Tricyclic compounds, preparation method therefor, and use thereof

Abstract

The present invention relates to tricyclic compounds, a preparation method therefor, and the use thereof. In particular, the present invention relates to compounds represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compounds, and the use thereof in treating diseases such as obesity, depression or epilepsy.

Description

Trifused ring compounds, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a trifused ring compound, its preparation method, and its application. Background Technology

[0002] Developmental and epileptic encephalopathy (DEE) is a heterogeneous group of neurodevelopmental disorders, typically diagnosed in childhood and adolescence. DEE is characterized by early-onset epilepsy, abnormal electroencephalograms (EEGs), and developmental delays or regressions. In addition to phenotypic complexity, drug resistance is also a hallmark of DEE. The overall incidence of DEE is (0.27–0.54) per 1000 newborns, with a mortality rate of 17%–50%. Even among survivors, the vast majority of affected children suffer from severe neurological disabilities, placing a heavy burden on families and society.

[0003] Serotonin (5-HT) is a neurotransmitter with 14 receptors, divided into 7 receptor families. Serotonin couples with various downstream signaling molecules, forming a complex serotonin signaling pathway that plays a crucial regulatory role in various brain functions, including mood, cognition, and sleep. Preclinical studies in genetic and induced epilepsy models have shown that dysregulation of 5-HTergic signaling increases susceptibility to seizures and is associated with multiple seizure types. Clinically, 5-HT receptor agonists have proven to be effective treatments for seizures. For example, the 5-HT2a / 5-HT2b / 5-HT2c receptor agonist fenfluramine (Fintepla) can reduce the frequency of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and other rare epilepsy conditions, improve comorbidities, and may reduce the risk of sudden epileptic death. However, due to the association between 5-HT2b receptor activation and the development of valvular heart disease, fenfluramine received a boxed warning from the FDA regarding cardiac monitoring. 5-HT2c is widely distributed in multiple brain regions, including the hypothalamus, hippocampus, amygdala, cortex, and basal ganglia. Preclinical studies in animal models have shown that mice lacking the 5-HT2C receptor exhibit greater susceptibility to epilepsy. We hope to develop highly selective 5-HT2C receptor agonists for seizure control to meet this significant market demand. Summary of the Invention

[0004] On one hand, the object of the present invention is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (I) has the following structure:

[0005] in:

[0006] Indicates a single bond or a double bond;

[0007] M1, M3, or M6 are each independently selected from bonds, N, O, C, and S(O). m S(O)NR a 、(CR a R b ) m 、(CR a ) m NR a C=O, C=S, or C=NR a ;

[0008] M2, M4, or M5 are each independently selected from N, C, or CR. a ;

[0009] M7 or M8 are each independently selected from bonds, N, and S(O). m NR b CR b NR b or C(R) b )2;

[0010] L1 is selected from key, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-14 4-14 membered heterocyclic alkyl groups, C 6-14 Metaaryl, 5-14 metaaryl, C 3-14 4-14 membered heterocyclic amino groups, C 6-14 5-14-membered heteroarylamines, C 3-14 4-14 cycloalkoxide, cycloalkoxide, C 6-14 5-14-membered heteroaryloxy, C 3-14 4-14 membered heterocyclic thiol group, C 6-14 5-14-membered heteroaryl mercapto, C 3-14 4-14 member heterocyclic methyl groups, C 6-14 5-14-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1C(=NR4)-,-NR4C=S-,-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -、-S(=O)(=NR4)R4 or -(CH2) m1 NR4CO(CH2) m2 O-, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-14 4-14 membered heterocyclic alkyl groups, C 6-14 Metaaryl, 5-14 metaaryl, C 3-14 4-14 membered heterocyclic amino groups, C 6-14 5-14-membered heteroarylamines, C 3-14 4-14 cycloalkoxide, cycloalkoxide, C 6-14 5-14-membered heteroaryloxy, C 3-14 4-14 membered heterocyclic thiol group, C 6-14 5-14-membered heteroaryl mercapto, C 3-14 4-14 member heterocyclic methyl groups, C 6-14 5-14-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2-、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents of 5-14 heteroaryl groups are substituted, preferably the bond, -CONR4 or -NR4-;

[0011] Preferably, L1 is selected from bonds, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-10 4-10 membered heterocyclic alkyl groups, C 6-10 Metaaryl, 5-10 metaaryl, C 3-10 4-10 membered heterocyclic amino groups, C6-10 5-10 methylamine, 5-10 methylamine, C 3-10 4-10 member cycloalkoxide, cycloalkoxide, C 6-10 5-10 arylene oxides, 5-10 heteroarylene oxides, C 3-10 4-10 membered heterocyclic thiol group, C 6-10 5-10 methyl aryl thiol, 5-10 methyl aryl thiol, C 3-10 4-10 member heterocyclic methyl groups, C 6-10 5-10-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=NR4)-,-NR4C=S-,-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-10 4-10 membered heterocyclic alkyl groups, C6-10 Metaaryl, 5-10 metaaryl, C 3-10 4-10 membered heterocyclic amino groups, C 6-10 5-10 methylamine, 5-10 methylamine, C 3-10 4-10 member cycloalkoxide, cycloalkoxide, C 6-10 5-10 arylene oxides, 5-10 heteroarylene oxides, C 3-10 4-10 membered heterocyclic thiol group, C 6-10 5-10 methyl aryl thiol, 5-10 methyl aryl thiol, C 3-10 4-10 member heterocyclic methyl groups, C 6-10 5-10-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents of 5-14 heteroaryl groups are substituted, preferably the bond, -CONR4 or -NR4-;

[0012] L2 is selected from bonds, NH, O, S, C. 1-6 Alkylene, C(O), C(O)O, -(CH2) m1 CONR4(CH2) m2 -or-(CH2) m1 NR4CO(CH2) m2 -;

[0013] R1, R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, wherein the amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0014] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3- 14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl mercapto, 5-14 heteroaryl mercapto, optionally further divided by one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0015] Or, R a R b Any two atoms connected to it from R1, R2, L1, or L2 form C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted by one or more R3 substituents;

[0016] Or, any two R a Or R2 and the atoms attached to it form C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl and 5-14 quinone heteroaryl, optionally further substituted with one or more R3 substituents;

[0017] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, cyano, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0018] R4 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, cyano, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 6-alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0019] m1 or m2 can be 0, 1, 2 or 3 independently;

[0020] m is 0, 1, or 2;

[0021] s is 1, 2, or 3;

[0022] r or t can be 0, 1 or 2 independently.

[0023] In some embodiments of the present invention,

[0024] L2 is selected from bonds, NH, O, S, C. 1-6 Alkylene, C(O) or C(O)O; in some embodiments,

[0025] Indicates a single bond or a double bond;

[0026] M1, M3, or M6 are each independently selected from bonds, N, O, S, C, and S(O). m S(O)NR a 、(CR a R b ) m 、(CR a ) m NR a C=O, C=S, or C=NR a ;

[0027] M2, M4, or M5 are each independently selected from N, C, or CR. a ;

[0028] M7 or M8 are each independently selected from bonds, N, and S(O). m NR b CR b NR b or C(R) b )2;

[0029] L1 is selected from L1, which is selected from key, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C3-10 4-10 membered heterocyclic alkyl groups, C 6- 10 Metaaryl, 5-10 metaaryl, C 3-10 4-10 membered heterocyclic amino groups, C 6-10 5-10 methylamine, 5-10 methylamine, C 3-10 4-10 member cycloalkoxide, cycloalkoxide, C 6-10 5-10 arylene oxides, 5-10 heteroarylene oxides, C 3-10 4-10 membered heterocyclic thiol group, C 6-10 5-10 methyl aryl thiol, 5-10 methyl aryl thiol, C 3-10 4-10 member heterocyclic methyl groups, C 6-10 5-10-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=NR4)-,-NR4C=S-,-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -or (CH2) m1 S(O)NR4(CH2) m2 -, wherein C1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-10 4-10 membered heterocyclic alkyl groups, C 6-10 Metaaryl, 5-10 metaaryl, C 3-10 4-10 membered heterocyclic amino groups, C 6-10 5-10 methylamine, 5-10 methylamine, C 3-10 4-10 member cycloalkoxide, cycloalkoxide, C 6-10 5-10 arylene oxides, 5-10 heteroarylene oxides, C 3-10 4-10 membered heterocyclic thiol group, C 6-10 5-10 methyl aryl thiol, 5-10 methyl aryl thiol, C 3-10 4-10 member heterocyclic methyl groups, C 6-10 5-10-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -or (CH2) m1 S(O)NR4(CH2) m2- Optional further additions of halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents of 5-14 heteroaryl groups are substituted, preferably the bond, -CONR4 or -NR4-;

[0030] L2 is selected from bond, O, S, C. 1-6 Alkylene, C(O) or C(O)O;

[0031] R1, R a or R b Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, wherein the amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, optionally further coated with halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0032] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl thiols, 5-14 heteroaryl thiols, optionally further divided by one or more halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, thiols, oxo groups, thiols, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0033] Or, R a R b Any two atoms connected to it from R1, R2, L1, or L2 form C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl and 5-14 quinone heteroaryl groups, optionally further bonded by halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, mercapto groups, oxo groups, thio groups, C- groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0034] Or, any two R a Or R2 and the atoms attached to it form C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl and 5-14 quinone heteroaryl groups, optionally further bonded by halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, mercapto groups, oxo groups, thio groups, C- groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0035] m1 or m2 can be 0, 1, 2 or 3 independently;

[0036] m is 1 or 2;

[0037] s is 1, 2, or 3;

[0038] r or t can be 0, 1 or 2 independently.

[0039] In some implementations, for general formula (I), where,

[0040] Indicates a single bond or a double bond;

[0041] M1, M3, or M6 are each independently selected from bonds, N, O, C, and S(O). m S(O)NR a 、(CR a R b ) m 、(CR a ) m NR a C=O, C=S, or C=NR a ;

[0042] M2, M4, or M5 are each independently selected from N, C, or CR. a ;

[0043] M7 or M8 are each independently selected from bonds, N, and S(O). m NR b CR b NR b or C(R) b )2;

[0044] L1 is selected from key, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Alynyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2)m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Alynyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2)m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents of 5-14 heteroaryl groups are substituted, preferably the bond, -CONR4 or -NR4-;

[0045] L2 is selected from bonds, NH, O, S, or C. 1-6 Alkylene;

[0046] R1, R a or R b Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C6-12 Aromatyl mercapto or 5-14 heteroaryl mercapto, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, optionally further coated with halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0047] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3- 14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl thiols, 5-14 heteroaryl thiols, optionally further divided by one or more halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, thiols, oxo groups, thiols, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0048] Or, R a R b Any two atoms connected to it from R1, R2, L1, or L2 form C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted by one or more R3 substituents;

[0049] Or, any two R aOr R2 and the atoms attached to it form C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl and 5-14 quinone heteroaryl, optionally further substituted with one or more R3 substituents;

[0050] R3 is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3- 10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6- 12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, cyano, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0051] R4 is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3- 10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6- 12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, cyano, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0052] m1 or m2 can be 0, 1, 2 or 3 independently;

[0053] m is 0, 1, or 2;

[0054] s is 1, 2, or 3;

[0055] r or t can be 0, 1 or 2 independently.

[0056] In some embodiments, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is further represented by the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0057] M1, M3, or M6 are each independently selected from bonds, N, O, S, C, or CR. a Preferably, at most one of M1, M3, or M6 is a key;

[0058] M7 or M8 are each independently selected from bond, O, and S(O). m S(O) m NR b NR b or C(R) b )2;

[0059] L1 is selected from key, -CONR4, -S(O) mNR4-, -NR4-, 4-6 membered heterocyclic groups containing 1-3 N, O or S atoms, 5-6 membered heteroaryl groups containing 1-3 N, O or S atoms, 4-6 membered heterocyclic amino groups containing 1-3 N, O or S atoms, or 5-6 membered heteroaryl amino groups containing 1-3 N, O or S atoms;

[0060] L2 is selected from bond, C(O), O, S, or C. 1-3 Alkylene;

[0061] R1, R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0062] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3- 8-membered cycloalkylamino, 3-10-membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0063] Or, R a R b Any two atoms from R1, R2, L1, or L2 that can be bonded to it can form C 3-14 Cycloalkyl groups, 4-14 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-12 The aryl group or containing 1-3 5-14 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-14 Cycloalkyl groups, 4-14 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-12 aryl and 5-14 heteroaryl groups containing 1-3 N, O or S atoms, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0064] R4 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C.1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3- 8-membered cycloalkylamino, 3-10-membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0065] In some implementations, for formula (I) or formula (II), L1 is selected from key, -CONR4, -S(O). m NR4-, -NR4-, 4-6 membered heterocyclic groups containing 1-3 N, O or S atoms, or 5-6 membered heteroaryl groups containing 1-3 N, O or S atoms.

[0066] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is further represented by the compound represented by formula (III) or a pharmaceutically acceptable salt thereof:

[0067] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 aryl compounds, optional.

[0068] Preferred C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group may contain 1-3 atoms selected from N, O, or S(O). m 5-10 membered heteroaryl groups of atoms;

[0069] More preferably C 3-7 Monocyclic cycloalkyl, C 6-10 Bicyclic cycloalkyl, 3-6 membered monocyclic heterocyclic, 5-6 membered monocyclic heteroaryl, C 6-10 Aryl, 7-10 membered bicyclic heterocyclic group, or 7-10 membered bicyclic heteroaryl group, wherein the heterocyclic group or heteroaryl group contains 1-3 atoms selected from N, O, or S(O). m heteroatoms;

[0070] Optionally, ring A may be further replaced by one or more R3s;

[0071] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3- 14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl mercapto, 5-14 heteroaryl mercapto, optionally further divided by one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0072] R3 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0073] In some embodiments, R3 and L1 or L2 respectively form C with the atoms they are connected to. 5-14 Cycloalkyl or 5-14 membered heterocyclic groups, wherein the C 5- 14 The cycloalkyl or 5-14 membered heterocyclic group is optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 One or more substituents in the alkynyl group are replaced.

[0074] In some implementations, R3 and R2 form C with the atoms they are bonded to. 5-14 Cycloalkyl or 5-14 membered heterocyclic groups, wherein the C 5-14 The cycloalkyl or 5-14 membered heterocyclic group is optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl or C 2-6 One or more substituents in the alkynyl group are replaced.

[0075] In some implementations, ring A is selected from C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group may contain 1-3 atoms selected from N, O, or S(O). m Atoms of 5-10 heteroaryl groups; optionally, further substituted with one or more R3 groups.

[0076] In some embodiments, ring A is selected from C, which is more preferred. 3-7 Monocyclic cycloalkyl, C 6-10 Bicyclic cycloalkyl, 3-6 membered monocyclic heterocyclic, 5-6 membered monocyclic heteroaryl, C 6-10 Aryl, 7-10 membered bicyclic heterocyclic group, or 7-10 membered bicyclic heteroaryl group, wherein the heterocyclic group or heteroaryl group contains 1-3 atoms selected from N, O, or S(O). m The heteroatoms are optionally further substituted by one or more R3 atoms.

[0077] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is further represented by the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof:

[0078] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3- 14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl mercapto, 5-14 heteroaryl mercapto, optionally further divided by one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0079] R3 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C.1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, amino, thiol, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0080] Alternatively, any two R3 atoms can form C with adjacent atoms. 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, wherein C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0081] Alternatively, any two R2 atoms can form C with adjacent atoms. 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, wherein C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0082] Alternatively, R2 and R3 form C with the adjacent atoms. 3-12 Cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, wherein C 3-12Cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0083] x is 1, 2, or 3;

[0084] p is 0, 1, 2, or 3; and

[0085] When -L1-L2-R1 is -CONHCH2CHF2 Not for

[0086] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is further represented by the compound represented by formula (IV-9) or a pharmaceutically acceptable salt thereof:

[0087] in,

[0088] The ring F is selected from C3-6 cycloalkyl, 4-6 heterocyclic groups containing 1-3 N, O or S atoms, or 5-6 heteroaryl groups containing 1-3 N, O or S atoms, and optionally further substituted by one or more -L2-R1;

[0089] Preferably, the ring F is a 5-6 membered heteroaryl group containing one or two atoms selected from N, O or S;

[0090] More preferably, ring F is selected from

[0091] L2 is independently selected from bonds, C(O), O, S, or C. 1-3 Alkylene;

[0092] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C(O)NR c R d C(O)R c C(O)OR c C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the oxo group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0093] R c or R d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic or 5-6 heteroaryl groups;

[0094] L1 is selected from either bond or NH.

