.12(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 51

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)azetidine-1-methamide

The first step: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)azetidine-1-methanamide

Add 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.11mmol) to a 10mL reaction flask successively , Diisopropylethylamine (88mg, 0.68mmol) and dichloromethane (10mL), N,N'-carbonyldiimidazole (28mg, 0.17mmol) was added with stirring. After the reaction solution was stirred at room temperature for 1 hour, cyclobutylamine (9.8 mg, 0.17 mmol) was added, and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was washed with water, the organic phase was dried, and the solvent was removed by rotary drying to obtain a crude product. The crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)azetidine-1-methyl Amine (11 mg, yield: 23%).

MS m/z(ESI): 411.2[M+H] ⁺ .

Example 51 can also be obtained by the following synthesis method:

Add 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (40mg, 0.11mmol), triethylamine ( 88 mg, 0.88 mmol) and N'N-carbonyldiimidazole (27 mg, 0.16 mmol) were dissolved in dichloromethane (2 mL). After the reaction solution was stirred at 30°C for 3 hours, the raw materials disappeared After the reaction was lost, azetidine hydrochloride (21 mg, 0.22 mmol) was added, and the reaction solution was stirred at 30°C for 48 hours. The solvent was spin-dried, and the crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)azetidine- 1-formamide (24mg, yield: 53.2%)

¹ H NMR(400MHz,CDCl3) δ 7.21-7.11(m,2H), 7.01-6.94(m,1H), 4.36(d, J =7.8Hz,1H), 4.16(d, J =7.2Hz,1H) ,4.11(s,1H),3.93(dd, J =10.2,4.8Hz,4H),3.16(s,4H),2.73(s,4H),2.49(dd, J =21.7,14.4Hz,4H), 2.23(dt, J =15.1,7.6Hz,2H), 2.16-2.07(m,1H), 2.05-1.83(m,2H), 1.73(s,2H), 1.46(s,2H).

MS m/z (ESI): 411.1 [M+H] ⁺ .

Example 52

N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3,3-difluoroazetidine-1-methan amine

The operation is the same as in Example 51.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.21-7.09 (m, 2H), 7.03-6.90 (m, 1H), 4.51-4.40 (m, 1H), 4.40-4.02 (m, 5H), 3.31-2.95 ( m, 4H), 2.89-2.59 (m, 4H), 2.59-2.47 (m, 2H), 2.46-2.28 (m, 2H), 2.28-1.84 (m, 2H), 1.83-1.38 (m, 3H). MS m/z(ESI): 447.2[M+H] ⁺ .

Example 53

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

The first step: 1-benzyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea

The reaction flask were added 10mL of 3- (2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclobutane-1-amine hydrochloride (30mg, 69 μ mol ), triethylamine (41mg, 0.41mmol) and dichloromethane (2mL), benzyl isocyanate (18mg, 0.14mmol) was added with stirring. After the reaction solution was stirred at room temperature for 1 hour, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 1-benzyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea ( 16mg, yield: 50%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.40-7.22 (m, 5H), 7.21-7.09 (m, 2H), 7.02-6.89 (m, 1H), 4.75 (br, J=43.0Hz, 2H), 4.44 -4.32 (m, 2H), 4.29-3.97 (m, 1H), 3.30-3.02 (m, 4H), 2.97-2.62 (m, 4H), 2.60-2.35 (m, 3H), 2.30-1.83 (m, 2H), 1.84-1.33 (m, 4H).

MS m/z(ESI): 461.2[M+H] ⁺ .

Example 54

1-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-(2-methoxyphenyl)urea

Combine 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (35mg, 0.10mmol) and triethylamine ( 48 mg, 0.48 mmol) was dissolved in dichloromethane (2 mL). room 1-isocyanato-2-methoxybenzene (28mg, 0.19mmol) was added to the reaction solution at room temperature and stirred for 12 hours, the solvent was spin-dried, and the crude product was separated by preparative HPLC to obtain 1-(3-( 2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-(2-methoxyphenyl)urea (18mg, yield: 39.3%)

¹ H NMR (400MHz, CDCl ₃ ) δ 8.03 (dd, J =7.4, 2.0Hz, 1H), 7.23-7.12 (m, 2H), 7.01-6.90 (m, 3H), 6.85 (dd, J =13.6, 8.1Hz, 2H), 5.03 (s, 1H), 4.40-4.12 (m, 1H), 3.86 (s, 3H), 3.21 (s, 4H), 2.83 (s, 4H), 2.63-2.45 (m, 4H) ), 2.20-2.04 (m, 1H), 1.96 (dd, J = 15.7, 8.0 Hz, 1H), 1.80 (s, 2H), 1.54 (dd, J = 20.3, 8.9 Hz, 2H).

MS m/z(ESI): 477.2[M+H] ⁺ .

Example 55

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

Dissolve 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine (50mg, 0.15mmol) in N,N-dimethyl Methamide (3mL), add 1H-indole-2-carboxylic acid (30mg, 0.18mmol), HATU (86mg, 0.23mmol) and diisopropylethylamine (58mg, 0.45mmol), and react at room temperature Stir overnight. The solvent was spin-dried, and the crude product was separated by a high performance liquid chromatography column 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 56

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)furan-2-carboxamide

The operation is the same as that of Example 48; Example 56 can also be obtained by referring to the synthesis method of Example 55.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.43 (br, J=0.8Hz, 1H), 7.21-7.05 (m, 3H), 7.03-6.89 (m, 1H), 6.63-6.29 (m, 2H), 4.74 -4.25(m,1H),3.31-2.89(m,4H),2.84-2.50(m,6H),2.49-2.33(m,2H),2.33-1.93(m,2H),1.90-1.48(m, 3H).

MS m/z(ESI): 422.1[M+H] ⁺ .

Example 57

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-fluoropyrimidin-2-amine

The first step: N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-fluoropyrimidin-2-amine

Add 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.11mol) to a 10mL reaction flask in sequence , Diisopropylethylamine (88mg, 0.86mmol) and methylpyrrolidone (2mL), add 2-bromo-5-fluoropyrimidine (33mg, 0.17mmol) with stirring. After the reaction solution was stirred at 90°C for 15 hours, a crude product was obtained. The crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-fluoropyrimidine-2- Amine (6 mg, yield: 12%).

¹ H NMR (400MHz, MeOD) δ 8.48 (br, 1H), 8.20 (s, 2H), 7.37-7.20 (m, 2H), 7.20-7.05 (m, 1H), 4.51-4.07 (m, 1H), 3.26-3.11 (m, 4H), 3.12-2.87 (m, 4H), 2.84-2.49 (m, 4H), 2.37-1.53 (m, 5H).

MS m/z(ESI): 424.1[M+H] ⁺ .

Example 58

2-((3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)amino)pyrimidine-5-carbonitrile

The operation is the same as in Example 57.

MS m/z(ESI): 431.1[M+H] ⁺ .

Example 59

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

Operation is the same as in Example 57.

MS m/z(ESI): 398.1[M+H] ⁺ .

Example 60

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

The operation is the same as in Example 57.

MS m/z(ESI): 395.1[M+H] ⁺ .

Example 61

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)benzo(d)oxazole-2-amine

The operation is the same as in Example 57.

MS m/z(ESI): 445.2[M+H] ⁺ .

Example 62

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)methanesulfonamide

Combine 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (40mg, 0.11mmol) and triethylamine ( 55 mg, 0.55 mmol) was dissolved in dichloromethane (2 mL). Methanesulfonyl chloride (25mg, 0.22mmol) was added to the reaction solution at room temperature and stirred at room temperature for 6 hours, the solvent was spin-dried, and the crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2 ,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)methanesulfonamide (27 mg, yield: 60.6%).

