WO2024094156A1

WO2024094156A1 - Amine compound and use thereof

Info

Publication number: WO2024094156A1
Application number: PCT/CN2023/129527
Authority: WO
Inventors: 王振玉; 滑新星; 胡继明; 安会; 高骏; 李子真; 田佳卉; 王矿磊; 王克柱; 刘喜宝
Original assignee: 石药集团中奇制药技术（石家庄）有限公司
Priority date: 2022-11-04
Filing date: 2023-11-03
Publication date: 2024-05-10

Abstract

Provided is a compound represented by formula (I), or a stereoisomer thereof, an optical isomer thereof, a solvate thereof, an isotope derivative thereof, or a pharmaceutically acceptable salt thereof. The compound can be used as a ligand of a Sigma-1 receptor and/or an M1-muscarinic acetylcholine receptor. Such compounds and pharmaceutical compositions comprising same have the use of preparing a drug for treating and/or preventing a nervous system disease. Ring A, ring B, ring C, RC, L, R1, R2, and n in formula (I) are as defined in the specification.

Description

Amine compounds and uses thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority and benefits of Chinese Patent Application No. 202211376690.1 filed with the State Intellectual Property Office of China on November 4, 2022 and Chinese Patent Application No. 202310155557.1 filed with the State Intellectual Property Office of China on February 23, 2023, and the contents disclosed in the said applications are incorporated herein by reference in their entirety.

Technical Field

The present application relates to the field of medical technology, and in particular, to a class of compounds that are Sigma-1 receptor ligands and their use in treating and/or preventing nervous system diseases; preferably, to a class of compounds that are Sigma-1 receptor and M1-muscarinic acetylcholine receptor ligands and their use in treating and/or preventing nervous system diseases.

Background technique

Neurological diseases have long been a common threat to human health worldwide, and the incidence rate has increased year by year. Common diseases include drug addiction, neuropsychiatric diseases (schizophrenia, depression, etc.), Alzheimer's disease, Parkinson's disease, pain, etc. For existing clinical neurological disease drugs, some of them are accompanied by certain side effects or adverse effects while providing certain therapeutic effects, or the therapeutic effects of existing drugs are limited or poor. For example, dopamine receptor antagonists (classic antipsychotic drugs) are prone to extrapyramidal reactions and metabolic side effects.

Sigma-1 receptor (σ-1 receptor or S1R) is a subtype of the Sigma family. It is a receptor protein with molecular chaperone activity. It exists in the form of a trimer and has a single transmembrane topology. S1R is widely distributed in the central nervous system, and is mainly distributed in the cerebellum and hippocampus in the brain. The ligand binding domain of S1R is highly conserved in different species. In mammals, S1R has more than 90% amino acid homology. In the central nervous system, S1R plays an important regulatory role in the cholinergic, γ-aminobutyric acid and dopaminergic nervous systems, and is involved in neuroprotection, neuroinflammation, neurotransmission and neuroplasticity. Pathophysiological studies have also found that S1R ligands can play a more ideal role in improving the symptoms of neurological diseases such as drug addiction, schizophrenia, and Alzheimer's disease. Currently, S1R has become one of the research hotspots for neurological diseases, including but not limited to neurodegenerative diseases, pain, stroke, retinal degeneration, Alzheimer's disease and depression, and some S1R ligands have entered Phase II/III clinical trials, but no drug has been approved yet.

Muscarinic acetylcholine receptors (mAChRs) belong to G protein-coupled receptors, with five subtypes (M1, M2, M3, M4 and M5), which play an important role in advanced cognitive activities such as learning and memory. Studies have shown that although cholinergic neurons are gradually lost in the brains of Alzheimer's patients, the density of M1 receptors in the postsynaptic membrane has not been lost compared with normal people, while the density of M2 receptors and M4 receptors in the presynaptic membrane has been significantly reduced. Therefore, M1 receptors are regarded as attractive targets for the treatment of Alzheimer's disease. In fact, more and more studies have shown that M1 agonists can improve many typical symptoms of Alzheimer's disease. Some M1 receptor agonists have entered clinical trials, but due to poor receptor subtype selectivity, the therapeutic effects of these M1 agonists have been greatly reduced due to some of their side effects, and their use in clinical practice has been severely limited.

Therefore, by activating S1R and/or M1 receptors, neurological symptoms can be improved and neurological diseases can be treated. For example, ANAVEX 2-73 exhibits anticonvulsant, anti-amnesic, neuroprotective and antidepressant properties in animal models, indicating its potential for treating other central nervous system diseases (including epilepsy) and is currently in clinical research. AF710B can be used as a potential treatment for Alzheimer's disease. It can clear amyloid protein in the brain, inhibit Tau protein hyperphosphorylation, inhibit neuroinflammation, reduce the loss of synapses in the brain, and show an improvement effect on cognitive dysfunction.

Summary of the invention

In a first aspect, the present application provides a compound represented by formula (I), or a stereoisomer, optical isomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, which has the following structure:

in,

Ring A and Ring B are each independently selected from the following groups which are unsubstituted or substituted: C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the substitution is substitution with m1 identical or different R ³ and/or R ⁴ ;

Alternatively, ring A is absent;

R ³ is independently selected at each occurrence from the following groups: unsubstituted or substituted: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl or 3-10 membered heterocyclyl, wherein the substitution is substituted by m2 identical or different R ⁴ ;

R ⁴ is independently selected at each occurrence from: hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -O(3-6 membered heterocyclyl), -NR ⁵ R ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -C(O)NR ⁵ R ⁵ , -OC(O)R ⁵ , -S(O) _0-2 R ⁵ , -S(O) ₂ NR ⁵ R ⁵ , -N(R ⁵ )S(O) ₂ R ⁵ , -N(R ⁵ )C(O)R ⁵ , -N(R ⁵ )C(O)NR ⁵ , oxo (＝O), imino (＝NH) or thiocarbonyl (＝S);

R ⁵ is independently selected at each occurrence from hydrogen, unsubstituted or substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the substitution is by m3 identical or different cyano, amino, hydroxyl or halogen;

Ring C is selected from 3-12 membered heterocyclyl or C _3-12 cycloalkyl;

Rc is independently selected at each occurrence from hydrogen, deuterium, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, -OC _1-6 alkyl, -C _1-6 alkylene OH, oxo (=O) or thiocarbonyl (=S);

n is selected from 0, 1, 2, 3, 4 or 5;

L is selected from the following groups which are unsubstituted or substituted: C _1-6 alkylene, -OC _1-6 alkylene, -OC _3-6 cycloalkyl, -O(3-6 membered heterocyclyl), C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen;

R ¹ is selected from hydrogen, unsubstituted or substituted: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _6-10 aryl, _3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substituted by m5 identical or different R ⁶ and/or R ⁷ ;

R ² is selected from the following groups which are unsubstituted or substituted: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkenyl, C _6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substitution by m5 identical or different R ⁶ and/or R ⁷ ;

Alternatively, ^R1 and ^R2 form an unsubstituted or substituted 4-12 membered heterocyclic group with the nitrogen atom to which they are attached, wherein the substitution is substitution by m8 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

Alternatively, ^R1 or ^R2 are each independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-12 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

R ⁶ is independently selected at each occurrence from the following groups: unsubstituted or substituted: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substitution by m6 identical or different R ⁷ and/or R ⁸ ;

R ⁷ at each occurrence is independently selected from deuterium, unsubstituted or substituted nitro, -OR ⁸ , -O(CH ₂ ) _1-3 R ⁸ , -NR ⁸ R ⁸ , halogen, -CN, -C(O)R ⁸ , -C(O)OR ⁸ , -C(O)NR ⁸ R ⁸ , -OC(O)R ⁸ , -S(O) _0-2 R ⁸ , -S(O) ₂ NR ⁸ R ⁸ , -N(R ⁸ )S(O) ₂ R ⁸ , -N(R ⁸ )C(O)R ⁸ , -N(R ⁸ )C(O)NR ⁸ , oxo (═O) and imino (═NH);

^R8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted: _C1-6 alkyl, _{C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is by m7 identical or different C1-6 alkyl, cyano, amino, hydroxyl, deuterium, -OC1-6} _alkyl _, _-C1-6 _alkylOH _, _C3-6 _cycloalkyl , halogen, _C1-6 haloalkyl, -S(O) _0-2C1-3 alkyl, -N( _C1-3 alkyl ₎ ₂ , phenyl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -C(O) _0-2C1-3 _alkyl , -OC(O) _C1-3 alkyl _, -OS(O) _2C1-3 _alkyl alkyl, -NHCOC _1-3 alkyl, -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHSO ₂ C _1-3 alkyl, -NHCONHC _1-3 alkyl or oxo;

m1, m2, m3, m4, m5, m6, m7, m8 and m9 are each independently selected from 1, 2, 3, 4, 5 or 6;

The prerequisite is that the definitions of the above variables (Ring A, Ring B, Ring C, Rc, n, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m1, m2, m3, m4, m5, m6, m7, m8 and/or m9) are combined to form a stable chemical structure;

Wherein the compound is not:

In some embodiments, the present application provides a compound represented by formula (I), or a stereoisomer, optical isomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, which has the following structure:

in,

Alternatively, ring A is absent;

R ⁴ is independently selected at each occurrence from: hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -OC _3-6 heterocyclyl, -NR ⁵ R ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -C(O)NR ⁵ R ⁵ , -OC(O)R ⁵ , -S(O) _0-2 R ⁵ , -S(O) ₂ NR ⁵ R ⁵ , -N(R ⁵ )S(O) ₂ R ⁵ , -N(R ⁵ )C(O)R ⁵ , -N(R ⁵ )C(O)NR ⁵ , oxo (＝O), imino (＝NH) or thiocarbonyl (＝S);

Ring C is selected from 3-12 membered heterocyclyl or C _3-12 cycloalkyl;

Rc is independently selected at each occurrence from hydrogen, deuterium, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

n is selected from 0, 1, 2 or 3;

^R1 and ^R2 are each independently selected from the following groups which are unsubstituted or substituted: _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, _C3-10 cycloalkenyl, _C6-10 aryl, _3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substitution by m5 identical or different ^R6 and/or ^R7 ;

^R7 at each occurrence is independently selected from deuterium, ^{unsubstituted} or substituted nitro, ^-OR8 , ^-NR8R8 , halogen, -CN, -C(O) ^R8 , -C(O) ^OR8 , -C(O) ^NR8R8 , -OC ₍ ^O ⁾ ^R8 , _-S (O ⁾ _0-2R8 ^, -S(O) ^2NR8R8 , -N( ^R8 )S(O)2R8, -N( ^R8 )C(O) ^R8 , -N(R ⁸ )C(O)NR ⁸ , oxo (═O) and imino (═NH);

^R8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, _C6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is by m7 identical or different _C1-6 alkyl, cyano, amino, hydroxyl or halogen;

Wherein, the compound does not include compounds Q1 to Q63 listed in the first aspect.

In some embodiments, the isotopic derivative is a deuterated form of the compound.

In some embodiments, the halogen is selected from fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine; and even more preferably fluorine.

In some embodiments, unless otherwise specified, each of the heterocyclyl groups independently contains 1, 2 or 3 heteroatoms independently selected from N, O and S. In some embodiments, unless otherwise specified, each of the heterocyclyl groups independently contains 1 or 2 heteroatoms independently selected from N and O.

In some embodiments, each of the heteroaryl groups independently contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, each of the heteroaryl groups independently contains 1 or 2 heteroatoms independently selected from N and O.

In some embodiments, the ring A and ring B are each independently selected from the following groups which are unsubstituted or substituted: C _4-10 cycloalkyl, 4-10 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; or, ring A is absent;

Preferably, the ring A and the ring B are each independently selected from the following groups which _are unsubstituted or substituted: C _4-9 cycloalkyl, 4-9 membered heterocyclyl, C _6-10 aryl or 5-9 membered heteroaryl; or, the ring A is absent;

Further preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C _4-8 cycloalkyl, 4-8 membered heterocyclyl, C _6-10 aryl or 5-8 membered heteroaryl; or, the ring A does not exist;

Further preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C _4-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; or, the ring A does not exist;

Further preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; or, the ring A does not exist;

The substitution is substitution by m1 identical or different R ³ and/or R ⁴ .

In some embodiments, the ring A and ring B are each independently selected from the following groups which are unsubstituted or substituted: C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; or, ring A is absent;

Preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C ₆ cycloalkyl, 6-membered heterocyclyl, phenyl or 6-membered heteroaryl; or, the ring A does not exist;

Further preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C ₆ cycloalkyl, 6-membered heterocyclyl, phenyl or 6-membered heteroaryl;

In some embodiments, the ring A and ring B are each independently selected from the following groups, which are unsubstituted or substituted: C _5-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl; or, ring A is absent, and ring B is independently selected from the following groups, which are unsubstituted or substituted: C _5-6 cycloalkyl, phenyl, or 5-6 membered heteroaryl; in some embodiments, the 5-6 membered heteroaryl contains 1 heteroatom selected from N, O, and S.

In some embodiments, the ring A and ring B are each independently selected from the following groups which are unsubstituted or substituted: _C6 cycloalkyl, phenyl or 5-6 membered heteroaryl; or, ring A is absent, and ring B is independently selected from the following groups which are unsubstituted or substituted: C ₆ cycloalkyl, phenyl or 5-6 membered heteroaryl; in some embodiments, the 5-6 membered heteroaryl contains 1 heteroatom selected from N, O and S.

In some embodiments, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: cyclohexyl, phenyl, thienyl, furanyl, pyrimidinyl or pyridinyl, wherein the substitution is substituted by 1, 2, 3, 4 or 5 identical or different R ³ and/or R ⁴ ; or, the ring A does not exist;

Further preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: cyclohexyl, phenyl, pyrimidinyl or pyridinyl, wherein the substitution is substitution with 1, 2 or 3 identical or different R ³ and/or R ⁴ ;

Further preferably, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: cyclohexyl, phenyl or pyridyl, wherein the substitution is substitution with 1, 2 or 3 identical or different R ³ and/or R ⁴ ;

Further preferably, the ring A and the ring B are each independently selected from the following unsubstituted or substituted groups: phenyl, wherein the substitution is substitution with 1, 2 or 3 identical or different R ³ and/or R ⁴ .

In some embodiments, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: cyclohexyl, phenyl, thienyl, furanyl or pyridyl, wherein the substitution is substituted by 1, 2, 3, 4 or 5 identical or different ^R3 and/or ^R4 ; or, the ring A is absent, and the ring B is selected from the following groups which are unsubstituted or substituted: phenyl, wherein the substitution is substituted by 1, 2 or 3 identical or different ^R3 and/or ^R4 .

In some embodiments, the ring A is selected from the following groups which are unsubstituted or substituted: pyridyl, phenyl, thienyl, cyclohexyl or furanyl, or the ring A is absent; the ring B is selected from the following groups which are unsubstituted or substituted: phenyl, pyridyl, thienyl or furanyl;

Preferably, the ring A is selected from the following groups which are unsubstituted or substituted: pyridyl, phenyl, thienyl, cyclohexyl or furyl, or the ring A does not exist; the ring B is selected from the following groups which are unsubstituted or substituted: phenyl or pyridyl;

Further preferably, the ring A is selected from the following groups which are unsubstituted or substituted: pyridyl, phenyl, thienyl, cyclohexyl or furanyl, or the ring A does not exist; the ring B is selected from the following groups which are unsubstituted or substituted: phenyl;

Further preferably, the ring A is selected from the following groups which are unsubstituted or substituted: pyridyl, phenyl, thienyl, cyclohexyl or furanyl; the ring B is selected from the following groups which are unsubstituted or substituted: phenyl;

Wherein, the substitution is substituted by 1, 2, 3, 4 or 5 identical or different R ³ and/or R ⁴ ; preferably, the substitution is substituted by 1, 2 or 3 identical or different R ³ and/or R ⁴ ; further preferably, the substitution is substituted by 1 or 2 identical or different R ³ and/or R ⁴ ; further preferably, the substitution is substituted by 1 R ³ or R ⁴ .

In some embodiments, the ring A and ring B are each independently selected from pyridyl, phenyl, thienyl, cyclohexyl or furanyl.

In some embodiments, the ring A is selected from pyridyl, phenyl, thienyl, cyclohexyl or furanyl, and the ring B is phenyl.

In some embodiments, Ring A and Ring B are both phenyl.

In some embodiments, the ring A is absent and the ring B is phenyl.

Herein, the term "non-existent" means that the substituent at that position does not exist, and the site is substituted with hydrogen.

In some embodiments, each occurrence of R ³ is independently selected from the following groups, which are unsubstituted or substituted: C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, or 3-8 membered heterocyclyl;

Preferably, each occurrence of R ³ is independently selected from the following groups, which are unsubstituted or substituted: C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl or 3-6 membered heterocyclyl;

Further preferably, each occurrence of R ³ is independently selected from the following groups, which are unsubstituted or substituted: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _4-6 cycloalkyl or 4-6 membered heterocyclyl;

Further preferably, each occurrence of R ³ is independently selected from the following groups, which are unsubstituted or substituted: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _5-6 cycloalkyl or 5-6 membered heterocyclyl;

Further preferably, the R ³ is independently selected from the following groups, unsubstituted or substituted, at each occurrence: C _1-3 alkyl;

Wherein, the substitution is substitution by m2 identical or different R ⁴ .

In some embodiments, each occurrence of R ³ is independently selected from the following groups: unsubstituted or substituted: methyl, ethyl, isopropyl, vinyl, ethynyl or cyclopropyl;

Preferably, the R ³ is independently selected from the following groups, unsubstituted or substituted, at each occurrence: methyl;

Wherein, the substitution is substitution by m2 identical or different R ⁴ ;

More preferably, the R ³ is a methyl group.

In some embodiments, said R ⁴ is independently selected at each occurrence from: hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC _1-4 alkyl, -OC _4-6 cycloalkyl, -O(4-6 membered heterocyclyl), -NR ⁵ R ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -C(O)NR ⁵ R ⁵ , -OC(O)R ⁵ , -S(O) _0-2 R ⁵ , -S(O) ₂ NR ⁵ R ⁵ , -N(R ⁵ )S(O) ₂ R ⁵ , -N(R ⁵ )C(O)R ⁵ , -N(R ⁵ )C(O)NR ⁵ , oxo (＝O), imino (＝NH) or thiocarbonyl (＝S);

Further preferably, said R ⁴ is independently selected at each occurrence from the group consisting of hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC _1-3 alkyl, -OC _5-6 cycloalkyl, -O(5-6 membered heterocyclyl), -NR ⁵ R ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -C(O)NR ⁵ R ⁵ , -OC(O)R ⁵ , -S(O) _0-2 R ⁵ , -S(O) ₂ NR ⁵ R ⁵ , -N(R ⁵ )S(O) ₂ R ⁵ , -N(R ⁵ )C(O)R ⁵ , -N(R ⁵ )C(O)NR ⁵ , oxo (＝O), imino (＝NH) or thiocarbonyl (＝S);

Further preferably, each occurrence of R ⁴ is independently selected from: hydrogen, deuterium, halogen, hydroxyl or -OCH ₃ ;

Further preferably, each occurrence of R ⁴ is independently selected from: hydrogen, deuterium, F, Cl or -OCH ₃ ;

Further preferably, each occurrence of R ⁴ is independently selected from: hydrogen.

In some embodiments, each occurrence of R ⁵ is independently selected from hydrogen, unsubstituted or substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl;

Preferably, said R ⁵ is independently selected at each occurrence from hydrogen, unsubstituted or substituted from the following groups: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl;

Further preferably, said R ⁵ is independently selected at each occurrence from hydrogen, unsubstituted or substituted from the following groups: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _4-6 cycloalkyl and 4-6 membered heterocyclyl;

Further preferably, said R ⁵ is independently selected at each occurrence from hydrogen, unsubstituted or substituted from the following groups: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _5-6 cycloalkyl and 5-6 membered heterocyclyl;

Wherein, the substitution is substitution by m3 identical or different cyano groups, amino groups, hydroxyl groups or halogen groups.

In some embodiments, each occurrence of R ⁵ is independently selected from hydrogen, unsubstituted or substituted methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl; wherein the substitution is substituted by 1 or 2 identical or different cyano, amino, hydroxyl or halogen.

In some embodiments, the ring A is absent or is selected from the following groups: Wherein, * indicates the connection site with ring C.

In some embodiments, the ring B is selected from the following groups: Wherein, * indicates the connection site with ring C.

In some embodiments, the ring C is selected from a 4-10 membered heterocyclyl or a C _4-10 cycloalkyl;

Preferably, the ring C is selected from a 5-10 membered heterocyclyl or a C _5-10 cycloalkyl;

Preferably, the ring C is selected from a 5-9 membered heterocyclyl or a C _5-9 cycloalkyl;

Further preferably, the ring C is selected from a 5-8 membered heterocyclic group or a C _5-8 cycloalkyl group;

Further preferably, the ring C is selected from a 5-6 membered heterocyclic group or a C _5-6 cycloalkyl group;

Further preferably, the ring C is selected from a 5-6 membered heterocyclic group;

Wherein, the heteroatom in the heterocyclic group is selected from O, N or S, and the number of heteroatoms is 1 or 2; preferably, the heteroatom in the heterocyclic group is selected from O or S, and the number of heteroatoms is 1;

Preferably, the heterocyclic group is a heterocycloalkyl group.

In some embodiments, the ring C does not include the following structural fragment: Wherein, * indicates the connection site with ring A and ring B, Indicates the attachment site to L.

In some embodiments, the ring C contains 1 heteroatom, the ring A and the ring B are located at the alpha position of the heteroatom (also referred to as: the ring A and the ring B are located at the ortho position of the heteroatom), and/or L is located at the alpha position of the heteroatom (also referred to as: L is located at the ortho position of the heteroatom) or the beta position of the heteroatom (also referred to as: L is located at the meta position of the heteroatom).

In some embodiments, the ring C is selected from 5-8 membered heterocycloalkyl or 5-6 membered heterocycloalkyl.

In some embodiments, the ring C is selected from a 5-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group contains 1 heteroatom selected from O, N or S; preferably, the heterocycloalkyl group contains 1 heteroatom selected from O or S; preferably, the ring A and the ring B are located at the alpha position to the heteroatom, and/or L is located at the alpha position or beta position to the heteroatom.

In some embodiments, the ring C is selected from: cyclopentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, hexahydropyrazinyl, morpholinyl, thiomorpholinyl, piperidinyl, 1,4-dioxanyl or hexahydropyrimidinyl;

Preferably, the ring C is selected from: cyclopentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl or 1,4-dioxanyl;

Further preferably, the ring C is selected from: Wherein, * indicates the connection site with ring A and ring B;

More preferably, the ring C is Wherein, * indicates the connection site with ring A and ring B.

In some embodiments, the ring C is selected from:

Preferably, the ring C is selected from:

Further preferably, the ring C is selected from:

Wherein, * indicates the connection site with ring A and ring B, Indicates the attachment site to L.

In some embodiments, the Rc is selected from hydrogen, deuterium _, halogen, C _1-4 alkyl, C 1-4 alkoxy, C _1-4 alkylene OH, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

Preferably, Rc is selected from hydrogen, deuterium, halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylene OH, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S).

In some embodiments, the Rc is selected from hydrogen, deuterium, halogen, C _1-4 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

Preferably, Rc is selected from hydrogen, deuterium, halogen, C _1-3 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S); further preferably, Rc is selected from hydrogen, deuterium, fluorine, methyl, hydroxyl or oxo (=O);

More preferably, the Rc is selected from hydrogen or deuterium.

In some embodiments, the Rc is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, hydroxyl, cyano, methoxy, ethoxy, _-CH2OH , oxo (=O), or thiocarbonyl (=S);

Preferably, Rc is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, hydroxyl, oxo (=O) or thiocarbonyl (=S);

More preferably, the Rc is selected from hydrogen, deuterium, fluorine, chlorine, methyl, hydroxyl, methoxy or oxo (=O).

In some embodiments, n is selected from 0, 1 or 2; preferably 0 or 1.

In some embodiments, the combination of Ring C and Rc is selected from:

Wherein, * indicates the connection site with ring A and/or ring B, represents the attachment site to L;

Preferably, the combination of ring C and Rc is selected from: Wherein, * indicates the connection site with ring A and/or ring B, represents the attachment site to L;

Further preferably, the combination of ring C and Rc is selected from: Wherein, * indicates the connection site with ring A and ring B, Indicates the attachment site to L.