[0095] In some embodiments, the compound represented by general formula (IV-9) or a pharmaceutically acceptable salt thereof is further represented as a compound represented by general formula (IV-9-a) or (IV-9-b) or a pharmaceutically acceptable salt thereof:

[0096] In some embodiments of the present invention,

[0097] Ring F is selected from C 3-6 Cycloalkyl, 4-6-membered heterocyclic groups containing 1-3 N, O or S atoms, or 5-6-membered heteroaryl groups containing 1-3 N, O or S atoms, optionally further substituted with one or more R6 groups;

[0098] R6 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C(O)NR c R d C(O)R c C(O)OR c C 3-6 Cycloalkyl, 4-6 heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, 4-6 heterocyclic hydroxyl, 5-6 heteroaryloxyl, 4-6 heterocyclic amino or 5-6 heteroarylamino, optionally, the hydroxyl, amino, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, 4-6 heterocyclic, 5-6 heteroaryloxy, 4-6 heterocyclic amino, or 5-6 heteroaryl amino is further atomized by one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy or C 3-6 One or more substituents in the cycloalkane amino group are substituted;

[0099] R c or R d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic or 5-6 heteroaryl;

[0100] L1 is selected from either bond or NH.

[0101] In some embodiments, ring F is a 5-6 membered heteroaryl group containing one or two N, O or S atoms;

[0102] In some implementations, ring F is selected from

[0103] In some implementations, ring F is selected from

[0104] In some implementations, ring F is selected from

[0105] In some embodiments, the compound represented by general formula (IV-9) or a pharmaceutically acceptable salt thereof is further represented as a compound represented by general formula (IV-16) or a pharmaceutically acceptable salt thereof:

[0106] L2 is independently selected from bonds, C(O), O, S, or C. 1-3 Alkylene;

[0107] R1 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C(O)NR c R d C(O)R c C(O)OR c C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the oxo group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0108] R c or R d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic or 5-6 heteroaryl;

[0109] R1' can be hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 The haloalkoxy group may optionally be further substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano or mercapto.

[0110] or,

[0111] R1' and L2 together with the attached carbon atom form C 3-8Cycloalkyl, 4-7 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, optionally further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0112] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0113] R7 is independently selected from hydrogen, deuterium, fluorine, chlorine, or C. 1-3 alkyl.

[0114] In some embodiments of the present invention,

[0115] L2 is independently selected from bonds, O, S, or C. 1-3 Alkylene;

[0116] R1 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C(O)NR c R d C(O)R c C(O)OR c C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the oxo group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1- 3-Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0117] R c or R d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic or 5-6 heteroaryl;

[0118] R1' is hydrogen; or,

[0119] R1' and L2 together with the attached carbon atom form C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, optionally further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0120] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0121] R7 is independently selected from hydrogen, deuterium, fluorine, chlorine, or C. 1-3 alkyl.

[0122] In some embodiments, the compound represented by general formula (IV-16) or a pharmaceutically acceptable salt thereof is further represented as a compound represented by general formula (IV-16-a) or (IV-16-b) or a pharmaceutically acceptable salt thereof:

[0123] In some embodiments, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0124] M1, M3, or M6 are each independently selected from bonds, N, O, S, or CH;

[0125] M7 or M8 are each independently selected from bond, O, and S(O). m S(O) m NR b NR b or C(R) b )2;

[0126] R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, C 3-7 Cycloalkoxy, 3-7 membered heterocyclic alkyl groups containing 1-3 atoms selected from N, O, or S, phenoxy, 5-6 membered heteroaryloxy groups containing 1-3 atoms selected from N, O, or S, C 3-7 Cycloalkylamino, 3-7 membered heterocyclic amino groups containing 1-3 atoms selected from N, O, or S, phenylamino, 5-6 membered heteroaromatic amino groups containing 1-3 atoms selected from N, O, or S, C 3-7 Cycloalkyl acyl, 3-7 membered heterocyclic acyl groups containing 1-3 N, O, or S atoms, benzoyl, 5-6 membered heteroaromatic acyl groups containing 1-3 N, O, or S atoms, C 3-7 Cycloalkyl mercapto, 3-7 membered heterocyclic mercapto groups containing 1-3 N, O, or S atoms, phenyl mercapto, or 5-6 membered heteroaryl mercapto groups containing 1-3 N, O, or S atoms, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, C 3-7 Cycloalkoxy, 3-7 membered heterocyclic alkyl groups containing 1-3 atoms selected from N, O, or S, phenoxy, 5-6 membered heteroaryloxy groups containing 1-3 atoms selected from N, O, or S, C 3-7 Cycloalkylamino, 3-7 membered heterocyclic amino groups containing 1-3 atoms selected from N, O, or S, phenylamino, 5-6 membered heteroaromatic amino groups containing 1-3 atoms selected from N, O, or S, C 3-7 Cycloalkyl acyl, 3-7 membered heterocyclic acyl groups containing 1-3 N, O, or S atoms, benzoyl, 5-6 membered heteroaromatic acyl groups containing 1-3 N, O, or S atoms, C 3-7 Cycloalkyl mercapto, 3-7 membered heterocyclic mercapto containing 1-3 N, O, or S atoms, phenyl mercapto, or 5-6 membered heteroaryl mercapto containing 1-3 N, O, or S atoms, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0127] or,

[0128] R b With R2, or any two R b The atoms that can be bonded to it can form C 3-7 Cycloalkyl, containing 1-3 4-7 membered heterocyclic groups selected from N, O or S atoms, C 6-12 The aryl group or containing 1-3 5-6 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-7 Cycloalkyl, containing 1-3 4-7 membered heterocyclic groups selected from N, O or S atoms, C 6-12 Aryl and 5-6 heteroaryl groups containing 1-3 N, O, or S atoms, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-6 Alkylthio, C 1-3 Alkylamino, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-12 It is substituted by one or more substituents in the aryl group and the 5-6 heteroaryl group.

[0129] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is further represented by the compound represented by formula (IV-14) or a pharmaceutically acceptable salt thereof:

[0130] L2 is selected from bond, O, S, or C. 1-3 Alkylene;

[0131] R1 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C6- 12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the oxo group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0132] R3 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0133] In some implementations, L1 is selected from bond, O, S, NH, CH2, CO, CONH or NHCO.

[0134] In some implementations, L2 is selected from bond, O, S, NH, CH2, CONH or NHCO.

[0135] In some implementations, L1 is selected from * indicates the connection site with L2.

[0136] In some implementations, L2 is selected from CONH or CONHCH2.

[0137] In some implementations, R3 is selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0138] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is further represented by the compound represented by formula (IV-15) or a pharmaceutically acceptable salt thereof:

[0139] L1 is selected from methylene, -NHC=S-, -CONH, -C(=NR4)-, -C=O-, -NHCO-, -S(=O)(=NH)-, Optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 10 It is substituted by one or more substituents in the aryl or 5-10 heteroaryl groups. Indicates the connection position with the ring;

[0140] L2 is selected from either bond or O;

[0141] R1 is selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl or carbonyl, wherein the C 1-3 Alkyl, C 1-3Hydroxyalkyl, C 1- 3-Hydroalkyl, C 3-6 Cycloalkyl or carbonyl, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0142] R2 is hydrogen;

[0143] R3 is selected from methyl or ethyl, wherein the methyl or ethyl group is optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0144] R4 is independently selected from hydrogen or C. 1-3 Alkyl, the C 1-3 Alkyl groups, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0145] In some embodiments, the compound represented by general formula (IV-15) or a pharmaceutically acceptable salt thereof is further represented as a compound represented by general formula (IV-15-a) or (IV-15-b) or a pharmaceutically acceptable salt thereof:

[0146] In some implementations of the above general formulas,

[0147] L1 is independently C 3-6 Monocyclic cycloalkylene, C 6-14 Confusing cycloalkyl, C 5-10 Subbridged cycloalkyl, C 5-10 Spirocycloalkyl, 3-6 membered monocyclic heterocyclic groups containing 1-3 N, O, or S atoms, 6-14 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, naphthyl, 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, or 6-14 membered fused heteroaryl groups containing 1-3 N, O, or S atoms, preferably C 3-6 Monocyclic cycloalkylene, C 6-10 Confusing cycloalkyl, C 5-10 Subbridged cycloalkyl, C 5-10 Spirocycloalkyl, 3-6 membered monocyclic heterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, naphthyl, 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, or 6-10 membered fused heteroaryl groups containing 1-3 N, O, or S atoms, more preferably...

[0148] L1 can be further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0149] In some embodiments of the present invention,

[0150] L1 is selected independently from each

[0151] In some embodiments of the present invention,

[0152] L1 is selected from -CONH-;

[0153] L2 is selected from either bond or O;

[0154] R1 is selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl or carbonyl, wherein the C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1- 3-Hydroalkyl, C 3-6 Cycloalkyl or carbonyl, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0155] R2 is hydrogen;

[0156] R3 is selected from methyl or ethyl, wherein the methyl or ethyl group is optionally further replaced by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0157] On the other hand, the present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I), formula (II), formula (III), formula (IV), (IV-1) to (IV-15), ((V), (VI) or (VII), formula (VIII) or formula (IX) and a specific compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or excipients.

[0158] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, preferably 0.5% to 70%, more preferably 1% to 50%.

[0159] In some embodiments of the invention, the pharmaceutical composition, calculated as free base, has a unit dose of the compound of 1-1000 mg; preferably 1-500 mg; exemplary doses are selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, etc. 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, or 1000mg.

[0160] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0161] In another aspect, the present invention relates to the use of any compound of general formula (I), general formula (II), general formula (III), general formula (IV), (IV-1) to (IV-8), ((V), (VI) or (VII), general formula (VIII) or general formula (IX) or the examples, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a 5-HT2c agonist medicament.

[0162] In some embodiments, the present invention relates to the use of compounds of general formula (I), general formula (II), general formula (III), general formula (IV), (IV-1) to (IV-8), ((V), (VI) or (VII), general formula (VIII) or general formula (IX) or the examples, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of mood disorders.

[0163] In some embodiments, the present invention relates to compounds of (I), general formula (II), general formula (III), general formula (IV), (IV-1) to (IV-8), ((V), (VI) or (VII), general formula (VIII) or general formula (IX) or the examples thereof for the prevention and / or treatment of mental disorders.

[0164] In some embodiments, the present invention also relates to a method for preventing and / or treating bipolar disorder, depression, atypical depression, mood episodes, adjustment disorder, anxiety, panic disorder, post-traumatic stress disorder, psychosis, schizophrenia, cognitive deficits in schizophrenia, memory loss, dementia, Alzheimer's disease, neuropsychiatric symptoms of Alzheimer's disease, behavioral and dementia-related disorders, social phobia, childhood mental disorders, attention deficit hyperactivity disorder, organic mental disorders, autism, silencing disorder, disruptive behavior disorder, impulse control disorder, borderline personality disorder, obsessive-compulsive disorder, migraine and other headache-related conditions or other pain, increased intracranial pressure, epilepsy, substance abuse, alcoholism, and other conditions. Caine abuse, tobacco abuse, smoking cessation, male sexual dysfunction / erectile dysfunction, female sexual dysfunction, premenstrual syndrome, post-luteal syndrome, chronic fatigue syndrome, sleep disorders, sleep apnea, chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis associated with Parkinson's disease, neuropsychiatric symptoms of Parkinson's disease, Lewy body dementia, neuropsychiatric symptoms of Lewy body dementia, spinal cord injury, trauma, stroke, pain, bladder dysfunction / urinary incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, high intraocular pressure, cardiovascular disease, gastrointestinal disease, diabetes insipidus, diabetes mellitus, type I diabetes mellitus, type II diabetes mellitus, type III diabetes mellitus, secondary to pancreatic... Methods of treating diabetes mellitus, steroid-related diabetes mellitus, diabetic complications, hyperglycemia, and insulin resistance, including administering to a patient a therapeutically effective dose of a compound of general formula (I), general formula (II), general formula (III), general formula (IV), (IV-1) to (IV-8), ((V), (VI) or (VII), general formula (VIII) or general formula (IX) or the examples shown, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The therapeutically effective dose includes, but is not limited to, 1-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, and 100-800 mg / day. The daily dose may be 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, or 200-400 mg / day. In some embodiments, the daily dose may include, but is not limited to, 1 mg / day, 2 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, or 1000 mg / day.

[0165] In some embodiments, the present invention also provides methods for administering compounds of general formula (I), general formula (II), general formula (III), general formula (IV), (IV-1) to (IV-8), ((V), (VI) or (VII), general formula (VIII) or general formula (IX) or examples thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to prevent and / or treat diseases, including but not limited to diseases related to 5-HT2c kinase dysfunction.

[0166] In some implementations, the disease is selected from bipolar disorder, depression, atypical depression, mood episodes, adjustment disorder, anxiety, panic disorder, post-traumatic stress disorder, psychosis, schizophrenia, cognitive deficits in schizophrenia, memory loss, dementia, Alzheimer's disease, neuropsychiatric symptoms of Alzheimer's disease, behavioral and dementia-related disorders, social phobia, childhood mental disorders, attention deficit hyperactivity disorder, organic mental disorders, autism, silencing disorder, disruptive behavior disorder, impulse control disorder, borderline personality disorder, obsessive-compulsive disorder, migraine and other headache-related conditions or other pain, increased intracranial pressure, epilepsy, substance abuse, alcoholism, cocaine abuse, tobacco abuse, smoking cessation, and male sexual dysfunction / erectile dysfunction. Functional disorders, female sexual dysfunction, premenstrual syndrome, post-luteal syndrome, chronic fatigue syndrome, sleep disorders, sleep apnea, chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis of Parkinson's disease, neuropsychiatric symptoms of Parkinson's disease, Lewy body dementia, neuropsychiatric symptoms of Lewy body dementia, spinal cord injury, trauma, stroke, pain, bladder dysfunction / urinary incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular hypertension, cardiovascular disease, gastrointestinal disease, diabetes insipidus, diabetes mellitus, type I diabetes mellitus, type II diabetes mellitus, type III diabetes mellitus, diabetes mellitus secondary to pancreatic disease, diabetes mellitus associated with steroid use, diabetic complications, hyperglycemia and insulin resistance.

[0167] In some embodiments, the present invention also relates to a method for preparing general formula (IV-15), comprising:

[0168] Formula (IV-15-a) is prepared by condensation with R1NH2 to obtain formula (IV-15-b), which is then deprotected to obtain general formula (IV-15).

[0169] Where L1-L2 are -CONH-; P is an amino protecting group; R1, R3 and s are defined as in general formula (IV-15).

[0170] Detailed description of the invention

[0171] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.

[0172] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 1 to 20 (C). 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1- 8) 1 to 6 (C) 1-6 ) or 1 to 3 (C 1-3 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 14 (C 3-14 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6 Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C... 1-6The alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group described elsewhere in this invention.

[0173] The term "alkylene" refers to a carbon-containing, saturated, straight-chain or branched divalent hydrocarbon group, wherein the definition of "alkyl" is as described above. Non-limiting examples of "alkylene" include: methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0174] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3- 8) or 3 to 6 (C) 3-6 A branched unsaturated hydrocarbon group with 16 carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0175] The term "alkenyl" refers to a divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group. Non-limiting examples of "alkenyl" include: C2 alkenyl (i.e., vinylene) refers to -CH=CH-, C3 alkenyl refers to -CH2-CH=CH- and -CH2=CH-CH2-, and C4 alkenyl refers to -CH2-CH=CH-CH2-, -CH2=CH-CH2-CH2- and -CH2-CH-CH=CH2-.

[0176] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkyne refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0177] The term "ynynyl" refers to a trivalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon triple bond can be located at any position within the ynynyl group. Non-limiting examples of "ynynyl" include: ethynyl (-C≡CH), propynyl (-CH2C≡CH), and 1-propynyl (-C≡C-CH3).

[0178] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0179] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10(e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0180] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0181] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C...) 5- 20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0182] The term "cycloalkylene" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "cycloalkylene".

[0183] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be oxidized, excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azirrocyclobutane, azirrocycloheptane, oxacyclobutane, oxacyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0184] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered bispirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0185] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0186] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0187] The term "subheterocyclic group" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "heterocyclic group".

[0188] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0189] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0190] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, a heteroaryl comprises 5 to 20, 5 to 14, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, a heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, a heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl,

[0191] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0192] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0193] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0194] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0195] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3,

[0196] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0197] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0198] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0199] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0200] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0201] The term "aminocarbonyl" refers to NH2-C(O)-.

[0202] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

[0203] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0204] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0205] The term "hydroxyl group" refers to the -OH group.

[0206] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0207] The term "amino" refers to -NH2.

[0208] The term "cyano" refers to -CN.

[0209] The term "nitro" refers to -NO2.

[0210] The term "carboxyl group" refers to -C(O)OH.

[0211] The term "acetyl" refers to -C(O)CH3.

[0212] The term "oxo" or "side oxygen" refers to =O.

[0213] The term "thiol" refers to -SH.

[0214] The term "THF" refers to tetrahydrofuran.

[0215] The term "EtOAc" refers to ethyl acetate.

[0216] The term "MeOH" refers to methanol.

[0217] The term "DMF" refers to N,N-dimethylformamide.

[0218] The term "DIPEA" refers to diisopropylethylamine.