¹ H NMR(400MHz, CDCl ₃ ) δ 7.20-7.12(m,2H), 6.97(dd, J =6.9,2.4Hz,1H), 4.69(d, J =7.5Hz,1H), 3.94(ddd, J =107.4,16.1,7.7Hz,1H),3.11(s,4H),2.93(s, 3H),2.72(d, J =27.0Hz,4H), 2.59(ddd, J =16.2,7.4,2.8Hz, 2H), 2.46-2.33 (m, 2H), 2.18 (tt, J = 21.3, 10.6Hz, 2H), 2.04-1.90 (m, 1H), 1.82-1.54 (m, 4H).

MS m/z(ESI): 406.1[M+H] ⁺ .

Example 63

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)dimethylaminosulfonamide

The operation is the same as in Example 46.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.23-7.10 (m, 2H), 7.03-6.88 (m, 1H), 4.35 (br, 1H), 4.07-3.56 (m, 1H), 3.36-3.04 (m, 4H), 3.01-2.63 (m, 10H), 2.62-2.32 (m, 4H), 2.28-2.03 (m, 2H), 2.00-1.05 (m, 3H).

MS m/z(ESI): 435.1[M+H] ⁺ .

Example 64

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

Combine 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (40mg, 0.11mmol) and triethylamine ( 55 mg, 0.55 mmol) was dissolved in dichloromethane (2 mL). Add p-toluenesulfonyl chloride (42mg, 0.22mmol) to the reaction solution at room temperature and stir for 6 hours at room temperature. The solvent was spin-dried, and the crude product was separated by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methyl Benzenesulfonamide (23mg, yield: 43.5%)

¹ H NMR(400MHz, CDCl ₃ ) δ 7.74(dd, J =8.2,2.6Hz,2H), 7.30(d, J =7.9Hz,2H), 7.20-7.09(m,2H), 6.99-6.92(m ,1H),4.82(d, J =7.7Hz,1H),3.77(ddd, J =24.1,15.9,7.7Hz,1H),3.07(s,4H),2.62(s,4H),2.43(s, 3H),2.35-2.23(m,3H),2.17-2.06(m,1H),1.88(ddd, J =33.6,15.6,8.2Hz,2H),1.61(ddd, J =29.4,15.2,7.5Hz, 2H), 1.40(ddd, J =18.8,9.4,2.8Hz,1H).

MS m/z(ESI): 482.1[M+H] ⁺ .

Example 65

N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)pyridine-3-sulfonamide

The operation is the same as in Example 46.

MS m/z(ESI): 469.1[M+H] ⁺ .

Example 66

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

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

Add 2-(3-((third-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (200mg, 0.54mmol) and potassium carbonate (224mg , 1.62mmol) and acetonitrile (10mL), slowly add 1-(benzo[b]thiophen-4-yl)piperazine (118mg, 0.54mmol). The reaction solution was added to reflux overnight. The reaction solution was cooled, dichloromethane (20 mL) was added, washed with water (30 mL×3), the organic phase was dried and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl (Yl)cyclobutane) tertiary butyl carbamate (120 mg, yield: 53%).

MS m/z(ESI): 416.2[M+H] ⁺ .

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

Add tert-butyl(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane)aminomethyl in a 25mL eggplant-shaped flask Ester (120mg, 0.29mmol) and ethyl acetate (1mL), add hydrochloric acid ethyl acetate solution (6mL, 4M) at 0°C. After the reaction solution was stirred at room temperature for 1 hour, it was spin-dried to remove the solvent to obtain crude hydrochloride (110 mg), which was directly used in the next step.

MS m/z(ESI): 316.1[M+H] ⁺ .

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

Add 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.12 mmol), triethylamine (71 mg, 0.70 mmol) and dichloromethane (2 mL), dimethylaminomethyl chloride (19 mg, 0.18 mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-di Methylurea (17 mg, yield: 37%).

MS m/z(ESI): 387.2[M+H] ⁺ .

Example 67

N-(3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)propanamide

The operation is the same as in Example 48.

MS m/z(ESI): 372.2[M+H] ⁺ .

Example 68

N-(3-(2-(4-(benzo(b)thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-3,3-difluoroazetidine-1- Formamide

The operation is the same as in Example 51.

MS m/z(ESI): 435.2[M+H] ⁺ .

Example 69

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

The operation is the same as in Example 48.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.63-7.51 (m, 1H), 7.49-7.36 (m, 3H), 7.34-7.27 (m, 1H), 7.14-7.04 (m, 1H), 6.96-6.84 ( m, 1H), 6.60-6.33 (m, 2H), 4.80-4.28 (m, 1H), 3.46-3.03 (m, 4H), 2.98-2.54 (m, 6H), 2.55-2.37 (m, 2H), 2.37-1.95(m,2H),1.92-1.47(m,3H).

MS m/z(ESI): 410.2[M+H] ⁺ .

Example 70

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

The first step: (3-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane) tertiary butyl carbamate

Add 2-(3-((third-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (200mg, 0.54mmol) and potassium carbonate (224mg , 1.62 mmol) and acetonitrile (10 mL), slowly add 4-(1,2-benzisothiazol-3-yl)-1-piperazine (118 mg, 0.54 mmol). The reaction solution was added to reflux overnight. The reaction solution was cooled, dichloromethane (20mL) was added, and washed with water (30 mLx3), the organic phase was dried and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (3-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl) (Ethyl)cyclobutane) tertiary butyl carbamate (90 mg, yield: 40%).

MS m/z(ESI): 417.2[M+H] ⁺ .

The second step: 3-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride

Add (3-(2-(4-(benzo(d)isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane) tertiary butyl carbamate to a 25mL eggplant-shaped bottle one by one (90mg, 0.21mmol) and ethyl acetate (1mL), add hydrochloric acid ethyl acetate solution (6mL, 4M) at 0°C. After the reaction solution was stirred at room temperature for 1 hour, it was spin-dried to remove the solvent to obtain crude 3-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl) ring Butane-1-amine hydrochloride (80mg), the crude product was used directly in the next step.

MS m/z(ESI): 317.1[M+H] ⁺ .

The third step: 3-(3-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethyl Urea

Add 3-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (50mg, 0.12mmol), triethylamine (71mg, 0.70mmol) and dichloromethane (2mL), dimethylaminomethyl chloride (19mg, 0.18mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3- (3-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (9mg, yield : 20%).

¹ H NMR(400MHz, CDCl ₃ ) δ 7.88(t,J=11.8Hz,1H), 7.82(d,J=8.1Hz,1H), 7.49(dd,J=17.1,9.9Hz,1H), 7.36( t,J=7.6Hz,1H),4.37(br,J=8.7Hz,1H),4.14-3.68(m,1H),3.74-3.44(m,4H),2.94-2.61(m,10H),2.62 -2.49(m,2H), 2.49-2.29(m,2H), 2.28-2.02(m,2H), 2.00-1.44(m,3H).

MS m/z(ESI): 388.2[M+H] ⁺ .

Example 71

1-(3-(2-(4-(benzo(d)isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-ethylurea

The operation is the same as in Example 59.

MS m/z(ESI): 388.2[M+H] ⁺ .

Example 72

3-(3-(2-(4-(6-Fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

The first step: (3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane) tertiary butyl carbamate

Add 2-(3-((third-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (200mg, 0.54mmol) and potassium carbonate (224mg , 1.62 mmol) and acetonitrile (10 mL), slowly add 6-fluoro-3-(piperazin-1-yl)benzo[d]isothiazole (119 mg, 0.54 mmol). The reaction solution was added to reflux overnight. The reaction solution was cooled, dichloromethane (20 mL) was added, washed with water (30 mL×3), the organic phase was dried and spin-dried to obtain a crude product. The crude product was separated by column chromatography (dichloromethane/methanol: 50/1) and purified to obtain (3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazine-1 -Yl)ethyl)cyclobutane) tertiary butyl carbamate (140 mg, yield: 62%).