In some embodiments, L is selected from the following groups which are unsubstituted or substituted: C _1-4 alkylene, -OC _1-4 alkylene, -OC _3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C _2-4 alkenyl, C _2-4 alkynyl, C _3-9 cycloalkyl, and 3-9 membered heterocyclyl;

Preferably, L is selected from the following groups which are unsubstituted or substituted: C _1-4 alkylene, -OC _1-4 alkylene, -OC _3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl;

Further preferably, L is selected from the following groups which are unsubstituted or substituted: C _1-3 alkylene, -OC _1-3 alkylene, -OC _3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl;

Further preferably, L is selected from the following groups which are unsubstituted or substituted: C _1-2 alkylene, -OC _1-2 alkylene, -OC _3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C _2-3 alkenyl, C _2-3 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl;

Further preferably, L is selected from the following groups which are unsubstituted or substituted: C _1-2 alkylene, -OC _1-2 alkylene, -OC _4-6 cycloalkyl, -O-(4-6 membered heterocyclyl), C _2-3 alkenyl, C _2-3 alkynyl, C _4-6 cycloalkyl and 4-6 membered heterocyclyl; further preferably, L is selected from the following groups which are unsubstituted or substituted: C _1-2 alkylene, -OC _1-2 alkylene, -OC _5-6 cycloalkyl, -O-(5-6 membered heterocyclyl), C _2-3 alkenyl, C _2-3 alkynyl, C _5-6 cycloalkyl and 5-6 membered heterocyclyl;

Wherein, preferably, the heterocyclic group is a heterocycloalkyl group;

Wherein, the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen.

_In some embodiments, L is selected from the following groups _, which are unsubstituted or substituted: _-CH2- , -CH2CH2-, _-OCH2-, _-OCH2CH2- , vinyl, ethynyl, cyclopropanyl, cyclobutanyl, _{cyclopentanyl} , cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl;

Preferably, L is selected from the following groups which are unsubstituted or substituted: -CH ₂ -, -CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, vinyl or ethynyl;

wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen;

Further preferably, L is selected from: -CH ₂ -, -CD ₂ -, -CH ₂ CH ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ -, vinyl or ethynyl;

More preferably, L is selected from: -CH ₂ -, -CD ₂ -, or -CH ₂ CH ₂ -.

In some embodiments, said L is -CH ₂ - or -CD ₂ -. In some embodiments, said L is -CH ₂ -.

In some embodiments, the R ¹ is selected from hydrogen, unsubstituted or substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-9 cycloalkyl, C _3-9 cycloalkenyl, C _6-10 aryl, _3-9 membered heterocyclyl, and 5-10 membered heteroaryl;

Preferably, R ¹ is selected from hydrogen, unsubstituted or substituted C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, _3-8 membered heterocyclyl and 5-9 membered heteroaryl;

Further preferably, the R ¹ is selected from hydrogen, unsubstituted or substituted groups: C _1-3 alkyl, C _3-6 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, the R ¹ is selected from hydrogen, unsubstituted or substituted groups: C _1-3 alkyl, C _3-6 cycloalkyl and 3-7 membered heterocyclyl;

Among them, the 3-7 membered heterocyclic group is preferably a 3-6 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, and more preferably a 5-6 membered heterocyclic group;

Wherein, preferably, the heterocyclic group is a heterocycloalkyl group;

Further preferably, the R ¹ is selected from hydrogen, unsubstituted or substituted following groups: C _1-3 alkyl;

Further preferably, the R ¹ is selected from hydrogen, unsubstituted or substituted groups: methyl;

Wherein, the substitution is substitution by m5 identical or different R ⁶ and/or R ⁷ .

Further preferably, the R ¹ is selected from hydrogen, methyl, deuterated methyl;

More preferably, the R ¹ is selected from hydrogen, methyl, and -CD ₃ .

In some embodiments, the R ¹ is selected from H, -CH ₃ , -CD ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ (cyclopropyl), -CH ₂ (phenyl), cyclopropyl, oxetanyl, tetrahydropyranyl, -C(O)O(tert-butyl), and -C(O)(cyclopropyl).

In some embodiments, the R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-9 cycloalkyl, C _3-9 cycloalkenyl, C _6-10 aryl, 3-9 membered heterocyclyl, and 5-10 membered heteroaryl;

Preferably, R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, phenyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl;

Further preferably, R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, the R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, C _3-7 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, the R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, C _3-7 cycloalkyl and 3-7 membered heterocyclic group;

Among them, the 3-7 membered heterocyclic group is preferably a 3-6 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, and further preferably a 5-6 membered heterocyclic group;

Wherein, preferably, the heterocyclic group is a heterocycloalkyl group;

Further preferably, the R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, azepanyl, cyclopropyl, cyclobutane, oxetanyl, azetidinyl, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furanyl, thiophene phenyl, cyclohexyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyrimidinyl, morpholinyl or tetrahydropyranyl;

Further preferably, R ² is selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, cyclopropyl, oxetanyl, tetrahydropyranyl or azepanyl;

Further preferably, the R ² is selected from the following groups which are unsubstituted or substituted: methyl, ethyl, propyl, isopropyl, oxetanyl, tetrahydropyranyl, cyclopropyl, -CH ₂ CH(CH ₃ ) ₂ or azepanyl;

Wherein, the substitution is substitution by m5 identical or different R ⁶ and/or R ⁷ ;

More preferably, the R ² is selected from methyl, ethyl, propyl, isopropyl, -CH ₂ CH(CH ₃ ) ₂ , deuterated methyl, azepanyl, oxetanyl, tetrahydropyranyl, cyclopropyl or -CH ₂ cyclopropyl; preferably, the deuterated methyl is -CD ₃ .

In some embodiments, the ^R2 is selected from _-CH3 _, _-CD3 , _-C2H5 _, _-C3H7 , -CH( _CH3 ) ₂ , -CH2(cyclopropyl), _-CH2 (phenyl), cyclopropyl, oxetanyl, tetrahydropyranyl, -C(O)O(tert-butyl), and -C( _O )(cyclopropyl).

In some embodiments, the "deuterated" refers to being substituted with 1, 2 or 3 deuteriums (D); preferably, being substituted with 3 deuteriums.

In some embodiments, the R ¹ and R ² are each independently selected from the following groups which are unsubstituted or substituted: C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-9 cycloalkyl, C _3-9 cycloalkenyl, C _6-10 aryl, _3-9 membered heterocyclyl and 5-10 membered heteroaryl;

Preferably, ^R1 and ^R2 are each independently selected from the following groups which are unsubstituted or substituted: _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C3-8 cycloalkyl, _C3-8 cycloalkenyl, phenyl, _3-8 membered heterocyclyl and 5-9 membered heteroaryl;

Further preferably, ^R1 and ^R2 are each independently selected from the following groups which are unsubstituted or substituted: _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C3-6 cycloalkyl, _C3-6 cycloalkenyl, phenyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl; further preferably, ^R1 and ^R2 are each independently selected from the following groups which are unsubstituted or substituted: _C1-3 alkyl, C2-3 alkenyl, _C2-3 alkynyl, _C4-6 cycloalkyl, _C4-6 cycloalkenyl, phenyl, _4-6 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, ^R1 and ^R2 are each independently selected from the following groups which are unsubstituted or substituted: _C1-3 alkyl, _C2-3 alkenyl, _C2-3 alkynyl, _C5-6 cycloalkyl, _C5-6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, the R ¹ and R ² are each independently selected from the following groups which are unsubstituted or substituted: C _1-3 alkyl;

Further preferably, R ¹ and R ² are each independently selected from the following groups which are unsubstituted or substituted: methyl, ethyl or propyl;

Further preferably, said R ¹ and R ² are each independently selected from unsubstituted or substituted methyl;

In some embodiments, both R ¹ and R ² are -CH ₃ ; in some embodiments, both R ¹ and R ² are -CH ₃ ; in some embodiments, both R ¹ and R ² are -CD ₃ _.

In some embodiments, ^R1 and ^R2 form an unsubstituted or substituted 4-10 membered heterocyclyl or 4-10 membered heterocycloalkyl with the nitrogen atom to which they are attached, wherein the substitution is substitution by m8 identical or different ^R6 and/or ^R7 , and the 4-10 membered heterocyclyl or 4-10 membered heterocycloalkyl contains 1 nitrogen atom, or the 4-10 membered heterocyclyl or 4-10 membered heterocycloalkyl contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S.

In some embodiments, the substitution is substituted by 1 R ⁶ or R ^7. In some embodiments, the R ¹ and R ² form the following groups which are unsubstituted or substituted with the nitrogen atom to which they are attached: 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, 11-membered heterocyclyl and 12-membered heterocyclyl;

Further preferably, the ^R1 and ^R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 7-membered spiro heterocyclic group, a 7-membered fused heterocyclic group, an 8-membered monocyclic heterocyclic group, an 8-membered bridged heterocyclic group, an 8-membered spiro heterocyclic group, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a 9-membered spiro heterocyclic group, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a 10-membered spiro heterocyclic group, a 10-membered fused heterocyclic group, an 11-membered bridged heterocyclic group, an 11-membered spiro heterocyclic group, a 11-membered fused heterocyclic group, a 12-membered bridged heterocyclic group, a 12-membered spiro heterocyclic group and a 12-membered fused heterocyclic group;

Further preferably, the ^R1 and ^R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 7-membered bridged heterocyclic group, 7-membered spiro heterocyclic group, 7-membered fused heterocyclic group, 8-membered monocyclic heterocyclic group, 8-membered bridged heterocyclic group, 8-membered spiro heterocyclic group, 8-membered fused heterocyclic group, 9-membered bridged heterocyclic group, 9-membered spiro heterocyclic group, 9-membered fused heterocyclic group, 10-membered monocyclic heterocyclic group, 10-membered cyclohetero ... 10-membered bridged heterocyclic group, 10-membered spiro heterocyclic group and 10-membered fused heterocyclic group;

Further preferably, the ^R1 and ^R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 3-membered/5-membered spiro heterocyclic group, a 4-membered/4-membered spiro heterocyclic group, a 7-membered fused heterocyclic group, an 8-membered monocyclic heterocyclic group, an 8-membered bridged heterocyclic group, a 3-membered/6-membered spiro heterocyclic group, a 4-membered/5-membered spiro heterocyclic group, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a 3-membered/7-membered spiro heterocyclic group, a 4-membered/6-membered spiro heterocyclic group, a 5-membered/5-membered spiro heterocyclic group, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a 4-membered/7-membered spiro heterocyclic group, a 5-membered/6-membered spiro heterocyclic group and a 10-membered fused heterocyclic group;

Further preferably, the ^R1 and ^R2 form the following groups which are unsubstituted or substituted with the nitrogen atom to which they are connected: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 3-membered/5-membered spiro heterocyclic group, a 4-membered/4-membered spiro heterocyclic group, an 8-membered monocyclic heterocyclic group, an 8-membered bridged heterocyclic group, a 3-membered/6-membered spiro heterocyclic group, a 4-membered/5-membered spiro heterocyclic group, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a 3-membered/7-membered spiro heterocyclic group, a 4-membered/6-membered spiro heterocyclic group, a 5-membered/5-membered spiro heterocyclic group, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a 4-membered/7-membered spiro heterocyclic group, a 5-membered/6-membered spiro heterocyclic group and a 10-membered fused heterocyclic group; further preferably, the R1 and R2 form the following groups which are unsubstituted or substituted with the nitrogen atom to which they are connected: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 3-membered/5-membered spiro heterocyclic group, a 4-membered/7-membered spiro heterocyclic group, a 5 ^- membered/6-membered spiro heterocyclic group and a 10-membered fused heterocyclic group. ² forms the following groups which are unsubstituted or substituted with the nitrogen atom to which it is attached: 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 7-membered bridged heterocyclic group, heterospiro[2.4]heptyl, heterospiro[2.4]heptenyl, heterospiro[3.3]heptyl, 8-membered monocyclic heterocyclic group, 8-membered bridged heterocyclic group, heterospiro[2.5]octanyl, heterospiro[2.5]octenyl, heterospiro[3.4]octanyl, heterospiro[3.4] octenyl, 8-membered fused heterocyclic group, 9-membered bridged heterocyclic group, heterospiro[2.6]nonanyl, heterospiro[2.6]nonenyl, heterospiro[3.5]nonanyl, heterospiro[3.5]nonanyl, heterospiro[4.4]nonanyl, heterospiro[4.4]nonenyl, 9-membered fused heterocyclic group, 10-membered bridged heterocyclic group, heterospiro[3.6]decanyl, heterospiro[3.6]decenyl, heterospiro[4.5]decanyl, heterospiro[4.5]decenyl and 10-membered fused heterocyclic group;

Further preferably, ^R1 and ^R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 7-membered bridged heterocyclic group, heterospiro[2.4]heptyl, heterospiro[3.3]heptyl, 8-membered heterocyclic group, 8-membered bridged heterocyclic group, heterospiro[2.5]octanyl, heterospiro[3.4]octanyl, 8-membered fused heterocyclic group, 9-membered bridged heterocyclic group, heterospiro[2.6]nonanyl, heterospiro[3.5]nonanyl, heterospiro[4.4]nonanyl, 9-membered fused heterocyclic group, 10-membered bridged heterocyclic group, heterospiro[3.6]decyl, heterospiro[4.5]decyl and 10-membered fused heterocyclic group;

Further preferably, ^R1 and ^R2 and the nitrogen atom to which they are attached form the following groups which are unsubstituted or substituted: 4-membered monocyclic heterocyclyl, 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, heterospiro[3.3]heptyl, heterospiro[3.4]octanyl, heterospiro[4.4]nonanyl, heterospiro[4.5]decyl, and heterospiro[3.5]nonanyl;

Wherein, the substitution is substitution by m8 identical or different R ⁶ and/or R ⁷ ; preferably, the substitution is substitution by 1 R ⁶ or R ⁷ ;

Wherein, the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S; preferably, the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N or O;

The "hetero" refers to a heteroatom, wherein the heteroatom is 1 nitrogen atom, or the heteroatom is 1 nitrogen atom and 1-2 atoms selected from N, O or S; preferably, the heteroatom is 1 nitrogen atom, or the heteroatom is 1 nitrogen atom and 1-2 atoms selected from N or O;

Wherein, for bridged heterocyclic groups, spiro heterocyclic groups and fused heterocyclic groups, the number of ring atoms in each ring includes the number of shared atoms;

More preferably, the heterocyclic group is a heterocycloalkyl group.

In some embodiments, the ^R1 and ^R2 form the following groups, which are unsubstituted or substituted, with the nitrogen atom to which they are attached: azetidine, pyrrolidine, tetrahydroimidazole, piperidine, piperazine, 1,4-oxazine, 1,4-tetrahydrooxazine, azepanyl, 1,4-diazepanyl, 1,4-oxaazepanyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxazaspiro[3.4]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxazaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, oxazaspiro[4.5]decanyl, azaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, and oxazaspiro[3.5]nonanyl;

Preferably, ^R1 and ^R2 form the following groups which are unsubstituted or substituted with the nitrogen atom to which they are attached: azetidine, pyrrolidine, tetrahydroimidazole, piperidine, piperazine, 1,4-oxazine, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxazaspiro[3.4]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxazaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, oxazaspiro[4.5]decyl, azaspiro[4.5]decyl, Spiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, and oxazaspiro[3.5]nonanyl;

Wherein, the substitution is substitution by m8 identical or different R ⁶ and/or R ⁷ .

In some embodiments, the heterocyclic group formed by R ¹ and R ² and the nitrogen atom to which they are attached is selected from the following unsubstituted or substituted groups:

The heterocyclic group formed by ^R1 and ^R2 and the nitrogen atom to which they are connected is selected from the following unsubstituted or substituted groups:

Wherein, * represents the N atom connected to L, and the substitution is substitution by m8 identical or different R ⁶ and/or R ⁷ ;

Preferably, the substitution is substituted by 1 R ⁶ or R ⁷ ;

More preferably, the substitution is substituted by a group selected from the group consisting of hydroxyl, acetyl, methyl, -N(CH ₃ ) ₂ , -NH(CH ₃ ), oxo, methoxy, -OCH ₂ phenyl, -CO phenyl, -COOC ₂ H ₅ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -CH ₂ OH, -NHCOCH ₃ , cyano, -CONH (cyclobutyl), -CONH (cyclopentyl) or vinyl, wherein the cyclobutyl is unsubstituted or substituted with one methyl group, Indicates the substitution site.

In some embodiments, the substitution is substituted by 1 group selected from the group consisting of hydroxy, acetyl, methyl, -N(CH ₃ ) ₂ , -NH(CH ₃ ), oxo, methoxy, -OCH ₂ phenyl, -CO phenyl, -COOC ₂ H ₅ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -CH ₂ OH, -NHCOCH ₃ , cyano, -CONH (cyclobutyl), -CONH (cyclopentyl), vinyl, -OCH ₂ (4-fluorophenyl) and -OCH ₂ (4-chlorophenyl), wherein the cyclobutyl group is unsubstituted or substituted with one methyl group, Indicates the substitution site.

Preferably, the heterocyclic group formed by ^R1 and ^R2 and the nitrogen atom to which they are connected is selected from the following unsubstituted or substituted groups:

Further preferably, the heterocyclic group formed by ^R1 and ^R2 and the nitrogen atom to which they are connected is selected from the following unsubstituted or substituted groups:

Preferably, the substitution is substituted by 1 R ⁶ or R ⁷ ;

Further preferably, the substitution is substitution by one group selected from the group consisting of hydroxyl, acetyl, methyl, -N(CH ₃ ) ₂ , -NH(CH ₃ ), oxo, -CH ₂ OH, -NHCOCH ₃ , cyano, -CONH (cyclobutyl), -CONH (cyclopentyl) or vinyl, wherein the cyclobutyl is unsubstituted or substituted by one methyl;

More preferably, the substitution is substitution by one group selected from the group consisting of hydroxyl, acetyl or methyl.

" ^R1 or ^R2 are each independently connected to a ring atom on ring C to form an unsubstituted or substituted 4-12 membered heterocyclic ring" means that the structural unit -LN( ^R1 ) ^-R2 or -LN( ^R2 ) ^-R1 in formula (I) is connected to a ring atom on ring C (for example, 1 or 2 ring atoms on ring C) to form an unsubstituted or substituted 4-12 membered heterocyclic ring. substituted or substituted 4-12 membered heterocyclic ring.

In some embodiments, L is -CH ₂ - or -CH ₂ CH ₂ -.

In some embodiments, the R ¹ or R ² is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-9 membered heterocyclic group;

Preferably, the R ¹ or R ² is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-8 membered heterocyclic group;

Further preferably, the R ¹ or R ² is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-7 membered heterocyclic group;

Further preferably, the R ¹ or R ² is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 5-7 membered heterocyclic group;

Further preferably, the R ¹ or R ² is independently connected to the ring atoms on the ring C to form an unsubstituted or substituted 4-6 membered heterocyclic group;

Further preferably, the R ¹ or R ² is independently connected to the ring atoms on the ring C to form an unsubstituted or substituted 5-6 membered heterocyclic group;

Wherein, the connection mode between the heterocyclic group and ring C is spiro connection, fusion or bridge connection;

Further preferably, the ^R1 is connected to the ring atoms on the ring C to form an unsubstituted or substituted 5-6 membered heterocyclic group, and the 5-6 membered heterocyclic group is connected to the ring C in a spiral or fused manner to form a bicyclic ring;

Further preferably, the R ² is connected to the ring atoms on the ring C to form an unsubstituted or substituted 5-6 membered heterocyclic group, and the 5-6 membered heterocyclic group is connected to the ring C in a spiral or fused manner to form a bicyclic ring;

Wherein, the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S; preferably, the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N or O; further preferably, the heterocyclic group contains 1 N atom;

Further preferably, the heterocyclic group is a heterocycloalkyl group;

Further preferably, the R ¹ is connected to the ring atoms on the ring C to form an unsubstituted or substituted heterocyclic ring: piperidine ring, tetrahydropyrrole ring, azetidine;

Further preferably, the R ¹ is connected to the ring atoms on the ring C to form the following unsubstituted or substituted heterocycle: Wherein, * represents the screw connection site or fusion site with ring C;

More preferably, the ring C in formula (I) and the structural unit -LN(R ² )-R ¹ together form the following structure: Wherein, * indicates the connection site with ring A and ring B;

Wherein, the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ ; preferably, the substitution is substitution by deuterium or methyl.

In some embodiments, R ² in the above structure is selected from the following substituted or unsubstituted groups: -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ (cyclopropyl), -CH ₂ (phenyl), cyclopropyl, oxetanyl or tetrahydropyranyl; preferably, R ¹ is selected from -CH ₃ , -CD ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ or -CH ₂ (cyclopropyl); preferably, the substitution is substitution with deuterium, methyl, -C(O)OR ⁸ and oxo (＝O); further preferably, the substitution is substitution with deuterium, methyl, -C(O)O tert-butyl and oxo (＝O).

In some embodiments, ^R2 in the above structures is selected from _-CH3 , _-CD3 , _-C2H5 _{, -C3H7} _, -CH( _CH3 ) ₂ , -CH2( _cyclopropyl ), _-CH2 (phenyl), cyclopropyl, oxetanyl, tetrahydropyranyl, -C(O)O(tert-butyl ₎ , and -C(O)(cyclopropyl).

In some embodiments, the R ² is connected to the ring atoms on ring C to form an unsubstituted or substituted heterocycle: Wherein, * represents the screw connection site or fusion site with ring C;

Preferably, the ring C in formula (I) and the structural unit -LN(R ¹ )-R ² together form the following structure: Wherein, * indicates the connection site with ring A and ring B;

Wherein, the substitution is substitution with m9 identical or different R ⁶ and/or R ⁷ ; preferably, the substitution is substitution with deuterium, methyl, -C(O)OR ⁸ and oxo (=O).

In some embodiments, R ¹ in the above structure is selected from H, substituted or unsubstituted following groups: -CH ₃ , -CD ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ , -CH ₂ (cyclopropyl), -CH ₂ (phenyl), cyclopropyl, oxetanyl or tetrahydropyranyl; preferably, R ¹ is selected from -CH ₃ , -CD ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -CH(CH ₃ ) ₂ or -CH ₂ (cyclopropyl); preferably, the substitution is substitution with deuterium, methyl, -C(O)OR ⁸ and oxo (＝O); further preferably, the substitution is substitution with deuterium, methyl, -C(O)O tert-butyl and oxo (＝O).

In some embodiments, ^R1 in the above structures is selected from H, _-CH3 , _-CD3 , _-C2H5 _, _-C3H7 , -CH( _CH3 ) ₂ , -CH2( _cyclopropyl ), _-CH2 (phenyl), cyclopropyl, oxetanyl, tetrahydropyranyl, -C ₍ O)O(tert-butyl), and -C(O)(cyclopropyl).

In some embodiments, Ring C in Formula (I) and the structural unit -LN(R ¹ )-R ² together form the following structure: Wherein, * represents the connection site with ring A and ring B. In some embodiments, ring C in formula (I) and the structural unit -LN(R ² )-R ¹ together form the following structure: Wherein, * indicates the connection site with ring A and ring B.

In some embodiments, Ring C in Formula (I) and the structural unit -LN(R ² )-R ¹ together form the following structure: Wherein, * indicates the connection site with ring A and ring B.

In some embodiments, each occurrence of R ⁶ is independently selected from the following groups, which are unsubstituted or substituted: C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;

Preferably, each occurrence of R ⁶ is independently selected from the following groups, which are unsubstituted or substituted: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;

Further preferably, each occurrence of R ⁶ is independently selected from the following groups, which are unsubstituted or substituted: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, phenyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, each occurrence of R ⁶ is independently selected from the following groups, which are unsubstituted or substituted: C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, each occurrence of R ⁶ is independently selected from the following groups, which are unsubstituted or substituted: C _1-3 alkyl, C _2-4 alkenyl or C _3-6 cycloalkyl;

Further preferably, each occurrence of R ⁶ is independently selected from the following groups: unsubstituted or substituted: methyl, vinyl or cyclopropyl;

Wherein, the substitution is substitution by m6 identical or different R ⁷ and/or R ⁸ .