[0219] The term "TFA" refers to trifluoroacetic acid.

[0220] The term "TEA" refers to triethylamine.

[0221] The term "MeCN" refers to ethinylene.

[0222] The term "DMA" refers to N,N-dimethylacetamide.

[0223] The term "Et2O" refers to diethyl ether.

[0224] The term "DCE" refers to 1,2-dichloroethane.

[0225] The term "DIPEA" refers to N,N-diisopropylethylamine.

[0226] The term "NBS" refers to N-bromosuccinimide.

[0227] The term "NIS" refers to N-iodosuccinimide.

[0228] The term "Cbz-Cl" refers to benzyl chloroformate.

[0229] The term “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0230] The term "Dppf" refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0231] The term "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0232] The term "KHMDS" refers to potassium hexamethyldisilamide.

[0233] The term "LiHMDS" refers to bis(trimethylsilyl)amine lithium.

[0234] The term "MeLi" refers to methyl lithium.

[0235] The term "n-BuLi" refers to n-butyllithium.

[0236] The term "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0237] The term "hydrogen" includes protons (1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotope-enriched analogs may be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atom described in this patent comprises its isotopes (H) and / or mixtures thereof. 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0238] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0239] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0240] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0241] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0242] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0243] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0244] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0245] "Pharmaceutically acceptable salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the intended biological activity.

[0246] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers".

[0247] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers and compounds enriched with enantiomers / non-corresponding isomers / stereoisomers.

[0248] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0249] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0250] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0251] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0252] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule. Detailed Implementation

[0253] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0254] Example

[0255] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0256] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0257] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0258] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0259] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0260] Intermediate 1

[0261] 8-Bromo-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indole

[0262] first step

[0263] (R)-8-bromo-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0264] (S)-8-bromo-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0265] The compound 8-bromo-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 1a (12 g, 0.033 mol) was prepared. Separation was performed using a chiral column (column: CHIRALCEL AY-H, 4.6*150mm, 5μm; detection wavelength (nm): 214; temperature (°C): 25; flow rate (mL / min): 1.0; mobile phase: Hexane:EtOH = 70:30; runtime (min): 12; linear mode: isocratic), yielding the product (R)-8-bromo-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole. 1_P1 of tert-butyl indole-2(1H)-carboxylate (4.8 g, RT (retention time) = 2.167 min, yield: 80.0%); product (S)-8-bromo-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylate tert-butyl indole (4.7 g, RT (retention time) = 2.397 min, yield: 78.3%).

[0266] Intermediate 2

[0267] 8-Bromo-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0268] first step

[0269] Compound 4-bromo-3-ethyl-1H-indole 2a (5.0 g, 0.022 mol) was dissolved in 100 mL of trifluoroacetic acid. 1 M boranetetrahydrofuran solution (33 mL, 0.033 mol) was added under ice bath conditions, and the reaction was carried out at 0 °C for 0.5 h. The reaction was quenched with 10 mL of methanol, and the pH was adjusted to greater than 10 with 2 mol / L sodium hydroxide (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 4-bromo-3-ethylindoline 2b (4.6 g, yield: 91.2%).

[0270] MS m / z (ESI): 226.2, 228.2 [M+1]

[0271] Step 2

[0272] Compound 4-bromo-3-ethylindoline 2b (4.2 g, 0.019 mol) was dissolved in anhydrous toluene (50 mL), followed by the sequential addition of compound 2,2-dioxanediol-2λ6-1,2,3-oxathiazacyclopentane-3-carboxylic acid-2-methylpropyl-2-yl ester (5.0 g, 0.022 mol) and N,N-diisopropylethylamine (7.2 g, 0.056 mol). The mixture was then heated to 70 °C and stirred for 12 hours. The mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give product (2-(4-bromo-3-ethylindoline-1-yl)ethyl)carbamate tert-butyl ester 2c (6.3 g, yield: 91.8%). MS m / z (ESI): 369.2, 371.2 [M+1]

[0273] Step 3

[0274] Compound (2-(4-bromo-3-ethylindolin-1-yl)ethyl)tert-butyl carbamate 2c (6.0 g, 0.016 mol) was dissolved in anhydrous dichloromethane (60 mL), and trifluoroacetic acid (12 mL) was added. The mixture was then stirred at 20 °C for 12 hours. The solution was directly concentrated under reduced pressure to obtain product 2-(4-bromo-3-ethylindolin-1-yl)ethyl-1-amine 2d (6.5 g, trifluoroacetate, crude product), which was directly used in the next reaction step.

[0275] MS m / z(ESI):269.1,271.1[M+1]

[0276] Step 4

[0277] 2-(4-bromo-3-ethylindololin-1-yl)ethyl-1-amine 2d (6.0 g) was dissolved in methanol (60 mL), followed by the addition of 37% formaldehyde aqueous solution (6 mL) and trifluoroacetic acid (6 mL). The mixture was then stirred at 80 °C for 2 hours. The reaction solution was cooled to 0 °C, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. Then, di-tert-butyl dicarbonate (6.0 g) was added, and the mixture was stirred at 25 °C for another 1 hour. Add water (100 mL) to the reaction solution, extract with ethyl acetate (50 mL × 2), separate the liquid and wash the organic phase with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain product 2 (4.8 g) of 8-bromo-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester.

[0278] Intermediate 3

[0279] 8-Bromo-7-(2,2,2-trifluoroethyl)-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptan[6,7,1-hi]indol-2-carboxylic acid-2-methylpropyl-2-yl ester

[0280] first step

[0281] 1-(4-bromo-1H-indol-3-yl)-2,2,2-trifluoroethyl-1-one

[0282] Compound 3a (10.0 g, 51.01 mmol) was dissolved in anhydrous N,N-dimethylformamide (200 mL), and trifluoroacetic anhydride (11.8 g, 56.11 mmol, 7.8 mL) was slowly added. The mixture was then heated to 40 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and slowly poured into water (1 L). The mixture was extracted with ethyl acetate (200 mL × 2), separated, and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (100 mL × 2) and saturated sodium chloride solution (100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 3b (10.0 g, yield: 67.1%).

[0283] MS m / z(ESI): 292.0 [M+1]

[0284] Step 2

[0285] 4-Bromo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole

[0286] Compound 3b (9.0 g, 30.82 mmol) was dissolved in trifluoroacetic acid (90 mL), and triethylsilane (14.3 g, 123.27 mmol, 19.7 mL) was added. The mixture was then stirred at 20 °C for 12 hours. Most of the trifluoroacetic acid was removed by concentration under reduced pressure. The residue was slowly poured into a saturated sodium bicarbonate solution (200 mL), extracted with ethyl acetate (100 mL × 2), separated, and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 3c (3.0 g, yield: 34.8%).

[0287] MS m / z(ESI): 280.0 [M+1]

[0288] Step 3

[0289] ({2-[4-bromo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indol-1-yl]ethyl}amino)methane-2-methylpropyl-2-yl ester)

[0290] Compound 3c (3.0 g, 10.71 mmol) was dissolved in anhydrous toluene (30 mL), and then compound 2,2-dioxane-2λ6-1,2,3-oxathiazacyclopentane-3-carboxylic acid-2-methylpropyl-2-yl ester (3.1 g, 13.92 mmol) and N,N-diisopropylethylamine (4.2 g, 32.13 mmol, 5.6 mL) were added sequentially. The mixture was then heated to 70 °C and stirred for 12 hours. The residue was directly concentrated under reduced pressure and purified by silica gel column chromatography using eluent system B to give product 3d (4.2 g, yield: 92.6%).

[0291] MS m / z(ESI): 423.1 [M+1]

[0292] Step 4

[0293] 2-[4-bromo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indol-1-yl]ethyl-1-amine

[0294] Compound 3d (4.2 g, 9.92 mmol) was dissolved in anhydrous dichloromethane (40 mL), and trifluoroacetic acid (8 mL) was added. The mixture was then stirred at 20 °C for 12 hours. The solution was directly concentrated under reduced pressure to give product 3e (4 g, trifluoroacetate, crude product), which was used directly in the next reaction.

[0295] MS m / z(ESI): 323.0 [M+1]

[0296] Step 5

[0297] 8-Bromo-7-(2,2,2-trifluoroethyl)-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptan[6,7,1-hi]indol-2-carboxylic acid-2-methylpropyl-2-yl ester

[0298] Compound 3e (4g) was dissolved in methanol (40mL), followed by the addition of 37% formaldehyde aqueous solution (4mL) and trifluoroacetic acid (4mL). The mixture was stirred at 80°C for 2 hours. The reaction solution was cooled to 0°C, and the pH was adjusted to 8–9 with saturated sodium carbonate solution. Then, di-tert-butyl dicarbonate (4g) was added, and the mixture was stirred at 25°C for another hour. Water (100mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50mL × 2). The liquid was separated, and the organic phase was washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain product 3 (3g).

[0299] MS m / z(ESI): 435.1 [M+1]

[0300] Intermediate 4'

[0301] N-(2,2-difluoroethyl)-2',3',4',4a',5',6'-hexahydro-1'H-spiro[cyclopropane-1,7'-naphtho[1,8-cd]azacycloheptane]-8'-formamide

[0302] first step

[0303] Under nitrogen protection at -78°C, 1.0 g (2.71 mmol) of tert-butyl-8-bromo-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid-3,3-d2 was dissolved in 20 mL of anhydrous tetrahydrofuran, and 1.41 mL of n-butyllithium (2.5 M) was added. The reaction was carried out at -78°C for 1 hour. A tetrahydrofuran solution (5.0 mL) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane (756 mg, 4.06 mmol) was added to the reaction solution. After the addition was complete, the volume was increased... The reaction was continued at 25°C for 1 hour. 50 mL of saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the product 7-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2 4'a (800 mg, yield: 71.0%).

[0304] MS m / z(ESI): 417.2 [M+1]

[0305] Step 2

[0306] 7-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2 4'a (640 mg, 1.54 mmol) was dissolved in 10 mL of 1,4-dioxane and water (V / V = 4:1). 2-Bromo-4-(difluoromethyl)oxazole (304 mg, 1.54 mmol), tetrakis(triphenylphosphine)palladium (213 mg, 0.18 mmol), and potassium carbonate (636 mg, 4.61 mmol) were added sequentially to the reaction system. The reaction mixture was heated at 100 °C for 5 hours. After cooling to room temperature, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the product 8-(4-(difluoromethyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2 4'b (580 mg, yield: 92.6%).

[0307] MS m / z(ESI): 408.2 [M+1]

[0308] Step 3

[0309] Compound 8-(4-(difluoromethyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2 4'b (60 mg, 0.15 mmol) was resolved by a chiral column (column: CHIRALPAK). IG, 4.6*150mm, 5μm; Detection wavelength (nm): 214; Temperature (°C): 25; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:MeOH:DEA=50:25:25:0.1%; Run time (min): 5; Linear mode: isocratic), yielding product (tert-butyl(S)-8-(4-(difluoromethyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid-3,3-d2 4'b_P1, (25 mg, RT (retention time) = 2.237 min, yield: 83.3%); product ((tert-butyl(R)-8-(4-(difluoromethyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid-3,3-d2 4'b_P2 (25 mg, RT (retention time) = 2.497 min, yield: 83.3%)).

[0310] Step 4

[0311] The compound ((tert-butyl(R)-8-(4-(difluoromethyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid-3,3-d2 4'b_P2 (25 mg, 0.061 mmol)) was dissolved in anhydrous dichloromethane (1.0 mL), and hydrochloric acid / dioxane (4.0 M, 1.0 mL) was added. The mixture was then stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (R)-4-(difluoromethyl)-2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indole-8-yl-3,3-d2)oxazol 4' (13 mg, yield: 68.9%).

[0312] MS m / z(ESI): 308.2 [M+1]

[0313] 1H NMR (400MHz, DMSO) δ8.57(t,J=2.8Hz,1H),7.28-7.22(m,1H),7.10(t,J=56.0Hz,1H),7.02-6.95(m,1H),3 .97-3.83(m,2H),3.59(d,J=15.3Hz,1H),3.28-3.13(m,3H),2.66(d,J=12.5Hz,1H),1.11(d,J=6.8Hz,3H).

[0314] Intermediate 4

[0315] 8-Bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0316] first step

[0317] 4-Bromo-6-fluoro-1H-indole int-4A (15 g, 70.08 mmol) and N,N-dimethylformamide (27.1 mL, 350.41 mmol) were dissolved in tetrahydrofuran (200 mL), and phosphorus oxychloride (13.1 mL, 140.16 mmol) was slowly added dropwise. The mixture was stirred at 30°C for 2 hours. The pH of the reaction solution was adjusted to 9 with ammonia, and most of the solvent was removed by concentration under reduced pressure. The precipitated solid was filtered, and the filter cake was washed with saturated sodium bicarbonate aqueous solution (20 mL × 2), pulped, filtered, and dried under reduced pressure to obtain product 4-bromo-6-fluoro-1H-indole-3-carboxaldehyde int-4B (14.0 g, yield: 82.5%).

[0318] MS m / z(ESI): 242.0 / 244.0 [M+1]

[0319] Step 2

[0320] 4-Bromo-6-fluoro-1H-indole-3-carboxaldehyde int-4B (13 g, 53.71 mmol) was dissolved in N,N-dimethylformamide (160 mL), and p-toluenesulfonyl hydrazine (16.0 g, 85.93 mmol) was added. After dissolving completely, p-toluenesulfonic acid monohydrate (1.53 g, 8.06 mmol) and sulfolane (160 mL) were added, and the mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, sodium cyanoborohydride (13.50 g, 214.84 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction solution was quenched with water (700 mL), extracted with a 50% ethyl acetate / petroleum ether mixed solvent (250 mL × 3), the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give 4-bromo-6-fluoro-3-methyl-1H-indole int-4C (10.0 g, yield: 81.6%).

[0321] MS m / z(ESI): 228.0 / 230.0 [M+1]

[0322] Step 3

[0323] 4-Bromo-6-fluoro-3-methyl-1H-indole int-4C (20 g, 87.70 mmol) was dissolved in 200 mL of trifluoroacetic acid, and triethylsilane (40.0 mL, 263.1 mmol) was added dropwise under ice bath conditions. The mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (100 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the product 4-bromo-6-fluoro-3-methylindoleline int-4D (14.0 g, yield: 69.4%).

[0324] MS m / z(ESI): 230.0 / 232.0 [M+1]

[0325] Step 4

[0326] 4-Bromo-6-fluoro-3-methylindoline int-4D (3.05 g, 14.58 mmol) and N,N-diisopropylethylamine (5.1 mL, 29.16 mmol) were dissolved in toluene (30 mL), and 1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-dioxide (3.91 g, 17.49 mmol) was added. The mixture was stirred at 70 °C for 12 hours. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate (40 mL × 3), and the organic phase was separated. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the product (2-(4-bromo-6-fluoro-3-methylindoline-1-yl)ethyl)carbamate tert-butyl ester int-4E (3.48 g, yield: 70.3%).

[0327] MS m / z(ESI): 373.0 / 375.0 [M+1]

[0328] Step 5

[0329] (2-(4-bromo-6-fluoro-3-methylindol-1-yl)ethyl)tert-butyl carbamate int-4E (3.48 g, 9.32 mmol) was dissolved in trifluoroacetic acid (6 mL, 78.93 mmol). After stirring at room temperature for 1 hour, methanol (80 mL) and 37% formaldehyde aqueous solution (3.47 mL, 46.62 mmol) were added sequentially, and the reaction was stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure and dissolved in tetrahydrofuran (80 mL). An aqueous solution of sodium bicarbonate (9.4 g, 111.88 mmol) (60 mL) and ditert-butyl dicarbonate (2.57 mL, 11.19 mmol) were added sequentially, and the reaction was stirred at 25°C for 1 hour. Add 150 mL of water to the reaction solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (200 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the product 8-bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester intermediate 4 (2.03 g, yield: 56.5%).

[0330] MS m / z (ESI): 385.1 / 387.1 [M+1]

[0331] 1H NMR (400MHz, CDCl3) δ = 6.66 (br d,J=9.4Hz,1H),5.08-4.82(m,1H),4.05-3.91(m,2H),3.54-3.42(m,2H),3. 35-3.22(m,2H),3.18-3.10(m,1H),3.08-2.96(m,1H),1.40(s,9H),1.26(br d,J=6.9Hz,3H).

[0332] Intermediate 4-P1 / P2

[0333] 8-Bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0334] 8-Bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester intermediate 4 (50 g, 129.84 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1, 300×50 mm ID, 10 μm; detection wavelength (nm): 254; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH=80:20%; runtime (min): 3.3; linear mode: isocratic), yielding the product 8-bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester intermediate 4-P1 / P2 (22.60 g, RT (retention time) = 2.639 min, yield: 45.2%); product 8-bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 4-P1 / P2 (25.56 g, RT (retention time) = 2.946 min, yield: 51.1%).