MS m/z(ESI): 419.2[M+H] ⁺ .

The second step: 3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride

Add (3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane)aminocarboxylic acid in a 25mL eggplant-shaped flask Ester (140mg, 0.33mmol) and ethyl acetate (2mL), add hydrochloric acid ethyl acetate solution (10mL, 4M) at 0°C. After the reaction solution was stirred at room temperature for 1 hour, it was spin-dried to remove the solvent to obtain crude 3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl Yl)cyclobutane-1-amine hydrochloride (130mg), the crude product was used directly in the next step.

MS m/z(ESI): 319.2[M+H] ⁺ .

The third step: 3-(3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1- Dimethylurea

Add 3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride to 10mL reaction flask (50mg, 0.12mmol), triethylamine (71mg, 0.70mmol) and dichloromethane (2mL), dimethylaminomethyl chloride (19mg, 0.18mmol) was added with stirring. After the reaction solution was stirred at room temperature for 12 hours, it was spin-dried to remove the solvent to obtain a crude product. The crude product was separated by preparative HPLC to obtain 3-(3-(2-(4-(6-fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-1 , 1-Dimethylurea (13mg, yield: 28%).

MS m/z(ESI): 390.2[M+H] ⁺ .

Example 73

N-(3-(2-(4-(6-Fluorobenzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-methyl Amide

The operation is the same as in Example 48.

The synthesis of Example 73 can also be obtained by referring to the synthesis method of Example 55.

MS m/z(ESI): 462.2[M+H] ⁺ .

Example 74

3-(3-(2-(4-(2,3-Dichlorophenyl)-1,4-diazoheptan-1-yl)ethyl)cyclobutyl)-1,1-dimethyl Urea

The operation is the same as in Example 46.

¹ H NMR (400MHz, DMSO) δ 10.99 (s, 0.68H), 10.80 (s, 0.27H), 7.31 (d, J = 4.7Hz, 2H), 7.26-7.21 (m, 1H), 3.97-3.86 ( m,2H),3.59-3.49(m,3H),3.43-3.20 (m,5H),3.08-2.97(m,2H),2.76(d, J =3.2Hz,6H),2.31-2.24(m, 2H),2.19-2.04(m,2H),1.95-1.89(m,1H),1.87-1.78(m,2H),1.64-1.57(m,1H).MS m/z(ESI): 413.2[M +H] ⁺ .

MS m/z(ESI): 413.2[M+H] ⁺ .

Example 75

1-Benzyl-3-(6-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)spiro[3.3]heptan-2-yl)urea

The operation is the same as in Example 53.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.37-7.24 (m, 5H), 7.19-7.09 (m, 2H), 6.99-6.90 (m, 1H), 4.43-4.35 (m, 2H), 4.35-4.24 ( m,1H),3.98(s,2H),3.83(s,2H),3.23-2.95(m,4H),2.82-2.58(m,4H),2.58-2.42(m,3H),2.41-2.27( m,2H),2.00-1.75(m,2H).

MS m/z(ESI): 487.2[M+H] ⁺ .

Example 76

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

Combine 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride (33mg, 0.09mmol) and triethylamine ( 46 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL). Add N-ethyl-N-methylaminomethyl chloride (22mg, 0.22mmol) at room temperature. After stirring for 12 hours at room temperature, the solvent was spin-dried. The crude product was separated by preparative HPLC to obtain 3-(3 -(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylurea (11mg, yield: 29.4% ).

¹ H NMR(400MHz, CDCl ₃ ) δ 7.20-7.10(m,2H), 6.97(dd,J=7.0,2.4Hz,1H), 4.41(dq,J=14.4,7.1Hz,1H), 4.16(dd ,J=16.4,8.8Hz,1H),3.35-3.24(m,2H),3.13(s,4H),2.85(d,J=3.7Hz,3H),2.71(s,4H),2.59-2.52( m,1H),2.41(s,2H),2.24-2.09(m,1H),1.95(ddd,J=24.0,16.7,9.0Hz,2H),1.82-1.64(m,2H),1.44(dt, J=11.4,9.3Hz,1H),1.11(t,J=7.1Hz,3H).

MS m/z(ESI): 413.2[M+H] ⁺ .

Example 77

(R)-N-(3-(2-(4-(2,3-Dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2 -Methylpropionamide

The first step: (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 Reference Example 116 The first step to obtain tertiary-butyl (R) -4-(2,3-Dichlorophenyl)-3-methylpiperazine-1-carboxylate (600 mg, yellow solid, yield: 32.6%).

MS m/z(ESI): 345.1[M+H] ⁺ .

¹ H N1MR (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). The second step: (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine

(R)-4-(2,3-Dichlorophenyl)-3-methylpiperazine-1-carboxylic acid third-ester was used as the raw material in Reference Example 116 to obtain (R)-1-( 2,3-Dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%).

MS m/z(ESI): 245.1[M+H] ⁺ .

¹ H NMR (400MHz, Methanol-d4) δ 7.36-7.29 (m, 1H), 7.27-7.16 (m, 2H), 3.60-3.44 (m, 1H), 3.42-3.27 (m, 2H), 3.21-3.13 (m, 2H), 3.02-2.81 (m, 2H), 0.88 (d, J=6.3Hz, 3H).

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

Refer to Example 46 in the sixth and seventh steps to obtain (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl) ring Butane-1-amine (280 mg).

MS m/z(ESI): 342.1[M+H] ⁺ .

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

Reference Example 55 gave (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)- 2-Hydroxy-2-methylpropanamide (18mg).

MS m/z(ESI): 428.1[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.25-7.20 (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).

Example 78

Tertiary-butyl(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-)carbamate

Reference Example 66 The first step to obtain the target compound tertiary-butyl (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane- 1-) Carbamate.

MS m/z(ESI): 416.2[M+H] ⁺ .

¹ H NMR(400MHz, Chloroform- d ) δ 7.63-7.49(m,1H),7.44-7.35(m,2H),7.28-7.21(m,1H),6.95-6.81(m,1H),4.85-4.55 (m,1H),4.30-3.85(m,1H),3.46-3.02(m,4H),2.95-2.58(m,4H),2.59-2.30(m,3H),2.26-1.83(m,3H) , 1.83-1.61 (m, 2H), 1.56-1.31 (m, 10H).

Example 79

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

Using 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, referring to Example 66, 3- (3-(2-(4-(Benzo(b)thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1-cyclopropyl-1-methylurea

MS m/z(ESI): 413.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.60-7.50 (m, 1H), 7.43-7.35 (m, 2H), 7.29-7.21 (m, 1H), 6.94-6.83 (m, 1H), 5.43-5.17 (m,1H),4.50-4.08(m,1H),3.44-3.12(m,4H),2.88(s,3H),2.84-2.65(m,4H),2.61-2.51(m,1H),2.49 -2.39(m,3H),2.28-2.10(m,1H),2.08-1.87(m,2H),1.87-1.65(m,2H),1.53-1.41(m,1H),0.90-0.78(m, 2H), 0.75-0.61 (m, 2H).

Example 80

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

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, refer to Example 66 to obtain N- (3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)dimethylaminosulfonamide.

MS m/z(ESI): 423.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.60-7.50 (m, 1H), 7.45-7.35 (m, 2H), 7.28-7.21 (m, 1H), 6.95-6.83 (m, 1H), 4.59-4.36 (m,1H),4.07-3.59(m,1H),3.32-3.07(m,4H),2.93-2.62(m,10H),2.59-2.47(m,1H),2.47-2.31(m,2H) , 2.28-1.83 (m, 3H), 1.83-1.44 (m, 3H).