In some embodiments, each occurrence of R ⁶ is independently selected from the following groups: unsubstituted or substituted: methyl, vinyl, or cyclopropyl, phenyl and

Preferably, each occurrence of R ⁶ is independently selected from the following groups: unsubstituted or substituted: methyl, vinyl or, cyclopropyl, Phenyl and in, represents the connection site with R2;

In some embodiments, the substitution is with 1 R ⁷ or R ⁸ .

In some embodiments, each occurrence of R ⁷ is independently selected from the group consisting of deuterium, nitro, -OR ⁸ , -O(CH ₂ ) R ⁸ , -O(CH ₂ ) ₂ R ⁸ , -NR ⁸ R ⁸ , halogen, -CN, -C(O)R ⁸ , -C(O)OR ⁸ , -N(R ⁸ )C(O)R ⁸ , -C(O)NR ⁸ R ⁸ , -OC(O)R ⁸ , -S(O) _0-2 R ⁸ , and oxo (＝O).

In some embodiments, each occurrence of R ⁷ is independently selected from the group consisting of deuterium, nitro, -OR ⁸ , -NR ⁸ R ⁸ , halogen, -CN, -C(O)R ⁸ , -C(O)OR ⁸ , -N(R ⁸ )C(O)R ⁸ , -C(O)NR ⁸ R ⁸ , -OC(O)R ⁸ , -S(O) _0-2 R ⁸ , and oxo (＝O);

Preferably, said R ⁷ at each occurrence is independently selected from the group consisting of: deuterium, -OR ⁸ , -NR ⁸ R ⁸ , -C(O)R ⁸ , -CN, -N(R ⁸ )C(O)R ⁸ , -C(O)NR ⁸ R ⁸ and oxo (=O).

In some embodiments, each occurrence of R ⁷ is independently selected from: deuterium, hydroxyl, methoxy, -N(CH ₃ ) ₂ , -NH(CH ₃ ), -COCH ₃ , -CN, -NHCOCH ₃ , -CONHCH ₃ , -CONH(cyclobutyl), -CONH(cyclopentyl), -OCH ₂ phenyl, -OCH ₂ (4-fluorophenyl), -OCH ₂ (4-chlorophenyl), -COphenyl, -COOC ₂ H ₅ , -CON(CH ₃ ) ₂ , or oxo, the cyclobutyl group is unsubstituted or substituted by 1 methyl group, Indicates the connection site.

In some embodiments, each occurrence of R ⁷ is independently selected from the group consisting of: deuterium, hydroxyl, methoxy, -N(CH ₃ ) ₂ , -NH(CH ₃ ), -COCH ₃ , -CN, -NHCOCH ₃ , -CONHCH ₃ , -CONH(cyclobutyl), -CONH(cyclopentyl), -OCH ₂ phenyl, -COphenyl, -COOC ₂ H ₅ , -CON(CH ₃ ) ₂ , or oxo, the cyclobutyl group is unsubstituted or substituted by 1 methyl group.

In some embodiments, each occurrence of R ⁷ is independently selected from: deuterium, hydroxyl, methoxy, -N(CH ₃ ) ₂ , -NH(CH ₃ ), -COCH ₃ , -CN, -NHCOCH ₃ , -CONHCH ₃ , -CONH(cyclobutyl), -CONH(cyclopentyl) or oxo, wherein the cyclobutyl is unsubstituted or substituted with 1 methyl.

In some embodiments, each occurrence of R ⁸ is independently selected from hydrogen, unsubstituted or substituted C _1-4 alkyl, C _2-4 alkenyl, C 2-4 alkynyl, C _3-10 cycloalkyl, C _6-10 aryl, 3-10 membered heterocyclyl, and _5-10 membered heteroaryl;

Preferably, each occurrence of R ⁸ is independently selected from hydrogen, unsubstituted or substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, each occurrence of R ⁸ is independently selected from hydrogen, unsubstituted or substituted groups: C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-6 cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl;

Further preferably, said R ⁸ is independently selected at each occurrence from hydrogen, unsubstituted or substituted following groups: C _1-3 alkyl, 4-6 membered heterocyclyl, phenyl, and C _3-5 cycloalkyl;

Further preferably, each occurrence of R ⁸ is independently selected from hydrogen, unsubstituted or substituted groups: methyl, ethyl, cyclopropane, cyclobutane, tetrahydropyrrolyl, phenyl, or cyclopentane;

Further preferably, each occurrence of R ⁸ is independently selected from hydrogen, unsubstituted or substituted groups: methyl, cyclobutane, cyclopropane, tetrahydropyrrolyl or cyclopentane;

wherein the substitution is by m7 identical or different C _1-4 alkyl, cyano, amino, hydroxyl, halogen, deuterium, -OC _1-4 alkyl, -C _1-4 alkylOH, C _3-5 cycloalkyl, C _1-4 haloalkyl, -S(O) ₀ - ₂ C _1-3 alkyl, -N(C 1-3 alkyl) ₂ , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl, -C(O) _0-2 C 1-3 alkyl, -OC(O)C _1-3 alkyl, -NHCOC _1-3 alkyl, -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) 2 , -NHSO 2 C 1-3 alkyl, -NHCONHC _1-3 alkyl or oxo; preferably, the substitution is by m7 identical or different C 1-3 alkyl, cyano, amino, hydroxyl, halogen, deuterium, -OC 1-3 alkyl, -C 3-5 cycloalkyl, C 1-4 haloalkyl, -S(O) 0 - 2 C _1-3 alkyl, -N(C _1-3 alkyl) ₂ , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl, -C(O) _0-2 C _1-3 alkyl, -OC(O)C _1-3 alkyl, -NHCOC 1-3 alkyl, -CONHC _1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHSO 2 C _1-3 alkyl, -NHCONHC _1-3 alkyl or oxo; ₂ , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl, -C(O) _0-2 C _1-3 _alkyl , -OC(O)C _1-3 alkyl, -NHCOC _1-3 alkyl, -CONHC _1-3 alkyl, -CON(C _1-3 alkyl) ₂ , -NHSO ₂ C _1-3 alkyl, -NHCONHC _1-3 _alkyl or oxo; further preferably, the substitution is substituted by m7 identical or different C _1-3 alkyl, cyano, _amino _{, hydroxyl, halogen, deuterium, -OC 1-3 alkyl, -C 1-3} _alkylOH _{, C 3-5} _{cycloalkyl, C 1-3} _haloalkyl _, _-N ₍ _C _1-3 _alkyl ) ₂ , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl or oxo; further preferably, the substitution is substituted by m7 identical or different C _1-4 alkyl, cyano, amino, hydroxyl or halogen; further preferably, the substitution is substituted by m7 identical or different C _1-3 alkyl, cyano, amino, hydroxyl or halogen; further preferably, the substitution is substituted by m7 identical or different methyl, ethyl, cyano, amino, hydroxyl or halogen; further preferably, the substitution is substituted by m7 identical or different methyl, fluorine or chlorine; further preferably, the substitution is substituted by 1 methyl.

In some embodiments, m1, m2, m3, m4, m5, m6, m7, m8 and m9 are each independently selected from 1, 2, 3, 4 or 5; preferably 1, 2 or 3; further preferably 1 or 2; further preferably 1.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (II):

Wherein, Ring A, Ring B, Rc, n, L, ^R1 and ^R2 are as defined in the compound shown in Formula (I);

X is selected from C, O or S;

Ring C is a 3- to 7-membered heterocyclic group.

In some embodiments, X is O or S.

In some embodiments, ring A and ring B are each independently selected from the following groups which are unsubstituted or substituted: C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably, ring A and ring B are each independently selected from the following groups which are unsubstituted or substituted: phenyl or 5-6 membered heteroaryl; wherein the substitution is substitution with m1 identical or different R ³ and/or R ⁴ .

In some embodiments, the ring A and ring B are each independently selected from the following groups which are unsubstituted or substituted: _C5-6 cycloalkyl, phenyl or 5-6 membered heteroaryl; or, ring A is absent, and ring B is independently selected from the following groups which are unsubstituted or substituted: _C5-6 cycloalkyl, phenyl or 5-6 membered heteroaryl; wherein the substitution is substitution with m1 identical or different ^R3 and/or ^R4 ; in some embodiments, the 5-6 membered heteroaryl contains 1 heteroatom selected from N, O and S.

In some embodiments, ring C is a 3-7 membered monocyclic heterocyclyl; preferably, ring C is a 4-6 membered monocyclic heterocyclyl; preferably, it is a 5-6 membered monocyclic heterocyclyl; further preferably, the heterocyclyl is a heterocycloalkyl.

In some embodiments, L is selected from the following groups which are unsubstituted or _substituted : _-CH2- or _-CH2CH2- ; wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen.

In some embodiments, L is selected from -CH ₂ - or -CH ₂ CH ₂ -.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (III):

in,

t is selected from 1 or 2;

X is C, O or S;

Y is C or O;

L is selected from the following groups which are unsubstituted or substituted: -CH ₂ - or -CH ₂ CH ₂ -; wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen;

Ring A, Ring B, Rc, n, m4, ^R1 and ^R2 are as defined for the compound represented by formula (I).

In some embodiments, L is selected from -CH ₂ - or -CH ₂ CH ₂ -.

In some embodiments, X is C and Y is C.

In some embodiments, X is O and Y is C.

In some embodiments, X is S and Y is C.

In some embodiments, X is O, and Y is O.

In some embodiments, Ring A and Ring B are each independently selected from the following groups which are unsubstituted or substituted: C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein the substitution is substitution with m1 identical or different R ³ and/or R ⁴ .

In some embodiments, the ring A and ring B are each independently selected from the following groups, which are unsubstituted or substituted: _C5-6 cycloalkyl, phenyl or 5-6 membered heteroaryl; or, ring A is absent, and ring B is independently selected from the following groups, which are unsubstituted or substituted: _C5-6 cycloalkyl, phenyl or 5-6 membered heteroaryl; wherein the substitution is substitution with m1 identical or different ^R3 and/or ^R4 ; in some embodiments, the 5-6 membered heteroaryl contains 1 heteroatom selected from N, O and S.

In some embodiments, Ring A and Ring B are both phenyl.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (IV):

in,

X is selected from C or O;

Ring A, Ring B, Rc, m4, ^R1 and ^R2 are as defined for the compound represented by formula (I).

In some embodiments, X is O; Rc is hydrogen;

(1) When R ¹ is -CD ₃ , R ² is -CH ₃ or -CD ₃ ; preferably, R ² is -CD ₃ ;

Alternatively, (2) ^R1 and ^R2 , together with the nitrogen atom to which they are attached, form an unsubstituted or substituted 4-12 membered heterocyclic group, wherein the substitution is substitution by m8 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

Alternatively, (3) ^R1 or ^R2 are each independently connected to a ring atom on ring C to form an unsubstituted or substituted 4-10 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different ^R6 and/or ^R7 , and the 4-10 membered heterocyclic group contains 1 nitrogen atom, or the 4-10 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S.

In some embodiments, X is O,

(1) When R ¹ is H or -CD ₃ , R ² is -CD ₃ , unsubstituted or substituted with the following groups: C _2-6 alkyl, C _3-7 cycloalkyl, 3-7 heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R ² is -CD ₃ , unsubstituted or substituted with the following groups: C _2-5 alkyl, C _3-6 cycloalkyl, 3-7 heterocyclyl, phenyl and 5-6 membered heteroaryl; further preferably, R ² is -CD ₃ , unsubstituted or substituted with the following groups: C _2-4 alkyl, C _3-6 cycloalkyl, 3-7 heterocyclyl, phenyl and 5-6 membered heteroaryl; further preferably, R ² is -CD ₃ , unsubstituted or substituted with the following groups: methyl, ethyl, propyl, isopropyl, CH ₂ CH(CH ₃ ) ₂ , cyclopropyl, -CH ₂ cyclopropyl; wherein the substitution is m5 identical or different R ⁶ and/or R ⁷ Replacement;

Alternatively, (2) when R ¹ is methyl, R ² is -CD ₃ , unsubstituted or substituted with the following groups: C _2-6 alkyl, C _3-7 cycloalkyl, 3-7 heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R ² is -CD ₃ , unsubstituted or substituted with the following groups: C _2-5 alkyl, C _3-6 cycloalkyl, 3-7 heterocyclyl, phenyl and 5-6 membered heteroaryl; further preferably, R ² is -CD ₃ , unsubstituted or substituted with the following groups: C _2-4 alkyl, C _3-6 cycloalkyl, 3-7 heterocyclyl, phenyl and 5-6 membered heteroaryl; further preferably, R ² is -CD ₃ , unsubstituted or substituted with the following groups: methyl, ethyl, propyl, isopropyl, CH ₂ CH(CH ₃ ) ₂ , cyclopropyl, -CH ₂ cyclopropyl; wherein the substitution is substitution by m5 identical or different R ⁶ and/or R ⁷ ;

Alternatively, (3) when R ¹ and R ² are both methyl and L is -CH ₂ -, Rc is selected from deuterium, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S); provided that ① when Rc is hydroxyl, L is not in the ortho position to X; ② when Rc is oxo, its substitution site is not in the ortho position to X.

In some embodiments, X is O; Rc is selected from deuterium, halogen, C _1-4 alkyl, cyano, hydroxy, nitro, oxo (=O) or thiocarbonyl (=S);

(1) R ¹ is -CH ₃ or -CD ₃ , R ² is -CH ₃ or -CD ₃ ;

Alternatively, (2) ^R1 and ^R2 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4-12 membered heterocyclic group, wherein the substitution is substitution by m8 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

Alternatively, (3) R ¹ or R ² are each independently connected to a ring atom on ring C to form an unsubstituted or substituted 4-10 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ , and the 4-10 membered heterocyclic ring contains 1 nitrogen atom, or the 4-10 membered heterocyclic ring contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

Provided that, when Rc is oxo or hydroxy, L and Rc are both located in the beta position to X (ie, meta position to X).

In some embodiments, X is C; Rc is selected from hydrogen, deuterium, halogen, _C1-4 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S); Rc is preferably oxo; provided that, when Rc is oxo, L is located in the β position of Rc (i.e., meta to _RC ).

In some embodiments, the compound represented by formula (I) is a compound represented by formula (V):

in,

t is 1 or 2;

X is S or O;

Y is C or O;

n is 0 or 1;

L is selected from the following groups which are unsubstituted or substituted: -CH ₂ - or -CH ₂ CH ₂ -; wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen; preferably, L is selected from: -CH ₂ - or -CH ₂ CH ₂ -;

In some embodiments, X is O, and Y is C, and t is 2.

In some embodiments, X is O, and Y is O, and t is 2.

In some embodiments, X is S, and Y is C, and t is 1.

^R1 and ^R2 form an unsubstituted or substituted 4-12 membered heterocyclic group with the nitrogen atom to which they are attached, wherein the substitution is substitution by m8 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

X is selected from C, O or S;

Wherein, Ring A, Ring B, Ring C, Rc, n, L, m8, ^R6 and ^R7 are as defined in the compound represented by Formula (I);

Provided that, when X is O and ring C is tetrahydrofuranyl, ^R1 and ^R2 form an unsubstituted 4-12 membered The heterocyclic group is not Wherein * indicates the connection site with L.

In some embodiments, L is selected from -CH ₂ - or -CH ₂ CH ₂ -.

^R1 or ^R2 are each independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-12 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

X is selected from C, O or S;

wherein ring A, ring B, ring C, Rc, n, L, m9, ^R6 and ^R7 are as defined in the compound represented by formula (I).

In some embodiments, the compound is not:

In some embodiments, L is selected from -CH ₂ - or -CH ₂ CH ₂ -.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (VI):

X is selected from C, O or S;

L is selected from -CH ₂ - or -CH ₂ CH ₂ -;

Wherein, Ring A, Ring B, Rc, n, m8, ^R6 and ^R7 are as defined in the compound represented by Formula (I);

Provided that, when X is O, the unsubstituted 4-12 membered heterocyclic group formed by ^R1 and ^R2 and the nitrogen atom to which they are attached is not Among them, * Indicates the attachment site to L.

In some embodiments, X is O.

In some embodiments, X is O; ^R1 and ^R2 form an unsubstituted or substituted 4-12 membered heterocyclic group with the nitrogen atom to which they are attached, wherein the substitution is substitution by m8 identical or different ^R6 and/or ^R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S.

X is selected from C, O or S;

L is selected from -CH ₂ - or -CH ₂ CH ₂ -;

wherein ring A, ring B, Rc, n, m9, ^R6 and ^R7 are as defined in the compound represented by formula (I).

In some embodiments, X is O.

In some embodiments, X is O; R ¹ or R ² are each independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-12 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (VII):

wherein Ring E is selected from an unsubstituted or substituted 4-10 membered heterocyclic group, wherein the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ , and the 4-10 membered heterocyclic group contains 1, 2 or 3 nitrogen atoms;

The connection between ring C and ring E is by spiral connection, fusion or bridge connection; preferably by spiral connection and fusion;

Ring C is Wherein * indicates the connection site with ring A and ring B;

X is selected from C, O or S; preferably O;

In some embodiments, the ring E is selected from unsubstituted or substituted 4-9 membered heterocyclyl;

Preferably, the ring E is selected from an unsubstituted or substituted 4-8 membered heterocyclic group;

Further preferably, the ring E is selected from an unsubstituted or substituted 5-7 membered heterocyclic group;

Further preferably, the ring E is selected from an unsubstituted or substituted 5-6 membered heterocyclic group;

Further preferably, the ring E is selected from an unsubstituted or substituted 5-6 membered heterocyclic group, and the 5-6 membered heterocyclic group is connected to the ring C in a spiral or fused manner to form a bicyclic ring;

Wherein, the heterocyclic group contains 1 or 2 nitrogen atoms; preferably, the heterocyclic group contains one nitrogen atom;

Further preferably, the heterocyclic group is a heterocycloalkyl group;

Wherein, the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ .

In some embodiments, the ring E is selected from the following heterocycles which are unsubstituted or substituted:

Preferably, the ring E is selected from the following unsubstituted or substituted groups: Wherein, * represents the screw connection site or fusion site with ring C;

Wherein, R ² is as defined in the compound of formula (I), and the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ ;

Preferably, the substitution is by 1 C _1-3 alkyl; more preferably, the substitution is methyl.

In some embodiments, Ring C is Wherein * indicates the connection site with ring A and ring B.

In some embodiments, ring A is selected from hydrogen, substituted or unsubstituted following groups: phenyl, cyclohexyl, pyridinyl or pyrimidinyl; ring B is selected from unsubstituted or substituted following groups: phenyl, cyclohexyl, pyridinyl or pyrimidinyl, wherein the substitution is substituted by m1 identical or different ^R3 and/or ^R4 .

In some embodiments, ring A is absent or selected from the following groups which are substituted or unsubstituted: phenyl, cyclohexyl, pyridyl, thienyl or furanyl; ring B is selected from the following groups which are unsubstituted or substituted: phenyl, cyclohexyl, pyridyl, thienyl or furanyl, wherein the substitution is substitution with m1 identical or different R ³ and/or R ⁴ .

In some embodiments, the Selected from the following unsubstituted or substituted groups:

Preferably, the Selected from the following unsubstituted or substituted groups:

, wherein R ² is as defined in the compound of formula (I), and the substitution is substitution by m9 identical or different R ⁶ and/or R ⁷ ;

Preferably, the substitution is by methyl.

In some embodiments, the Selected from the following groups:

Preferably, the Selected from the following groups:

In some embodiments, the compound represented by formula (I), or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt, wherein the compound is selected from the following structures:

In a second aspect, the present application provides a pharmaceutical composition comprising the compound represented by formula (I) or its stereoisomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts.

In some embodiments, the pharmaceutical composition comprises the compound represented by formula (I) or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

The administration of the compound shown in the formula (I) described in the present application or its stereoisomer, optical isomer, solvate, isotopic derivative or its pharmaceutically acceptable salt can be carried out in pure form or in the form of a suitable pharmaceutical composition by providing any acceptable mode of administration of a medicine of similar use. The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable adjuvant. The pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations. Generally, the above-mentioned pharmaceutical composition can be prepared by conventional preparation methods using conventional excipients in the field of preparations.

In the third aspect, the present invention provides the use of the compound represented by formula (I) or its stereoisomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition as Sigma-1 receptor and/or M1-muscarinic acetylcholine receptor ligands.

In some embodiments, the use is use as a Sigma-1 receptor ligand.

In some embodiments, the use is the use of Sigma-1 receptor and M1-muscarinic acetylcholine receptor ligand.

In some embodiments, the ligand is an agonist.

In a fourth aspect, the present application provides the use of the compound represented by formula (I) or its stereoisomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs as Sigma-1 receptor and/or M1-muscarinic acetylcholine receptor ligands.

In some embodiments, the ligand is an agonist. In some embodiments, the drug is a drug with a neuroprotective effect.

In some embodiments, the medicament is a medicament for treating and/or preventing a neurological disease.

In some embodiments, the present application provides the compound represented by formula (I) or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a drug for treating and/or preventing a nervous system disease. the use of.

In some embodiments, the neurological disease is a neurological disease related to memory, cognition, mood, pain, etc.

In some embodiments, the neurological disease is a central nervous system disease.

In some embodiments, the neurological disease is a neurodegenerative disease.

In some embodiments, the neurological disorders include drug addiction and its resulting neurotoxicity, schizophrenia, depression, obsessive-compulsive disorder, anxiety, stroke, Parkinson's disease, Parkinson's disease dementia, Rett syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, and pain.

In a fifth aspect, the present application provides a method for preventing and/or treating nervous system diseases, comprising administering to a subject a therapeutically effective amount of a compound represented by formula (I) or its stereoisomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition.

In some embodiments, the neurological disease is a neurodegenerative disease.

In some embodiments, the neurological disease comprises drug addiction, schizophrenia, depression, obsessive compulsive disorder, anxiety, stroke, Parkinson's disease, Parkinson's disease dementia, Rett syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, and pain.

In a sixth aspect, the present application provides a compound represented by formula (I) or its stereoisomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition for preventing and/or treating nervous system diseases.

In some embodiments, the neurological disease is a neurodegenerative disease.

In a seventh aspect, the present application provides the use of the compound represented by formula (I) or its stereoisomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition in the treatment and/or prevention of nervous system diseases.

In some embodiments, the neurological disease is a neurodegenerative disease.

In some embodiments, in the uses or methods provided herein, the compound represented by formula (I) or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application is used in combination with another, two or more drugs for nervous system diseases.

On the other hand, the compounds described herein can be prepared by one or more of the following methods:

plan 1:

Among them, 1A reacts with triethylphosphonoethyl (formate) ester compounds under alkaline conditions to generate 1B; 1B reacts with manganese acetate and acetic anhydride in acetic acid solution to generate 1C; 1C generates 1D under reducing conditions; 1D is cyclized to generate 1E; 1E is converted into 1F with a leaving group, and 1F reacts with a primary (secondary) amine to generate the target compound;

Scenario 2:

Wherein, 2A reacts with a halogenated malonate diethyl (methyl) ester compound under the action of a catalyst to generate 2B; 2B generates 2C under reduction conditions; 2C is cyclized to generate 2D; 2D is converted into 2E with a leaving group, and 2E reacts with a primary (secondary) amine to generate the target compound;

Scenario 3:

Among them, 3A reacts with methyl (ethyl) acrylate compounds under alkaline conditions to generate 3B; 3B removes the ester group to generate 3C; 3C reacts with trimethyl sulfoxide iodide under alkaline conditions to generate 3D1; 3D1 reacts with primary (secondary) amine to generate 3D2; 3D2 undergoes a substitution reaction to generate the target Compound. Alternatively, 3C can react with (quasi) halides under alkaline conditions to generate 3E1; 3E1 reacts with primary (secondary) amines to generate 3E2; Alternatively, 3C can also directly generate 3E2 under alkaline conditions; 3E2 is reduced to generate the target compound. Alternatively, 3C can react with DMF-DMA reagent to generate 3F1; 3F1 is reduced to generate the target compound;

Solution 4:

Among them, 4A reacts with methyl (ethyl) haloacetate compounds under alkaline conditions to generate 4B; 4B reacts with 1,2-haloethane under alkaline conditions to generate 4C; 4C is cyclized and hydrolyzed under alkaline conditions to generate 4D; 4D is reduced to generate 4E; 4E is converted to 4F with a leaving group; 4F reacts with primary (secondary) amine to generate the target compound;

Solution 5:

Among them, the 5A series compounds react with the Grignard reagent to generate 5B; 5B is cyclized to generate the target compound;

Solution 6:

Wherein, 6A reacts with an N-heterocycloalkyl compound to generate 6B; 6B is cyclized to generate the target compound;

Wherein, ring A, ring B, R ¹ and R ² are as defined in the above formula (I), formula (II), formula (III), formula (IV), formula (V) or formula (VI).

definition

The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond, such as imino (=NH) or thiocarbonyl (=S).