[0335] Intermediate 4-P1 / P2

[0336] MS m / z (ESI): 385.1 / 387.1 [M+1]

[0337] Intermediate 5

[0338] 8-Bromo-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0339] first step

[0340] 4-Bromo-6-fluoro-1H-indole int-5A (23 g, 107.46 mmol) was dissolved in dichloromethane (345 mL), and diethylaluminum chloride (2 M, 80.5 mL, 161.19 mmol) was slowly added dropwise. After stirring at 0°C for 0.5 hours, an acetyl chloride solution (15.3 mL, 214.92 mmol) in dichloromethane (92 mL) was slowly added dropwise, and the reaction was continued at 0°C with stirring for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (300 mL), extracted with ethyl acetate (200 mL * 5), the organic phases were combined, washed with saturated brine (800 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 1-(4-bromo-6-fluoro-1H-indole-3-yl)ethyl-1-one int-5B (26.5 g, yield: 96.3%).

[0341] MS m / z(ESI): 256.0 / 258.0 [M+1]

[0342] Step 2

[0343] 1-(4-bromo-6-fluoro-1H-indol-3-yl)ethyl-1-one int-5B (25 g, 97.63 mmol) was dissolved in tetrahydrofuran (500 mL), and sodium borohydride (11.1 g, 292.89 mmol) was added at 0°C. Finally, boron trifluoride diethyl ether complex (55.5 g, 390.52 mmol) was slowly added dropwise, and the reaction was stirred at 0°C for 1.5 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (120 mL), extracted with ethyl acetate (60 mL * 2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 4-bromo-3-ethyl-6-fluoro-1H-indol int-5C (23.0 g, yield: 97.3%).

[0344] MS m / z(ESI): 242.0 / 244.0 [M+1]

[0345] Steps 3 through 5, referencing the synthesis method of intermediate 4, yield intermediate 5.

[0346] MS m / z(ESI): 399.0 / 401.0 [M+1]

[0347] 1H NMR (400MHz, CDCl3) δ = 6.63 (d, J = 9.5Hz, 1H), 5.19–4.71 (m, 1H), 4.06–3.88 (m, 2H), 3.56–3.33 (m, 3H),3.23–2.96(m,3H),1.86–1.67(m,1H),1.60–1.50(m,1H),1.41(s,9H),0.95(t,J=6.5Hz,3H).

[0348] Intermediate 5-P1 / P2

[0349] 8-Bromo-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester intermediate 5 (6 g, 15.03 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1, 300×50 mm ID, 10 μm; detection wavelength (nm): 280; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH=80:20%; runtime (min): 4; linear mode: isocratic), yielding the product 8-bromo-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl formate intermediate 5-P1 / P2 (2.83 g, RT (retention time) = 2.609 min, yield: 47.2%); product 8-bromo-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 5-P1 / P2 (2.62 g, RT (retention time) = 2.948 min, yield: 43.7%).

[0350] Intermediate 5-P1 / P2

[0351] MS m / z(ESI): 399.1 / 401.1 [M+1]

[0352] Intermediate 6

[0353] 2-(tert-butyl)8-methyl-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester

[0354] Following the synthesis method of intermediate 4, intermediate 6 was obtained.

[0355] MS m / z (ESI): 365.2 [M+1]

[0356] 1 H NMR (400MHz, CDCl3) δ = 7.06 (d, J = 10.8Hz, 1H), 5.20-4.89 (m, 1H), 4.04 (br d,J=16.0Hz,1H),3.98-3.90(m,1H),3.87(s,3H),3.84-3.74(m,1H),3.56-3.40(m,1H),3.40-3.31(m,1H),3.29-3.21(m,1H),3.14(br d,J=12.8Hz,1H),3.07-2.90(m,1H),1.38(s,9H),1.18(d,J=6.9Hz,3H).

[0357] Intermediate 6-P1 / P2

[0358] 2-(tert-butyl)8-methyl-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid intermediate 6 (8.58 g, 23.56 mmol) was chirally resolved by SFC (column: ChiralCel OJ, 300×50 mm ID, 10 μm; detection wavelength (nm): 220; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH = 85:15%; runtime (min): 3.7; linear mode: isocratic) to give the product 2-(tert-butyl)-8-methyl-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester intermediate 6-P1 / P2 (2.91 g, RT (retention time) = 1.760 min, yield: 33.9%); product 2-(tert-butyl)-8-methyl-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester intermediate 6-P1 / P2 (2.75 g, RT (retention time) = 2.045 min, yield: 32.1%).

[0359] Intermediate 6-P1 / P2

[0360] MS m / z (ESI): 365.2 [M+1]

[0361] Intermediate 7-P1 / P2

[0362] Following the synthesis method of intermediate 5 in the reference embodiment, intermediate 7 was obtained.

[0363] MS m / z(ESI): 379.2 [M+1]

[0364] 1 H NMR (400MHz, CDCl3) δppm 7.05-7.15(m,1H),4.89-5.19(m,1H),3.93-4.11(m,2H),3.87(s,3H),3.63-3.73(m,1H),3.49-3.62(m,1H),3.41-3.48(m,1H),3.25 -3.38(m,1H),3.13-3.23(m,1H),2.90-3.11(m,1H),1.53-1.62(m,1H),1.45-1.52(m,1H),1.36-1.45(m,9H),0.94(t,J=7.38Hz,3H).

[0365] 2-(tert-butyl)8-methyl-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid intermediate 7 (6.9 g, 18.24 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1 250×30 mm ID, 10 μm; detection wavelength (nm): 254; temperature (°C): 38; flow rate (mL / min): 120; mobile phase: CO2:i-PrOH=75:25%; runtime (min): 4; linear mode: isocratic), yielding the product 2-(tert-butyl)-8-methyl-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester intermediate 7-P1 / P2 (3.45 g, RT (retention time) = 2.974 min, yield: 50%); product 2-(tert-butyl)-8-methyl-10-fluoro-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester intermediate 7-P1 / P2 (3.4 g, RT (retention time) = 3.306 min, yield: 49.3%).

[0366] Intermediate 7-P1 / P2

[0367] MS m / z(ESI): 379.2 [M+1]

[0368] Intermediate 8

[0369] Following the synthesis method of intermediate 4, intermediate 8 was obtained.

[0370] 8-Bromo-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester intermediate 8 (26 g, 68.24 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1, 300×50 mm ID, 10 μm; detection wavelength (nm): 254; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH=40:60%; runtime (min): 3.5; linear mode: isocratic), yielding the product (S)-8-bromo-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl formate intermediate 8-P1 (13 g, RT (retention time) = 3.102 min, yield: 50%); product (R)-8-bromo-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 8-P2 (13 g, RT (retention time) = 3.801 min, yield: 50%).

[0371] MS m / z(ESI): 381.1 / 383.1 [M+1]

[0372] Intermediate 9

[0373] Following the synthesis method of intermediate 4, intermediate 9 was obtained.

[0374] 8-Bromo-7-deuterated ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 9 (11.8 g, 30.56 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1, 300×50 mm ID, 10 μm; detection wavelength (nm): 325; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH=40:60%; runtime (min): 4; linear mode: isocratic), yielding the product (S)-8-bromo-7-deuterated ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 9-P1 (5.56 g, RT (retention time) = 3.079 min, yield: 47.1%); product (R)-8-bromo-7-deuterated ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 9-P2 (5.63 g, RT (retention time) = 3.780 min, yield: 47.7%).

[0375] MS m / z(ESI): 386.1 / 388.1 / [M+1]

[0376] Intermediate 10

[0377] Following the synthesis method of intermediate 4, intermediate 10 was obtained.

[0378] 8-Bromo-10-fluoro-7-deuterated ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 10 (24 g, 59.3 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1, 300×50 mm ID, 10 μm; detection wavelength (nm): 325; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH=70:30%; runtime (min): 2; linear mode: isocratic), yielding the product (R)-8-bromo-10-fluoro-7-deuterated ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 10-P1 (11.24 g, RT (retention time) = 2.574 min, yield: 46.8%); product (S)-8-bromo-10-fluoro-7-deuterated ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2(1H)-tert-butyl carboxylate intermediate 10-P2 (10.86 g, RT (retention time) = 2.931 min, yield: 45.3%).

[0379] MS m / z(ESI): 404.1 / 406.1 [M+1]

[0380] Intermediate 11

[0381] Following the synthesis method of intermediate 5 in the reference embodiment, intermediate 11 was obtained.

[0382] 2-(tert-butyl)8-methyl-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid intermediate 11 (49 g, 13.60 mmol) was chirally resolved by SFC (column: (S,S)Whelk O1 250×50 mm ID, 10 μm; detection wavelength (nm): 220; temperature (°C): 38; flow rate (mL / min): 200; mobile phase: CO2:i-PrOH=70:30%; runtime (min): 7; linear mode: isocratic), yielding the product 2-(tert-butyl)-8-methyl-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester intermediate 11-P1 (23.34 g, RT (retention time) = 3.523 min, yield: 47.6%); product 2-(tert-butyl)-8-methyl-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza [6,7,1-hi]indole-2,8(1H)-dicarboxylic acid ester intermediate 11-P2 (25 g, RT (retention time) = 4.117 min, yield: 51.0%).

[0383] Intermediate 11-P1 / P2: MS m / z (ESI): 361.2 [M+1]

[0384] Example 1

[0385] N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indole-8-sulfonamide-3,3-d2

[0386] first step

[0387] 8-(benzylthio)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2

[0388] Under nitrogen atmosphere, compound 1 (1 g, 2.71 mmol), benzyl mercaptan (0.4 g, 3.25 mmol), and Cs₂CO₃ (1.76 g, 5.42 mmol) were added to DMF (60 mL). The reaction solution was stirred at 90 °C for 2 hours, 60 mL of water was added, and the mixture was extracted with 80 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product compound 2 (1 g, yield: 89.5%).

[0389] MS m / z(ESI): 413.2 [M+1]

[0390] Step 2

[0391] 8-(chlorosulfonyl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2

[0392] Compound 2 (1 g, 2.42 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (0.67 g, 3.4 mmol) were added to acetonitrile (10 ml), acetic acid (1 ml), and water (0.2 ml). The reaction solution was stirred at 25 °C for 1 hour and then evaporated to dryness to give compound 2 (0.9 g, yield: 95%).

[0393] MS m / z(ESI): 389.2 [M+1]

[0394] Step 3

[0395] 8-(N-(2,2-difluoroethyl)aminosulfonyl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester-3,3-d2

[0396] Compound 2 (0.5 g, 1.29 mmol), difluoroethylamine (0.125 g, 1.54 mmol), and triethylamine (0.39 g, 3.87 mmol) were added to dichloromethane (10 mL). The reaction solution was stirred at 25 °C for 1 hour, 20 mL of water was added, and the mixture was extracted with 30 mL of ethyl acetate. After the organic phase was concentrated under reduced pressure, the residue was purified by preparative HPLC to give product compound 3 (300 mg, yield: 54%).

[0397] MS m / z(ESI): 434.2 [M+1]

[0398] Step 4

[0399] N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indole-8-sulfonamide-3,3-d2

[0400] Compound 3 (0.1 g, 1.29 mmol) was added to 4 M HCl / Dioxane (8 mL). The reaction solution was stirred at 25 °C for 1 hour, concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to obtain product Example 1 (50 mg, yield: 65%).

[0401] MS m / z(ESI): 334.2 [M+1]

[0402] Example 2

[0403] 4-(difluoromethyl)-2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indole-8-yl-3,3-d2)oxazole

[0404] The synthesis method of Example 2 was the same as that of Example 1, and the title compound Example 2 (27 mg) was obtained, which was then resolved to obtain 2-P1 and 2-P2.

[0405] MS m / z (ESI): 308.1 [M+H] +

[0406] The preparation methods of the following examples are the same as those in Example 2:

[0407] Example 10

[0408] 8-(5-Fluoropyrimidin-2-yl)-7-methyl-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptan[6,7,1-hi]indole

[0409] first step

[0410] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (55.6 mg, 68.1 μmol) was added to a mixed solution of 8-bromo-7-methyl-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptanno[6,7,1-hi]indol-2-carboxylic acid-2-methylpropyl-2-yl ester (500 mg, 1.36 mmol), pinacol diboronate (691 mg, 2.72 mmol), and potassium carbonate (376 mg, 2.72 mmol) in 1,4-dioxane (8 mL). After the reaction solution was purged with nitrogen three times, the reaction was carried out at 120 °C for 12 hours. The reaction was quenched by adding water (100 mL) to the reaction solution, and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography with eluent system C to obtain the product 7-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptanzo[6,7,1-hi]indol-2-carboxylic acid-2-methylpropyl-2-yl ester (0.42 g, yield: 74.5%).

[0411] MS m / z (ESI): 415.3 [M+1]

[0412] Step 2

[0413] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (6.90 mg, 8.45 μmol) was added to a mixture of 7-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptameno[6,7,1-hi]indol-2-carboxylic acid-2-methylpropyl-2-yl ester (70 mg, 169 μmol), 2-bromo-5-fluoropyrimidine (35.9 mg, 203 μmol), and potassium carbonate (47 mg, 338 μmol) in water (0.2 mL) and 1,4-dioxane (1.5 mL). The reaction mixture was purged with nitrogen three times and reacted at 120 °C for 12 hours. The reaction was quenched by adding water (100 mL) to the reaction solution, and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography with eluent system C to obtain the product 8-(5-fluoropyrimidin-2-yl)-7-methyl-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptanzo[6,7,1-hi]indol-2-carboxylic acid-2-methylpropyl-2-yl ester (40 mg, yield: 61.5%).

[0414] MS m / z(ESI): 385.2 [M+1]

[0415] Step 3

[0416] A hydrochloric acid / dioxane solution (4M, 325 μL) was added to an ethanol solution (0.5 mL) of 8-(5-fluoropyrimidin-2-yl)-7-methyl-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptan[6,7,1-hi]indole-2-carboxylic acid-2-methylpropyl-2-yl ester (50 mg, 130 μmol). The reaction mixture was stirred at room temperature for 2 hours. The residue obtained by concentration under reduced pressure was purified by preparative HPLC to give the product 8-(5-fluoropyrimidin-2-yl)-7-methyl-1,2,3,4,6,7-hexahydro[1,4]diazacycloheptan[6,7,1-hi]indole (8.6 mg, yield: 23.3%).

[0417] MS m / z(ESI):285.1[M+1].

[0418] The preparation methods of the following examples are the same as those in Example 10:

[0419] Example 58

[0420] 2-[4-(2,2-difluoroethyl)-1,3-oxazacyclopentan-2-yl]-12-methyl-7,10-diazatricyclo[8.2.1.05,13]deca-1(13),2,4-triene

[0421] first step

[0422] Compound 58a (2.0 g, 5.77 mmol, synthesized via patent CN107873030A) was dissolved in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL), and sodium hydroxide solution (10 mL, 2 M) was added. The mixture was then stirred at 20 °C for 12 hours. Most of the methanol and tetrahydrofuran were removed by vacuum concentration. The residue was cooled to 0 °C, and dilute hydrochloric acid (~10 mL, 2 M) was added dropwise until the pH of the system was 3-4. A large amount of solid precipitated. The solid was filtered under vacuum, and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dried under vacuum to obtain product 2-methyl-7-{[(2-methylpropyl-2-yl)oxy]carbonyl}-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-trien-12-carboxylic acid 58b (1.5 g, crude product).

[0423] MS m / z(ESI): 333.2 [M+1]

[0424] Step 2

[0425] Compound 58b (1.0 g, 3.01 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and oxalyl chloride (1.15 g, 9.03 mmol, 764 μL) and N,N-dimethylformamide (22 mg, 300.85 μmol, 23 μL) were added sequentially. The mixture was then stirred at 20 °C for 1 hour. The residue of oxalyl chloride was removed by concentration under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 mL) and slowly added dropwise to a mixture of ice-cold anhydrous tetrahydrofuran (10 mL) and 28% ammonia (10 mL). The mixture was then naturally heated to 20 °C and stirred for another hour. Add water (40 mL) and ethyl acetate (20 mL) to the reaction solution, separate the liquid and wash the organic phase with saturated sodium chloride solution (10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the product 2-formamido-12-methyl-7,10-diazatricyclo[8.2.1.05,13]tridecyl-1(13),2,4-trien-7-carboxylic acid-2-methylpropyl-2-yl ester 58c (1.0 g, crude product).

[0426] MS m / z(ESI): 332.2 [M+1]

[0427] Step 3

[0428] Compound 58c (1.0 g, 3.02 mmol) was dissolved in a mixture of anhydrous toluene (10 mL) and anhydrous 1,4-dioxane (10 mL), and ethyl chloroacetoacetate (3.1 g, 13.92 mmol) was added. The mixture was then heated to 120 °C and stirred for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the product [2-(3-methyl-10-{[(2-methylprop-2-yl)oxy]carbonyl}-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-5-yl)-1,3-oxazacyclopentanyl-4-yl]ethyl acetate 58d (300.0 mg, yield: 22.5%).