Example 81

N-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxy-3-methylazetidine Pyridine-1-carboxamide

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, refer to Example 51 to obtain N- (3-(2-(4-(Benzo(b)thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxy-3-methylazetidine- 1-Formamide.

MS m/z(ESI): 443.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.59-7.53 (m, 1H), 7.45-7.36 (m, 2H), 7.29-7.22 (m, 1H), 6.94-6.85 (m, 1H), 4.46-4.06 (m,2H),3.96-3.83(m,2H),3.74-3.56(m,2H),3.36-3.13(m,7H),2.89-2.60(m,4H),2.59-2.48(m,1H) , 2.48-2.32 (m, 2H), 2.28-1.85 (m, 3H), 1.82-1.34 (m, 6H).

Example 82

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

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, refer to Example 48 to obtain N- (3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide.

MS m/z(ESI): 388.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.62-7.54 (m, 1H), 7.45-7.34 (m, 2H), 7.32-7.28 (m, 1H), 6.97-6.89 (m, 1H), 6.76-6.51 (m,1H),4.63-4.23(m,1H),3.94-3.77(m,2H),3.43(s,3H),3.39-3.21(m,4H),3.10-2.75(m,4H),2.66 -2.46 (m, 3H), 2.38-1.73 (m, 5H), 1.69-1.49 (m, 1H).

Example 83

N-(3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide

Using 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material in Reference Example 55, N- (3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide.

MS m/z(ESI): 411.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.83-7.75 (m, 1H), 7.59-7.51 (m, 1H), 7.45-7.36 (m, 2H), 7.29-7.25 (m, 1H), 7.25-7.08 (m,2H),6.96-6.84(m,1H), 4.74-4.31(m,1H),3.35-3.06(m,4H), 2.89-2.66(m,4H),2.66-2.55(m,1H) , 2.50-2.13 (m, 4H), 2.13-1.92 (m, 1H), 1.90-1.55 (m, 3H).

Example 84

N-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-5-fluoropyrimidin-2-amine

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, refer to Example 57 to obtain N- (3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-5-fluoropyrimidin-2-amine.

MS m/z(ESI): 412.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 8.21-8.10 (m, 2H), 7.63-7.53 (m, 1H), 7.46-7.34 (m, 2H), 7.32-7.27 (m, 1H), 6.97-6.84 (m,1H),5.30-5.09(m,1H),4.52-4.14(m,1H),3.42-3.14(m,4H),2.98-2.71(m,4H),2.70-2.39(m,3H) ,2.37-1.92(m,3H),1.95-1.40(m,3H).

Example 85

N-(3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, refer to Example 48 to obtain N- (3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonamide.

MS m/z(ESI): 420.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.60-7.51 (m, 1H), 7.45-7.35 (m, 2H), 7.29-7.22 (m, 1H), 6.94-6.85 (m, 1H), 4.69-4.50 (m, 1H), 4.18-3.73 (m, 1H), 3.36-3.07 (m, 4H), 2.88-2.65 (m, 4H), 2.64-2.50 (m, 1H), 2.49-2.31 (m, 3H) ,2.30-1.85(m,3H),1.85-1.49(m,3H),1.22-1.11(m,2H),1.04-0.92(m,2H).

Example 86

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

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, Reference Example 57 to obtain N- (3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)pyrimidin-2-amine.

MS m/z(ESI): 394.2[M+H] ⁺ .

¹ H NMR (400MHz, Methanol- d ₄ ) δ 8.35-8.14 (m, 2H), 7.69-7.52 (m, 2H), 7.51-7.40 (m, 1H), 7.38-7.20 (m, 1H), 7.04 6.90 (m, 1H), 6.67-6.50 (m, 1H), 4.55-4.15 (m, 1H), 3.35 (s, 8H), 3.05-2.74 (m, 3H), 2.71-2.13 (m, 3H), 2.13-1.54 (m, 3H).

Example 87

N-(3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-methyl Amide

With 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutane-1-amine hydrochloride as a raw material, refer to Example 51 to obtain N- (3-(2-(4-(Benzo(b)thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-methamide .

MS m/z(ESI): 429.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.55-7.45 (m, 1H), 7.38-7.27 (m, 2H), 7.25-7.21 (m, 1H), 6.91-6.79 (m, 1H), 4.35-4.04 (m,3H),4.04-3.94(m,2H),3.82-3.68(m,2H),3.43-3.10(m,7H),2.96-2.60(m,4H),2.55-2.37(m,3H) ,2.25-1.31(m,6H).

Example 88

(S)-N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxypropanamide

Reference Example 55 gave (S)-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxy Acetamide.

MS m/z(ESI): 414.1[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 7.18-7.11 (m, 2H), 6.99-6.94 (m, 1H), 6.77-6.56 (m, 1H), 4.54-4.17 (m, 1H), 3.75-3.67 (m,1H),3.44-3.35(m,3H), 3.17-3.02(m,4H), 2.69-2.58(m,4H), 2.57-2.52(m,1H), 2.39-2.31(m,2H) ,2.26-1.94(m,3H),1.78-1.71(m,1H),1.68-1.62(m,1H),1.55-1.47(m,1H),1.36(dd, J =6.8,2.4Hz,3H) .

Biological test evaluation

The following further describes the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

1. Radioligand receptor binding experiment

Test Example 1. Determination of the binding ability of the compound of the present invention to dopamine D3 receptor

1. Experiment purpose:

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

2. Experimental instruments and reagents:

2.1 Experimental equipment:

Vortex mixer (IKA; MS3 basic)

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

Micro plate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer; NTX)

Universal Harvester (PerkinElmer; UNIFILTER-96)

2.2 Experimental reagents and consumables:

[ ³ H]-methylspiperone (PerkinElmer; NET856250UC)

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

GR 103691 (Sigma; 162408-66-4)

ULTIMA GOLD (Perkin Elmer; 77-16061)

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 tube (BD, 352096; 352070)

Loading slot(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)

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

3. Experimental method:

Experiment buffer: 50mM Tris-HCl pH 7.4, 10mm MgCl _2. Washing solution: 50mM Tris-HCl pH 7.4, 4℃ storage; 0.5% PEI solution: 0.5g PEI dissolve in 100mL ddH ₂ O, 4℃ storage of spare .

The test compound added 5 μ L assay plates (0.005nM-100nM, a total of 10 concentrations) and 100 μ L buffer - 96 holes. Added to each well and 1 μ L membrane 300 μ L buffer, 600rpm shaking 5min. Each well was added 100 μ L buffer with ^[3 H] -methylspiperone (final concentration of 0.5 nM) to a mixture of the reaction system, 600rpm shaking 5min, 27 ℃ incubated for 30min. Wash the UNIFILTER-96 GF/B filter plate pre-incubated with 0.5% PEI for 1 hour with 1ml/well buffer twice, and add the cell membrane suspension to UNIFILTER-96 GF/B filter plate, and wash 4 times at 55℃ incubated for 10min, added to each well 40 μ L ULTIMA GOLD, for liquid scintillation counting.

4. Experimental data processing method:

Read CPM (Counts per minute) value by TopCount. Such as High control (DMSO control) and Low control (100nM positive compound) experimental group of readings calculated percentage inhibition of [ ³ H]-methylspiperone binding data {% inhibition rate = (CPM _sample -CPM _{low control} )/(CPM _{high control} -CPM _{low control} )×100}. The concentration of the compound is 100 nM to 0.005 nM in 10 concentrations after the reaction system is diluted 3 times. Using GraphPad prism to fit percent inhibition rate and ten-point concentration data to a parameter nonlinear logic formula, the IC ₅₀ value of the compound was calculated.

5. Experimental results:

The binding activity of the compound of the present invention to D3 was determined by the above test, and the measured IC ₅₀ value is shown in Table 1.