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C _1-10 alkyl), further preferably containing 1-8 carbon atoms (C _1-8 alkyl), and more preferably containing 1-6 carbon atoms (i.e., C _1-6 alkyl). For example, "C _1-6 alkyl" means that the group is an alkyl group, and the number of carbon atoms on the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C _2-10 alkenyl), further preferably 2-8 carbon atoms (C _2-8 alkenyl), more preferably 2-6 carbon atoms (i.e., C _2-6 alkenyl), 2-5 carbon atoms (i.e., C _2-5 alkenyl), 2-4 carbon atoms (i.e., C _2-4 alkenyl), 2-3 carbon atoms (i.e. _{, C 2-3 alkenyl), 2 carbon atoms (i.e., C 2 alkenyl), for example, "C 2-6} _alkenyl _" _means that the group is an alkenyl group, and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms with at least one triple bond. Alkynyl may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C _2-10 alkynyl), further preferably 2-8 carbon atoms (C _2-8 alkynyl), more preferably 2-6 carbon atoms (i.e., C _2-6 alkynyl), 2-5 carbon atoms (i.e., C _2-5 alkynyl), 2-4 carbon atoms (i.e., C _2-4 alkynyl), 2-3 carbon atoms (i.e. _{, C 2-3 alkynyl), 2 carbon atoms (i.e., C 2 alkynyl), for example, "C 2-6} _alkynyl _" _means that the group is an alkynyl, and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl, etc.

Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, including _{3-14 carbon atoms (i.e., C 3-14} _cycloalkyl ), preferably 3-12 carbon atoms (i.e., C _3-12 cycloalkyl), more preferably 3-10 carbon atoms (C _3-10 cycloalkyl), more preferably 3-9 carbon atoms (C _3-10 cycloalkyl) or 4-9 carbon atoms (C _4-9 cycloalkyl), more preferably 3-8 carbon atoms (C _3-8 cycloalkyl) or 4-8 carbon atoms (C _4-8 cycloalkyl), further preferably 3-7 carbon atoms (C _3-7 cycloalkyl), 4-6 carbon atoms (C _4-6 cycloalkyl), 5-6 carbon atoms (C _5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

Unless otherwise specified, the term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, which has a monocyclic or polycyclic ring and has at least one double bond and preferably 1 to 2 double bonds. In some embodiments, the cycloalkenyl group is a cyclopentenyl group (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or a cyclohexenyl group (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl).

Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, the alkyl being as defined above, i.e., containing 1-20 carbon atoms, preferably, containing 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I.

Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1-6 ring heteroatoms, containing 3-20 ring atoms, of which 1, 2, 3, 4, 5 or 6 ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3-14 ring atoms (i.e., 3-14 membered heterocyclyl, the same below), preferably contains 3-12 ring atoms, preferably contains 4-12 ring atoms, preferably contains 4-10 ring atoms, further preferably contains 3-10 ring atoms, or 3-9 ring atoms, or 3-8 ring atoms, or 3-7 ring atoms, or 3-6 ring atoms, or 4-8 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include aziridine, 1,4-dioxane, hexahydropyran, tetrahydrothiophene, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, oxazolidinyl, dioxanyl, dithiolanyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidine, homomorpholine, azepane, diazepane, etc. The monocyclic heterocyclic group is preferably a heterocycloalkyl group. Polycyclic heterocyclyl includes spiro, fused and bridged heterocyclyl, i.e., a "polycyclic heterocyclyl" may be a fused ("fused heterocyclyl" or "heterofused cyclyl"), bridged ("heterobridged cyclyl" or "bridged heterocyclyl") or spiro ("heterospirocyclyl" or "spiro heterocyclyl") ring system, and the polycyclic heterocyclyl is preferably a bicyclic system ("bicyclic heterocyclyl"). The heterocyclyl bicyclic system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl as defined above is fused with one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of atoms in the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of a heterocyclyl is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl").

The term "spirocyclic radical", "spiro heterocyclic radical" or "spiro heterocyclic radical" etc. refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5-10 yuan of monocyclic rings, which may contain one, 2 or more double bonds, but no ring has a completely conjugated π electron system, such as spirocyclic alkenyl, spirocyclic alkyl, heterospirocyclic alkenyl, heterospirocyclic alkyl. Preferably 6-14 yuan, preferably 7-12 yuan, preferably 7-10 yuan (for example, 7 yuan, 8 yuan, 9 yuan, 10 yuan). According to the number of shared spiral atoms between rings, spirocyclic radicals are divided into single spiral cyclic radicals, double spiral cyclic radicals or multiple spiral cyclic radicals. More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 5 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan single spiral cyclic radicals. For example, non-limiting examples of azaspirocyclic radicals include:

The term "fused cyclic group", "fused heterocyclic group" or "fused ring heterocyclic group" refers to a polycyclic system of 5-20 members, each ring in the system shares a pair of adjacent carbon atoms and/or heteroatoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably 6-14 members, preferably 6-12 members, preferably 7-10 members, preferably 8-10 members. Non-limiting examples of fused heterocyclic groups include:

The term "bridged ring group" or "bridged heterocyclic group" refers to a polycyclic group of 5-20 members, any two rings sharing 2 carbon atoms and/or heteroatoms that are not directly connected, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably 6-14 members, preferably 6-12 members, preferably 7-10 members, preferably 8-10 members. Non-limiting examples of bridged heterocyclic groups include:

Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6-10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc. "Aryl" also includes ring systems in which an aryl group as defined above is fused to one or more cycloalkyl, heterocyclyl or heteroaryl groups, wherein the point of attachment is on the aryl ring. In some embodiments, each instance of an aryl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted aryl group") or substituted with one or more substituents (a "substituted aryl group").

Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing 5-14 membered structures, or preferably 5-10 membered structures, or preferably 5-9 membered structures, or preferably 5-8 membered structures, more preferably 5-6 membered structures, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl. "Heteroaryl" also includes ring systems in which a heteroaryl as defined above is fused with one or more cycloalkyl, heterocyclyl or aryl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases the number of members of the heteroaryl ring system is the number of atoms in the ring system after the fusion.

Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for contact with mammalian, especially human tissues without excessive toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit/risk ratio within the scope of reasonable medical judgment, such as amines, carboxylic acids and other types of medically acceptable salts of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

Unless otherwise specified, the term "isotopic derivative" or "isotopic form" means that the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes commonly used as isotope labels are: hydrogen isotopes, ² H (deuterated form) and ³ H; carbon isotopes: ¹³ C and ¹⁴ C, etc. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. In particular, ² H and ¹³ C are more widely used because they are easy to label and convenient to detect. Substitution of certain heavy isotopes, such as deuterium ( ² H), can enhance metabolic stability and prolong half-life to achieve the purpose of reducing dosage and provide therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques like non-isotope-labeled compounds.

Unless otherwise specified, the terms "solvate" and "solvate" mean a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular arrangement and/or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include optical isomers, enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization based on the differences in the physicochemical properties of the components.

"Pharmaceutically acceptable carrier" is also called "pharmaceutically acceptable adjuvant" or "pharmaceutically acceptable excipient", and refers to a pharmaceutically acceptable material, composition or vehicle involved in the transport of the target active ingredient from one organ or part of the body or to another organ or part of the body, such as a liquid or solid excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is harmless to the patient. The preparation of the pharmaceutical composition described herein includes, but is not limited to, for example, mixing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect with a pharmaceutically acceptable carrier.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one.

Abbreviations used in the Preparative Examples, Examples, and elsewhere herein are:

THF: tetrahydrofuran; NaH: sodium hydride; Ac ₂ O: acetic anhydride; TsOH·H ₂ O: p-toluenesulfonic acid monohydrate; 2,6-Lutidine: 2,6-lutidine; DMSO: dimethyl sulfoxide; EtOH: ethanol; DMF-DMA: N,N-dimethylformamide dimethyl acetal; MeOH: methanol; Boc: tert-butyloxycarbonyl; PEI: polyethyleneimine; Tris-HCl: tris(hydroxymethyl)aminomethane hydrochloride; PBS: phosphate buffered saline; BSA: bovine serum albumin; PVDF: polyvinylidene fluoride; RIPA lysis buffer: radioimmunoprecipitation lysis buffer; TBST: contains Tris-HCl, NaCl and Tween20, and is a buffer solution commonly used in Western BLOT.

The present application has one or more of the following beneficial effects:

(1) This application relates to a class of compounds with novel structures, which provide a new direction for the treatment and/or prevention of neurological diseases;

(2) The results of the biological activity test show that, compared with the prior art, the compounds of the present application have comparable or stronger affinity activity for the Sigma-1 receptor; or, the compounds of the present application have comparable or stronger affinity activity for the M1 receptor; preferably, they have comparable affinity activity for the Sigma-1 receptor and stronger affinity activity for the M1 receptor; further preferably, they have stronger affinity activity for the Sigma-1 receptor and the M1 receptor;

(3) The compounds of the present application have good neuroprotective effects; for example, they have good protective effects on cell damage induced by 6-hydroxydopamine (6-OHDA); or, they have good protective effects on cell damage induced by other substances (for example, H2O2, glutamate, Aβ1-42 oligomers, Aβ25-35, etc.);

(4) The compounds of the present application have good pharmacokinetic properties, for example, good oral absorption performance;

(5) The compounds of the present application can effectively reduce the aggregation of erroneous proteins in cells.

Detailed ways

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to professionals in the field. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). The instrument used for NMR determination is Bruker AVANCE III 600MHz, the instrument used for LC-MS is LCMS WATERS ACQUITY UPLC H-Class PLUS or/and SQD2; the instrument used for HPLC is WATERS e2695_2998 or/and Agilent 1100.

The starting materials in the examples of the present application are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

Example 1: Synthesis of Compound 1

Synthesis of intermediate 1-1

Triethylphosphonoacetate (18.46 g, 82.32 mmol) was added to THF (50 mL), the mixture was cooled to 0 ° C, NaH (1.65 g) was added, and benzophenone (5.00 g) was dissolved in THF (10 mL) and added to the mixture. The reaction system was stirred at 0 ° C for 1 h. Water (60 mL) was added to quench the reaction, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1, volume ratio, the same below) to obtain intermediate 1-1 (3.43 g).

Synthesis of intermediate 1-2

Intermediate 1-1 (3.43 g, 13.59 mmol), Mn(OAc) ₃ ·2H ₂ O (10.96 g) and Ac ₂ O (21 mL) were added to acetic acid (140 mL), and the reaction system was stirred at 120°C for 1 h. Water (60 mL) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude Product 1-2 (3.40g).

Synthesis of intermediate 1-3

Intermediate 1-2 (1.00 g, 3.22 mmol) was dissolved in THF (32 mL), and then LiAlH ₄ (611 mg) was added at 0°C under nitrogen protection. The reaction system was stirred at 0°C for 3 h. Water (0.6 mL) and 10% NaOH aqueous solution (0.36 mL) were slowly added dropwise to the reaction system, and then water (1.8 mL) was added, and the mixture was filtered to obtain a crude product 1-3 (830 mg).

Synthesis of intermediates 1-4

Intermediate 1-3 (501 mg, 1.84 mmol) was dissolved in dichloromethane (22 mL), and then TsOH·H ₂ O (80 mg) was added, and the temperature was raised to 40°C and reacted for 24 h. The dichloromethane in the mixed solution was removed by vacuum concentration, and water (20 mL) was added to the residue, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 1-4 (290 mg).

Synthesis of intermediates 1-5

Intermediate 1-4 (239 mg, 0.94 mmol) was dissolved in dichloromethane (12 mL), and then trifluoromethanesulfonic anhydride (401 mg) and 2,6-dimethylpyridine (152 mg) were added dropwise at 0 ° C for 8 h. Water (20 mL) was added to quench, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 1-5 (215 mg).

Synthesis of compound 1:

Intermediate 1-5 (201 mg, 0.52 mmol) was added to THF (5 mL), nitrogen was replaced, the temperature was lowered to 0°C, morpholine (1.5 mL) was then added dropwise to the reaction solution, the reaction solution was gradually warmed to room temperature, and the reaction was continued for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 1 (64 mg), ESI-MS (m/z): 324.25 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO-d6) δ7.57 (d, J = 7.2 Hz, 2H), 7.36-7.29 (m, 4H), 7.27-7.19 (m, 3H), 7.19-7.10 (m, 1H), 4.10-4.02 (m, 1H), 3.75-3.60 (m, 1H), 3.58-3.47 (m, 4H), 3.26 (d, J = 5.4 Hz, 1H), 2.40-2.35 (m, 2H), 2.25-2.13 (m, 2H), 2.13-2.03 (m, 1H), 1.94-1.83 (m, 2H), 1.83-1.74 (m, 1H).

Example 2: Synthesis of Compound 2

Synthesis of compound 2

Intermediate 1-5 (100 mg, 0.26 mmol) was added to dichloromethane (5 mL), and then dimethyl-D6-amine hydrochloride (21 mg) and triethylamine (79 mg) were added to the reaction solution, and the reaction was carried out at room temperature for 12 h. The solvent was removed under reduced pressure, and water (20 mL) was added to the residue, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 2 (17 mg) was obtained by column chromatography separation and purification (petroleum ether: ethyl acetate = 15:1-3:1). ESI-MS (m/z): 288.17 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO-d6) δ7.56 (d, J=7.2 Hz, 2H), 7.33-7.30 (m, 4H), 7.26-7.22 (m, 3H), 7.20-7.10 (m, 1H), 4.07-4.02 (m, 1H), 3.71-3.65 (m, 1H), 3.19-3.15 (m, 1H), 2.08-2.06 (m, 1H), 1.82-1.72 (m, 3H).

Example 3: Synthesis of Compound 3

Intermediate 1-5 (100 mg, 0.26 mmol) was added to THF (10 mL), nitrogen was replaced, the temperature was lowered to 0 ° C, and then azetidine (44 mg) was added to the reaction solution, and the reaction solution was gradually restored to room temperature for 12 h. The solvent was removed under reduced pressure, water (20 mL) was added to the residue, and ethyl acetate was extracted (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 3 (31 mg) was obtained by column chromatography separation and purification (petroleum ether: ethyl acetate = 15: 1-3: 1). ESI-MS (m/z): 294.18 [M + H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.57 (d, J = 7.2 Hz, 2H), 7.38-7.32 (m, 6H), 7.28-7.23 (m, 2H), 4.49-4.40 (m, 2H), 4.24-4.23 (m, 1H), 3.87-3.85 (m, 1H), 3.72-3.61 (m, 2H), 3.43-3.37 (m, 1H), 2.89-2.80 (m, 1H), 2.76-2.70 (m, 2H), 2.45-2.37 (m, 1H), 2.33-2.18 (m, 2H).

Example 4: Synthesis of Compound 4

Intermediate 1-5 (100 mg, 0.26 mmol) was added to THF (10 mL), nitrogen was replaced, the temperature was lowered to 0°C, and then azetidine-3-ol (57 mg) was added to the reaction solution, and the reaction solution was gradually restored to room temperature for 12 hours. The solvent was removed under reduced pressure, water (20 mL) was added to the residue, and ethyl acetate was extracted (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 50: 1-20: 1) to obtain compound 4 (33 mg). ESI-MS (m/z): 310.16 [M + H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.52 (d, J = 7.2 Hz, 2H), 7.37-7.34 (m, 2H), 7.29-7.25 (m, 5H), 7.21-7.18 (m, 1H), 4.46-4.42 (m, 1H), 4.23-4.19 (m, 1H), 3.86-3.82 (m, 1H), 3.70-3.67 (m, 1H), 3.64-3.62 (m, 1H), 2.95-2.91 (m, 1H), 2.86-2.83 (m, 2H), 2.26-2.23 (m, 1H), 2.09-2.01 (m, 4H).

Example 5: Synthesis of Compound 5

Synthesis of intermediate 5-1

Dissolve 1,1-phenylethylene (2.00 g, 11.10 mmol) in acetonitrile (50 mL), then add diethyl bromomalonate (5.31 g), copper (II) trifluoromethanesulfonate (401 mg), 1,10-phenanthroline (400 mg), silver carbonate (3.06 g) and water (800 mg), and the whole system is protected by nitrogen. Stir and react at 120 ° C for 10 h. Add water (100 mL) to the reaction solution, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated sodium chloride (30 mL × 2), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate and purify by column chromatography (petroleum ether: ethyl acetate = 50: 1-10: 1) to obtain intermediate 5-1 (1.00 g).

Synthesis of intermediate 5-2

The intermediate 5-1 (1.00 g, 3.23 mmol) was dissolved in anhydrous ethanol (50 mL), and then sodium borohydride (244 mg) was added, and the system was reacted at room temperature for 4 h. The ethanol was removed under reduced pressure, and water (50 mL) was added to the residue, and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 5-2 (501 mg) was obtained by column chromatography separation and purification (petroleum ether: ethyl acetate = 10:1-3:1).

Synthesis of intermediate 5-3

Intermediate 5-2 (501 mg, 1.84 mmol) was dissolved in dichloromethane (40 mL), and then p-toluenesulfonic acid (95 mg) was added. The reaction was carried out at room temperature for 8 hours. The solvent was removed under reduced pressure, water (30 mL) was added to the residue, and ethyl acetate was extracted (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 5-3 (300 mg) was obtained by column chromatography separation and purification (petroleum ether: ethyl acetate = 50: 1-10: 1).

Synthesis of intermediate 5-4

The intermediate 5-3 (300 mg, 1.18 mmol) was dissolved in dichloromethane (40 mL), and then 2,6-dimethylpyridine (190 mg) and trifluoromethanesulfonic anhydride (499 mg) were added, and the system was reacted at room temperature for 1.5 h. The solvent was removed under reduced pressure, and water (30 mL) was added to the residue, and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 5-4 (300 mg) was obtained by separation and purification by column chromatography (petroleum ether: ethyl acetate = 50:1-15:1).

Synthesis of compound 5

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of morpholine (1 mL), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and water (20 mL) was added to the residue, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 5 (200 mg), ESI-MS (m/z): 324.20 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.48-7.45 (m, 4H), 7.34-7.29 (m, 4H), 7.24-7.20 (m, 2H), 4.19-4.17 (m, 1H), 3.79-3.77 (m, 1H), 3.70-3.69 (m, 4H), 2.91-2.88 (m, 1H), 2.60-2.54 (m, 1H), 2.43-2.33 (m, 6H), 2.27-2.24 (m, 1H).

Example 6: Synthesis of Compound 6

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of dimethyl-D6-amine hydrochloride (95 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 6 (150 mg), ESI-MS (m/z): 288.18 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.48-7.45 (m, 4H), 7.34-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.22-4.19 (m, 1H), 3.78-3.75 (m, 1H), 2.97-2.93 (m, 1H), 2.58-2.50 (m, 1H), 2.34-2.29 (m, 2H), 2.27-2.22 (m, 1H).

Example 7: Synthesis of Compound 7

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of azetidine (67 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 7 (101 mg), ESI-MS (m/z): 294.14 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.46-7.43 (m, 4H), 7.32-7.29 (m, 4H), 7.22-7.19 (m, 2H), 4.20-4.17 (m, 1H), 3.74-3.72 (m, 1H), 3.37-3.21 (m, 4H), 2.95-2.92 (m, 1H), 2.56-2.50 (m, 2H), 2.41-2.35 (m, 1H), 2.23-2.19 (m, 1H), 2.17-2.09 (m, 2H).

Example 8: Synthesis of Compound 8

Intermediate 5-4 (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of azetidine-3-ol (19 mg) and triethylamine (40 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, and water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=50:1-20:1) to obtain compound 8 (20 mg), ESI-MS (m/z): 310.26 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.45-7.43 (m, 4H), 7.33-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.47-4.43 (m, 1H), 4.16 (dd, J=8.4 Hz, 8.4 Hz, 1H), 3.73 (dd, J=8.4 Hz, 8.4 Hz, 1H), 3.68-3.65 (m, 2H), 2.92-2.89 (m, 3H), 2.56-2.50 (m, 2H), 2.38-2.33 (m, 1H), 2.21-2.17 (m, 1H).

Example 9: Synthesis of Compound 9

Synthesis of intermediate 9-1

Methyl benzyl alcohol (10.00 g, 41.28 mmol) was added to tetrahydrofuran (10 mL), and NaH (1.65 g) was added to stir the reaction for 0.5 h, and then the reaction solution was concentrated to remove the reaction solution, and finally the mixture was added to DMSO (10 mL), and then methyl acrylate (11.15 mL) was added and stirred at room temperature for 12 h. Ammonium chloride (20 mL) was added to quench the reaction, and ethyl acetate was extracted (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain intermediate 9-1 (5.20 g).

Synthesis of intermediate 9-2

Intermediate 9-1 (2.00 g, 6.75 mmol) was added to a concentrated H ₂ SO ₄ (2 mL) and H ₂ O (20 mL) solution, and then the mixture was heated to 100°C and stirred for 16 h. The pH was adjusted to 7-8 with NaHCO ₃ , extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 9-2 (500 mg).

Synthesis of intermediate 9-3

Trimethylsulfoxide iodide (693 mg) was added to tetrahydrofuran (10 mL), and then the mixture was cooled to 0°C and NaH (126 mg) was added and stirred for 0.5 h. Intermediate 9-2 (500 mg, 2.10 mmol) was dissolved in DMSO (10 mL) and added dropwise to the reaction solution at 0°C and stirred for 1.5 h. Water (10 mL) was added to quench the reaction, and ethyl acetate was used for extraction (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain intermediate 9-3 (205 mg).

Synthesis of compound 9

Intermediate 9-3 (184 mg, 0.73 mmol) and dimethylamine hydrochloride (179 mg) were dissolved in EtOH (9 mL), and N,N-diisopropylethylamine (284 mg) was added dropwise, and then the temperature was raised to 80°C and reacted for 2 h under nitrogen protection. The crude product was concentrated under reduced pressure and purified by preparative thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain compound 9 (32 mg). ESI-MS (m/z): 298.20 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.84-7.82 (m, 2H), 7.65-7.63 (m, 2H), 7.32-7.22 (m, 6H), 4.23-4.20 (m, 1H), 4.13-4.11 (m, 1H), 3.20-3.13 (m, 1H), 3.02-2.92 (m, 1H), 2.91-2.84 (m, 7H), 2.26-2.20 (m, 1H).

Example 10: Synthesis of Compound 10

Intermediate 5-4 (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 2-oxa-6-aza-spiro[3,3]heptane oxalate (49 mg) and triethylamine (39 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol=50:1-20:1) to obtain compound 10 (15 mg), ESI-MS (m/z): 336.29 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.45-7.42 (m, 4H), 7.32-7.28 (m, 4H), 7.23-7.19 (m, 2H), 4.74-4.72 (m, 4H), 4.14 (dd, J=8.4 Hz, 8.4 Hz, 1H), 3.70 (dd, J=8.4 Hz, 8.4 Hz, 1H), 3.34-3.32 (m, 4H), 2.89-2.85 (m, 1H), 2.44-2.39 (m, 2H), 2.33-2.28 (m, 1H), 2.17-2.14 (m, 1H).

Example 11: Synthesis of Compound 11

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of 1-piperidin-4-ethanone (149 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 11 (200 mg), ESI-MS (m/z): 364.19 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.47-7.44 (m, 4H), 7.34-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.19-4.17 (m, 1H), 3.77-3.74 (m, 1H), 2.90-2.84 (m, 3H), 2.57-2.53 (m, 1H), 2.42-2.39 (m, 1H), 2.28-2.22 (m, 3H), 2.16 (s, 3H), 1.97-1.94 (m, 2H), 1.90-1.82 (m, 2H), 1.69-1.63 (m, 2H).