[0429] MS m / z(ESI): 442.2 [M+1]

[0430] Step 4

[0431] Compound 58d (300 mg, 679.47 μmol) was dissolved in anhydrous dichloromethane (10 mL), and diisobutylaluminum hydrogen (815 μL, 1 M) was slowly added at -78 °C under nitrogen protection, and the mixture was stirred at -78 °C for 1 hour. The reaction was quenched by slowly adding 1 mL of saturated potassium sodium tartrate solution at -78℃, and the mixture was naturally heated to room temperature and stirred for 0.5 hours. Excess anhydrous sodium sulfate was added for drying, diatomaceous earth was used as a filter aid, and the mixture was washed multiple times with ethyl acetate. The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the product 5-[4-(formylmethyl)-1,3-oxazacyclopentanyl-2-yl]-3-methyl-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester 58e (120 mg, yield: 44.4%).

[0432] MS m / z(ESI): 398.2 [M+1]

[0433] Step 5

[0434] Compound 58e (100 mg, 251.59 μmol) was dissolved in anhydrous dichloromethane (5 mL), and thiotrifluoride-morpholine (132 mg, 754.78 μmol, 92 μL) was slowly added under nitrogen protection at 0 °C. The mixture was then stirred at 20 °C for 1 hour. The reaction was quenched and diluted by adding saturated sodium bicarbonate solution (10 mL) dropwise to the reaction solution at 0 °C. The mixture was extracted with dichloromethane (10 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the product 5-[4-(2,2-difluoroethyl)-1,3-oxazacyclopentanyl-2-yl]-3-methyl-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester 58f (80 mg, yield: 75.8%).

[0435] MS m / z(ESI): 420.2 [M+1]

[0436] Step 6

[0437] Compound 58f (80 mg, 190.72 μmol) was dissolved in anhydrous dichloromethane (2 mL), and a solution of 1,4-dioxane in hydrogen chloride (2 mL, 4 M) was added. The mixture was then stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). A small amount of triethylamine was added to alkalize the system, and then the mixture was directly resolved by chiral separation (OD - 70% Hexane: 15% MeOH: 15% EtOH: 0.1% DEA - 12 min - 1 mL / min - 35 °C) and lyophilized under vacuum to give chiral isomers 58-P1 (20 mg, retention time: 3.040 min) and 58-P2 (19.8 mg, retention time: 3.860 min), with a yield of 32.5%.

[0438] MS m / z(ESI): 320.2 [M+1]

[0439] 58-P2: 1 H NMR(400MHz,DMSO)δ8.10(s,1H),7.30(d,1H),7.14(d,1H),6.47–6.20(m,1H),4.23(d,1H),3.96– 3.87(m,2H),3.28(dd,2H),3.25–3.20(m,2H),3.17–3.05(m,2H),2.90(q,3H),1.18–1.14(d,3H).

[0440] The preparation of the following examples is based on Example 58:

[0441] Example 63

[0442] N-Ethyl-2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-carboxamide

[0443] first step

[0444] 7-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)

[0445] - tert-butyl carboxylate

[0446] Referring to the synthesis method in step 1 of Example 2, using intermediate 1-P1 as the starting material, the product 7-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 63a was obtained.

[0447] MS m / z (ESI): 415.2 [M+1]

[0448] Step 2

[0449] 2-(2-(tert-Butoxycarbonyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-carboxylic acid ethyl ester

[0450] Following the synthesis method in step 2 of Example 2, product 2-(2-(tert-butoxycarbonyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-carboxylic acid ethyl ester 63b was obtained.

[0451] MS m / z(ESI): 428.2 [M+1]

[0452] Step 3

[0453] 2-(2-(tert-Butoxycarbonyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid

[0454] Following the synthetic method in step 11 of Example 97, product 2-(2-(tert-butoxycarbonyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid 63c was obtained.

[0455] MS m / z(ESI): 400.2 [M+1]

[0456] Step 4

[0457] 8-(4-(ethylcarbamoyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0458] Following the synthetic method in step 12 of Example 97, product 8-(4-(ethylcarbamoyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 63d was obtained.

[0459] MS m / z(ESI): 427.2 [M+1]

[0460] Step 5

[0461] N-Ethyl-2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-carboxamide

[0462] Following the synthetic method in step 13 of Example 97, product N-ethyl-2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-carboxamide 63 was obtained.

[0463] MS m / z(ESI): 327.2 [M+1]

[0464] The preparation of the following examples is based on Example 63:

[0465] Example 71

[0466] first step

[0467] 7-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0468] Under nitrogen protection at -78°C, intermediate 1-P1 (1.0 g, 2.71 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and n-butyllithium (2.5 M, 1.41 mL) was added. The reaction was carried out at -78°C for 1 hour. A tetrahydrofuran solution (5.0 mL) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane (756 mg, 4.06 mmol) was added to the reaction solution. After the addition was complete, the temperature was raised to 25°C and the reaction was continued for 1 hour. 50 mL of saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 63a (800 mg, yield: 71.0%).

[0469] Step 2

[0470] 8-(4-(ethoxycarbonyl)-1H-imidazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0471] Following the synthesis method in step 2 of Example 2, product 8-(4-(ethoxycarbonyl)-1H-imidazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 71a was obtained.

[0472] MS m / z(ESI): 427.2 [M+1]

[0473] Step 3

[0474] 2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)-1H-imidazol-4-carboxylic acid ethyl ester

[0475] Following the synthesis method in step 4 of Example 2, product 2-(7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)-1H-imidazol-4-carboxylic acid ethyl ester 71 was obtained.

[0476] MS m / z(ESI): 327.2 [M+1]

[0477] 1H NMR (400MHz, DMSO) δ7.21 (s, 1H), 6.92 (d, J = 7.9Hz, 1H), 6.67 (s, 1H), 4.32-4.20 (m, 2H), 4.11-3.98 (m ,1H),3.88-3.55(m,1H),3.45-3.38(m,2H),3.30-3.00(m,3H),2.00-1.92(m,2H),1.34-1.17(m,6H).

[0478] The preparation of the following examples is based on Example 71:

[0479] Example 88

[0480] (2R)-12-(4-cyclopropyl-1,3-oxazacyclopentanyl-2-yl)-2-ethyl-10-fluoro-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0481] first step

[0482] (12R)-12-ethyl-4-fluoro-7-{[(2-methylprop-2-yl)oxy]carbonyl}-7,10-diazatricyclo[8.2.1.05,13]tetradecyl-1(13),2,4-trien-2-carboxylic acid

[0483] Intermediate 7-P1 (300 mg, 0.79 mmol) was dissolved in a mixed solvent of methanol (30 mL), tetrahydrofuran (3 mL), and water (3 mL). Lithium hydroxide (39.9 mg, 108.91 μmol) was added, and the mixture was stirred at 20 °C for 12 hours. The mixture was diluted with water (10 mL), and the pH of the system was adjusted to 3–4 with dilute hydrochloric acid (2 M) under ice bath conditions. The mixture was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain product (12R)-12-ethyl-4-fluoro-7-{[(2-methylpropyl-2-yl)oxy]carbonyl}-7,10-diazatricyclo[8.2.1.05,13]tridecyl-1(13),2,4-trien-2-carboxylic acid 88a (300 mg, crude product).

[0484] MS m / z (ESI): 365.2 [M+1]

[0485] Step 2

[0486] (3R)-5-formamido-3-ethyl-7-fluoro-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester

[0487] Compound 88a (300 mg, 823.25 μmol) was dissolved in anhydrous tetrahydrofuran (6 mL). Under nitrogen protection, oxaloyl chloride (313.5 mg, 2.47 mmol, 209 μL) and anhydrous N,N-dimethylformamide (6.4 μL) were added slowly in sequence, and the mixture was stirred at 20 °C for 1 hour. The reaction solution was then concentrated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (3 mL). This residue was then added dropwise at 0 °C to a mixed solvent of tetrahydrofuran (3 mL) and ammonia (3 mL) under stirring. The mixture was allowed to return to 20 °C and the reaction was continued with stirring for another hour. Dilute with water (20 mL), extract with ethyl acetate (10 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the target product (3R)-5-carbamoyl-3-ethyl-7-fluoro-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester 88b (200 mg, yield: 66.9%).

[0488] MS m / z(ESI): 364.2 [M+1]

[0489] Step 3

[0490] (2R)-12-(4-cyclopropyl-1,3-oxazacyclopentanyl-2-yl)-2-ethyl-10-fluoro-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0491] Compound 88b (100 mg, 275.16 μmol) was dissolved in ethyl acetate (5 mL), and silver trifluoromethanesulfonate (88.4 mg, 343.95 μmol) and 2-bromo-1-cyclopropyl ethyl ketone (56.1 mg, 343.95 μmol, 33 μL) were added sequentially. The mixture was purged with nitrogen three times, and then stirred at 60 °C for 12 hours. The reaction solution was cooled to room temperature, filtered with diatomaceous earth, washed with ethyl acetate, the filtrate was collected and concentrated under reduced pressure, the residue was dissolved in methanol (2 mL), and then purified by high performance liquid chromatography (0.1% formic acid / acetonitrile / water) and lyophilized under vacuum to obtain product (2R)-12-(4-cyclopropyl-1,3-oxazacyclopentanyl-2-yl)-2-ethyl-10-fluoro-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-triene 88 (25.5 mg, yield: 24.0%).

[0492] MS m / z(ESI): 328.2 [M+1]

[0493] 1 H NMR(400MHz,DMSO)δ9.06(d,2H),8.02(s,1H),7.06(d,1H),4.53(d,1H),4.06(d,1H),3.69(t,1H),3.61–3.55(m,1H),3.52(dd,1H) ,3.43–3.37(m,2H),3.30(d,1H),3.11(ddd,1H),1.91(tt,1H),1.51(ddd,1H),1.35(ddd,1H),0.93–0.87(m,5H),0.83–0.72(m,2H).

[0494] Example 89

[0495] (R)-4-(difluoromethyl)-2-(10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazole

[0496] first step

[0497] (R)-8-(4-(difluoromethyl)oxazol-2-yl)-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0498] (R)-10-fluoro-8-(4-formyloxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247A (102 mg, 254.09 μmol) was dissolved in dichloromethane (2 mL), and diethylaminotrifluoride (101 μL, 762.27 μmol) was added at -78°C. The mixture was stirred at 20°C for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (10 mL × 3), and the organic phase was separated. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (R)-8-(4-(difluoromethyl)oxazol-2-yl)-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine. [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 89A (107.0 mg, yield: 99.5%).

[0499] MS m / z(ESI): 424.2 [M+1]

[0500] Step 2

[0501] (R)-4-(difluoromethyl)-2-(10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazole

[0502] (R)-8-(4-(difluoromethyl)oxazol-2-yl)-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 89A (107.0 mg, 252.70 μmol) was dissolved in 2 mL of methanol, and 0.2 mL (0.8 mmol) of 4 M dioxane chloride solution was added. The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (R)-4-(difluoromethyl)-2-(10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazide). [6,7,1-hi]indol-8-yl)oxazole 89 (21.2 mg, yield: 25.9%).

[0503] MS m / z(ESI): 324.1 [M+1]

[0504] 1H NMR (400MHz, CDCl3) δ = 7.90 (s, 1H), 7.10 (d, J = 11.0Hz, 1H), 6.71 (t, J = 54.9Hz, 1H), 4.41 (d, J = 16.0Hz, 1H), 4.05-3.86 (m, 1H ),3.67(d,J=16.0Hz,1H),3.50-3.38(m,1H),3.35-3.16(m,3H),3.09-2.95(m,1H),2.95-2.81(m,1H),1.22(d,J=6.9Hz,3H).

[0505] Example 90

[0506] (2R)-2-ethyl-10-fluoro-12-(1,3-oxazacyclopentan-2-yl)-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0507] first step

[0508] (3R)-5-(dihydroxyboryl)-3-ethyl-7-fluoro-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester

[0509] Intermediate 5-P1 (1 g, 2.50 mmol) was dissolved in anhydrous methanol (30 mL), and tetrahydroxydiboron (449.1 mg, 5.01 mmol), cataCxium APd G3 (91.2 mg, 125.22 μmol), and N,N-diisopropylethylamine (971.0 mg, 7.51 mmol, 1.31 mL) were added sequentially. The mixture was purged with nitrogen three times, and then heated to 50 °C and stirred for 1 hour under nitrogen protection. The reaction mixture was cooled to room temperature, filtered with diatomaceous earth as an aid, washed with methanol, and the filtrate was collected and concentrated under reduced pressure to obtain product (3R)-5-(dihydroxyboronyl)-3-ethyl-7-fluoro-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester 90a (1.7 g, crude product).

[0510] MS m / z (ESI): 365.2 [M+1]

[0511] Step 2

[0512] (2R)-2-ethyl-10-fluoro-12-(1,3-oxazacyclopentan-2-yl)-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-trien-7-carboxylic acid-2-methylpropyl-2-yl ester

[0513] Compound 90a (200 mg, 549.12 μmol) and 2-bromooxazole (200 mg, 549.12 μmol) were dissolved in a mixed solvent of anhydrous 1,4-dioxane (4 mL) and water (0.8 mL). 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (40.2 mg, 54.91 μmol) and potassium carbonate (227.7 mg, 1.65 mmol) were added sequentially. The mixture was purged with nitrogen three times, and then stirred at 90 °C for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the target product (2R)-2-ethyl-10-fluoro-12-(1,3-oxazacyclopentanyl-2-yl)-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-trien-7-carboxylic acid-2-methylpropyl-2-yl ester 90b (500 mg, crude product).

[0514] MS m / z(ESI): 388.2 [M+1]

[0515] Step 3

[0516] (2R)-2-ethyl-10-fluoro-12-(1,3-oxazacyclopentan-2-yl)-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0517] Compound 90b (500 mg) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 5 mL) was added. The mixture was then stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure, and methanol (2 mL) was added to the residue. The residue was filtered, and the filtrate was purified by high performance liquid chromatography (0.1% ammonia / acetonitrile / water) and lyophilized under vacuum to give product (2R)-2-ethyl-10-fluoro-12-(1,3-oxazacyclopentanyl-2-yl)-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-triene 90 (3.0 mg, yield: 0.8%).

[0518] MS m / z(ESI): 288.2 [M+1]

[0519] 1H NMR(400MHz,DMSO)δ6.87(dd,1H),6.40(dd,1H),3.85(d,1H),3.70(d,1H),3.55 –3.48(m,1H),3.07–2.84(m,6H),1.74(ddd,1H),1.49–1.40(m,1H),0.90(t,3H).

[0520] Example 91

[0521] (R)-2-(3-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-5-yl)propane-2-ol

[0522] first step

[0523] Intermediate 8-P2 (10 g, 26.23 mmol), zinc cyanide (6.14 g, 52.45 mmol), and Pd(dppf)Cl2 (3.83 g, 5.25 mmol) were dissolved in DMF (120 mL), purged with nitrogen, and the reaction was stirred at 170 °C for 5 hours. LC-MS showed the formation of approximately 50% product and approximately 50% deBoc byproduct. K2CO3 (7.16 g, 51.91 mmol), Boc2O (6.73 g, 31.15 mmol), H2O (20 mL), and dioxane (20 mL) were added to the above solution, and the reaction was stirred at 20 °C for 1 hour. LC-MS showed product formation. Water (200 mL) was added, the aqueous phase was extracted with EA (200 mL × 2), washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 1 / 1) to give compound 91-1 (7.5 g, 88.25% yield).

[0524] Step 2

[0525] Compound 91-1 (7.5 g, 22.91 mmol) was dissolved in EtOH (100 mL), and K2CO3 (9.48 g, 68.72 mmol) and NH2OH·H2O (424.53 mg, 30 mL) were added. The reaction was stirred at 90 °C for 5 hours. LC-MS showed product formation. The solvent was evaporated to dryness, and water (30 mL) was added. The aqueous phase was extracted with EA (30 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 1 / 1) to obtain compound 91-2 (7 g).

[0526] Step 3

[0527] Compound 91-2 (7 g, 19.42 mmol) was dissolved in pyr. (80 mL), and (2-chloro-1,1-dimethyl-2-oxoethyl) acetate (4.79 g, 29.13 mmol) was added. The reaction was stirred at 120 °C for 6 hours. LC-MS showed product formation. Water (300 mL) was added, and the aqueous phase was extracted with EA (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 1 / 1) to give compound 91-3 (6.5 g).

[0528] Step 4

[0529] Compound 91-3 (6.5 g, 13.81 mmol) was dissolved in MeOH (60 mL), and K₂CO₃ (5.72 g, 41.44 mmol) was added. The reaction was stirred at 20 °C for 1 hour. LCMS (NBK2040-806-1) showed product formation. The solvent was evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 1 / 1) to give compound 91-4 (5.5 g).