6. Experimental conclusion:

The compound of the present invention has good affinity with dopamine receptor D3.

Test Example 2. Determination of the compound of the present invention for binding to 5-HT2A receptor

1. Experiment purpose:

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

2. Experimental instruments and reagents:

2.1 Instrument:

Vortex mixer (IKA; MS3 basic)

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

Micro plate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer; NTX)

Universal Harvester (PerkinElmer; UNIFILTER-96)

2.2 Experimental reagents and consumables:

[ ³ H]-Ketanserin(PerkinElmer NET791)

Human Dopamine 5-HT2A Receptor membrane(PerkinElmer)

ULTIMA GOLD (Perkin Elmer; 77-16061)

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 tube (BD, 352096; 352070)

Loading slot(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)

Calcium chloride (Sigma)

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

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

L-Ascorbic acid(Tianjin Guangfu)

3. Experimental method:

Experimental buffer: 50mM Tris-HCl pH 7.4, 4mM CaCl _2. Washing solution: 50mM Tris-HCl pH 7.4, 4℃ storage; 0.5% PEI solution: 0.5g PEI dissolve in 100mL ddH ₂ O, 4℃ storage of spare

The test compound added 5 μ L assay plates (0.005nM-100nM, a total of 10 concentrations) and 100 μ L buffer - 96 holes. Each well was added 1.5 μ L membrane and 300 μ L buffer. Shake at 600rpm for 5min. Each well was added 100 μ L buffer with ^[3 H] -Ketanserin (final concentration 2nM) mixed solution to the reaction system, 600rpm shaking 5min, 27 ℃ incubated for 30min. Wash the UNIFILTER-96 GF/B filter plate pre-incubated with 0.5% PEI for 1 hour with 1mL/well buffer twice, and add the cell membrane suspension to UNIFILTER-96 GF/B filter plate, and wash 4 times at 55℃ Incubate for 10 min. Each well was added 40 μ L ULTIMA GOLD, for liquid scintillation counting.

4. Experimental data processing method:

Read CPM (Counts per minute) value by TopCount, such as High control (DMSO control) and Low control (100nM positive compound) experimental group. Percent inhibition [ ³ H]-Ketanserin binding data {% inhibition Rate=(CPM _sample -CPM _{low control} )/(CPM _{high control} -CPM _{low control} )×100}, the concentration of the compound is 3 times diluted by the reaction system and the 10 concentrations are 100nM to 0.005nM, using GraphPad prism to fit the percentage inhibition and ten-point concentration data to calculate the linear equation parameters and logic IC ₅₀ values of the compounds.

5. Experimental results:

The binding activity of the compound of the present invention to 5-HT2A was determined by the above test, and the measured IC ₅₀ value is shown in Table 2.

6. Experimental conclusion:

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

2. Cell function experiment

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

1. Experiment purpose:

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

2. Experimental instruments and reagents:

2.1 Instrument:

384-well test plate (Perkin Elmer; 6007680)

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

EnVision (Perkin Elmer).

2.2 Reagents:

Fetal Bovine Serum (Gibco, 10999141)

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

Penicillin-Streptomycin, Liquid (Gibco; 15140122)

G418(invitrogen; 0131-027)

Forskolin (Selleck, S2449)

BSA stabilizer (Perkin Elmer; CR84-100)

cAMP kit(Cisbio; 62AM4PEC)

IBMX (Sigma; I5879)

HEPES(Gibco;15630080)

HBSS (Gibco; 14025076)

TrypLE (ThermoFisher; 12604021).

3. Experimental method:

1. Preparation of Buffer: 1 * HBSS + 20mM HEPES + 0.1% BSA + 500 μ M IBMX.

Complete medium: Ham's F12K + 10% FBS + penicillin-streptomycin, 1 * +400 μ g / mLG418.

2. Cultivate the CHO-D3 cell line in a complete medium at 37°C and 5% CO ₂ ; after TrypLE digestion, resuspend the cells in the experimental buffer and plant them in a 384 cell culture plate with a seeding density of 8000 per well .

3. Prepare test buffer: 1 * HBSS, 0.1% BSA, 20mM HEPES and 500 μ M IBMX; Compound diluted with buffer; μ L of compound 2.5 was added to each well, cultivate 37 ℃ 10 min; forskolin was diluted with the assay buffer To 8 μ M (8*); add 2.5 μ L of diluted 8* forskolin and incubate at 37°C for 30 minutes; freeze-thaw cAMP-d2 and Anti-cAMP-Eu3+, and dilute them 20 times with lysis buffer; add 10 μ L cAMP-d2 to experimental wells, L Anti-cAMP-Eu3 + to the experimental wells was then added 10 μ; the reaction plate, 25 ℃ was allowed to stand at room temperature for 1h after centrifugation 200g 30s, using data collected Envision

Experimental data processing method:

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

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

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

4) S/B=Singal/Background;

5) non-linear fitting using GraphPad compound of formula EC _50:

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

X: compound concentration log value; Y: Activation%

4. Experimental results:

5. Experimental conclusion:

It can be seen from the data in the table that the compounds of the examples shown in the present invention show good agonistic activity in the experiment of stably expressing the D3 receptor on cAMP.

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

1. Experiment purpose:

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

2. Experimental instruments and reagents:

2.1 Instrument:

384-well test plate (Corning; 3712);

FLIPR (Molecular Devices).

2.2 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 method:

1) Buffer preparation: 1 x HBSS, 20mM HEPES, 2.5mM probenecid (probenecid is 400mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were freshly added on the day of the experiment. Experiment buffers include dye buffers and compound dilution buffers.

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) The cell line is cultured in complete medium at 37°C, 5% CO ₂ to 70%-90% confluence. After digestion with TrypLE, seed the 384-well test plate at a density of 1×10 ⁴ cells/well and incubate for 16-24 hours (at least overnight).

4) Freeze and thaw 20X Component A to room temperature, dilute it with experiment buffer to 2X working concentration containing 5mM Probenecid, and keep it at room temperature for later use.

5) Remove the cell culture plate, allowed to stand at room temperature 10min, FBS was diluted to a concentration of 0.03% Apricot using assay buffer and finally left at 20 μ L 3764 culture plate, followed by addition of 20 μ L 2X Component A containing 5mM Probenecid To each experimental well, centrifuge at 200g for 3-5sec at RT, and incubate at 37°C for 2hr.

6) DMSO prepares the positive control compound and the working solution of the test compound (6X).

7) Remove the cell culture plate was left at room temperature for 10 min; 6X experimental wells was added the appropriate compound of the working fluid into 384-well cell culture plate 10 μ L in step 5, incubated at room temperature for 30 minutes.

8) The assay buffer is diluted to 5HT 6nM (6X), transfer 50 μ L to 384-well plates (Corning, 3657), left at room temperature until use. Use FLIPR Tetra to add 10ul diluted 5HT to each experimental well and read the value.

4. Experimental data processing method:

Read the calcium signal value by FLIPR. The calculated output result of each sampling time point in the experiment is the ratio of the wavelength signal of 340/510nm and 380/510nm. The calculation of the maximum minus the minimum is derived from the ratio signal curve. Using GraphPad prism to fit percent inhibition rate and ten-point concentration data to a parameter nonlinear logic formula, the IC ₅₀ value of the compound was calculated.

5. Experimental results:

6. Experimental conclusion:

It can be seen from the data in the table that the compounds of the examples of the present invention show good inhibitory activity in the functional calcium flux test of cells stably expressing 5-HT2A.

3. Determination of pharmacokinetics in Balb/C mice

1. Research purpose:

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

2. Experimental program:

2.1 Experimental drugs:

The example compounds of the present invention are self-made.

2.2 Experimental animals:

There are 12 Balb/C Mouse in each group, male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 Formulation prescription:

0.5% CMC-Na (1% Tween80), dissolve by ultrasonic, prepare as a clear solution or homogeneous suspension.