Example 12: Synthesis of Compound 12

Intermediate 1-5 (100 mg, 0.26 mmol) was added to THF (5 mL), nitrogen was replaced, the temperature was lowered to 0°C, and then 1-acetylpiperazine (1.0 mL) was added dropwise to the reaction solution, and the reaction solution was gradually restored to room temperature for 3 h. The solvent was removed under reduced pressure, water (20 mL) was added to the residue, and ethyl acetate was extracted (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 12 (34 mg), ESI-MS (m/z): 365.21 [M+H] ⁺ . ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.57 (d, J = 6.0 Hz, 2H), 7.36-7.34 (m, 4H), 7.27-7.25 (m, 3H), 7.19-7.17 (m, 1H), 4.21-4.17 (m, 1H), 3.87-3.83 (m, 1H), 3.63-3.44 (m, 4H), 3.24-3.13 (m, 1H), 2.48-2.26 (m, 4H), 2.19-1.98 (m, 4H), 2.09 (s, 3H).

Example 13: Synthesis of Compound 13

The synthesis of compound 13 was carried out by referring to the synthesis method of compound 5, wherein diethyl bromomalonate was replaced by diethyl 2-bromo-2-methylmalonate, and finally compound 13 was obtained, ESI-MS (m/z): 338.24 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.51-7.46 (m, 4H), 7.32-7.28 (m, 4H), 7.21-7.17 (m, 2H), 3.85 (d, J=8.4 Hz, 1H), 3.67 (d, J=8.4 Hz, 1H), 3.66-3.64 (m, 4H), 2.69 (d, J=13.2 Hz, 1H), 2.53 (d, J=13.2 Hz, 1H), 2.44-2.42 (m, 2H), 2.40-2.36 (m, 2H), 2.26 (s, 2H), 1.07 (s, 3H).

Example 14: Synthesis of Compound 14

Intermediate 13-4 (312 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of dimethyl-D6-amine hydrochloride (95 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 14 (134 mg), ESI-MS (m/z): 302.26 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.49-7.46 (m, 4H), 7.29-7.26 (m, 4H), 7.18-7.14 (m, 2H), 3.82 (d, J=8.4 Hz, 1H), 3.70 (d, J=8.4 Hz, 1H), 2.70-2.64 (m, 1H), 2.57 (d, J=13.2 Hz, 1H), 2.29-2.25 (m, 2H), 1.09 (s, 3H).

Example 15: Synthesis of Compound 15

The synthesis of compound 15 was carried out by referring to the synthesis method of compound 14, wherein dimethyl-D6-amine was replaced by dimethylamine, and finally compound 15 was obtained, ESI-MS (m/z): 296.21 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.51-7.47 (m, 4H), 7.29-7.26 (m, 4H), 7.18-7.14 (m, 2H), 3.82 (d, J = 8.4 Hz, 1H), 3.70 (d, J = 8.4 Hz, 1H), 2.67 (d, J = 13.2 Hz, 1H), 2.57 (d, J = 13.2 Hz, 1H), 2.31-2.21 (m, 8H), 1.08 (s, 3H).

Example 16: Synthesis of Compound 16

Intermediate 5-4 (301 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of tetrahydropyrrole (83 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 16 (100 mg), ESI-MS (m/z): 308.24 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.42 (m, 4H), 7.30-7.26 (m, 4H), 7.20-7.16 (m, 2H), 4.23-4.20 (m, 1H), 3.77-3.74 (m, 1H), 3.00-2.96 (m, 1H), 2.62-2.55 (m, 7H), 2.28-2.25 (m, 1H), 1.89-1.78 (m, 4H).

Example 18: Synthesis of Compound 18

Synthesis of intermediate 18-1

Intermediate 9-2 (200 mg, 0.84 mmol) was added to DMF-DMA (2 mL), and the mixture was heated to 60°C and stirred for 4 h. Water (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride (10 mL×5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 18-1 (360 mg), ESI-MS (m/z): 294.20 [M+H] ⁺ .

Synthesis of compound 18

Intermediate 18-1 (200 mg, 0.68 mol) was added to MeOH (2 mL), and then concentrated HCl (74 μL) and NaBH ₃ CN (86 mg) were added, and the reaction solution was stirred at room temperature for 2 h. Water (0.2 mL) was added to quench the reaction, and the solvent was removed under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=15:1-3:1) to obtain compound 18 (34 mg), ESI-MS (m/z): 296.19 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.52-7.50 (m, 2H), 7.40-7.27 (m, 8H), 5.03-4.98 (m, 1H), 4.07-4.03 (m, 1H), 3.43-3.40 (m, 2H), 3.03-3.02 (m, 1H), 2.85-2.80 (m, 6H).

Example 19: Synthesis of Compound 24:

Synthesis of Intermediate 24-1

1,1,2-Ethanetricarboxylic acid triethyl ester (20.3 g) was dissolved in anhydrous tetrahydrofuran (300 mL), the system was cooled to -78°C, and then dropwise added Add lithium diisopropylamide (9.00 g) and continue stirring for 1 hour, add benzophenone (10.0 g, 54.9 mmol), and continue stirring for 2 hours. Add 10 mL of glacial acetic acid to quench the reaction, add p-toluenesulfonic acid (500 mg), warm to room temperature and continue stirring overnight. Add 100 mL of water to the reaction solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride (50 mL × 2), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, separate and purify by column chromatography (petroleum ether: ethyl acetate = 50: 1-10: 1), and obtain intermediate 24-1 (10.0 g), ESI-MS (m/z): 383.02 [M+H] ⁺ . Synthesis of intermediate 24-2

Intermediate 24-1 (10.0 g, 26.2 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and then lithium aluminum tetrahydride (3.98 g) was added, and the system was refluxed for 8 h. Water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride (40 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1-3:1) to obtain intermediate 24-2 (1.70 g), ESI-MS (m/z): 303.21 [M+H] ⁺ .

Synthesis of intermediate 24-3

The intermediate 24-2 (1.70 g, 5.63 mmol) was dissolved in dichloromethane (40 mL), and then p-toluenesulfonic acid monohydrate (321 mg) was added, and the system was reacted at room temperature for 3 h. The solvent was removed under reduced pressure, 30 mL of water was added to the residue, and ethyl acetate was extracted (40 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 24-3 (1.20 g) was obtained by column chromatography separation and purification (petroleum ether: ethyl acetate = 50:1-10:1), ESI-MS (m/z): 285.14 [M+H] ⁺ .

Synthesis of Intermediate 24-4

The intermediate 24-3 (1.20 g, 4.23 mmol) was dissolved in dichloromethane (40 mL), followed by the addition of lutidine (906 mg) and trifluoromethanesulfonic anhydride (1.79 g), and the system was reacted at room temperature for 1.5 h. The solvent was removed under reduced pressure, 30 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 24-4 (1.20 g) was obtained by separation and purification by column chromatography (petroleum ether: ethyl acetate = 50: 1-15: 1), ESI-MS (m/z): 549.12 [M+H] ⁺ .

Synthesis of compound 24

Intermediate 24-4 (1.20 g, 2.19 mmol) was dissolved in tetrahydrofuran (30 mL), and then an aqueous solution of methylamine (containing 136 mg, 4.38 mmol of methylamine) was added, and the system was reacted at room temperature for 4 h. The solvent was removed under reduced pressure, and 20 mL of water was added to the residue, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15:1-3:1) to obtain compound 24 (250 mg), ESI-MS (m/z): 280.12 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.36 (d, J = 7.2 Hz, 2H), 7.33-7.30 (m, 2H), 7.28-7.17 (m, 6H), 4.28 (dd, J = 7.2, 7.2 Hz, 1H), 3.79 (dd, J = 10.8, 7.2 Hz, 1H), 3.66-3.54 (m, 1H), 3.33-3.27 (m, 1H), 3.15-3.05 (m, 1H), 2.99-2.90 (m, 1H), 2.79-2.74 (m, 1H), 2.66 (s, 3H), 2.47-2.42 (m, 1H).

Example 20: Synthesis of Compound 26:

Synthesis of Intermediate 26-1

Dissolve 1-oxo-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (500 mg, 1.96 mmol) in tetrahydrofuran (20 mL), then add phenylmagnesium bromide (9.8 mL, 1 M tetrahydrofuran solution), and react at -78 °C for 2 h under nitrogen protection, slowly warm to room temperature for 2 h. Quench with water, remove the solvent under reduced pressure, add 20 mL of water to the residue, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride (20 mL × 2), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate and purify by column chromatography (dichloromethane: methanol = 100: 1-30: 1) to obtain intermediate 26-1 (480 mg). ESI-MS (m/z): 412.32 [M+H] ⁺ .

Synthesis of intermediate 26-2

The intermediate 26-1 (480 mg, 0.33 mmol) was dissolved in dichloromethane (20 mL), and then p-toluenesulfonic acid monohydrate (126 mg) was added and reacted at room temperature for 16 h. The solvent was removed under reduced pressure, 5 mL of water was added to the residue, and saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), and extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Chromatographic separation and purification (dichloromethane:methanol=10:1-5:1) gave Intermediate 26-2 (260 mg). ESI-MS (m/z): 294.11 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.79 (d, J = 7.8 Hz, 1H), 7.57-7.55 (m, 3H), 7.28-7.23 (m, 4H), 7.19-7.16 (m, 2H), 4.27 (t, J = 7.2 Hz, 2H), 3.50-3.48 (m, 2H), 2.96-2.90 (m, 2H), 2.54-2.50 (m, 2H), 2.01 (t, J = 7.2 Hz, 2H), 1.47-1.45 (m, 2H).

Synthesis of compound 26

Intermediate 26-2 (100 mg, 0.34 mmol) was dissolved in methanol (10 mL), followed by the addition of 1 mL of 37% formaldehyde aqueous solution and one drop of formic acid, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (216 mg) was added and the reaction was continued at room temperature for 8 h. The solvent was removed under reduced pressure, 5 mL of water was added to the residue, and the saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), and extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 20:1-8:1) to obtain compound 26 (37 mg), ESI-MS (m/z): 308.26 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.84-7.83 (m, 1H), 7.58-7.56 (m, 3H), 7.29-7.26 (m, 3H), 7.24-7.23 (m, 1H), 7.19-7.16 (m, 2H), 4.26 (t, J=7.2 Hz, 2H), 3.43-3.41 (m, 2H), 2.74 (s, 3H), 2.73-2.71 (m, 3H), 2.07-1.98 (m, 3H), 1.44-1.42 (m, 2H).

Example 21: Synthesis of Compound 27:

Synthesis of Intermediate 27-1

Dissolve tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (500 mg, 1.96 mmol) in tetrahydrofuran (20 mL), then add phenylmagnesium bromide (1.07 g, 1 M tetrahydrofuran solution), and react at -78 °C for 2 h under nitrogen protection, then slowly warm to room temperature for 2 h. Quench with water, remove the solvent under reduced pressure, add 20 mL of water to the residue, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride (20 mL × 2), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate and purify by column chromatography (dichloromethane: methanol = 100: 1-30: 1) to obtain intermediate 27-1 (250 mg). ESI-MS (m/z): 412.30 [M+H] ⁺ .

Synthesis of Intermediate 27-2

The intermediate 27-1 (135 mg, 0.33 mmol) was dissolved in dichloromethane (20 mL), and then p-toluenesulfonic acid monohydrate (126 mg) was added and reacted at room temperature for 12 h. The solvent was removed under reduced pressure, 5 mL of water was added to the residue, and the saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), and extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 27-2 (50 mg) was obtained by column chromatography separation and purification (dichloromethane: methanol = 10: 1-5: 1). ESI-MS (m/z): 294.12 [M+H] ⁺ .

Synthesis of compound 27

Intermediate 27-2 (50 mg, 0.17 mmol) was dissolved in methanol (10 mL), followed by the addition of 1 mL of 37% formaldehyde aqueous solution and one drop of formic acid, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (108 mg, 0.51 mmol) was added and the reaction was carried out at room temperature for 8 h. The solvent was removed under reduced pressure, 5 mL of water was added to the residue, and the saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), and extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 20:1-8:1) to obtain compound 27 (30 mg), ESI-MS (m/z): 308.32 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.49-7.47 (m, 4H), 7.32-7.29 (m, 4H), 7.21-7.19 (m, 2H), 3.80 (s, 2H), 2.58 (s, 2H), 2.51-2.50 (m, 2H), 2.33-2.30 (m, 5H), 1.63-1.60 (m, 4H).

Example 22: Synthesis of Compound 31

Synthesis of compound 31

Intermediate 5-4 (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 3-oxoazetidine hydrochloride (28 mg) and potassium carbonate (54 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=50:1-20:1) to obtain compound 31 (13 mg), ESI-MS (m/z): 308.25 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.42 (m, 4H), 7.31-7.27 (m, 4H), 7.21-7.18 (m, 2H), 4.17 (dd, J = 8.4, 8.4 Hz, 1H), 4.03-4.02 (m, 4H), 3.81 (dd, J = 7.8, 7.8 Hz, 1H), 2.94-2.90 (m, 1H), 2.72 (d, J = 12.0 Hz, 2H), 2.40-2.37 (m, 1H), 2.30-2.24 (m, 1H).

Example 23: Synthesis of Compound 61

Intermediate 1-5 (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 2-oxa-6-aza-spiro[3,3]heptane oxalate (49 mg) and potassium carbonate (54 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=50:1-25:1) to obtain compound 61 (30 mg), ESI-MS (m/z): 336.32 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.52-7.51 (m, 2H), 7.37-7.34 (m, 2H), 7.30-7.23 (m, 5H), 7.22-7.16 (m, 1H), 4.74 (s, 4H), 4.19 (dd, J=13.2, 8.4 Hz, 1H), 3.83 (dd, J=13.8, 7.8 Hz, 1H), 3.33 (s, 4H), 2.96-2.86 (m, 1H), 2.16-2.14 (m, 1H), 2.04-1.97 (m, 3H).

Example 24: Synthesis of Compound 62

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of 2-azaspiro[3.3]heptan-6-one (130 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=15:1-3:1) to obtain compound 62 (200 mg), ESI-MS (m/z): 348.25 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.45-7.43 (m, 4H), 7.33-7.28 (m, 4H), 7.23-7.20 (m, 2H), 4.18 (dd, J=7.8, 7.8 Hz, 1H), 3.74 (dd, J=7.8, 7.8 Hz, 1H), 3.42 (s, 4H), 3.23 (s, 4H), 2.93-2.90 (m, 1H), 2.61-2.51 (m, 2H), 2.40-2.37 (m, 1H), 2.23-2.19 (m, 1H).

Example 25: Synthesis of Compound 63

The intermediate 5-4 (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 2-azaspiro[3.3]heptane hemioxalate (74 mg) and potassium carbonate (108 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated by column chromatography. Purification (dichloromethane:methanol=50:1-20:1) gave compound 63 (40 mg), ESI-MS (m/z): 334.36 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.45-7.43 (m, 4H), 7.32-7.28 (m, 4H), 7.22-7.19 (m, 2H), 4.17 (dd, J=8.4, 8.4 Hz, 1H), 3.72 (t, J=7.8, 7.8 Hz, 1H), 3.26-3.24 (m, 4H), 2.91-2.89 (m, 1H), 2.51-2.49 (m, 2H), 2.42-2.34 (m, 1H), 2.21-2.19 (m, 1H), 2.13-2.10 (m, 4H), 1.82-1.79 (m, 2H).

Example 26: Synthesis of Compound 64

Intermediate 5-4 (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (15 mL), followed by the addition of 3-methoxy-azetidine hydrochloride (64 mg) and potassium carbonate (108 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=50:1-20:1) to obtain compound 64 (40 mg), ESI-MS (m/z): 324.30 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.45-7.43 (m, 4H), 7.32-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.17 (dd, J=7.8, 7.8 Hz, 1H), 4.05-4.03 (m, 1H), 3.73 (dd, J=8.4, 8.4 Hz, 1H), 3.64-3.63 (m, 2H), 3.25 (s, 3H), 2.92-2.87 (m, 3H), 2.54-2.52 (m, 2H), 2.39-2.34 (m, 1H), 2.22-2.18 (m, 1H).

Example 27: Synthesis of Compound 65

Intermediate 5-4 (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 3-(benzyloxy)azetidine hydrochloride (52 mg) and potassium carbonate (54 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1-1:1) to obtain compound 65 (20 mg), ESI-MS (m/z): 400.46 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.32 (m, 15H), 4.44 (s, 2H), 4.24-4.16 (m, 2H), 3.72-3.68 (m, 3H), 2.92-2.89 (m, 3H), 2.56-2.55 (m, 2H), 2.37-2.30 (m, 2H).

Example 28: Synthesis of Compound 66

Intermediate 5-4 (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of N-piperidin-4-yl-acetamide (55 mg) and potassium carbonate (108 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 30: 1-10: 1) to obtain compound 66 (40 mg), ESI-MS (m/z): 379.41 [M+H] ⁺ .

¹ HNMR (600MHz, CDCl ₃ )δ7.47-7.43 (m, 4H), 7.33-7.28 (m, 4H), 7.23-7.19 (m, 2H), 5.44 (d, J = 6.0 Hz, 1H), 4.19-4.16 (m, 1H), 3.80-3.74 (m, 2H), 2.91-2.87 (m, 1H), 2.80-2.75 (m, 2H), 2.58-2.51 (m, 1H), 2.44-2.40 (m, 1H), 2.38-2.33 (m, 1H), 2.24-2.21 (m, 1H), 2.10-2.03 (m, 2H), 1.97 (s, 3H), 1.91-1.87 (m, 2H), 1.45-1.42 (m, 2H).

Example 29: Synthesis of Compound 67

Intermediate 5-4 (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 1-oxa-8-aza-spiro[4,5]decan-2-one hydrochloride (75 mg) and potassium carbonate (108 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=80:1-30:1) to obtain compound 67 (42 mg), ESI-MS (m/z): 392.40 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.48-7.45 (m, 4H), 7.34-7.29 (m, 4H), 7.24-7.20 (m, 2H), 4.18 (dd, J = 8.4, 8.4 Hz, 1H), 3.77 (dd, J = 7.8, 7.8 Hz, 1H), 2.91-2.88 (m, 1H), 2.63-2.54 (m, 5H), 2.47-2.35 (m, 4H), 2.25-2.23 (m, 1H), 2.03 (t, J = 6.0 Hz, 2H), 1.87-1.85 (m, 2H), 1.77-1.75 (m, 2H).

Example 30: Synthesis of Compound 68

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of 4-dimethylaminopiperidine (150 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=15:1-3:1) to obtain compound 68 (192 mg), ESI-MS (m/z): 365.15 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.47-7.44 (m, 4H), 7.33-7.28 (m, 4H), 7.23-7.19 (m, 2H), 4.17 (dd, J=7.8, 7.8 Hz, 1H), 3.75 (dd, J=7.2, 7.2 Hz, 1H), 2.91-2.87 (m, 3H), 2.55-2.51 (m, 1H), 2.47-2.46 (m, 7H), 2.42-2.39 (m, 1H), 2.35-2.31 (m, 1H), 2.25-2.21 (m, 1H), 1.97-1.89 (m, 4H), 1.63-1.59 (m, 2H).

Example 31: Synthesis of Compound 69

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of 4-methoxypiperidine (135 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=15:1-3:1) to obtain compound 69 (213 mg), ESI-MS (m/z): 352.25 [M+H] ⁺ .

¹ HNMR (600MHz, CDCl ₃ )δ7.48-7.45 (m, 4H), 7.34-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.19 (dd, J = 8.4, 8.4 Hz, 1H), 3.76 (dd, J = 7.8, 7.8 Hz, 1H), 3.35 (s, 3H), 3.23-3.21 (m, 1H), 2.92-2.89 (m, 1H), 2.75-2.63 (m, 2H), 2.59-2.53 (m, 1H), 2.44-2.39 (m, 1H), 2.36-2.33 (m, 1H), 2.26-2.23 (m, 1H), 2.19-2.09 (m, 2H), 1.95-1.84 (m, 2H), 1.65-1.52 (m, 2H).

Example 32: Synthesis of Compound 70

Intermediate 5-4 (100 mg, 0.26 mmol) was added to THF (10 mL), cooled to 0°C, and then 4-benzoylpiperidine (74 mg) and potassium carbonate (108 mg) were added to the reaction solution, and the reaction solution was gradually restored to room temperature for 3 hours. The solvent was removed under reduced pressure, and the product was separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-1: 1) to obtain compound 70 (55 mg), ESI-MS (m/z): 426.24 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.95 (d, J = 7.8 Hz, 2H), 7.60-7.57 (m, 1H), 7.50-7.45 (m, 6H), 7.34-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.20 (dd, J = 7.8, 7.8 Hz, 1H), 3.78 (dd, J = 7.8, 7.8 Hz, 1H), 3.35-3.16 (m, 1H), 3.00-2.83 (m, 3H), 2.67-2.54 (m, 1H), 2.52-2.35 (m, 2H), 2.30-2.27 (m, 1H), 2.18-2.00 (m, 2H), 1.97-1.77 (m, 4H).

Example 33: Synthesis of Compound 71

Intermediate 5-4 (100 mg, 0.26 mmol) was added to THF (10 mL), cooled to 0°C, and then 7-azaspiro[3.5]nonane-2-one hydrochloride (69 mg) and potassium carbonate (108 mg) were added to the reaction solution, and the reaction solution was gradually restored to room temperature for 3 hours. The solvent was removed under reduced pressure, and the product was separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-1: 1) to obtain compound 71 (21 mg), ESI-MS (m/z): 376.21 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.48-7.45 (m, 4H), 7.33-7.29 (m, 4H), 7.24-7.20 (m, 2H), 4.21-4.18 (m, 1H), 3.80-77 (m, 1H), 3.04-2.86 (m, 1H), 2.86-2.71 (m, 4H), 2.71-2.29 (m, 7H), 1.90-1.57 (m, 5H).

Example 34: Synthesis of Compound 72

Intermediate 5-4 (100 mg, 0.26 mmol) was added to THF (10 mL), cooled to 0°C, and then ethyl 4-piperidinylcarboxylate (62 mg) and potassium carbonate (108 mg) were added to the reaction solution, and the reaction solution was gradually restored to room temperature for 3 hours. The solvent was removed under reduced pressure, and the product was separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-1: 1) to obtain compound 72 (53 mg), ESI-MS (m/z): 394.20 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.47-7.44 (m, 4H), 7.34-7.29 (m, 4H), 7.23-7.19 (m, 2H), 4.20-4.13 (m, 3H), 3.77-3.75 (m, 1H), 2.95-2.90 (m, 1H), 2.81-2.73 (m, 2H), 2.65-2.50 (m, 1H), 2.40-2.25 (m, 4H), 2.05-1.90 (m, 2H), 1.90-1.82 (m, 2H), 1.80-1.70 (m, 2H), 1.27 (t, J=6.0 Hz, 3H).

Example 35: Synthesis of Compound 73

Synthesis of Intermediate 73-1

Compound 72 (200 mg, 0.51 mmol) was dissolved in water and ethanol (10+10 mL), and then lithium hydroxide monohydrate (107 mg) was added. The whole system was stirred at 80°C for 4 h. 20 mL of water was added to the reaction solution, and ethyl acetate was extracted (20 mL×3). The organic phase was washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol=100:1-20:1) to obtain intermediate 73-1 (150 mg), ESI-MS (m/z): 366.26 [M+H] ⁺ .

Synthesis of compound 73

Intermediate 73-1 (75 mg, 0.21 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of methylamine hydrochloride (22 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg) and N,N-diisopropylethylamine (54 mg), and the whole system was stirred at room temperature for 6 h. 100 mL of water was added to the reaction solution, and dichloromethane was extracted (30 mL×3), the organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure, and purified by plate chromatography (dichloromethane: methanol = 25:1) to obtain compound 73 (25 mg), ESI-MS (m/z): 379.23 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.41 (m, 4H), 7.30-7.26 (m, 4H), 7.20-7.17 (m, 2H), 5.47 (s, 1H), 4.16-4.13 (m, 1H), 3.74-3.72 (m, 1H), 2.88-2.84 (m, 3H), 2.80 (s, 3H), 2.59-2.53 (m, 1H), 2.40-2.33 (m, 2H), 2.24-2.20 (m, 1H), 2.06-1.96 (m, 3H), 1.80-1.65 (m, 4H).