[0530] Step 5

[0531] Compound 91-4 (5.5 g, 12.83 mmol) was dissolved in DCM (20 mL), and HCl / dioxane (60 mL) was added. The reaction was stirred at 20 °C for 1 hour. LCMS showed product formation. The solvent was evaporated to dryness. Sodium carbonate solution (50 mL) was added, and the aqueous phase was extracted with DCM (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by prep-HPLC (basic). The resulting extract was extracted with DCM (100 mL), followed by extraction with EA (100 mL × 3). The organic phase was evaporated to dryness, leaving approximately 10 mL of water. The extract was transferred to MeCN, concentrated, sonicated, and then sonicated again with the addition of an appropriate amount of deionized water. The extract was then lyophilized to obtain Example 91 (2.32 g, 55.04% yield).

[0532] MS m / z(ESI): 329.2 [M+1]

[0533] 1H NMR (400MHz, DMSO-d6) δ7.27(d,J=7.8Hz,1H),7.00(d,J=7.9Hz,1H),6.04(s,1H),3.93(d,J=15.4Hz,1H),3.69–3.56(m,2H),3. 44–3.39(m,1H),3.26–3.07(m,4H),2.79–2.64(m,2H),1.60(s,6H),1.48–1.41(m,1H),1.39–1.29(m,1H),0.88(t,J=7.4Hz,3H).

[0534] Example 92

[0535] (R)-5-Cyclopropyl-3-(7-Ethyl-1,2,3,4,6,7-Hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole

[0536] Referring to the synthesis method of Example 91, (R)-5-cyclopropyl-3-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole 92 was obtained.

[0537] MS m / z(ESI): 311.2 [M+1]

[0538] 1 H NMR (400MHz, DMSO-d6) δ7.30(d,J=8.0Hz,1H),7.10(d,J=7.9Hz,1H),3.76–3.61(m,2H),3.23–3.19(m,2H),2.90–2.74(m ,2H),2.24–2.16(m,2H),2.02–1.96(m,3H),1.49–1.42(m,2H),1.16–1.10(m,2H),1.01–0.93(m,2H),0.89–0.84(m,3H).

[0539] Example 93

[0540] (R)-1-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-yl)cyclopropane-1-ol

[0541] The synthesis method of Example 93 is the same as that of Example 91, using intermediate 5-P1 as raw material, with a yield of 68%.

[0542] MS m / z(ESI): 344.2 [M+1]

[0543] 1 H NMR (400MHz, DMSO) δ8.23(s,1H),7.59(d,J=9.0Hz,1H),4.77(s,1H),4.07(dd,J=7.1,4.8Hz,2H),3.86(dd,J=10.7,3.4Hz,1H),3.67–3.48(m,5H),3 .04(td,J=5.2,4.2Hz,2H),2.29–2.20(m,2H),2.04–1.94(m,2H),1.80(dt d,J=19.6,7.3,6.4Hz,1H),1.61–1.50(m,1H),0.83(td,J=7.3,1.5Hz,3H).

[0544] Example 94

[0545] 3-Cyclopropyl-5-[(3R)-3-ethyl-7-fluoro-1,10-diazabicyclo[6.4.1.04,13]tetane-4(13),5,7-trien-5-yl]-1,2,4-oxadiazole

[0546] first step

[0547] Intermediate 4-P1 (500 mg, 1.30 mmol), ethyl oxazol-4-carboxylate (274.72 mg, 1.95 mmol), tri-n-butylphosphine (787.71 mg, 3.89 mmol), and cesium carbonate (1.27 g, 3.89 mmol) were dissolved in 1,4-dioxane (10 mL). Palladium acetate (58.27 mg, 259.56 μmol) was added, and the reaction was purged with nitrogen. The mixture was stirred at 120 °C for 18 hours. Water (30 mL) was added, and the aqueous phase was extracted with EA (30 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 1 / 1) to give compound 94a (570 mg, yield: 98.59%).

[0548] MS m / z(ESI): 446.0 [M+H] +

[0549] Step 2

[0550] Compound 94a (578 mg, 1.30 mmol) was dissolved in 1,4-dioxane (2 mL), and 7 mL of dioxane hydrochloride solution was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain compound 94b (448 mg, 1.30 mmol), which was used directly in the next step.

[0551] MS m / z(ESI): 346.0 [M+H] +

[0552] Step 3

[0553] Compound 94b (448 mg, 1.30 mmol) and triethylamine (5 mL) were dissolved in dichloromethane (10 mL), and benzyl chloroformate (331.93 mg, 1.95 mmol) was slowly added at 0 °C. The reaction was stirred at room temperature for 30 minutes. Dichloromethane and water were added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography to give compound 94c (460 mg, yield: 73.96%).

[0554] MS m / z(ESI): 480.0 [M+H] +

[0555] Step 4

[0556] Compound 94c (400 mg, 834.20 μmol) was dissolved in tetrahydrofuran (4 mL), and tetraisopropyl titanate (474.18 mg, 1.67 mmol, 493.94 μL) was added. Ethyl magnesium bromide (1 M, 4.17 mL) was then added at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and extracted twice with the aqueous phase. The organic phases were combined, evaporated to dryness, and the crude product was purified by column chromatography to give compound 94d (90.5 mg, yield: 23.41%).

[0557] MS m / z(ESI): 464.0 [M+H] +

[0558] Step 5

[0559] Compound 94d (90.5 mg, 195.25 μmol) was dissolved in ethanol (5 mL), and wet palladium on carbon (90 mg, 741.05 μmol) was added under a nitrogen atmosphere. The mixture was purged three times with hydrogen balloons. The mixture was stirred at room temperature for 30 minutes. After filtration through diatomaceous earth, the solution was evaporated to dryness and then sent to a reverse phase converter to prepare compound 94 (24.9 mg, yield: 38.72%).

[0560] MS m / z(ESI): 330.0 [M+H] +

[0561] 1H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.96(s,1H),6.93(d,J=11.2Hz,1H),4.25(d,J=15.7Hz,1H),3.82(s,1H),3.49(s,1H),3.36(d,J= 8.7Hz,1H),3.27(dd,J=9.5,1.6Hz,1H),3.19(dd,J=16.6,11.0Hz,2H),2.86–2.77(m,2H),1.10(d,J=6.8Hz,3H),1.02(d,J=4.0Hz,4H).

[0562] Example 95

[0563] 2-{2-[(3R)-7-chloro-3-ethyl-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-5-yl]-1,3-oxazacyclopentanol-4-yl}prop-2-ol

[0564] first step

[0565] Compound 95a (300 mg, 721.59 μmol, synthesized according to published patent CN107873030A) and ethyl 4-oxazolylcarboxylate (305.5 mg, 2.16 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL), and palladium acetate (16.2 mg, 72.16 μmol), tributylphosphine (146.0 mg, 721.59 μmol), and cesium carbonate (705.3 mg, 2.16 mmol) were added sequentially. Nitrogen gas was bubbled for 30 seconds, and then the mixture was sealed in a tube and stirred for 12 hours at 120 °C. The reaction solution was cooled to room temperature, and insoluble matter was removed by diatomaceous earth filtration. The solution was washed with ethyl acetate, and the filtrate was collected and concentrated under reduced pressure to obtain 95b (800mg, crude product) of 2-(7-chloro-3-ethyl-10-{[(2-methylprop-2-yl)oxy]carbonyl}-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-5-yl)-1,3-oxazacyclopentane-4-carboxylic acid ethyl ester.

[0566] MS m / z(ESI): 476.2 [M+1]

[0567] Step 2

[0568] Compound 95b (800 mg, 1.68 mmol) was dissolved in anhydrous dichloromethane (4 mL), and a 4 M, 4 mL solution of 1,4-dioxane hydrogen chloride was added. The mixture was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, and anhydrous dichloromethane (8 mL) was added to the residue. The reaction mixture was cooled to 0 °C, and triethylamine (510.2 mg, 5.04 mmol, 703 μL) and benzyl chloroformate (430.1 mg, 2.52 mmol, 355 μL) were added slowly in sequence. The mixture was then naturally heated to 20 °C and stirred for another hour. The residue was concentrated under direct reduced pressure and purified by silica gel column chromatography with eluent system B to obtain the product 2-{7-[(benzyloxy)carbonyl]-10-chloro-2-ethyl-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-trien-12-yl}-1,3-oxazacyclopentane-4-carboxylic acid ethyl ester 95c (400 mg, yield: 46.7%).

[0569] MS m / z (ESI): 510.2 [M+1]

[0570] Step 3

[0571] Compound 95c (400 mg, 784.34 μmol) was dissolved in anhydrous tetrahydrofuran (8 mL). Methyl magnesium bromide (3 M in 2-MeTHF, 2.61 mL) was added under nitrogen protection at 0 °C, and the mixture was then naturally heated to 20 °C with stirring for 1 hour. The reaction mixture was cooled to 0 °C, and the reaction was quenched and diluted with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the racemic product (360 mg). This product was then resolved chirally (OJ-70% Hexane: 30% EtOH: 0.1%). DEA-12min-1mL / min-35℃), yielded the chiral isomer (3S)-7-chloro-3-ethyl-5-[4-(2-hydroxypropyl-2-yl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tetradecyl-4(13),5,7-trien-10-carboxylic acid benzyl ester 95d-1 (100mg, retention time: 3.10). 7 min, ee% = 100%) and (3R)-7-chloro-3-ethyl-5-[4-(2-hydroxypropyl-2-yl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid benzyl ester 95d-2 (100 mg, retention time: 3.553 min, ee% = 97.86%).

[0572] MS m / z(ESI): 496.2 [M+1]

[0573] Step 4

[0574] Compound 95d-1 (100 mg) was dissolved in methanol (5 mL), and wet palladium on carbon (20 mg) was added under nitrogen protection. The mixture was purged three times with hydrogen, and then stirred at 20 °C for 0.5 hours under a hydrogen balloon atmosphere (~15 psi). The filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), and then purified by high performance liquid chromatography (0.1% ammonia / acetonitrile / water) and lyophilized under vacuum to obtain product (3S)-7-chloro-3-ethyl-5-[4-(2-hydroxypropyl-2-yl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid benzyl ester 95-1 (38.8 mg, yield: 66.5%).

[0575] MS m / z(ESI): 362.2 [M+1]

[0576] 1 H NMR(400MHz,DMSO)δ7.89(s,1H),7.24(s,1H),5.12(s,1H),4.35(d,1H),3.73(td,1H),3.57(d,1H),3.46–3.42(m,1H) ,3.30(d,1H),3.17(dd,1H),3.06(dd,1H),2.89–2.76(m,2H),1.50(ddd,1H),1.44(s,6H),1.35(ddd,1H),0.90(t,3H).

[0577] Compound 95d-2 (100 mg) was dissolved in methanol (5 mL), and wet palladium on carbon (20 mg) was added under nitrogen protection. The mixture was purged three times with hydrogen, and then stirred at 20 °C for 0.5 h under a hydrogen balloon atmosphere (~15 psi). The filter cake was washed with methanol, the filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). The residue was then purified by high performance liquid chromatography (0.1% ammonia / acetonitrile / water) and lyophilized under vacuum to give product (3R)-7-chloro-3-ethyl-5-[4-(2-hydroxypropyl-2-yl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid benzyl ester 95 (32.8 mg, yield: 45.0%).

[0578] MS m / z(ESI): 362.2 [M+1]

[0579] 1 H NMR (400MHz, DMSO) δ7.89(s,1H),7.24(s,1H),5.13(s,1H),4.35(d,1H),3.77–3.69(m,1H),3.58(d,1H),3.45(s,1H),3 .31(s,1H),3.17(dd,1H),3.06(dd,1H),2.89–2.77(m,2H),1.58–1.48(m,1H),1.44(s,6H),1.35(ddd,1H),0.90(t,3H).

[0580] Example 96

[0581] 3-Cyclopropyl-5-[(3R)-3-ethyl-7-fluoro-1,10-diazabicyclo[6.4.1.04,13]tetane-4(13),5,7-trien-5-yl]-1,2,4-oxadiazole

[0582] first step

[0583] Intermediate 7-P1 (200 mg, 509.60 μmol), tetrahydrofuran (0.8 mL), methanol (0.2 mL), and water (0.2 mL) were added to a single-necked flask. Lithium hydroxide monohydrate (106.91 mg, 2.55 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, methanol and tetrahydrofuran were removed by rotary evaporation. The pH was adjusted to 6 with dilute hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, and concentrated to give compound 96a (185 mg, 507.67 μmol), which was used directly in the next step.

[0584] MS m / z(ESI): 365.0 [M+H] +

[0585] Step 2

[0586] Compound 96a (170 mg, 466.51 μmol), N'-hydroxycyclopropaneformamide (70.06 mg, 699.76 μmol), and N,N-diisopropylethylamine (180.87 mg, 1.40 mmol, 243.77 μL) were dissolved in DMF (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (264.00 mg, 699.76 μmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 96b (200 mg, yield: 96.01%).

[0587] MS m / z(ESI): 447.0 [M+H]+

[0588] Step 3

[0589] Compound 96b (200 mg, 447.91 μmol) was dissolved in DMF (5 mL) and heated to 120 °C with stirring for 6 hours. The mixture was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 96c (180 mg, yield: 93.78%).

[0590] MS m / z(ESI): 429.0 [M+H] +

[0591] Step 4

[0592] Compound 96c (160 mg, 373.40 μmol) was dissolved in 5 mL of dioxane hydrochloride solution and stirred at room temperature for 1 hour. The reaction solution was concentrated and reversed to prepare compound 96 (16.2 mg, yield: 13.21%).

[0593] MS m / z(ESI): 329.0 [M+H] +

[0594] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 2H), 7.19 (d, J = 10.8Hz, 1H), 4.57 (d, J = 15.5Hz, 1 H),4.12(d,J=15.5Hz,1H),3.68(d,J=8.9Hz,1H),3.62–3.52(m,2H),3.50–3.40( m,2H),3.38–3.32(m,2H),3.22–3.12(m,1H),2.22(tt,J=8.2,4.8Hz,1H),1.56–1 .33(m,2H),1.15(dq,J=7.2,1.9Hz,2H),1.06–0.93(m,2H),0.90(t,J=7.3Hz,3H).

[0595] Example 97

[0596] N-(2,2-difluoroethyl)-1,2,5,6,7,8-hexahydro-4-thio-6,8-diazacyclopentane[cd]azacyclopentane-3-carboxamide

[0597] first step

[0598] 4-(2-ethoxy-2-oxoethyl)thiophene-3-carboxylic acid

[0599] Under a nitrogen atmosphere, sodium metal (1.3 g, 57 mmol) was dissolved in 75 mL of anhydrous ethanol. The reaction mixture was stirred at 45 °C for one hour. Ethyl acetoacetate (4.6 mL, 36 mmol) was added, and the mixture was stirred at 45 °C for 10 minutes. Then, 4-bromothiophene-3-carboxylic acid 97a (5.0 g, 24 mmol) and copper (247 mg, 3.9 mmol) were added, and the reaction mixture was stirred at 90 °C for 12 hours. 100 mL of water was added to the reaction mixture, and the mixture was filtered. The filtrate was collected, and the pH was adjusted to 3-5 with 2 M hydrochloric acid. The mixture was filtered again, washed with 50 mL of water, and the filter cake was collected and dried to give the title product 97b (5.1 g, yield: 99%).

[0600] MS m / z(ESI): 215.0 [M+1]

[0601] Step 2

[0602] 2-(4-(tert-Butoxycarbonyl)amino)thiophen-3-yl)ethyl acetate

[0603] 97b (2.0 g, 9.3 mmol) was dissolved in 30 mL of tert-butanol, and triethylamine (1.0 g, 10.3 mmol) and diphenyl azidophosphate (2.8 g, 10.3 mmol) were added. After purging with nitrogen three times, the reaction mixture was stirred at 90 °C for 12 hours. The solvent was evaporated, and the crude product was purified by silica gel column chromatography with eluent system B to obtain the title product 97c (1.8 g, yield: 68%).

[0604] MS m / z(ESI): 286.1 [M+1]

[0605] Step 3

[0606] 2-(4-(tert-Butoxycarbonyl)amino)thiophen-3-yl)lithium acetate

[0607] 97c (1.8 g, 6.3 mmol) was dissolved in tetrahydrofuran-methanol (30 mL, v / v 1:1), and a water solution (5.0 mL) of lithium hydroxide monohydrate (794.1 mg, 18.9 mmol) was added. The reaction mixture was stirred at 50°C for 2 hours. The solvent was evaporated to give the title product 97d (2.6 g, crude).

[0608] MS m / z(ESI): 258.1 [M+1]

[0609] Step 4

[0610] 2-O-2,3-dihydro-1H-thieno[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester

[0611] 97d (2.6 g, crude product) was dissolved in 40 mL of acetonitrile, and O-benzotriazole-N,N,N,N-tetramethylurea tetrafluoroboron (2.2 g, 6.9 mmol) and DIEA (1.6 g, 12.6 mmol) were added. The mixture was stirred at 50 °C for 5 hours. The solvent was evaporated, and the crude product was purified by silica gel column chromatography using eluent system B to obtain the title product 97e (1.3 g, yield: 86%).