2.4 Administration:

Balb/C mice were 12 males in each group; they were p.o. after one night fast, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.

2.5 Sample collection:

Before and after the administration, the mice were sacrificed with CO ₂ at 1, 2, 4, 8 and 24 hours, 0.2 mL of blood was collected from the heart, placed in an EDTA-K ₂ test tube, and centrifuged at 4°C at 6000 rpm for 6 min to separate the plasma. Store at -80°C; after the whole brain tissue is taken out and weighed, it is placed in a 2mL centrifuge tube and stored at -80°C.

2.6 Sample processing:

1) 40uL plasma sample was precipitated with 160uL acetonitrile, mixed and centrifuged at 3500×g for 5-20 minutes.

2) 30μL of plasma and brain homogenate samples were added to 90μL of acetonitrile containing internal standard (100ng/mL) to precipitate, mixed and centrifuged at 13000rpm for 8 minutes.

3) Take 70 μL of the supernatant solution after treatment and add 70 μL of water, vortex and mix for 10 minutes, and then take 20 μL for LC/MS/MS analysis of the concentration of the test compound. LC/MS/MS analysis instrument: AB Sciex API 4000 Qtrap.

2.7 Liquid phase analysis:

●Liquid phase conditions: Shimadzu LC-20AD pump

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

●Flow rate: 0.4mL/min

●The extraction time: 0-4.0 minutes, the extraction solution is as follows:

3. Experimental results and analysis:

The main parameters of pharmacokinetics are calculated with WinNonlin 6.1. The results of the mouse drug metabolism experiment are shown in Table 5 below:

4. Experimental conclusion:

From the results of the mouse drug metabolism experiment in the table, it can be seen that the compounds of the examples of the present invention exhibit good metabolic properties, and both the exposure amount AUC and the maximum blood drug concentration C _max perform well.

Fourth, the model of active evasion of experimental drugs in rats

1. Purpose

The anti-schizophrenia effect of the compound was evaluated by using a rat active evasion experimental drug effect model.

2. Laboratory equipment and reagents

2.1 Instrument:

2.2 Reagents:

2.3 Test compound

The example compounds of the present invention are self-made.

3. Experimental animals:

4. Solvent and compound preparation:

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

Weigh a certain mass (such as 1.0g) of CMC-Na into a glass bottle, add a certain volume (such as 200mL) of purified water, stir to make it evenly dispersed, such as adding 1% (v/v) Tween80 to the solution volume, and stir Obtain a clear and uniform clear solution overnight, store it at 2-8°C for later use.

4.2 Compound preparation:

Weigh the prescription amount of the compound into the 0.5% CMC-Na+1% Tween80 solution of the prescription volume, prepare before administration, store at 2-8°C, and use it within 4 days.

The actual sample volume needs to be calculated during compound solution preparation and administration. The conversion formula is as follows: compound actual sample volume=theoretical sample volume*purity/salt coefficient.

5. Experimental operation:

After the animals arrive at the experimental facility, they adapt to the experiment one week later.

5.1 Establishment of the drug effect model:

5.1.1 Put the animal into the shuttle box and start to give sound and light stimulation for 10 seconds after adapting for 5 seconds;

5.1.2 If the animal avoids to the other side under 10 seconds of sound and light stimulation, it will not be shocked, it will be recorded as active avoidance (avoids), and the single training will end;

5.1.3 If the animal does not move to the other side after 10 seconds of sound and light stimulation, give an electric shock with a current intensity of 0.6 mA and a duration of 10 seconds. If the animal escapes to the other side within 10 seconds of the electric shock , The electric shock is stopped, recorded as passive escapes, and the single training ends;

5.1.4 If the animal has not evaded within 10 seconds of the electric shock, the electric shock will stop, recorded as escape failures, and the single training will end;

5.1.5 Each animal is trained 30 times a day. After the training, it is returned to the cage for a total of 6 days of training.

5.2 Baseline test and grouping

The day before the compound screening test, a baseline test is required. The test procedure is the same as 5.1.1~5.1.3. The number of baseline tests is 20 times. Animals with active evasion times up to 16 times (80%) will be divided into groups. Group 10; the first group was given the vehicle orally, and the other groups were given the corresponding test compound according to the experimental design.

5.3 Compound screening test

One hour before the start of the test, the administration method is oral, 5mL/kg;

The test process is the same as 5.1.1~5.1.4, and the number of tests is 20 times.

6. data processing

The software collects the following data for data analysis:

The number of active avoidance of animals (avoids);

The number of animal escape failures (escape failures);

The incubation period of passive escape of animals (escape latency);

All measurement data are expressed as mean±standard error (Mean±SEM). Graphpad 6 statistical software is used for test analysis. The significance of the difference is considered to be significant with p <0.05.

7. Experimental results

8. Experimental results

The above data shows that the compounds of the examples of the present invention show a good effect in the model of active evasion of experimental drugs in rats, indicating that they have anti-schizophrenia effects.

Claims (30)

A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

among them: L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb (CH ₂ ) _n2 -; Ring A is selected from aryl or heteroaryl, Ring B is selected from cycloalkyl or heterocyclic group; Ring C is selected from cycloalkyl or heterocyclyl; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O) (CH ₂ ) _n1 OR _aa , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)R _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)NR _aa R _bb ,- P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ; R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O) (CH ₂ ) _n1 OR _aa , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)R _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)NR _aa R _bb ,- P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ; Or, two R ₂ on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group, If necessary, it may be further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, oxy, sulfur Group, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or Unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R _cc , -(CH ₂ ) _n1 OR _cc , -(CH ₂ ) _n1 SR _cc , -(CH ₂ ) _n1 C(O)R _cc , -(CH ₂ ) _n1 C(O)OR _cc , -(CH ₂ ) _n1 S(O) _m1 R _cc , -(CH ₂ ) _n1 NR _cc R _dd , -(CH ₂ ) _n1 C(O)NR _cc R _dd , -(CH ₂ ) _n1 C(O)NHR _cc , -(CH ₂ ) _n1 NR _cc C(O ) R _dd and -(CH ₂ ) _n1 NR _cc S(O) _m1 R _dd are substituted by one or more substituents; R _{3 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , the alkyl group, Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amine, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxyheterocyclyl, thioheterocyclyl, aryl And heteroaryl groups, optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, Oxy, thio, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy Group, substituted or unsubstituted hydroxyalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n1 R _cc , -(CH ₂ ) _n1 OR _cc , -(CH ₂ ) _n1 SR _cc , -(CH ₂ ) _n1 C(O)R _cc , -(CH ₂ ) _n1 C(O)OR _cc ,-(CH ₂ ) _n1 S(O) _m1 R _cc , -(CH ₂ ) _n1 NR _cc R _dd , -(CH ₂ ) _n1 C(O)NR _cc R _dd , -(CH ₂ ) _n1 C(O)NHR _cc , -(CH ₂ ) _n1 NR _cc C(O)R _dd and -(CH ₂ ) _n1 NR _cc S(O) _m1 R _dd are substituted by one or more substituents ； R _aa , R _bb , R _cc and R _dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, Nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted The amine, oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Substituted by one or more substituents in substituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, oxy, thio, nitro, cyano, hydroxyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocycle Substituted by one or more substituents in a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; and n2 is 0, 1, 2, 3, 4, or 5. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in the first scope of the patent application, wherein the general formula (I) is further represented by the general formula (II):