Example 36: Synthesis of Compound 74

Intermediate 73-1 (75 mg, 0.21 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of (1-ethylcyclopropyl)amine (27 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg) and N,N-diisopropylethylamine (54 mg), and the whole system was stirred at room temperature for 6 h. 100 mL of water was added to the reaction solution, and dichloromethane was extracted (30 mL×3), the organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure, and purified by plate chromatography (dichloromethane: methanol = 25:1) to obtain compound 74 (28 mg), ESI-MS (m/z): 433.34 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.41 (m, 4H), 7.30-7.26 (m, 4H), 7.20-7.17 (m, 2H), 5.80 (s, 1H), 4.17-4.15 (m, 1H), 3.75-3.72 (m, 1H), 3.02-2.87 (m, 3H), 2.58-2.34 (m, 4H), 2.26-2.22 (m, 1H), 2.15-2.00 (m, 2H), 1.82-1.74 (m, 4H), 1.58 (q, J = 7.8 Hz, 2H), 0.90 (t, J = 7.8 Hz, 3H), 0.68-0.62 (m, 4H).

Example 37: Synthesis of Compound 75

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of N,N-dimethylpiperidine-4-carboxamide (183 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=15:1-3:1) to obtain compound 75 (186 mg), ESI-MS (m/z): 393.25 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.44-7.42 (m, 4H), 7.30-7.26 (m, 4H), 7.20-7.16 (m, 2H), 4.21-4.15 (m, 1H), 3.75-3.73 (m, 1H), 3.02 (s, 3H), 2.93 (s, 3H), 2.90-2.81 (m, 3H), 2.61-2.20 (m, 5H), 2.05-1.85 (m, 4H), 1.75-1.62 (m, 2H).

Example 38: Synthesis of Compound 76

Intermediate 5-4 (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of 4-piperidinyl (1-pyrrolidinyl) ketone (213 mg) and triethylamine (158 mg), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 15: 1-3: 1) to obtain compound 76 (170 mg), ESI-MS (m/z): 419.25 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.45-7.42 (m, 4H), 7.30-7.26 (m, 4H), 7.20-7.16 (m, 2H), 4.18-4.12 (m, 1H), 3.75-3.72 (m, 1H), 346-3.42 (m, 4H), 2.90-2.84 (m, 3H), 2.60-2.20 (m, 5H), 1.94-1.82 (m, 8H), 1.70-1.60 (m, 2H).

Example 39: Synthesis of Compound 77

1-5 (150 mg, 0.39 mmol) was dissolved in THF (10 mL), cooled to 0°C, and then methyl-D3-amine hydrochloride (41 mg) and potassium carbonate (108 mg) were added to the reaction solution, and the reaction solution was returned to room temperature for 3 hours. The solvent was removed under reduced pressure, and the compound was separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-1: 1) to obtain compound 77 (26 mg), ESI-MS (m/z): 271.27 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.53 (d, J = 7.2 Hz, 2H), 7.34-7.31 (m, 4H), 7.27-7.22 (m, 3H), 7.19-7.16 (m, 1H), 4.20-4.16 (m, 1H), 3.82-3.78 (m, 1H), 3.23-3.19 (m, 1H), 2.54-2.51 (m, 1H), 2.22-2.19 (m, 1H), 2.11-2.01 (m, 2H).

Example 40: Synthesis of Compound 78

Synthesis of Intermediate 78-1

Intermediate 1-4 (501 mg, 1.97 mmol) was dissolved in water (20 mL), followed by the addition of potassium permanganate (934 mg), and the whole system was stirred at 100°C for 8 h. 100 mL of water was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure, separated and purified by column chromatography (dichloromethane: methanol = 50:1-15:1), to obtain Intermediate 78-1 (300 mg), ESI-MS (m/z): 269.01 [M+H] ⁺ .

Synthesis of Intermediate 78-2

The intermediate 78-1 (300 mg, 1.12 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of dimethyl-D6-amine hydrochloride (147 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (852 mg) and N,N-diisopropylethylamine (289 mg), and the whole system was stirred at room temperature for 6 h. 100 mL of water was added to the reaction solution, and the dichloromethane extraction (50 mL×3) was performed. The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The intermediate 78-2 (185 mg) was obtained by column chromatography separation and purification (dichloromethane: methanol = 100:1-25:1), ESI-MS (m/z): 302.20 [M+H] ⁺ .

Synthesis of compound 78

Intermediate 78-2 (185 mg, 0.61 mmol) was dissolved in tetrahydrofuran (20 mL), and then lithium aluminum tetrahydride deuterate (51 mg) was added, and the whole system was stirred at room temperature for 2 h. 10 mL of water was added to the reaction solution, and ethyl acetate was extracted (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure, and separated and purified by column chromatography (dichloromethane: methanol = 100: 1-20: 1) to obtain compound 78 (85 mg), ESI-MS (m/z): 290.22 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.53-7.52 (m, 2H), 7.34-7.29 (m, 4H), 7.26-7.21 (m, 3H), 7.17-7.15 (m, 1H), 4.20-4.16 (m, 1H), 3.85-3.82 (m, 1H), 3.11-3.09 (m, 1H), 2.12-2.08 (m, 1H), 2.07-2.03 (m, 1H).

Example 41: Synthesis of Compound 79

Intermediate 5-4 (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of 1,4-oxazepane (53 mg) and triethylamine (79 mg), and the system was reacted at room temperature overnight. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-20: 1) to obtain compound 79 (40 mg), ESI-MS (m/z): 338.19 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.47 (dd, J = 13.6, 7.7 Hz, 4H), 7.35-7.29 (m, 4H), 7.25-7.19 (m, 2H), 4.18 (dd, J = 7.8, 7.8 Hz, 1H), 3.80-3.78 (m, 3H), 3.71 (t, J = 3.6 Hz, 2H), 2.90 (dd, J = 12.4, 6.5 Hz, 1H), 2.69-2.66 (m, 4H), 2.61-2.49 (m, 3H), 2.27 (dd, J = 12.4, 8.0 Hz, 1H), 1.90-1.86 (m, 2H).

Example 42: Synthesis of Compound 80

Intermediate 5-4 (100 mg, 0.26 mmol) was added to THF (10 mL), cooled to 0°C, and then azepan-4-one hydrochloride (58 mg) and triethylamine (79 mg) were added to the reaction solution, and the reaction solution was returned to room temperature for 3 hours. The solvent was removed under reduced pressure, and the product was separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-1: 1) to obtain compound 80 (32 mg), ESI-MS (m/z): 350.21 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.48-7.44 (m, 4H), 7.34-7.29 (m, 4H), 7.24-7.20 (m, 2H), 4.21-4.11 (m, 1H), 3.83-3.74 (m, 1H), 2.94-2.81 (m, 1H), 2.70-2.37 (m, 10H), 2.30-2.18 (m, 1H), 1.90-1.60 (m, 3H).

Example 43: Synthesis of Compound 81

Synthesis of Intermediate 81-1

Intermediate 5-4 (236 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of tert-butyl 1,4-diazepane-1-carboxylate (368 mg), and the system was reacted at room temperature overnight. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-20: 1) to obtain intermediate 81-1 (150 mg). ESI-MS (m/z): 437.27 [M+H] ⁺ .

Synthesis of compound 81

The intermediate 81-1 (100 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (1 mL), and the system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), followed by the addition of triethylamine (70 mg) and ethyl chloroformate (50 mg), and the system was reacted at room temperature for 3 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=50:1-30:1) to obtain compound 81 (30 mg), ESI-MS (m/z): 409.36 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.43 (dd, J = 14.4, 7.7 Hz, 4H), 7.29 (dd, J = 15.7, 7.8 Hz, 4H), 7.21-7.16 (m, 2H), 4.14-4.11 (m, 3H), 3.78-3.73 (m, 1H), 3.54-3.40 (m, 4H), 2.90-2.81 (m, 1H), 2.68-2.39 (m, 7H), 2.22 (dd, J = 12.7, 7.7 Hz, 1H), 1.88-1.68 (m, 2H), 1.28-1.22 (m, 3H).

Example 44: Synthesis of Compound 82

Synthesis of Intermediate 82-1

Intermediate 5-4 (250 mg, 0.65 mmol) was dissolved in acetonitrile (10 mL), and then 40% aqueous methylamine solution (2 mL) was added, and the system was reacted at room temperature overnight. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 82-1 (160 mg) was obtained by column chromatography separation and purification (dichloromethane: methanol = 50: 1-20: 1), ESI-MS (m/z): 268.18 [M+H] ⁺ .

Synthesis of Intermediate 82-2

Intermediate 82-1 (160 mg, 0.60 mmol) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of tert-butyl 4-oxoazepane-1-carboxylate (128 mg) and sodium triacetoxyborohydride (317 mg), and the system was reacted at room temperature overnight. Dichloromethane (50 mL) was added, washed with water (10 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 82-2 (100 mg) was obtained by separation and purification by column chromatography (dichloromethane: methanol = 50: 1-30: 1), ESI-MS (m/z): 465.25 [M+H] ⁺ .

Synthesis of Intermediate 82-3

Intermediate 82-2 (100 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (1 mL) was added. The system was reacted at room temperature for 1 h. The solvent was removed under reduced pressure, and the product was used directly in the next step without purification. ESI-MS (m/z): 365.29 [M+H] ⁺ . Synthesis of Compound 82

The intermediate 82-3 was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (67 mg) and ethyl chloroformate (48 mg), and the system was reacted at room temperature for 3 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane:methanol=50:1-30:1) to obtain compound 82 (30 mg), ESI-MS (m/z): 437.49 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.46-7.41 (m, 4H), 7.31-7.26 (m, 4H), 7.20-7.16 (m, 2H), 4.14-4.10 (m, 3H), 3.77-3.71 (m, 1H), 3.63-3.43 (m, 2H), 3.29-3.15 (m, 2H), 2.96-2.85 (m, 1H), 2.62-2.31 (m, 4H), 2.22-2.19 (m, 4H), 1.96-1.79 (m, 3H), 1.75-1.65 (m, 1H), 1.56-1.45 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).

Example 45: Synthesis of Compound 83

Synthesis of Intermediate 83-1

2-Oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (500 mg, 1.96 mmol) was dissolved in tetrahydrofuran (20 mL), and then phenylmagnesium bromide (1.07 g, 1 M tetrahydrofuran solution) was added. The system was reacted at -78 °C for 2 h under nitrogen protection, and then slowly warmed to room temperature for 2 h. Water was added to quench, and the solvent was removed under reduced pressure. 20 mL of water was added to the residue, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 83-1 (300 mg) was obtained by column chromatography separation and purification (dichloromethane: methanol = 100: 1-30: 1), ESI-MS (m/z): 412.29 [M+H] ⁺ .

Synthesis of Intermediate 83-2

Intermediate 83-1 (270 mg, 0.66 mmol) was dissolved in dichloromethane (20 mL), and then p-toluenesulfonic acid monohydrate (251 mg) was added and reacted at room temperature for 12 h. The solvent was removed under reduced pressure, and the product was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-5: 1) to obtain Intermediate 83-2 (200 mg), ESI-MS (m/z): 294.19 [M+H] ⁺ .

Synthesis of compound 83

Intermediate 83-2 (50 mg, 0.11 mmol) was dissolved in methanol (10 mL), followed by the addition of 1 mL of 37% formaldehyde aqueous solution and one drop of formic acid, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (70 mg) was added and the reaction was continued at room temperature for 8 h. The solvent was removed under reduced pressure, 10 mL of water was added to the residue, and the saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), and extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 20:1-8:1) to obtain compound 83 (15 mg). ESI-MS (m/z): 308.32 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.49-7.47 (m, 4H), 7.31-7.28 (m, 4H), 7.22-7.19 (m, 2H), 2.76-2.74 (m, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.58-2.56 (m, 2H), 2.42 (s, 3H), 1.86 (t, J = 6.0 Hz, 2H), 1.80-1.78 (m, 4H).

Example 46: Synthesis of Compound 84

Synthesis of Intermediate 84-1

The intermediate 83-2 (140 mg, 0.30 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of cyclopropanecarboxylic acid (39 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg), and triethylamine (91 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane:methanol=20:1-5:1) to obtain the intermediate 84-1 (95 mg), ESI-MS (m/z): 362.29 [M+H] ⁺ .

Synthesis of compound 84

Intermediate 84-1 (95 mg, 0.26 mmol) was dissolved in tetrahydrofuran (20 mL), and then lithium aluminum tetrahydride (20 mg) was added, and the system was reacted at room temperature for 2 h. The reaction solution was quenched with water, and the solvent was evaporated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-10: 1) to obtain compound 84 (40 mg), ESI-MS (m/z): 348.35 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.50-7.49 (m, 4H), 7.31-7.28 (m, 4H), 7.21-7.19 (m, 2H), 2.77-2.68 (m, 4H), 2.67 (t, J = 6.0 Hz, 2H), 2.34 (d, J = 6.0 Hz, 2H), 1.84 (t, J = 6.0 Hz, 2H), 1.83-1.79 (m, 2H), 1.73-1.71 (m, 2H), 0.95-0.93 (m, 1H), 0.60-0.52 (m, 2H), 0.18-0.13 (m, 2H).

Example 47: Synthesis of Compound 85

Synthesis of Intermediate 85-1

N-BOC-4-benzoylpiperidine (1.00 g, 3.46 mmol) was dissolved in tetrahydrofuran (20 mL), and potassium bis(trimethylsilyl)amide (1.04 g, 1 M tetrahydrofuran solution) was added under nitrogen protection, and the system was reacted at room temperature for 1 h, and then methyl chloroacetate (751 mg) was added under ice bath, and the system was reacted at room temperature for 8 h. Water was added to quench the reaction, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-3: 1) to obtain intermediate 85-1 (370 mg), ESI-MS (m/z): 362.25 [M+H] ⁺ .

Synthesis of Intermediate 85-2

Intermediate 85-1 (280 mg, 0.78 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum tetrahydride (90 mg) was added. The reaction was carried out at room temperature for 2 h. The reaction solution was quenched with water, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1-1:1) to obtain intermediate 85-2 (200 mg), ESI-MS (m/z): 336.15 [M+H] ⁺ .

Synthesis of Intermediate 85-3

The intermediate 85-2 (170 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 60% sodium hydride (24 mg), triphenylphosphine (160 mg), and 1,2-diiodoethane (172 mg), and the system was reacted at room temperature for 24 h. 20 mL of water was added to the reaction solution, and ethyl acetate was extracted (20 mL × 3), the organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 85-3 (40 mg) was obtained by column chromatography separation and purification (petroleum ether: ethyl acetate = 3:1-1:1), ESI-MS (m/z): 318.23 [M+H] ⁺ .

Synthesis of Intermediate 85-4

Intermediate 85-3 (40 mg, 0.13 mmol) was dissolved in ethanol hydrochloric acid (10 mL) and the system was reacted at room temperature for 2 h. The solvent was removed under reduced pressure to obtain intermediate 85-4 (25 mg), ESI-MS (m/z): 218.27 [M+H] ⁺ .

Synthesis of compound 85

Intermediate 85-4 (25 mg, 0.10 mmol) was dissolved in methanol (10 mL), followed by the addition of 1 mL of 37% formaldehyde aqueous solution and one drop of formic acid, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (64 mg) was added and the reaction was continued at room temperature for 8 h. The solvent was removed under reduced pressure, 10 mL of water was added to the residue, the saturated sodium bicarbonate aqueous solution was adjusted, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-5: 1) to obtain compound 85 (10 mg), ESI-MS (m/z): 232.21 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.35-7.33 (m, 2H), 7.30-7.23 (m, 1H), 7.10-7.08 (m, 2H), 5.69-5.67 (m, 1H), 4.00-3.99 (m, 2H), 2.95-2.93 (m, 2H), 2.30 (s, 3H), 2.24-2.18 (m, 2H), 2.00-1.96 (m, 2H), 1.75-1.74 (m, 2H), 1.60-1.55 (m, 2H).

Example 48: Synthesis of Compound 86

Intermediate 24-4 (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (30 mL), followed by addition of deuterated methylamine hydrochloride (25 mg) and cesium carbonate (117 mg) and the reaction was carried out at room temperature for 4 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether:ethyl acetate=15:1-3:1) to obtain compound 86 (20 mg), ESI-MS (m/z): 283.32 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.39 (d, J = 7.2 Hz, 2H), 7.32-7.30 (m, 2H), 7.28-7.17 (m, 6H), 4.24 (dd, J = 7.2, 7.2 Hz, 1H), 3.74 (dd, J = 10.8, 7.2 Hz, 1H), 3.24-3.21 (m, 1H), 3.17-3.12 (m, 1H), 2.77-2.72 (m, 2H), 2.68-2.61 (m, 1H), 2.40-2.37 (m, 1H).

Example 49: Synthesis of Compound 87

The intermediate 83-2 (154 mg, 0.34 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of isopropyl bromide (84 mg) and cesium carbonate (333 mg), and the system was reacted at room temperature for 12 h. The solvent was removed under reduced pressure, and the residue was added with 10 mL of water, extracted with dichloromethane (20 mL × 3), and combined. The organic phase was washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane:methanol=20:1-8:1) to obtain compound 87 (40 mg). ESI-MS (m/z): 336.33 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.49-7.48 (m, 4H), 7.31-7.23 (m, 4H), 7.21-7.19 (m, 2H), 2.83-2.81 (m, 3H), 2.68-2.56 (m, 4H), 1.85-1.73 (m, 6H), 1.16-1.14 (m, 6H).

Example 50: Synthesis of Compound 88

Intermediate 83-2 (109 mg, 0.24 mmol) was dissolved in methanol (10 mL), followed by the addition of 1 mL of acetaldehyde and one drop of formic acid, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (153 mg) was added and the reaction was continued at room temperature for 8 h. The solvent was removed under reduced pressure, 10 mL of water was added to the residue, and the saturated aqueous sodium bicarbonate solution was adjusted to alkaline (pH 7-8), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 20: 1-8: 1) to obtain compound 88 (30 mg). ESI-MS (m/z): 322.32 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.49-7.48 (m, 4H), 7.31-7.28 (m, 4H), 7.21-7.19 (m, 2H), 2.72-2.56 (m, 8H), 1.85-1.80 (m, 6H), 1.20-1.18 (m, 3H).

Example 51: Synthesis of Compound 89

The intermediate 83-2 (154 mg, 0.34 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of bromopropane (84 mg) and cesium carbonate (333 mg), and the system was reacted at room temperature for 12 h. The solvent was removed under reduced pressure, 10 mL of water was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-8: 1) to obtain compound 89 (40 mg). ESI-MS (m/z): 336.35 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.50-7.48 (m, 4H), 7.31-7.28 (m, 4H), 7.21-7.19 (m, 2H), 2.77-2.56 (m, 6H), 2.43-2.40 (m, 2H), 1.85-1.83 (m, 4H), 1.74-1.65 (m, 2H), 1.62-1.55 (m, 2H), 0.95 (t, J=6.0 Hz, 3H).

Example 52: Synthesis of Compound 90

Intermediate 26-2 (100 mg, 0.34 mmol) was dissolved in methanol (10 mL), and then acetaldehyde (30 mg) and one drop of formic acid were added, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (216 mg) was added and the reaction was carried out at room temperature for 8 h. The solvent was removed under reduced pressure, 5 mL of water was added to the residue, and saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane: methanol = 15:1) to obtain compound 90 (35 mg), ESI-MS (m/z): 322.23 [M+H] ⁺ .

¹ HNMR (600MHz,CDCl ₃ )δ7.62-7.61(m,4H),7.29-7.26(m,4H),7.18-7.15(m,2H),4.21(t,J＝7.2Hz,2H), 3.03-2.86 (m, 2H), 2.50-2.35 (m, 2H), 2.20-2.12 (m, 2H), 2.07-2.03 (m, 2H), 1.96 (t, J = 7.2 Hz, 2H), 1.38-1.36 (m, 2H), 1.12-1.05 (m, 3H).

Example 53: Synthesis of Compound 91

Synthesis of Intermediate 91-1

Intermediate 26-2 (100 mg, 0.34 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of cyclopropylacyl chloride (53 mg) and N,N-diisopropylethylamine (88 mg), and the system was reacted at room temperature for 3 h. The solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 15: 1) to obtain intermediate 91-1 (85 mg), ESI-MS (m/z): 362.26 [M+H] ⁺ .

Synthesis of compound 91

Intermediate 91-1 (85 mg, 0.24 mmol) was dissolved in tetrahydrofuran (20 mL), and then lithium aluminum tetrahydride (27 mg) was added, and the system was reacted at room temperature for 4 h. The reaction solution was quenched with water, and the solvent was evaporated under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-10: 1) to obtain compound 91 (25 mg), ESI-MS (m/z): 348.25 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.63-7.62 (m, 4H), 7.29-7.26 (m, 4H), 7.18-7.15 (m, 2H), 4.20 (t, J = 7.2 Hz, 2H), 3.01-2.99 (m, 2H), 2.25 (d, J = 6.6 Hz, 2H), 2.15-2.10 (m, 2H), 2.05-2.02 (m, 2H), 1.96 (t, J = 7.2 Hz, 2H), 1.37-1.35 (m, 2H), 0.85-0.83 (m, 1H), 0.50-0.47 (m, 2H), 0.08-0.05 (m, 2H).

Example 54: Synthesis of Compound 92

Intermediate 1-5 (130 mg, 0.51 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of isobutylamine (112 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-30: 1) to obtain compound 92 (50 mg), ESI-MS (m/z): 310.13 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO-d6) δ7.54-7.52 (m, 2H), 7.34-7.31 (m, 4H), 7.26-7.20 (m, 3H), 7.16-7.14 (m, 1H), 4.09-4.06 (m, 1H), 3.71-3.67 (m, 1H), 3.21 (s, 1H), 2.39-2.35 (m, 2H), 2.28-2.20 (m, 2H), 2.07-2.02 (m, 2H), 1.89-1.84 (m, 1H), 1.61-1.55 (m, 1H), 0.82-0.80 (m, 6H).

Example 55: Synthesis of Compound 93

Intermediate 1-5 (330 mg, 1.30 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of cyclopropylamine (222 mg), and the system was reacted at room temperature for 8 h. The solvent was removed under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-30: 1) to obtain compound 93 (280 mg), ESI-MS (m/z): 294.27 [M+H] ⁺ .

¹ H NMR (600 MHz, DMSO-d6) δ7.54-7.50 (m, 2H), 7.34-7.29 (m, 4H), 7.26-7.19 (m, 3H), 7.17-7.14 (m, 1H), 4.08-4.04 (m, 1H), 3.69-3.65 (m, 1H), 3.14-3.10 (m, 1H), 2.46-2.44 (m, 1H), 2.03-2.01 (m, 1H), 1.99-1.93 (m, 2H), 1.87-1.82 (m, 1H), 0.33-0.26 (m, 2H), 0.18-0.15 (m, 1H), 0.10-0.06 (m, 1H).

Example 56: Synthesis of Compound 94

Compound 93 (100 mg, 0.34 mmol) was dissolved in methanol (10 mL), and then 2 mL of 37% formaldehyde aqueous solution and 2 drops of formic acid were added, and the system was reacted at room temperature for 2 h. Then sodium acetate borohydride (216 mg) was added and reacted at room temperature for 2 h. The solvent was removed under reduced pressure, 10 mL of water was added to the residue, and saturated sodium bicarbonate aqueous solution was adjusted to alkaline (pH 7-8), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 94 (60 mg, yield 57%), ESI-MS (m/z): 308.35 [M+H] ⁺ .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.56-7.55 (m, 2H), 7.36-7.34 (m, 4H), 7.28-7.24 (m, 3H), 7.20-7.18 (m, 1H), 4.18-4.14 (m, 1H), 3.87-3.83 (m, 1H), 3.26-3.18 (m, 1H), 2.34 (s, 3H), 2.17-1.99 (m, 5H), 0.48-0.28 (m, 4H).

The following compounds were prepared by referring to the preparation process routes and operations of the above examples and using corresponding starting materials.