[0612] MS m / z(ESI): 240.1 [M+1]

[0613] Step 5

[0614] 2,3-Dihydro-1H-thieno[3,4-b]pyrrole

[0615] 97e (1.3 g, 5.4 mmol) was dissolved in 20 mL of tetrahydrofuran, and a 2M tetrahydrofuran solution of the borane dimethyl sulfide complex (8.1 mL, 16.2 mmol) was added. The mixture was stirred at 75°C for 5 hours. 2M hydrochloric acid-ethanol solution (10.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the title product 97f (2.4 g crude).

[0616] MS m / z(ESI): 126.0 [M+1]

[0617] Step 6

[0618] 2-(2,3-dihydro-1H-thieno[3,4-b]pyrrolo-1-yl)ethyl-1-amine hydrochloride

[0619] 2-Bromoethylamine hydrobromide (1.2 g, 5.9 mmol) was added to 97f (2.4 g, crude product), and the mixture was stirred at 120 °C for 12 hours. 2M hydrochloric acid (20 mL) was added to the reaction mixture, and the crude product was purified by reverse preparative HPLC to give the title product 97 g (678.5 mg, yield: 61%). MS m / z (ESI): 169.1 [M+1]

[0620] Step 7

[0621] 1,2,5,6,7,8-Hexahydro-4-thio-6,8a-diazacyclopentane [cd]zacyclopentane

[0622] 97 g (600 mg, 2.9 mmol) was dissolved in methanol (20 mL), and formaldehyde (261.6 mg, 37% wt.% in H2O, 3.2 mmol) and trifluoroacetic acid (312.8 mg, 3.2 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. The solvent was evaporated, and the crude product was purified by silica gel column chromatography using eluent system B to give the title product 97 h (428.4 mg, yield: 81%).

[0623] MS m / z(ESI): 181.1 [M+1]

[0624] Step 8

[0625] 1,2,7,8-Tetrahydro-4-thio-6,8a-diazacyclopentane[cd]azacyclopentane-6(5H)-carboxylic acid tert-butyl ester

[0626] 97h (420.4 mg, 2.3 mmol) was dissolved in tetrahydrofuran (20 mL), and di-tert-butyl dicarbonyl ester (1.0 g, 4.7 mmol) and triethylamine (708.0 mg, 7.0 mmol) were added. The reaction mixture was stirred at 50 °C for 1 hour. The solvent was evaporated, and the crude product was purified by silica gel column chromatography using eluent system B to give the title product 97i (618.4 mg, yield: 95%).

[0627] MS m / z(ESI): 281.1 [M+1]

[0628] Step 9

[0629] 3-Bromo-1,2,7,8-Tetrahydro-4-thia-6,8-diazacyclopentane [cd] azacyclopentane-6(5H)-carboxylic acid tert-butyl ester

[0630] 97i (500 mg, 1.8 mmol) was dissolved in DMF (20 mL), and N-bromosuccinimide (152.1 mg, 2.7 mmol) was added. The reaction mixture was stirred at 80 °C for 12 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title product 97j (622.6 mg, yield: 97%).

[0631] MS m / z(ESI): 359.0 [M+1]

[0632] Step 10

[0633] 6-(tert-butyl)-3-methyl-1,2,7,8-tetrahydro-4-thio-6,8a-diazacyclopentane[cd]azacyclopentane-3,6(5H)-dicarboxylic acid ester

[0634] 97k (500 mg, 1.4 mmol) was dissolved in DMSO (10 mL) and methanol (10 mL), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (102.4 mg, 0.1 mmol) and triethylamine (2 mL) were added. After three CO purgings, the reaction mixture was stirred at 100 °C for 12 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title product 97k (434.5 mg, yield: 92%).

[0635] MS m / z(ESI): 339.1 [M+1]

[0636] Step 11

[0637] 6-(tert-Butoxycarbonyl)-1,2,5,6,7,8-hexahydro-4-thio-6,8a-diazacyclopentane[cd]azacyclopentane-3-carboxylic acid potassium

[0638] 97k (434.5 mg, 1.3 mmol) was dissolved in 10 mL of tetrahydrofuran, and potassium trimethylsilanolate (247.1 mg, 1.9 mmol) was added. The reaction was stirred at room temperature for 1 hour. The solvent was evaporated to obtain the title product 97l (700 mg, crude product).

[0639] MS m / z(ESI): 325.1 [M+1]

[0640] Step Twelve

[0641] 3-(2,2-difluoroethyl)carbamoyl)-1,2,7,8-tetrahydro-4-thio-6,8-diazacyclopentane[cd]azacyclopentane-6(5H)-carboxylic acid tert-butyl ester

[0642] 97l (700 mg, crude product) was dissolved in 15 mL of DMF, and 2,2-difluoroethane-1-amine (158.1 mg, 2.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (760.5 mg, 2.0 mmol), and N,N-diisopropylethylamine (840.0 mg, 6.5 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title product 97m (486.3 mg, yield: 97%).

[0643] MS m / z(ESI): 388.1 [M+1]

[0644] Step Thirteen

[0645] N-(2,2-difluoroethyl)-1,2,5,6,7,8-hexahydro-4-thio-6,8-diazacyclopentane[cd]azacyclopentane-3-carboxamide

[0646] 97m (486.3 mg, 1.3 mmol) was dissolved in 10 mL of 1,4-dioxane, and 4.0 M dioxane hydrochloride solution was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the crude product was purified by reverse preparative HPLC to obtain the title product 97 (280.7 mg, yield: 78%).

[0647] MS m / z(ESI): 288.1 [M+1]

[0648] Example 98

[0649] 2-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-yl)prop-2-ol

[0650] first step

[0651] Intermediate 5 (200 mg, 500.88 μmol) and ethyl 4-oxazolylcarboxylate (212.1 mg, 1.50 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL), and palladium acetate (32.3 mg, 50.09 μmol), tributylphosphine (101.3 mg, 500.88 μmol), and cesium carbonate (489.6 mg, 1.50 mmol) were added sequentially. Nitrogen gas was bubbled for 30 seconds, and then the mixture was heated to 120 °C under nitrogen protection, sealed, and stirred for 12 hours. The reaction solution was cooled to room temperature, and insoluble matter was removed by diatomaceous earth filtration. The solution was washed with ethyl acetate, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the product 2-(3-ethyl-7-fluoro-10-{[(2-methylprop-2-yl)oxy]carbonyl}-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-5-yl)-1,3-oxazacyclopentane-4-carboxylic acid ethyl ester 98b (250 mg, yield 72.4%).

[0652] MS m / z(ESI): 460.2 [M+1]

[0653] Step 2

[0654] Compound 98b (250 mg, 544.06 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Methyl magnesium bromide (3 M in 2-MeTHF, 1.81 mL) was added under nitrogen protection at 0 °C, and the mixture was then naturally heated to 20 °C with stirring for 1 hour. The reaction mixture was cooled to 0 °C, and the reaction was quenched and diluted with saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (10 mL × 2), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the racemic product (150 mg). Chiral resolution (OJ-70% Hexane: 15% MeOH: 15% EtOH: 0.1%) was then performed. DEA (12 min - 1 mL / min - 35 °C) yielded the chiral isomer (3S)-3-ethyl-7-fluoro-5-[4-(2-hydroxypropyl-2-yl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tetradecyl-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester 98c-1 / 2 (50 mg, retention time: 2.07) 3 min, ee% = 100% and (3R)-3-ethyl-7-fluoro-5-[4-(2-hydroxypropyl-2-yl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-10-carboxylic acid-2-methylpropyl-2-yl ester 98c-1 / 2 (50 mg, retention time: 2.250 min, ee% = 98.90%).

[0655] MS m / z(ESI): 446.2 [M+1]

[0656] Step 3

[0657] Compound 98c-1 / 2 (50 mg) was dissolved in anhydrous dichloromethane (2 mL), and a solution of 1,4-dioxane in hydrogen chloride (2 mL, 4 M) was added. The mixture was then stirred at 20 °C for 1 hour. The mixture was directly concentrated under reduced pressure, and the residue was dissolved in acetonitrile (2 mL). A small amount of triethylamine was added to alkalize the system, and the mixture was then purified by high performance liquid chromatography (0.1% ammonia / acetonitrile / water) and lyophilized under vacuum to give product 2-{2-[3-ethyl-7-fluoro-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-5-yl]-1,3-oxazacyclopentan-4-yl}prop-2-ol 98-1 / 2 (10.5 mg, yield: 26.1%).

[0658] MS m / z(ESI): 346.2 [M+1]

[0659] 1 H NMR (400MHz, CDCl3) δ7.52(s,1H),7.07(d,1H),4.42(d,1H),3.86–3.77(m,1H),3.66(d,1H),3.47(d,1H),3.38–3.30( m,1H),3.28–3.20(m,1H),3.03(t,1H),2.89(t,1H),2.22(s,1H),1.60(s,6H),1.46(dd,1H),1.29(d,1H),0.95(t,3H).

[0660] 2-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-yl)prop-2-ol

[0661] Compound 98c-1 / 2 (50 mg) was dissolved in anhydrous dichloromethane (2 mL), and a solution of 1,4-dioxane in hydrogen chloride (2 mL, 4 M) was added. The mixture was then stirred at 20 °C for 1 hour. The mixture was directly concentrated under reduced pressure, and the residue was dissolved in acetonitrile (2 mL). A small amount of triethylamine was added to alkalize the system, and the mixture was then purified by high performance liquid chromatography (0.1% ammonia / acetonitrile / water) and lyophilized under vacuum to give product 2-{2-[3-ethyl-7-fluoro-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-5-yl]-1,3-oxazacyclopentan-4-yl}prop-2-ol 98-1 / 2 (12.0 mg, yield: 30.8%).

[0662] MS m / z(ESI): 346.2 [M+1]

[0663] 1 H NMR(400MHz, CDCl3)δ7.52(s,1H),7.07(d,1H),4.42(d,1H),3.80(ddd,1H),3.66(d,1H),3.47(dd,1H),3.34(t,1H), 3.30–3.19(m,2H),3.02(ddd,1H),2.88(ddd,2.0Hz,1H),1.73–1.62(m,1H),1.60(s,6H),1.47(dtd,1H),0.95(t,3H).

[0664] The preparation of the following examples is based on Example 98:

[0665] The preparation of the following examples is based on Example 95:

[0666] Example 193

[0667] 2-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indol-8-yl)-5-fluoropyrimidin-4-yl)prop-2-ol

[0668] first step

[0669] (S)-7-ethyl-10-fluoro-8-(5-fluoro-4-(2-hydroxypropyl-2-yl)pyrimidin-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-tert-butyl carboxylate (R)-7-ethyl-10-fluoro-8-(5-fluoro-4-(2-hydroxypropyl-2-yl)pyrimidin-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-tert-butyl carboxylate

[0670] Compound 193-5 (90 mg, 0.19 mmol, obtained from intermediate 5 according to the method in Example 98) was separated by a chiral column (column: CHIRALPAK OZ, 4.6*150 mm, 5 μm; detection wavelength (nm): 254; temperature (°C): 25; flow rate (mL / min): 1.0; mobile phase: Hexane:EtOH:DEA = 85:15:0.1%; run time (12 min): 5; linear mode: isocratic) to obtain product (193-P1, 35 mg, RT (retention time) = 2.800 min, yield: 49%); product (193-P2, 35 mg, RT (retention time) = 3.133 min, yield: 49%).

[0671] Step 2

[0672] 7-Ethyl-10-fluoro-8-(5-fluoro-4-(2-hydroxypropyl-2-yl)pyrimidin-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0673] Compound 193-P2 (35 mg, 0.054 mmol) was dissolved in 10 mL of 4 M HCl / dioxane, and the reaction was stirred at 20 °C for 0.5 h. The reaction solution was analyzed by p-HPLC (FA) to give compound 193 (20 mg, yield: 72%).

[0674] MS m / z (ESI): 375.2 [M+1]

[0675] 1 H NMR (400MHz, DMSO) δ8.84(d,J=3.6Hz,1H),7.27(d,J=12.0Hz,1H),5.50(s,1H),4.18(d,J=15.6Hz,1H),4.08(s,1H),3.53–3.39(m,2H),3.31 (d,J=9.2Hz,1H),3.13(ddd,J=33.5,10.4,4.5Hz,2H),2.80(t,J=9.6Hz,2H),1.57(d,J=3.9Hz,6H),1.31–1.21(m,2H),0.79(t,J=7.3Hz,3H).

[0676] Example 194

[0677] 1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)-2,2,2-trifluoroethanol-1-ol)

[0678] first step

[0679] Following the synthetic method in step 1 of Example 98, product 7-ethyl-8-(4-formyloxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 194a was obtained.

[0680] MS m / z(ESI): 398.2 [M+1]

[0681] Step 2

[0682] 7-Ethyl-8-(4-formyloxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazaphena[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 194a (400 mg, 1.01 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and (trifluoromethyl)trimethylsilyl (429 mg, 3.02 mmol) and cesium fluoride (458 mg, 3.02 mmol) were added. The reaction was carried out at 25 °C for 0.5 h. Tetrabutylammonium fluoride (1.0 M, 1.51 mL) was added, and the reaction was continued at 25 °C for another 0.5 h. Add 20 mL of saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (20 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain 450 mg of tert-butyl 7-ethyl-8-(4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid 194b, yield: 95.6%.

[0683] Compound 7-ethyl-8-(4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 194b (380 mg, 0.96 mmol) was resolved by a chiral column (column: CHIRALPAK). IG, 4.6*150mm, 5μm; Detection wavelength (nm): 254; Temperature (°C): 35; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:MeOH:DEA = 70:15:15:0.1%; Run time (min): 12; Linearity mode: isocratic, yielding compound 194b_P1 (155mg, RT (retention time) = 2.160min, yield: 81.6%); compound 194b_P2 (155mg, RT (retention time) = 2.473min, yield: 81.6%).

[0684] Compound 194b_P1, MS m / z (ESI): 468.2 [M+1]

[0685] Compound 194b_P2, MS m / z (ESI): 468.2 [M+1]

[0686] Step 3

[0687] The compound 7-ethyl-8-(4-(2,2,2-trifluoro-1-hydroxyethyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 194b_P2 (155 mg, 0.33 mmol) was separated by a chiral column (column: CHIRALPAK). IB, 4.6*150mm, 5μm; Detection wavelength (nm): 254; Temperature (°C): 35; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; Run time (min): 12; Linearity mode: isocratic, yielding compound 194c_P1 (70mg, RT (retention time) = 2.237min, yield: 90.3%); compound 194c_P2 (60mg, RT (retention time) = 2.877min, yield: 77.4%).

[0688] Compound 194c_P1, MS m / z (ESI): 468.2 [M+1]

[0689] Compound 194c_P2, MS m / z (ESI): 468.2 [M+1]

[0690] Step 4

[0691] Referring to the synthesis method in step 4 of Example 2, product 1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)-2,2,2-trifluoroethanol-1-ol 194 was obtained from compound 194c_P1.

[0692] MS m / z(ESI): 368.1 [M+1]

[0693] 1 H NMR (400MHz, DMSO) δ8.23(d,J=1.0Hz,1H),7.21(d,J=7.8Hz,1H),7.04-6.94(m,2H),5.17(q,J=6.9Hz,1H),3.96(d,J=15.3Hz,1H),3.75(d, J=8.2Hz,1H),3.62(d,J=15.3Hz,1H),3.42(d,J=9.7Hz,1H),3.26-3.11(m,3H),2.86-2.64(m,2H),1.54-1.26(m,2H),0.86(t,J=7.3Hz,3H).

[0694] Example 195

[0695] 1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)-4,4,4-trifluorobut-1-ol

[0696] first step

[0697] 7-Ethyl-8-(4-formyloxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazaporon[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 194a (230 mg, 0.58 mmol) was dissolved in 5.0 mL of anhydrous tetrahydrofuran, and (3,3,3-trifluoropropyl)magnesium chloride (0.5 M, 1.2 mL) was added. The reaction was carried out at 25 °C for 0.5 h. Add 20 mL of saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (20 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain 195a 260 mg of 7-ethyl-8-(4-(4,4,4-trifluoro-1-hydroxybutyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester, yield: 90.6%.

[0698] MS m / z(ESI): 496.2 [M+1]

[0699] Step 2

[0700] The compound 7-ethyl-8-(4-(4,4,4-trifluoro-1-hydroxybutyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 195a (315 mg, 0.64 mmol) was resolved by a chiral column (column: CHIRALPAK). AD, 4.6*150mm, 5μm; Detection wavelength (nm): 254; Temperature (°C): 35; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; Run time (min): 12; Linearity mode: isocratic, yielding compound 195b_P1 (120mg, RT (retention time) = 3.393min, yield: 76.2%); compound 195b_P2 (110mg, RT (retention time) = 4.527min, yield: 69.8%).