among them: L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb (CH ₂ ) _n2 -; Ring A is selected from aryl or heteroaryl; Ring B is selected from cycloalkyl or heterocyclic group; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , the alkyl group, Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amine, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxyheterocyclyl, thioheterocyclyl, aryl And heteroaryl groups, optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, Oxy, thio, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy Group, substituted or unsubstituted hydroxyalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n1 R _cc , -(CH ₂ ) _n1 OR _cc , -(CH ₂ ) _n1 SR _cc , -(CH ₂ ) _n1 C(O)R _cc , -(CH ₂ ) _n1 C(O)OR _cc , -(CH ₂ ) _n1 S(O) _m1 R _cc , -(CH ₂ ) _n1 NR _cc R _dd , -(CH ₂ ) _n1 C(O)NR _cc R _dd , -(CH ₂ ) _n1 C(O)NHR _cc , -(CH ₂ ) _n1 NR _cc C(O)R _dd and -(CH ₂ ) _n1 NR _cc S(O) _m1 R _dd are substituted by one or more substituents ； R _aa , R _bb , R _cc and R _dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, Nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted The amine, oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Substituted by one or more substituents in substituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, oxy, thio, nitro, cyano, hydroxyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocycle Substituted by one or more substituents in a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; and n2 is 0, 1, 2, 3, 4, or 5. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further represented by the general formula (III):

among them: L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb (CH ₂ ) _n2 -; Ring A is selected from aryl or heteroaryl; Ring C is selected from cycloalkyl or heterocyclyl; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; R _{3 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa ,-(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ; R _aa and R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, amine Group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from hydrogen, halogen, hydroxy, cyano, pendant oxy, alkyl, haloalkyl and alkoxy Substituted by one or more substituents in the group; Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are further selected from deuterium, Substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, thio, nitro, cyano, hydroxyl , Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted One or more substituents in the heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group; m is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; and n2 is 0, 1, 2, 3, 4, or 5. The compound described in item 1 of the scope of patent application, its stereoisomers or its pharmaceutically Acceptable salts, wherein the general formula (I) is further represented by the general formula (IV):

among them: R _{5 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; Or, two R ₅ on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups are Group, optionally further selected from deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amine, pendant oxy, thio, nitro, cyano, hydroxyl, ester, alkenyl, alkynyl, Substituted by one or more substituents among alkoxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl and heteroaryl; t is 0, 1, 2 or 3; L, ring B, ring C, R ₂ , R ₃ , y and z are as described in item 1 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further represented by the general formula (V):

among them: M is selected from -NR _aa -or -CR _aa R _bb -; R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ; n is 0, 1, 2 or 3; Ring A, Ring B, R ₁ , R ₂ , _Raa , R _bb , x and y are as described in item 1 of the scope of patent application. The compound described in item 1 of the scope of patent application, its stereoisomers or its pharmaceutically Acceptable salts, wherein the general formula (I) is further represented by the general formula (VI):

among them: L is selected from -(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR _aa -or -(CH ₂ ) _n1 CR _aa R _bb -; R ₂ , R ₃ , R ₅ , m, y, t, and z are as described in item 4 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the ring C is

. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further represented by the general formula (VII):

among them: R _{6 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; p is an integer from 0 to 8; Ring B, R ₂ , R ₅ , y and t are as described in item 4 of the scope of patent application; M, R ₄ and n are as described in item 5 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further represented by the general formula (VIII):

among them: Ring A is selected from aryl or heteroaryl; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group; R _{2 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl group or heteroaryl group, Or, two R2s on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group, depending on Need to be further selected from hydrogen, deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amine, pendant oxy, thio, nitro, cyano, hydroxy, ester, alkenyl, alkynyl, alkyl Substituted by one or more substituents among oxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl and heteroaryl; R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, oxy heterocyclic group, thio heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa ,- (CH ₂ ) _n1 C(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa R _bb , -(CH ₂ ) _n1 NHC(O)NR _aa C(O)R _bb , -( CH ₂ ) _n1 S(O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , -(CH ₂ ) _n1 NHS(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -NR _aa C(O)(CH ₂ ) _n1 OR _bb , -NR _aa C(=S)(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _n1 SR _aa , -(CH ₂ ) _n1 C(O)OR _aa , -(CH ₂ ) _n1 (O=S=NR _aa )R _bb , -P(O)R _aa R _bb , -(CH ₂ ) _n1 NR _aa C(O)R _bb or -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb ; R _aa and R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, amine Group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from hydrogen, halogen, hydroxy, cyano, pendant oxy, alkyl, haloalkyl and alkoxy Is substituted by one or more substituents in the group, Alternatively, R _aa and R _{bb are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further selected from deuterium, substituted Or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amine, oxy, thio, nitro, cyano, hydroxyl, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocycle Substituted by one or more substituents in a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; m is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; and n1 is 0, 1, 2, 3, 4, or 5. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further as general formula (VIII-A) and general formula (VIII-B) Shown:

among them: Ring A, R ₁ , R ₄ , m and x are as described in item 9 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt according to item 9 of the scope of patent application, wherein the general formula (VIII) is further as general formula (VIII-C) and general formula (VIII-D) Shown:

The compound, its stereoisomer or its pharmaceutically acceptable salt according to item 9 of the scope of patent application, wherein the ring A is selected from a C _6-14 aryl group or a 5-14 membered heteroaryl group; Preferably phenyl or benzo contains 1-2 N, S or O 5-6 membered heteroaryl groups; More preferably, phenyl, benzothienyl, benzisoxazolyl or benzisothiazolyl. The compound, its stereoisomer or its pharmaceutically acceptable salt according to item 9 of the scope of patent application, wherein the R _{1 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkane Group, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _{2- 6-} alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 heteroaryl; Preferred are hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 9 of the scope of patent application, wherein: The

Selected from the following groups:

The compound, its stereoisomer or its pharmaceutically acceptable salt according to item 9 of the scope of patent application, wherein the R _{2 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkane Group, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5-14 heteroaryl, Preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C ₁₃ alkoxy, C _1-3 haloalkoxy, halogen, amino, Nitro, hydroxy, cyano, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 5-6 heterocyclic group, C _6-14 aryl or 5-6 heteroaryl base. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 9 of the scope of patent application, wherein: The R _{4 is} selected from -NHR _bb , -NHC(O)(CH ₂ ) _n1 R _bb , -NHC(O)NR _aa (CH ₂ ) _n1 R _bb or -NHS(O) ₂ R _bb ; The R _aa and R _bb are each independently selected from hydrogen, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 Membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group, wherein the amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _{3 -8} cycloalkyl, 3-8 membered heterocyclic group, C _6-14 aryl and 5-14 membered heteroaryl, optionally further selected from halogen, hydroxy, cyano, oxy, C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl Or multiple substituents, Preferably, the R _aa and R _bb are each independently selected from hydrogen, amino, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkane Group, 3-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group, wherein the amino group, C _1-3 alkyl group, C _1-3 haloalkyl group, C _1-3 alkoxy group, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, optionally further selected from halogen, hydroxy, cyano, oxy, C _1-3 alkyl, C _{1 -3} haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group substituted by one or more substituents , Alternatively, R _aa and R _{bb are} linked to form a 5-6 membered heterocyclic group or heteroaryl group, and the heterocyclic group or heteroaryl group may be further selected from halogen, hydroxyl, cyano, oxy, C _{1-3 if necessary} One or more of alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl Substituted by a substituent; Wherein, the heterocyclic group or heteroaryl group contains 1-2 identical or different nitrogen, oxygen or sulfur atoms; n1 is 0, 1, 2, or 3. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further represented by the general formula (IX):

among them: R ₅ and t are as described in item 4 of the scope of patent application; Ring B, R ₂ , R ₄ and y are as described in item 5 of the scope of patent application. The compound described in item 9 of the scope of patent application, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (VIII) is further represented by the general formula (IX-A):

among them: R _{2 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen , Amine, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5 -14 heteroaryl, preferably hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl; R _{4 is} selected from 5-6 membered N-containing heterocyclic groups,