Compound No. 95: ¹ H NMR (600 MHz, CDCl ₃ ) δ7.54-7.53 (m, 2H), 7.48-7.47 (m, 2H), 7.29-7.26 (m, 4H), 7.20-7.17 (m, 2H), 4.11-4.03 (m, 2H), 2.89-2.88 (m, 1H), 2.80-2.77 (m, 1H), 2.53-2.51 (m, 1H), 2.39-2.35 (m, 1H), 2.33 (s, 3H), 2.32-2.28 (m, 1H), 2.22-2.18 (m, 1H), 2.14-2.10 (m, 1H), 1.70-1.66 (m, 1H).

Biological activity test experiment:

1. Sigma-1R radioligand affinity test

The Sigma-1R binding experiment uses the isotope binding amount to detect the binding ability of the test compound to the receptor. Before the experiment, the HEK293 stable cell line was used to collect the cell membrane rich in Sigma 1R, and [3H]DTG (NET986250UC) was used as the reflective ligand. In the experiment, the test compound and the positive control (haloperidol (Haloperidol), 500nM, sigma-H1512) with a gradient dilution of 3 times were added to the mixture of cell membrane and isotope ligand (total volume of 0.2mL), and the negative control was DMSO, and the mixture was shaken and incubated (300rpm). At the same time, the Unifilter-96GF/C filter plate (Perkin Elmer) was immersed in (50μL) 0.3% PEI (Sigma, Cat: P3143) for half an hour at room temperature. After the shaking incubation, the mixture was filtered and recovered through a GF/B plate in a Filtermate Harvester (Perkin Elmer, C961961) and washed 6 times with 50 Mm Tris-HCl (pH 7.4). The washed plate was placed in a 50°C constant temperature incubator and dried for 1 hour. After drying, 50 μL of Microscint 20 cocktai (Perkin Elmer, Cat: 6013329) was added to the bottom of the plate and sealed. The 3H value was read using MicroBeta2 (Perkin Elmer).

Calculate the inhibition rate (formula: %Inhibition=100-100×(sample signal value-Low Control signal value)/(high Control signal value-Low Control signal value)) and use Prism 5 to analyze the data.

The compounds of the present application have excellent affinity for Sigma-1 receptors. The data of some compounds are shown in the following table:

Note: For S1R binding activity: A means ≥7; B means 6≤B<7; C means <6.

2. M1R radioligand affinity test

The M1R binding assay uses isotope binding to detect the binding ability of the test compound to the receptor. Before the experiment, the HEK293 stable cell line was used to collect M1R-rich cell membranes, and [3H]NMS (PE-NET636250UC) was used as a radioactive ligand. In the experiment, the test compound and the positive control (Pirenzepine, 1μM, sigma-P7412) diluted 3 times were added to the mixture of cell membrane and isotope ligand (total volume of 0.2mL), and the negative control was DMSO, and the mixture was shaken and incubated (300rpm). At the same time, the Unifilter-96GF/C filter plate (Perkin Elmer) was immersed in (50μL) 0.3% PEI (Sigma, Cat: P3143) for half an hour at room temperature. After the shaking incubation, the mixture was filtered and recovered through the GF/B plate in Filtermate Harvester (Perkin Elmer, C961961) and washed 6 times with 50mM Tris-HCl (pH7.4). The washed plate was placed in a 50℃ constant temperature incubator and dried for 1 hour. After drying, 50μL of Microscint20cocktai (Perkin Elmer, Cat: 6013329) was added to the bottom of the plate and sealed. The 3H value was read using MicroBeta2 (Perkin Elmer).

3. Experimental results

The compounds of the present application have excellent affinity for M1 receptors. The data of some compounds are shown in the following table:

Note: For the binding activity of M1R: A means ≥7; B means 6≤B<7; C means <6.

Cellular autophagy level detection test

Sigma-1 receptor activation can degrade proteins through autophagy and reduce the aggregation of erroneous proteins in cells. The content of LC3-II in cells is proportional to the degree of autophagy. The expression of LC3-II can be detected by Western blotting to reflect the level of autophagy in cells.

experiment material:

SH-SY5Y cell line (human neuroblastoma cells), PC-12 cell line (rat adrenal pheochromocytoma cells), bafilomycin-A1 (MCE, HY-100558), LC3-II antibody (Abcam, 192890), α-tubulin antibody (CST, 3873S), trypsin (Gibco, 25200072), 6-well plate (Corning, 3516), RIPA lysis buffer (Thermofisher, 89900), protease inhibitor (Roche, 4693159001), PBS (Huiyou Bio, C10010500BT), BSA (Aibixin, 9048-46-8), PVDF (Millipore, 64855665)

experiment procedure

PC12 or SH-SY5Y cell lines were used. The frozen cell lines were quickly thawed in a 37°C water bath, fresh cell culture medium preheated at 37°C was added, and centrifuged at 1000rpm for 3min. After centrifugation, the supernatant was discarded, the cell pellet was resuspended in culture medium, the volume was made up to 10mL after blowing off, and transferred to a 10cm diameter cell culture dish, and shaken left and right. Cultured at 37°C and 5% _CO2 , when the cell confluence reached 80%, the cells were passaged (can be used for experiments after 3 passages). The cell culture medium was aspirated, 0.25% trypsin digestion solution was added for digestion, and the cells were planted in 6cm culture plates. When a certain degree of confluence was reached, the cells were incubated with Yangshen (e.g., ANAVEX2-73) and each group of test compounds in the presence or absence of bafilomycin-A1 for 2h. The cells were rinsed with PBS and lysed with RIPA lysis buffer containing protease inhibitors. The lysate was centrifuged at 12,000 rpm for 15 min, and the protein supernatant was collected. The extracted protein was determined using a BCA protein quantitative analysis kit to calculate the protein concentration. The sample was heated at 90°C for 10 min, electrophoresed using SDS-PAGE gel, transferred to PVDF, and blocked in TBST buffer containing 5% BSA. LC3-II antibody and α-tubulin antibody were used at dilution ratios of 1:3000 and 1:5000, respectively, for Western blot analysis, and the signal was detected using HRP-labeled secondary antibody and chemiluminescent substrate.

data analysis:

The developed bands were analyzed by ImageJ and the optical density values were calculated. GraphPad Prism 8.0program software was used for data processing and statistics. The intergroup differences between the two groups of data were analyzed using Student's t-test; p<0.05 was considered statistically significant.

Compounds protect against H ₂ O ₂ induced cell damage assay

H ₂ O ₂ can cause intracellular oxidative stress, generate a large number of free radicals and ROS (reactive oxygen species), damage the cell structure and function, and induce inflammatory response in cells. The MTT method was used to detect cell proliferation and determine the protective effect of the compound on oxidative stress damage.

experiment material:

SH-SY5Y cell line, PC-12 cell line, H ₂ O ₂ (Kermione)

experiment procedure:

Find the appropriate modeling dose: digest the cells with trypsin, resuspend and count, blow and evenly inoculate them in a 96-well plate at a certain density (5×10 ⁴ or 1×10 ⁵ ), and add H ₂ O ₂ to the cell plate in a gradient dilution. The final concentration of H ₂ O ₂ is 0, 50, 100, 200, 300, 400, 500 μM. Detect by MTT method after 4h or 24h, and calculate the damage rate by reading the value with an enzyme marker.

After determining the modeling conditions, the experimental drugs were added to the cell plate in gradient dilutions, and the concentrations of the test compounds and ANAVEX 2-73 were 0.00128μM, 0.0064μM, 0.032μM, 0.16μM, 0.8μM, 4μM, 20μM, 100μM, 500μM, and 1000μM for gradient incubation; H ₂ O ₂ was added after 3 hours; the detection reagent was added after 5 hours, and the values were read on an enzyme-labeled instrument.

data analysis:

Each experiment was repeated at least twice, and the cell survival rate and statistical differences between groups were calculated using GraphPad Prism 8.0program software. The intergroup differences between the two groups of data were analyzed using Student's t-test; p<0.05 was considered statistically significant.

Compounds protect against cell damage induced by Aβ1-42 oligomers

Aβ1-42 oligomers can be taken up by nerve cells and bind to cell membrane surface receptors at the same time, mediating cell apoptosis through endogenous and exogenous sources. Co-incubation of Aβ1-42 oligomers with neural cell lines can establish an Alzheimer's disease cell model and test the protective effect of the compound.

experiment material:

SH-SY5Y cell line, Aβ1-42 protein (Macklin, A834109), tau (Abcam, 76128), p-tau (p-Tau) (Abcam, 109390), DMSO (Solarbio, D8371)

experiment procedure:

The cells were inoculated in a 10 cm cell culture dish, with 2.5×10 ⁵ cells in each cell culture dish (final volume: 10 mL). The human Aβ1-42 protein was dissolved in DMSO, vortexed for 30 min at room temperature, and then diluted with PBS; cultured at 4°C for a certain period of time to form oligomers; a certain volume of Aβ1-42 was added to the cells and treated for a certain period of time to establish the model.

Before Aβ1-42 drug treatment, a certain concentration of the test compound and Yangshen (e.g., ANAVEX 2-73) were added to the cells and cultured. After a certain period of time, the cells were collected and the effect of the compound on cell activity was detected by CCK-8 method; the effect of the compound on cell reactive oxygen species and mitochondrial membrane potential was detected by ROS and JC-10; the expression of tau and p-tau (p-Tau protein) was detected by immunofluorescence.

data analysis:

Compounds protect against glutamate-induced cell damage assay

Excess glutamate can induce excitotoxicity in cell lines and can be used to evaluate the protective effect of compounds against cellular excitotoxicity.

experiment material:

SH-SY5Y cell line, PC-12 cell line, Glutamate (sigma, G8415)

experiment procedure:

Explore the appropriate dosage for modeling: treat each cell line with 1mM, 2mM, 5mM, 10mM, 15mM, 20mM, and 25mM glutamate, detect by MTT method for 24 hours, and calculate the damage rate with the reading of the microplate reader.

After determining the modeling conditions, the cells were cultured to the logarithmic growth phase, pre-incubated with Yangshen (eg, ANAVEX2-73) and each group of test compounds for 30 min, then treated with glutamate for 24 h, and MTT was used to detect cell death. The cell survival rate of each group was counted.

data analysis:

Compounds protect against 6-hydroxydopamine (6-OHDA)-induced cell damage assay

6-OHDA-induced PCI2 can trigger cellular oxidative stress and inflammatory responses, which can be used to screen the neuroprotective effects of compounds and is also a common model for screening drugs for Parkinson's disease.

experiment material:

PC-12 cell line, 6-OHDA (sigma, H4381)

experiment procedure:

PC-12 cells were inoculated in 96-well plates and cultured to the logarithmic growth phase. 6-OHDA was used to culture cells at 100 μM. Compounds were tested at a concentration of 10 nM. After 24 h of incubation, cell survival was detected by MTT assay.

data analysis:

Each experiment was repeated three times, and the cell survival rate was calculated and the statistical differences between the groups were compared. GraphPad Prism 8.0 program software was used for statistics, and the data were expressed as Mean ± SEM. The intergroup differences between the two groups of data were compared using Student's t-test analysis; p < 0.05 was considered statistically significant.

test results:

The compounds of the present invention all have certain neuroprotective effects. The test results of exemplary compounds are shown in the following table. Compared with the model group, 10 nM ANAVEX2-73 and the test compounds in each group have certain neuroprotective effects, among which some compounds have more significant neuroprotective effects.

Note: # indicates: compared with the normal group, p<0.01; * indicates: compared with the control group, p<0.05; ** indicates: compared with the control group, p<0.01.

Evaluation of the efficacy of compounds in the Aβ25-35 mouse AD model

By injecting Aβ25-35 into the mouse brain area, short-term acute damage can be achieved, and AD (Alzheimer's disease)-related behavioral disorders and pathological damage can be induced, which can be used to screen AD therapeutic drugs.

Experimental animals:

CD1(ICR) mice or C57 mice

experiment procedure:

Aβ25-35 was prepared into a mother solution with a concentration of 1μg/mL using sterile water before the experiment, and was incubated at 37℃ to allow it to aggregate and age. After being divided, it was stored at -20℃ for later use. The experiment was carried out after the animals were adaptively raised for 7 days. The animals were randomly divided into groups. The head was shaved and disinfected with _iodine , and then an incision was made. The meninges were burned with _H2O2 . The anterior bregma was found, the injection site was determined according to the site, a skull drill was used to drill a hole, and then Aβ25-35 was injected with a microsyringe at a dose of 10nmol. The injection site of mice was the hippocampus or lateral ventricle. The specific parameters were as follows: the hippocampus was taken from the AP: -2.46mm behind the anterior bregma and the ML: ±2.2mm on the left and right sides of the median sagittal suture. A dental drill was used to drill a hole, and the needle insertion depth was DV: 2.1mm; the lateral ventricle was taken from the AP: -0.3mm behind the anterior bregma and the ML: ±1.0mm on the left and right sides of the median sagittal suture was drilled, and the needle insertion depth was DV: 2.5mm.

The experiment was divided into two parts: pre-drug administration and post-drug administration. Each experiment was divided into a control group, a model group, a positive drug ANAVEX 2-73, and a test compound group. In the pre-drug experiment, ANAVEX 2-73 (0.1, 0.3 mg/kg) and the test compound were given by gavage once a day from the 7th day to the 1st day before Aβ25-35 brain localization (brain localization was day 0), and the control group was given normal saline. The Y maze was used to detect behavioral indicators on the 11th to 13th day after modeling, and samples were collected on the 14th day to detect the level of lipid peroxidation in brain tissue. In the subsequent administration, from the 7th day to the 13th day after brain localization of Aβ25-35 (brain localization is day 0), ANAVEX2-73 (0.1, 0.3 mg/kg) and the test compound were gavaged once a day, and the control group was given normal saline. The behavioral indicators on the 11th to 13th day after modeling included open field test, Y maze test, and novel object location recognition test. Samples were collected on the 14th day to detect the level of lipid peroxidation in brain tissue.

The open field test detects spontaneous movement ability. Mice are placed in an open box device and their spontaneous movement is observed in a quiet environment. The mice are gently placed in the center of the inner box, and the machine automatically records and analyzes the spontaneous activity time, activity distance, upright time, and residence time of the mice within a certain period of time.

The novel object recognition test of mice's cognitive function was to prepare three objects, A, B, and C. A and B were exactly the same, and C was different from A and B. First, place two objects A and B on the left and right ends of one side wall in an open box, and let the mice explore freely for 10 minutes, and record the contact time with the two objects. Then replace object B with object C, record the contact time in the same period of time, and count the number, time and distance of the mice's exploration of the new and old objects. The recognition index (RI) is calculated as follows: RI = new object/(new object + old object) × 100%.

The Y-maze test tests spatial working memory. The Y-maze has three arms, all of which are 40cm (long) × 10cm (wide) × 20cm (high), and the angle between each two arms is 120°. Two indicators, spontaneous alternation and spatial recognition, are tested. In the spontaneous alternation experiment, all arms are open, and the animal is placed in one of the arms. The number of times and time the mouse enters the three arms are observed, and the total test time is 8 minutes. Spontaneous alternation behavior is defined as entering three arms in sequence (such as ABC, BCA, CAB, .....). The recording index is the spontaneous alternation rate (alternation score%) = (Number of alternation) / (Total arm entries-2) * 100%. Spatial recognition includes two tests, with an interval of 2h (the length of the interval can be used to examine the short-term memory and long-term memory of the animal respectively). The first test is the acquisition period (also called the learning period). One of the arms is closed, and the animal is allowed to explore the other two arms freely for 3 minutes. The test phase (recall phase) is carried out 2h later. That is, the closed arms are opened, and the animals are allowed to freely explore the three arms for 3 minutes. The time, distance, number of explorations in each arm are recorded. The indicator for judging memory damage is a significant reduction in the exploration time and distance in the new arm.

In the lipid peroxidation assay, the mouse hippocampus was collected and homogenized, centrifuged at 1000 g for 5 min, and the supernatant was collected. The quantitative peroxide detection kit (ThermoFisher, 23285) was used in combination with an enzyme reader to read the detection value.

data analysis:

The behavioral indicators such as spontaneous activity time, cognitive index, spontaneous alternation rate, etc. were counted among the groups, the lipid peroxidation level of brain tissue was counted, and the statistical differences between the groups were calculated. The statistics were analyzed using GraphPad Prism 8.0program software. The intergroup differences between the two groups of data were analyzed using Student's t-test; p<0.05 was considered statistically significant (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

Evaluation of the efficacy of compounds in 6-OHDA-induced PD rat model

The PD animal model (Parkinson’s disease) was established by stereotaxic injection of 6-OHDA into the brain of SD rats, which can induce behavioral disorders and pathological characteristics of PD such as damage to dopaminergic neurons, and is used to evaluate the efficacy of the test compounds in the treatment of PD.

Experimental Animals:

SD rats, male, 8 weeks old

experiment procedure:

After 7 days of adaptive feeding, the animals were divided into control group, model group, positive drug ANAVEX 2-73, and test compound group. Brain localization injection was used for modeling: about 1 μL of 3 μg/mL 6-OHDA solution was pre-inhaled into a 33G Hamilton syringe or glass electrode. The mice were anesthetized and fixed on a stereotaxic instrument. Injections were performed in the substantia nigra (AP-2.90mm; ML+1.10mm; DV-4.50mm) or medial forebrain bundle (AP-1.20mm; ML+1.10mm; DV-5.00mm) or striatum (AP+0.2mm; ML±2.00mm; DV-2.60mm). The glass electrode or injection needle was slowly inserted into the injection site, and 6-OHDA was injected into the target brain area at a rate of 0.2 μL/min.

Starting from the second day of modeling, the drug was administered by gavage once a day for 21 consecutive days, and behavioral tests were performed on the 22nd day. Behavioral tests included: apomorphine-asymmetric rotation, balance beam, rotating rod, and grip test. After behavioral tests, pathological tests (TH, Iba1 immunofluorescence staining), neurotransmitter content determination (DA, DOPAC, HVA), and enzyme-linked immunosorbent assay (ELISA) were performed to detect related inflammatory factors (IL-6, IL-1β, TNF-α).

data analysis:

Behavioral data, pathological test data, neurotransmitter content and inflammatory factor content were collected, and the statistical differences between the experimental groups were calculated using GraphPad Prism 8.0 program software. The intergroup differences between the two groups of data were compared using Student's t-test analysis; p<0.05 was statistically significant (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

Pharmacokinetic studies

This section studied the pharmacokinetics of Yangshen ANAVEX2-73, test compound 2, in CD1 mice to obtain basic pharmacokinetic parameters and provide data support for further drug development.

Experimental Animals:

CD1(ICR) mice, male

experiment procedure:

The dosage and route of administration are shown in the figure below. The compound solvent is 5% DMSO + 40% PEG400 + 55% H ₂ O

(iv means intravenous administration, ig means oral administration)

After administration, plasma was collected into centrifuge tubes containing K ₂ EDTA at 5 min, 15 min, 30 min, 1, 2, 4, 8, and 24 h. Plasma samples were subsequently analyzed by HPLC using an LC-MS/MS system. Plasma samples were diluted with 50% acetonitrile aqueous solution to obtain the required series of working solutions. 10 μL of working solution (1, 2, 5, 10, 20, 50, 100, 500 ng/mL) was added to 10 μL of blank plasma homogenate to obtain calibration standards of 1 to 500 ng/mL (1, 2, 5, 10, 20, 50, 100, 500 ng/mL) in a total volume of 20 μL. Five quality control samples of 1 ng/mL, 2 ng/mL, 50 ng/mL, and 400 ng/mL in plasma homogenate were prepared independently from the samples used for the calibration curve. These quality control samples were prepared on the day of analysis in the same manner as the calibration standards.

Before loading, 20 μL of standard sample, 20 μL of QC sample and 20 μL of unknown sample (10 μL of plasma homogenate and 10 μL of blank solution) were added to 200 μL of the mixture containing IS to precipitate proteins. After centrifugation at 4 °C and 4700 rpm for 15 min, the supernatant was diluted with ultrapure water at a ratio of 1:2 (V/V), and then 10 μL of the diluted supernatant was injected into the LC-MS/MS system for quantitative analysis.

test results:

PK data of compounds in CD1 mice

Conclusion: Compound 2 has significantly better pharmacokinetic properties than Anavex2-73 and significantly higher oral bioavailability.

Claims

The compound represented by formula (I), or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt:

in,

Ring A and Ring B are each independently selected from the following groups which are unsubstituted or substituted: C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the substitution is substitution with m1 identical or different R 3 and/or R 4 ;

Alternatively, ring A is absent;

R 3 is independently selected at each occurrence from the following groups: unsubstituted or substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, wherein the substitution is substituted by m2 identical or different R 4 ;

R 4 is independently selected at each occurrence from: hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -OC 3-6 heterocyclyl, -NR 5 R 5 , -C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -OC(O)R 5 , -S(O) 0-2 R 5 , -S(O) 2 NR 5 R 5 , -N(R 5 )S(O) 2 R 5 , -N(R 5 )C(O)R 5 , -N(R 5 )C(O)NR 5 , oxo (＝O), imino (＝NH) or thiocarbonyl (＝S);

R 5 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the substitution is by m3 identical or different cyano, amino, hydroxyl or halogen;

Ring C is selected from 3-12 membered heterocyclyl or C 3-12 cycloalkyl;

Rc is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, -OC 1-6 alkyl, -C 1-6 alkylene OH, oxo (=O) or thiocarbonyl (=S);

n is selected from 0, 1, 2, 3, 4 or 5;

L is selected from the following groups which are unsubstituted or substituted: C 1-6 alkylene, -OC 1-6 alkylene, -OC 3-6 cycloalkyl, -O 3-6 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl and 3-10 membered heterocyclyl, wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen;

R 1 is selected from hydrogen, unsubstituted or substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substituted by m5 identical or different R 6 and/or R 7 ;

R 2 is selected from the following groups which are unsubstituted or substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substitution by m5 identical or different R 6 and/or R 7 ;

Alternatively, R1 and R2 form an unsubstituted or substituted 4-12 membered heterocyclic group with the nitrogen atom to which they are attached, wherein the substitution is substitution by m8 identical or different R6 and/or R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

Alternatively, R1 or R2 are each independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-12 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different R6 and/or R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

R 6 is independently selected at each occurrence from the following groups: unsubstituted or substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is substitution by m6 identical or different R 7 and/or R 8 ;

R 7 at each occurrence is independently selected from deuterium, unsubstituted or substituted nitro, -OR 8 , -O(CH 2 ) 1-3 R 8 , -NR 8 R 8 , halogen, -CN, -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R 8 , -OC(O)R 8 , -S(O) 0-2 R 8 , -S(O) 2 NR 8 R 8 , -N(R 8 )S(O) 2 R 8 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)NR 8 , oxo (═O) and imino (═NH);

R8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the substitution is by m7 identical or different C1-6 alkyl, cyano, amino, hydroxyl, deuterium, -OC1-6 alkyl, -C1-6 alkylOH, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, -S(O) 0-2C1-3 alkyl, -N( C1-3 alkyl ) 2 , phenyl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -C(O) 0-2C1-3 alkyl, -OC(O) C1-3 alkyl, -OS(O)2C1-3 alkyl , -NHCOC 1-3 alkyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHSO 2 C 1-3 alkyl, -NHCONHC 1-3 alkyl or oxo replace;

m1, m2, m3, m4, m5, m6, m7, m8 and m9 are each independently selected from 1, 2, 3, 4, 5 or 6;

The prerequisite is that the definitions of the above variables (Ring A, Ring B, Ring C, Rc, n, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m1, m2, m3, m4, m5, m6, m7, m8 and/or m9) are combined to form a stable chemical structure;

Wherein the compound is not:
The compound according to claim 1, or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt, wherein the isotope derivative is a deuterated form of the compound.
The compound according to claim 1 or 2, or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: a C 4-10 cycloalkyl group, a 4-10 membered heterocyclyl group, a C 6-10 aryl group or a 5-10 membered heteroaryl group; or, the ring A is absent;

Alternatively, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C 4-9 cycloalkyl, 4-9 membered heterocyclyl, C 6-10 aryl or 5-9 membered heteroaryl; or, the ring A does not exist;

Alternatively, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C 4-8 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-8 membered heteroaryl; or, the ring A is absent;

Alternatively, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C 4-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl; or, the ring A is absent;

Alternatively, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C 5-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl; or, the ring A does not exist;

Alternatively, the ring A and the ring B are each independently selected from the following groups which are unsubstituted or substituted: C 5-6 cycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl; or, the ring A does not exist;

Wherein, the substitution is substitution by m1 identical or different R 3 and/or R 4 ;

Alternatively, the ring A is selected from the following groups which are unsubstituted or substituted: pyridyl, phenyl, thienyl, cyclohexyl or furanyl, or the ring A does not exist; the ring B is selected from the following groups which are unsubstituted or substituted: phenyl, pyridyl, thienyl or furanyl; wherein the substitution is substitution with 1, 2, 3, 4 or 5 identical or different R 3 and/or R 4 ; or, the substitution is substitution with 1 identical or different R 3 or R 4 .
The compound according to any one of claims 1 to 3, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the R 3 is independently selected at each occurrence from the following groups which are unsubstituted or substituted: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl;

Alternatively, the R 3 is independently selected at each occurrence from the following groups, which are unsubstituted or substituted: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

Alternatively, the R 3 is independently selected at each occurrence from the following groups, which are unsubstituted or substituted: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 4-6 cycloalkyl or 4-6 membered heterocyclyl;

Alternatively, the R 3 is independently selected at each occurrence from the following groups, which are unsubstituted or substituted: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 5-6 cycloalkyl or 5-6 membered heterocyclyl;

Alternatively, said R 3 is independently selected at each occurrence from the following groups, unsubstituted or substituted: methyl, ethyl, isopropyl, vinyl, ethynyl or cyclopropyl;

Alternatively, the R 3 is independently selected at each occurrence from the following groups, unsubstituted or substituted: methyl;

Wherein, the substitution is substitution by m2 identical or different R 4 ;

Alternatively, the R 3 is methyl.
The compound according to any one of claims 1 to 4, or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein the R 4 is independently selected at each occurrence from the group consisting of hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC 1-4 alkyl, -OC 4-6 cycloalkyl, -OC 4-6 heterocyclyl, -NR 5 R 5 , -C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -OC(O)R 5 , -S(O) 0-2 R 5 , -S(O) 2 NR 5 R 5 , -N(R 5 )S(O) 2 R 5 , -N(R 5 )C(O)R 5 , -N(R 5 )C(O)NR 5 , oxo (═O), imino (═NH) or thiocarbonyl (═S);

Alternatively, said R 4 is independently selected at each occurrence from the group consisting of hydrogen, deuterium, hydroxyl, amino, halogen, cyano, nitro, -OC 1-3 alkyl, -OC 5-6 cycloalkyl, -OC 5-6 heterocyclyl, -NR 5 R 5 , -C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -OC(O)R 5 , -S(O) 0-2 R 5 , -S(O) 2 NR 5 R 5 , -N(R 5 )S(O) 2 R 5 , -N(R 5 )C(O)R 5 , -N(R 5 )C(O)NR 5 , oxo (＝O), imino (＝NH) or thiocarbonyl (＝S);

Alternatively, said R 4 is independently selected at each occurrence from: hydrogen, deuterium, halogen, hydroxyl or -OCH 3 ;

Alternatively, said R 4 is independently selected at each occurrence from: hydrogen, deuterium, F, Cl or -OCH 3 ;

Alternatively, said R 4 is independently selected at each occurrence from: hydrogen.
A compound according to any one of claims 1 to 5, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the R 5 is independently selected at each occurrence from hydrogen, unsubstituted or substituted from the following groups: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

Alternatively, said R 5 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C 1-3 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

Alternatively, said R 5 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C 1-3 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 4-6 cycloalkyl and 4-6 membered heterocyclyl;

Alternatively, said R 5 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C 1-3 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 5-6 cycloalkyl and 5-6 membered heterocyclyl;

Wherein, the substitution is substitution by m3 identical or different cyano groups, amino groups, hydroxyl groups or halogen groups;

Alternatively, said R 5 is independently selected at each occurrence from hydrogen, unsubstituted or substituted groups: methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl; wherein said substitution is substitution by 1 or 2 identical or different cyano, amino, hydroxyl or halogen.
The compound according to any one of claims 1 to 6, or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein the ring C is selected from a 4-10 membered heterocyclic group or a C4-10 cycloalkyl group;

Alternatively, the ring C is selected from a 5-10 membered heterocyclyl or a C 5-10 cycloalkyl;

Alternatively, the ring C is selected from a 5-9 membered heterocyclyl or a C 5-9 cycloalkyl;

Alternatively, the ring C is selected from a 5-8 membered heterocyclyl or a C 5-8 cycloalkyl;

Alternatively, the ring C is selected from a 5-6 membered heterocyclyl or a C 5-6 cycloalkyl;

Alternatively, the ring C is selected from a 5-6 membered heterocyclic group;

Wherein, the heteroatom in the heterocyclic group is selected from O, N or S, and the number of heteroatoms is 1 or 2; or, the heteroatom in the heterocyclic group is selected from O or S, and the number of heteroatoms is 1;

Alternatively, the heterocyclyl group is a heterocycloalkyl group;

Alternatively, the ring C is selected from a 5-8 membered heterocycloalkyl or a 5-6 membered heterocycloalkyl, the heterocycloalkyl contains 1 heteroatom selected from O, N or S, and the ring A and ring B are located at the alpha position to the heteroatom, and/or L is located at the alpha position or beta position to the heteroatom.
The compound according to any one of claims 1 to 7, or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein the ring C is selected from: cyclopentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, tetrahydropyranyl, hexahydropyrazinyl, morpholinyl, thiomorpholinyl, piperidinyl, 1,4-dioxane or hexahydropyrimidinyl;

Alternatively, the ring C is selected from: cyclopentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl or 1,4-dioxane;

Alternatively, the ring C is selected from: Wherein, * indicates the connection site with ring A and ring B;

Alternatively, the ring C is selected from:

Wherein, * indicates the connection site with ring A and ring B, Indicates the attachment site to L.
The compound according to any one of claims 1 to 8, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein L is selected from the following groups which are unsubstituted or substituted: C 1-4 alkylene, -OC 1-4 alkylene, -OC 3- 6 cycloalkyl, -O-(3-6 membered heterocyclyl), C 2-4 alkenyl, C 2-4 alkynyl, C 3-9 cycloalkyl and 3-9 membered heterocyclyl;

Alternatively, L is selected from the following groups which are unsubstituted or substituted: C 1-4 alkylene, -OC 1-4 alkylene, -OC 3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

Alternatively, L is selected from the following groups which are unsubstituted or substituted: C 1-3 alkylene, -OC 1-3 alkylene, -OC 3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

Alternatively, L is selected from the following groups which are unsubstituted or substituted: C 1-2 alkylene, -OC 1-2 alkylene, -OC 3-6 cycloalkyl, -O-(3-6 membered heterocyclyl), C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

Alternatively, wherein the heterocyclyl group is a heterocycloalkyl group;

Alternatively, L is selected from the following groups which are unsubstituted or substituted: -CH2- , -CH2CH2-, -OCH2- , -OCH2CH2- , vinyl, ethynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydrothienyl ;

Alternatively, L is selected from the following groups which are unsubstituted or substituted: -CH 2 -, -CH 2 CH 2 -, -OCH 2 -, -OCH 2 CH 2 -, vinyl or ethynyl;

wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen;

Alternatively, L is selected from: -CH 2 -, -CD 2 -, -CH 2 CH 2 -, -OCH 2 -, -OCH 2 CH 2 -, vinyl or ethynyl;

Alternatively, said L is selected from: -CH 2 -, CD 2 - or -CH 2 CH 2 -.
The compound according to any one of claims 1 to 9, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, unsubstituted or substituted with the following groups: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-9 cycloalkyl, C 3-9 cycloalkenyl, C 6-10 aryl, 3-9 membered heterocyclyl and 5-10 membered heteroaryl;

Alternatively, R 1 is selected from hydrogen, unsubstituted or substituted C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl;

Alternatively, R 1 is selected from hydrogen, unsubstituted or substituted C 1-3 alkyl, C 3-6 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

Wherein, the 3-7 membered heterocyclic group is a 3-6 membered heterocyclic group, or a 4-6 membered heterocyclic group, or a 5-6 membered heterocyclic group;

Alternatively, the R 1 is selected from hydrogen, unsubstituted or substituted: C 1-3 alkyl;

Alternatively, the R 1 is selected from hydrogen, unsubstituted or substituted: methyl;

Wherein, the substitution is substitution by m5 identical or different R 6 and/or R 7 .
The compound according to any one of claims 1 to 10, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the following groups which are unsubstituted or substituted: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-9 cycloalkyl, C 3-9 cycloalkenyl, C 6-10 aryl, 3-9 membered heterocyclyl and 5-10 membered heteroaryl;

Alternatively, R 2 is selected from the following groups which are unsubstituted or substituted: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 3-8 membered heterocyclyl and 5-9 membered heteroaryl;

Alternatively, R 2 is selected from the following groups which are unsubstituted or substituted: C 1-4 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

Alternatively, said R 2 is selected from the following groups which are unsubstituted or substituted: C 1-4 alkyl, C 3-7 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl;

Wherein, the 3-7 membered heterocyclic group is a 3-6 membered heterocyclic group, or a 4-6 membered heterocyclic group, or a 5-6 membered heterocyclic group;

Alternatively, R 2 is selected from the following groups which are unsubstituted or substituted: C 1-4 alkyl, azepanyl, cyclopropyl, cyclobutane, oxetanyl, azetidinyl, cyclopentane, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, cyclohexane, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyrimidinyl, morpholinyl or tetrahydropyranyl;

Alternatively, R 2 is selected from the following groups which are unsubstituted or substituted: C 1-4 alkyl, cyclopropyl, oxetanyl, tetrahydropyranyl or azepanyl;

Alternatively, said R 2 is selected from the following groups which are unsubstituted or substituted: methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CH(CH 3 ) 2 or azepanyl;

Wherein, the substitution is substitution by m5 identical or different R 6 and/or R 7 .
The compound according to any one of claims 1 to 9, or its stereoisomers, optical isomers, solvates, isotopic derivatives An organism or a pharmaceutically acceptable salt thereof, wherein R1 and R2 form the following groups which are unsubstituted or substituted with the nitrogen atom to which they are attached: a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 7-membered heterocyclyl, an 8-membered heterocyclyl, a 9-membered heterocyclyl, a 10-membered heterocyclyl, an 11-membered heterocyclyl and a 12-membered heterocyclyl;

Alternatively, R1 and R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 7-membered spiro heterocyclic group, a 7-membered fused heterocyclic group, an 8-membered monocyclic heterocyclic group, an 8-membered bridged heterocyclic group, an 8-membered spiro heterocyclic group, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a 9-membered spiro heterocyclic group, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a 10-membered spiro heterocyclic group, a 10-membered fused heterocyclic group, an 11-membered bridged heterocyclic group, an 11-membered spiro heterocyclic group, an 11-membered fused heterocyclic group, a 12-membered bridged heterocyclic group, a 12-membered spiro heterocyclic group and a 12-membered fused heterocyclic group;

Alternatively, the R1 and R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 3-membered/5-membered spiro heterocyclic group, a 4-membered/4-membered spiro heterocyclic group, a 7-membered fused heterocyclic group, an 8-membered monocyclic heterocyclic group, an 8-membered bridged heterocyclic group, a 3-membered/6-membered spiro heterocyclic group, a 4-membered/5-membered spiro heterocyclic group, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a 3-membered/7-membered spiro heterocyclic group, a 4-membered/6-membered spiro heterocyclic group, a 5-membered/5-membered spiro heterocyclic group, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a 4-membered/7-membered spiro heterocyclic group, a 5-membered/6-membered spiro heterocyclic group and a 10-membered fused heterocyclic group;

Alternatively, the R1 and R2 and the nitrogen atom to which they are connected form the following groups which are unsubstituted or substituted: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a 3-membered/5-membered spiro heterocyclic group, a 4-membered/4-membered spiro heterocyclic group, an 8-membered monocyclic heterocyclic group, an 8-membered bridged heterocyclic group, a 3-membered/6-membered spiro heterocyclic group, a 4-membered/5-membered spiro heterocyclic group, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a 3-membered/7-membered spiro heterocyclic group, a 4-membered/6-membered spiro heterocyclic group, a 5-membered/5-membered spiro heterocyclic group, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a 4-membered/7-membered spiro heterocyclic group, a 5-membered/6-membered spiro heterocyclic group and a 10-membered fused heterocyclic group;

Alternatively, the R1 and R2 and the nitrogen atom to which they are attached form the following groups which are unsubstituted or substituted: a 4-membered monocyclic heterocyclic group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 7-membered bridged heterocyclic group, a heterospiro[2.4]heptyl group, a heterospiro[2.4]heptenyl group, a heterospiro[3.3]heptyl group, an 8-membered heterocyclic group, an 8-membered bridged heterocyclic group, a heterospiro[2.5]octanyl group, a heterospiro[2.5]octenyl group, a heterospiro[3.4]octanyl group, a heterospiro[3.4 ... alkenyl, an 8-membered fused heterocyclic group, a 9-membered bridged heterocyclic group, a heterospiro[2.6]nonanyl, a heterospiro[2.6]nonenyl, a heterospiro[3.5]nonanyl, a heterospiro[3.5]nonenyl, a heterospiro[4.4]nonanyl, a heterospiro[4.4]nonenyl, a 9-membered fused heterocyclic group, a 10-membered bridged heterocyclic group, a heterospiro[3.6]decanyl, a heterospiro[3.6]decenyl, a heterospiro[4.5]decanyl, a heterospiro[4.5]decenyl and a 10-membered fused heterocyclic group;

Alternatively, the R1 and R2 and the nitrogen atom to which they are attached form the following groups which are unsubstituted or substituted: azetidine, pyrrolidine, tetrahydroimidazole, piperidine, piperazine, 1,4-oxazine, 1,4-tetrahydrooxazine, azepanyl, 1,4-diazepanyl, 1,4-oxaazepanyl, azaspiro[3.3]heptyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, azaspiro[3.3]heptyl, azaspiro[3.3]heptyl, 4]octanyl, diazaspiro[3.4]octanyl, oxazaspiro[3.4]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxazaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, oxazaspiro[4.5]decanyl, azaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl and oxazaspiro[3.5]nonanyl;

Wherein, the substitution is substitution by m8 identical or different R 6 and/or R 7 ;

Wherein, the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S; or, the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N or O;

The "hetero" refers to a heteroatom, wherein the heteroatom is 1 nitrogen atom, or the heteroatom is 1 nitrogen atom and 1-2 atoms selected from N, O or S; or, the heteroatom is 1 nitrogen atom, or the heteroatom is 1 nitrogen atom and 1-2 atoms selected from N or O;

Alternatively, the heterocyclyl group is a heterocycloalkyl group.
The compound according to any one of claims 1 to 11, or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, wherein the R 1 or R 2 is each independently connected to the ring atom on the ring C to form an unsubstituted or substituted 4-9 membered heterocyclic group;

Alternatively, the R 1 or R 2 is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-8 membered heterocyclic group;

Alternatively, the R 1 or R 2 is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-7 membered heterocyclic group;

Alternatively, the R 1 or R 2 is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 5-7 membered heterocyclic group;

Alternatively, the R 1 or R 2 is independently connected to the ring atoms on the ring C to form an unsubstituted or substituted 4-6 membered heterocyclic group;

Alternatively, the R 1 or R 2 is independently connected to the ring atoms on ring C to form an unsubstituted or substituted 5-6 membered heterocyclic group;

Wherein, the connection mode between the heterocyclic group and ring C is spiro connection, fusion or bridge connection;

Alternatively, the R1 is connected to the ring atoms on the ring C to form an unsubstituted or substituted 5-6 membered heterocyclic group, and the 5-6 membered heterocyclic group is connected to the ring C in a spiral or fused manner to form a bicyclic ring;

wherein the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S; or the heterocyclic group contains 1 nitrogen atom, or the heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N or O; or the heterocyclic group contains 1 N atom;

Alternatively, the heterocyclyl group is a heterocycloalkyl group;

Alternatively, the R 1 is connected to the ring atoms on the ring C to form an unsubstituted or substituted heterocyclic ring: piperidine ring, tetrahydropyrrole ring, azetidine;

Alternatively, the R 1 is connected to the ring atoms on the ring C to form an unsubstituted or substituted heterocycle: Wherein, * represents the screw connection site or fusion site with ring C;

Alternatively, the ring C and the structural unit -LN(R 2 )-R 1 together form the following structure: Wherein, * indicates the connection site with ring A and ring B;

Wherein, the substitution is substitution by m9 identical or different R 6 and/or R 7 .
The compound according to any one of claims 1 to 13, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the R 6 is independently selected at each occurrence from the following groups which are unsubstituted or substituted: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;

Alternatively, each occurrence of R 6 is independently selected from the following groups, which are unsubstituted or substituted: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;

Alternatively, each occurrence of R 6 is independently selected from the following groups, which are unsubstituted or substituted: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl;

Wherein, the substitution is substitution by m6 identical or different R 7 and/or R 8 .
The compound according to any one of claims 1 to 14, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the R 7 is independently selected at each occurrence from the group consisting of deuterium, nitro, -OR 8 , -O(CH 2 ) R 8 , -O(CH 2 ) 2 R 8 , -NR 8 R 8 , halogen, -CN, -C(O)R 8 , -C(O)OR 8 , -N(R 8 )C(O)R 8 , -C(O)NR 8 R 8 , -OC(O)R 8 , -S(O) 0- 2 R 8 and oxo (＝O);

Alternatively, said R 7 is independently selected at each occurrence from the group consisting of deuterium, nitro, -OR 8 , -NR 8 R 8 , halogen, -CN, -C(O)R 8 , -C(O)OR 8 , -N(R 8 )C(O)R 8 , -C(O)NR 8 R 8 , -OC(O)R 8 , -S(O) 0-2 R 8 and oxo (=O);

Alternatively, said R 7 at each occurrence is independently selected from the group consisting of: deuterium, -OR 8 , -NR 8 R 8 , -C(O)R 8 , -CN, -N(R 8 )C(O)R 8 , -C(O)NR 8 R 8 and oxo (=O).
A compound according to any one of claims 1 to 15, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the R 8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted with the following groups: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl , 3-10 membered heterocyclyl and 5-10 membered heteroaryl;

Alternatively, each occurrence of R 8 is independently selected from hydrogen, unsubstituted or substituted C 1-4 alkyl, C 2-4 alkenyl, C 2- 4- membered alkynyl, C 3-6- cycloalkyl, C 6-10- aryl, 3-6-membered heterocyclyl, and 5-6-membered heteroaryl;

Alternatively, said R 8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, phenyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl;

Alternatively, said R 8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted C 1-3 alkyl, 4-6 membered heterocyclyl, phenyl and C 3-5 cycloalkyl;

Alternatively, said R 8 is independently selected at each occurrence from hydrogen, unsubstituted or substituted with methyl, ethyl, cyclopropane, cyclobutane, phenyl, tetrahydropyrrolyl or cyclopentane;

wherein the substitution is by m7 identical or different C 1-4 alkyl, cyano, amino, hydroxyl, halogen, deuterium, -OC 1-4 alkyl, -C 1-4 alkylOH, C 3-5 cycloalkyl, C 1-4 haloalkyl, -S(O) 0 - 2 C 1-3 alkyl, -N(C 1-3 alkyl) 2 , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl, -C(O) 0-2 C 1-3 alkyl, -OC(O)C 1-3 alkyl, -NHCOC 1-3 alkyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHSO 2 C 1-3 alkyl, -NHCONHC 1-3 alkyl or oxo; or, the substitution is by m7 identical or different C 1-3 alkyl, cyano, amino, hydroxyl, halogen, deuterium, -OC 1-4 alkyl, -C 3-5 cycloalkyl, C 1-4 haloalkyl, -S(O) 0 - 2 C 1-3 alkyl, -N(C 1-3 alkyl) 2 , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl, -C(O) 0-2 C 1-3 alkyl, -OC(O)C 1-3 alkyl, -NHCOC 1-3 alkyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHSO 2 C 1-3 alkyl, -NHCONHC 1-3 alkyl or oxo; 2 , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl, -C(O) 0-2 C 1-3 alkyl, -OC(O)C 1-3 alkyl, -NHCOC 1-3 alkyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl) 2 , -NHSO 2 C 1-3 alkyl, -NHCONHC 1-3 alkyl or oxo; or, the substitution is by m7 identical or different C 1-3 alkyl, cyano, amino , hydroxyl, halogen, deuterium, -OC 1-3 alkyl, -C 1-3 alkylOH, C 3-5 cycloalkyl , C 1-3 haloalkyl , -N ( C 1-3 alkyl ) 2 , phenyl, 5-6 membered heteroaryl, 3-7 membered heterocyclyl or oxo; or, C 1-4 alkyl, cyano, amino, hydroxyl or halogen substituted; or, the substitution is substituted by m7 identical or different C 1-3 alkyl, cyano, amino, hydroxyl or halogen; or, the substitution is substituted by m7 identical or different methyl, ethyl, cyano, amino, hydroxyl or halogen; or, the substitution is substituted by m7 identical or different methyl, fluorine or chlorine; or, the substitution is substituted by 1 methyl.
The compound according to any one of claims 1 to 16, or a stereoisomer, optical isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein Rc is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylene OH, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

Alternatively, Rc is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene OH, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

Alternatively, Rc is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

Alternatively, Rc is selected from hydrogen, deuterium, halogen, C 1-3 alkyl, cyano, hydroxyl, nitro, oxo (=O) or thiocarbonyl (=S);

Alternatively, the Rc is selected from hydrogen, deuterium, fluorine, methyl, hydroxyl or oxo (=O).
A compound according to any one of claims 1 to 17, or a stereoisomer, optical isomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (III):

in,

t is selected from 1 or 2;

X is C, O or S;

Y is C or O;

L is selected from the following groups which are unsubstituted or substituted: -CH 2 - or -CH 2 CH 2 -; wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen; or, L is selected from -CH 2 - or -CH 2 CH 2 -;

Ring A, Ring B, Rc, n, m4, R1 and R2 are as defined in any one of claims 1 to 17.
A compound according to any one of claims 1 to 18, or a stereoisomer, optical isomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (III):

R1 and R2 form an unsubstituted or substituted 4-12 membered heterocyclic group with the nitrogen atom to which they are attached, wherein the substitution is substitution by m8 identical or different R6 and/or R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

in,

t is 1 or 2;

X is C, O or S;

Y is C or O;

n is 0 or 1;

L is selected from the following groups which are unsubstituted or substituted: -CH 2 - or -CH 2 CH 2 -; wherein the substitution is substitution by m4 identical or different deuterium, cyano, amino, hydroxyl or halogen; preferably, L is selected from: -CH 2 - or -CH 2 CH 2 -;

Ring A, Ring B, m4, m8, R 6 , R 7 and Rc are as defined in any one of claims 1 to 18.
A compound according to any one of claims 1 to 18, or a stereoisomer, optical isomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (VI):

R1 or R2 are each independently connected to the ring atoms on ring C to form an unsubstituted or substituted 4-12 membered heterocyclic ring, wherein the substitution is substitution by m9 identical or different R6 and/or R7 , and the 4-12 membered heterocyclic group contains 1 nitrogen atom, or the 4-12 membered heterocyclic group contains 1 nitrogen atom and 1-2 heteroatoms selected from N, O or S;

X is selected from C, O or S;

L is selected from -CH 2 - or -CH 2 CH 2 -;

wherein Ring A, Ring B, Rc, n, m9, R6 and R7 are as defined in any one of claims 1 to 18.
The compound according to any one of claims 1 to 18, or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein the compound is selected from:
The compound according to any one of claims 1 to 18, or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein the compound is selected from:
A pharmaceutical composition comprising the compound according to any one of claims 1 to 22 or its stereoisomer, optical isomer, solvate, isotope derivative or pharmaceutically acceptable salt.
Use of the compound according to any one of claims 1 to 22 or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 23 as a Sigma-1 receptor and/or M1-muscarinic acetylcholine receptor ligand; or, the ligand is an agonist.
Use of a compound according to any one of claims 1 to 22 or its stereoisomer, optical isomer, solvate, isotopic derivative or pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 23 in the preparation of a medicament as a Sigma-1 receptor and/or M1-muscarinic acetylcholine receptor ligand.