,

,

or

R _{aa is} selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-12 aryl or 5 -12 heteroaryl; R _{bb is} selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl or 5-12 heteroaryl, the amino group, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-12 aryl and 5-12 hetero Aryl group, if necessary, is further substituted by hydrogen, deuterium, halogen, amine, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl Group or 5-12 heteroaryl, the C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkyl One of oxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl and 5-12 heteroaryl, or Replaced by multiple substituents; R _{5 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen , Amine, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5 -14 heteroaryl; Or, two R ₅ on the same carbon atom or different carbon atoms are linked to form a C _3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C _6-14 aryl group or a 5-14 heteroaryl group. C _3-12 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl and 5-14 heteroaryl, optionally further selected from hydrogen, deuterium, C _1-6 alkyl, C _{1- 6} Deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C _2-6 alkenyl , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-12 aryl and 5-12 heteroaryl substituted by one or more substituents; r is 0, 1 or 2; m is 1, 2 or 3; y is 0, 1, 2 or 3; preferably 0 or 1; and t is 0, 1, 2, or 3. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein the general formula (I) is further represented by general formula (X) and general formula (X-A):

among them: R ₄ and m are as described in item 9 of the scope of patent application; R ₅ and t are as described in item 15 of the scope of patent application. The compound, its stereoisomer or its pharmaceutically acceptable salt according to item 18 of the scope of patent application, wherein the R _{4 is} selected from oxazolidinone,

,

,

R _{aa is} selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-12 aryl or 5 -12 heteroaryl, preferably hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl; R _{bb is} selected from hydrogen, amino, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, C _{6 -10} aryl or 5-10 heteroaryl, the amino group, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-6 Membered heterocyclic group, C _6-10 aryl group and 5-10 heteroaryl group, optionally further selected from hydrogen, halogen, hydroxyl, cyano, C _1-3 alkyl or C _1-3 alkoxy Substituted by one or more substituents; and r is 0, 1, or 2. The compound, its stereoisomer or its pharmaceutically acceptable salt according to item 18 of the scope of patent application, wherein the R _{5 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkane Group, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C _2-6 alkenyl, C _{2- 6-} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-12 aryl or 5-12 heteroaryl, preferably hydrogen, cyano, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _3-6 cycloalkyl; Alternatively, any two adjacent R ₅ links to form a 5-6 membered heterocyclic group or 5-6 membered heteroaryl group, preferably a 5-6 membered heteroaryl group containing 1-2 N, S or O heteroatoms Group, more preferably thienyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl. The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein: Ring A is selected from the following groups:

Ring B is selected from the following groups:

Ring C is selected from the following groups:

The compound, its stereoisomer or its pharmaceutically acceptable salt as described in item 1 of the scope of patent application, wherein: R _{1 is} selected from hydrogen, cyano, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-6 cycloalkyl; R _{2 is} selected from hydrogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl, Or, two R ₂ on the same carbon atom or different carbon atoms are linked to form a C _3-8 cycloalkyl group or a 3-8 membered heterocyclic group. The cycloalkyl group and the heterocyclic group may be further selected from Deuterium, C _1-6 alkyl, halogen, amino, oxy, thio, cyano, hydroxyl, C _3-8 alkoxy, C _3-8 haloalkoxy and C _3-8 hydroxyalkyl Substituted by one or more substituents; R _{3 is} selected from 3-8 membered heterocyclic groups, -NR _aa R _bb , -C(O)R _aa , -C(O)NR _aa R _bb , -NHC(O)NR _aa R _bb , -NHC(O )NR _aa C(O)R _bb , -S(O) ₂ R _aa , -NR _aa S(O) ₂ R _bb , -NHS(O) _m1 NR _aa R _bb , -S(O)NR _aa R _bb , -S(O) ₂ NR _aa R _bb , -OR _aa , -NR _aa C(O)NH(CH ₂ ) _n1 R _bb , -C(O)OR _aa , -(CH ₂ ) _n1 (O=S =NR _aa )R _bb or -NR _aa C(O)R _bb ; R _{aa is} selected from hydrogen, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _{6 -14} aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 3- 8-membered heterocyclic group, C _6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from hydrogen, halogen, hydroxy, cyano, pendant oxy, C _1-6 alkyl, C _1-6 Substituted by one or more substituents in haloalkyl and C _1-6 alkoxy; R _{bb is} selected from hydrogen, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _{6 -14} aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, 3- 8-membered heterocyclic group, C _6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from hydrogen, halogen, hydroxy, cyano, pendant oxy, C _1-6 alkyl, C _1-6 Substituted by one or more substituents in haloalkyl and C _1-6 alkoxy, Or, R _aa and R _{bb are} linked to form a heterocyclic group, and the heterocyclic group may be further selected from hydrogen, C _1-6 alkyl, halogen, amino, oxy, thio, cyano, hydroxyl, C _It is substituted by one or more substituents of _3-8 alkoxy, C _3-8 haloalkoxy and C _3-8 hydroxyalkyl. The compound described in any one of items 1 to 23 in the scope of the patent application, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

A method for preparing the compound represented by the general formula (VIII) described in item 16 of the scope of patent application or its stereoisomer and pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

The general formula (VIII-1) reacts with the chlorine, amine, carboxylic acid or sulfonyl chloride represented by the general formula (VIII-2) to obtain the compound represented by the general formula (VIII) or its stereoisomer and its pharmacy Acceptable salt The general formula (VIII-2) is selected from R _bb -Br , R _bb -NH ₂ ,

,

,

or

If necessary, it also includes N,N-carbonyldiimidazole. A method for preparing the compound represented by the general formula (IX-A) described in item 18 of the scope of patent application or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:

The general formula (IX-A-1) is reacted with the general formula (VIII-2) to obtain the compound represented by the general formula (IX-A) or its stereoisomers and pharmaceutically acceptable salts thereof; The definition of general formula (VIII-2) is as described in item 25 of the scope of patent application. A method for preparing the compound represented by intermediate (VIII-5) or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:

The general formula (VIII-3) is reacted with the general formula (VIII-4) to obtain the compound represented by the general formula (VIII-5) or its stereoisomers and pharmaceutically acceptable salts thereof; among them: Pg ₁ is a hydrogen or amino protecting group, selected from allyloxycarbonyl, trifluoroacetoxy, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, and methoxycarbonyl , P-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tertiary butoxycarbonyl, benzyl or p-methoxyphenyl; preferably tertiary butoxycarbonyl; Pg ₂ is a hydrogen or hydroxyl protecting group, selected from methyl, tertiary butyl, triphenyl, methyl sulfide methyl ether, 2-methoxyethoxy methyl ether, methoxy methyl ether, p-methoxy Benzyl ether, p-pentanyl, benzyl ether, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldimethylsilyl, acetyl, benzyl, or p-toluenesulfonyl Group; preferably p-toluenesulfonyl; The definitions of ring A, R ₁ , R ₂ , x and y are as described in item 1 of the scope of patent application. A pharmaceutical composition comprising a therapeutically effective dose of the compound described in any one of items 1 to 24, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable Carrier, diluent or excipient. A compound described in any one of items 1 to 24 in the scope of patent application, its stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in item 28 of the scope of patent application is in preparation Preparation of G protein-coupled receptor modulators, preferably, application in dopamine D3 receptor and 5-HT2A receptor modulator drugs. A compound described in any one of items 1 to 24 in the scope of patent application, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in item 28 of the scope of patent application in the treatment or prevention of central nervous system Use in nervous system diseases and/or mental diseases; neurological diseases and/or mental diseases are preferably schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and/or cognitive disorders, Dyskinesia, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus, depression, autism, dementia, Alzheimer Syndrome, seizures, neuralgia or detoxification symptoms, severe depression and manic diseases.