[0701] MS m / z(ESI): 496.2 [M+1]

[0702] Step 3

[0703] The compound 7-ethyl-8-(4-(4,4,4-trifluoro-1-hydroxybutyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 195b_P2 (110 mg, 0.22 mmol) was resolved by a chiral column (column: CHIRALPAK). OD, 4.6*150mm, 5μm; Detection wavelength (nm): 254; Temperature (°C): 35; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; Run time (min): 12; Linearity mode: isocratic, yielding compound 195c_P1 (50mg, RT (retention time) = 2.223min, yield: 90.9%); compound 195c_P2 (50mg, RT (retention time) = 2.533min, yield: 90.9%).

[0704] MS m / z(ESI): 496.2 [M+1]

[0705] Step 4

[0706] Following the synthesis method in step 4 of Example 2, product 195-P1 was obtained using compound 195c_P1 as a starting material. Product 195-P2 was obtained using compound 195c_P2 as a starting material.

[0707] MS m / z(ESI): 396.2 [M+1]

[0708] 195-P1: 1 H NMR (400MHz, DMSO) δ7.95(d,J=1.2Hz,1H),7.20(d,J=7.8Hz,1H),6.98(d,J=7.9Hz,1 H),5.60(d,J=5.1Hz,1H),4.69(q,J=5.1Hz,1H),3.93(d,J=15.4Hz,1H),3.78-3.71(m ,1H),3.59(d,J=15.3Hz,1H),3.41(d,J=9.7Hz,1H),3.26-3.07(m,3H),2.83-2.62(m ,3H),2.46-2.22(m,2H),2.06-1.82(m,2H),1.55-1.28(m,2H),0.89(t,J=7.3Hz,3H).

[0709] 195-P2: 1H NMR (400MHz, DMSO) δ7.98(d,J=0.9Hz,1H),7.20(d,J=7.8Hz,1H),6.97(d,J=7.9Hz,1 H),5.53(d,J=5.2Hz,1H),4.65(q,J=5.4Hz,1H),3.92(d,J=15.4Hz,1H),3.80-3.69( m,1H),3.58(d,J=15.3Hz,1H),3.45-3.40(m,1H),3.25-3.07(m,3H),2.81-2.62(m,3 H),2.42-2.29(m,2H),2.07-1.87(m,2H),1.57-1.17(m,2H),0.87(t,J=10.2Hz,3H).

[0710] Example 196

[0711] 1-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-yl)-3,3,3-trifluoroprop-1-ol

[0712] The synthesis of Example 196 was obtained by referring to the method of Example 195.

[0713] MS m / z(ESI): 400.2 [M+1]

[0714] Example 197

[0715] 1-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-yl)-4,4,4-trifluorobut-1-ol

[0716] first step

[0717] Following the synthesis method in step 1 of Example 98, product 7-ethyl-10-fluoro-8-(4-formyloxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 197a was obtained.

[0718] MS m / z(ESI): 416.2 [M+1]

[0719] Step 2

[0720] 7

[0721] Following the synthetic method of step 1 in Example 195, product 7-ethyl-10-fluoro-8-(4-(4,4,4-trifluoro-1-hydroxybutyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 197b was obtained.

[0722] MS m / z (ESI): 514.2 [M+1]

[0723] Step 3

[0724] The compound 7-ethyl-10-fluoro-8-(4-(4,4,4-trifluoro-1-hydroxybutyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 197b (260 mg, 0.51 mmol) was resolved by a chiral column (column: CHIRALPAK). IG, 4.6*150mm, 5μm; Detection wavelength (nm): 254; Temperature (°C): 35; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:MeOH:DEA = 70:15:15:0.1%; Run time (min): 12; Linearity mode: isocratic, yielding compound 197c_P1 (80mg, RT (retention time) = 2.110min, yield: 61.5%); compound 197c_P2 (80mg, RT (retention time) = 2.300min, yield: 61.5%).

[0725] MS m / z (ESI): 514.2 [M+1]

[0726] Step 4

[0727] Following the synthesis method in step 4 of Example 2, product 1-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-yl)-4,4,4-trifluorobut-1-ol 197d was obtained.

[0728] MS m / z(ESI): 414.2 [M+1]

[0729] Step 5

[0730] The compound 1-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-yl)-4,4,4-trifluorobut-1-ol was resolved at 197 days (50 mg, 0.12 mmol) using a chiral column (column: CHIRALPAK). IG, 4.6*150mm, 5μm; Detection wavelength (nm): 254; Temperature (°C): 35; Flow rate (mL / min): 1.0; Mobile phase: Hexane:EtOH:MeOH:DEA = 70:15:15:0.1%; Run time (min): 12; Linearity mode: isocratic, yielding compound 197_P1 (16mg, RT (retention time) = 4.783min, yield: 64.0%); compound 197_P2 (18mg, RT (retention time) = 5.553min, yield: 72.0%).

[0731] MS m / z(ESI): 414.2 [M+1]

[0732] 1 H NMR (400MHz, DMSO) δ8.02(d,J=0.9Hz,1H),6.94(d,J=11.2Hz,1H),5.55(d,J=5.2Hz,1H),4.66(t,J=6.3Hz,1H),4.21(d,J=15.7Hz,1H),3.69(t,J =8.5Hz,1H),3.49-3.40(m,2H),3.24-3.06(m,3H),2.84-2.65(m,2H),2. 42-2.26(m,3H),2.08-1.84(m,2H),1.57-1.27(m,2H),0.92-0.79(m,3H).

[0733] Example 198

[0734] 4,4-Difluoro-1-(2-(10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-yl)but-1-ol

[0735] The synthesis of Example 198 was obtained by referring to the method of Example 195.

[0736] MS m / z(ESI): 382.2 [M+1]

[0737] Example 199

[0738] 1-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indol-8-yl)-5-fluoropyrimidin-4-yl)cyclopropane-1-ol

[0739] first step

[0740] 2-(2-(tert-Butoxycarbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid ethyl ester

[0741] Intermediate 8 (250 mg, 626.10 μmol), ethyl oxazole-4-carboxylate (140 mg, 939.15 μmol), tri-n-butylphosphine (383.92 mg, 751.32 μmol), and cesium carbonate (610.45 mg, 1.88 mmol) were dissolved in 1,4-dioxane (8 mL). Palladium acetate (28.05 mg, 125.22 μmol) was added, and the atmosphere was purged with nitrogen. The reaction was stirred at 120 °C for 18 hours. LC-MS showed product formation. Water (30 mL) was added, and the aqueous phase was extracted with EA (30 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 3 / 1) to give compound 199-2 (200 mg, yield: 67%).

[0742] MS m / z(ESI): 442.2 [M+1]

[0743] Step 2

[0744] 2-(7-Ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-carboxylic acid ethyl ester

[0745] Compound 199-2 (0.4 g, 0.85 mmol) was dissolved in 5 mL of dioxane, and 4 M HCl / dioxane (20 mL) was added. The reaction mixture was stirred at 20 °C for 0.5 h. The reaction solution was concentrated under reduced pressure to give compound 199-3 (350 mg, yield: 100%).

[0746] MS m / z(ESI): 342.2 [M+1]

[0747] Step 3

[0748] 2-(2-(benzyloxy)carbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid ethyl ester

[0749] 10 mL of dichloromethane and 0.5 mL of triethylamine were added to compound 199-3 (350 mg, 1 mmol). The mixture was cooled to 0 °C, and benzylformyl chloride (262 mg, 1.5 mmol) was added. The reaction was stirred at 20 °C for 1 hour. Silica gel was added directly and the sample was mixed. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 1 / 1) to obtain compound 199-4 (400 mg, yield: 82%).

[0750] MS m / z(ESI): 476.2 [M+1]

[0751] Step 4

[0752] 7-Ethyl-8-(4-(2-hydroxypropyl-2-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid benzyl ester

[0753] Compound 199-4 (400 mg, 0.8 mmol) was dissolved in 10 mL of anhydrous THF, cooled to 0 °C, and methyl magnesium bromide (1.3 mL, 4 mmol, 3 M) was slowly added dropwise. The reaction was stirred at 20 °C for 0.5 h. An aqueous solution of ammonium chloride (20 mL) was added, and the aqueous phase was extracted with EA (30 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1–2 / 1) to give compound 199-5 (300 mg, yield: 77%).

[0754] MS m / z(ESI): 462.2 [M+1]

[0755] Step 5

[0756] (S)-7-ethyl-8-(4-(2-hydroxypropyl-2-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-benzyl carboxylate (R)-7-ethyl-8-(4-(2-hydroxypropyl-2-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-benzyl carboxylate

[0757] Compound 199-5 (70 mg, 0.15 mmol) was separated by a chiral column (column: CHIRALPAK OJ, 4.6*150 mm, 5 μm; detection wavelength (nm): 254; temperature (°C): 25; flow rate (mL / min): 1.0; mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; run time (12 min): 5; linear mode: isocratic), yielding product (199-P1, (25 mg, RT (retention time) = 3.610 min, yield: 36%)) and product (199-P2, (25 mg, RT (retention time) = 4.187 min, yield: 36%)).

[0758] Step 6

[0759] 2-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)prop-2-ol

[0760] Compound 199-P2 (25 mg, 0.054 mmol) was dissolved in 10 mL of tetrahydrofuran, and Pd / C (10 mg) was added to displace hydrogen gas. The reaction mixture was stirred at 20 °C for 0.5 h. The reaction solution was filtered and evaporated to dryness to give compound 199 (12 mg, yield: 68%).

[0761] MS m / z(ESI): 328.2 [M+1]

[0762] 1H NMR (400MHz, DMSO) δ7.84(s,1H),7.18(d,J=7.8Hz,1H),6.96(d,J=7.9Hz,1H),5.08(s,1H),3.95–3.73(m,2H),3.58(d ,J=15.3Hz,1H),3.41(dd,J=9.7,1.5Hz,1H),3.23–3.09(m,3H),2.79–2.62(m,2H),1.45(s,8H),0.90(t,J=7.3Hz,3H).

[0763] Example 200

[0764] 2-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)-1H-imidazol-5-yl)prop-2-ol

[0765] first step

[0766] (S)-7-Ethyl-10-fluoro-8-(4-(2-hydroxypropyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-tert-butyl carboxylate (R)-7-Ethyl-10-fluoro-8-(4-(2-hydroxypropyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-tert-butyl carboxylate

[0767] Compound 200-5 (80 mg, 0.19 mmol, obtained from intermediate 5 according to the method in Example 98) was separated by a chiral column (column: CHIRALPAK OZ, 4.6*150 mm, 5 μm; detection wavelength (nm): 254; temperature (°C): 25; flow rate (mL / min): 1.0; mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; runtime (12 min): 5; linear mode: isocratic) to obtain product (200-P1, (30 mg, RT (retention time) = 2.443 min, yield: 47%); product (200-P2, (30 mg, RT (retention time) = 3.270 min, yield: 47%)).

[0768] Step 2

[0769] 2-(2-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)-1H-imidazol-4-yl)prop-2-ol

[0770] Compound 200-P2 (30 mg, 0.05 mmol) was dissolved in 10 mL of 4 M HCl / dioxane, and the reaction was stirred at 20 °C for 0.5 h. The reaction solution was analyzed by p-HPLC (FA) to obtain compound 200 (20 mg, yield: 72%).

[0771] MS m / z(ESI): 345.2 [M+1]

[0772] 1H NMR (400MHz, DMSO) δ12.12(d,J=3.6Hz,1H),8.80(d,J=3.6Hz,1H),7.25(d,J =12.0Hz,1H),5.53(s,1H),4.18(d,J=15.6Hz,1H),4.08(s,1H),3.53–3.39( m,2H),3.31(d,J=9.2Hz,1H),3.13(ddd,J=33.5,10.4,4.5Hz,2H),2.80(t,J =9.6Hz,2H),1.57(d,J=3.9Hz,6H),1.31–1.21(m,2H),0.79(t,J=7.3Hz,3H).

[0773] Example 201

[0774] 2-(5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-3-yl)prop-2-ol

[0775] The synthesis of Example 201 was obtained by referring to the method of Example 98.

[0776] MS m / z(ESI): 347.2 [M+1]

[0777] or,

[0778] first step

[0779] tert-Butyl(R,Z)-8-((2-ethoxy-1-(oxime)-2-carbonylethyl)carbamoyl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester

[0780] Tert-butyl(R,Z)-8-((2-ethoxy-1-(oxime)-2-carbonylethyl)carbamoyl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 201a (0.35 g, 0.96 mmol), ethyl(Z)-2-amino-2-(oxime)acetic acid ester (0.15 g, 1.15 mmol), obtained by hydrolysis of intermediate 7-P1, was dissolved in 10 mL of N,N-dimethylformamide. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.43 g, 1.15 mmol) and N,N-diisopropylethylamine (0.6 g, 4.8 mmol) were added, and the reaction was stirred at 20 °C for 1 hour. Add 50 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the product tert-butyl(R,Z)-8-((2-ethoxy-1-(oxime)-2-carbonylethyl)carbamoyl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 201b (0.3 g, yield: 65%).

[0781] MS m / z(ESI): 479.2 [M+1]

[0782] Step 2

[0783] Ethyl(R)-5-(2-(tert-butoxycarbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester

[0784] 0.3 g, 0.6 mmol) of tert-butyl(R,Z)-8-((2-ethoxy-1-(oxime)-2-carbonylethyl)carbamoyl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptanzo[6,7,1-hi]indole-2(1H)-carboxylic acid ester 201b was dissolved in 5 mL of N,N-dimethylformamide, and the reaction was stirred at 120 °C for 18 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the product ethyl(R)-5-(2-(tert-butoxycarbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester 201c (200 mg, yield: 69%).

[0785] MS m / z(ESI): 461.2 [M+1]

[0786] Step 3

[0787] Ethyl(R)-5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester

[0788] Ethyl(R)-5-(2-(tert-butoxycarbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester 201c (0.2 g, 0.43 mmol) was dissolved in 1 mL of dichloromethane, and 6 mL of 4M hydrochloric acid / dioxane was added. The reaction was stirred at 20 °C for 1 hour. The solvent was concentrated under reduced pressure to give ethyl(R)-5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester 201d (0.15 g, yield: 99%).

[0789] MS m / z(ESI): 361.2 [M+1]

[0790] Step 4

[0791] Ethyl(R)-5-(2-((benzyloxy)carbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester

[0792] Ethyl(R)-5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester 201d (0.15 g, 0.4 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (0.22 g, 2.2 mmol) and benzyloxycarbonyl chloride (0.11 g, 0.6 mmol) were added. The reaction was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the product ethyl(R)-5-(2-((benzyloxy)carbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester 201e (0.2 g, yield: 93%).

[0793] MS m / z(ESI): 495.2 [M+1]

[0794] Step 5

[0795] Benzyl(R)-7-ethyl-10-fluoro-8-(3-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-5-yl)-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester

[0796] Ethyl(R)-5-(2-((benzyloxy)carbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptanno[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole-3-carboxylic acid ester 201e (1.35 mL, 0.4 mmol) was dissolved in 10 mL of tetrahydrofuran, nitrogen gas was purged, the mixture was cooled to 0 °C, methyl magnesium bromide (0.11 g, 4 mmol) was added, and the reaction was stirred at 20 °C for 1 hour. Add 50 mL of ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the product benzyl(R)-7-ethyl-10-fluoro-8-(3-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-5-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 201f (0.18 g, yield: 92%).

[0797] MS m / z(ESI): 481.2 [M+1]

[0798] Step 6

[0799] (R)-2-(5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-3-yl)propane-2-ol

[0800] Benzyl(R)-7-ethyl-10-fluoro-8-(3-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-5-yl)-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 201f (0.18 g, 0.37 mmol) was dissolved in 8 mL of tetrahydrofuran, hydrogen gas was substituted, palladium on carbon (0.1 g) was added, and the reaction was stirred at 20 °C for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain product (R)-2-(5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-3-yl)propane-2-ol 201 (47 mg, yield: 36%).

[0801] MS m / z(ESI): 347.2 [M+1]

[0802] 1 H NMR (400MHz, DMSO-d6) δ7.06(d,J=10.7Hz,1H),5.62(s,1H),4.23(d,J=16.0Hz,1H),3.71-3.69(m,1H),3.48-3 .45(m,2H),3.26–3.08(m,3H),2.81-2.75(m,2H),1.61–1.50(m,6H),1.43-1.39(m,2H),0.89(t,J=7.4Hz,3H).

[0803] Example 202

[0804] 1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)cycloprop-1-ol

[0805] The synthesis of Example 202 was obtained by referring to the method of Example 98.

[0806] or,

[0807] first step

[0808] 2-[(12R)-12-ethyl-7-{[(2-methylprop-2-yl)oxy]carbonyl}-7,10-diazatricyclo[8.2.1.05,13]tetrazol-1(13),2,4-trien-2-yl]-1,3-oxazacyclopentane-4-carboxylic acid ethyl ester

[0809] Intermediate 8-P2 (1 g, 2.62 mmol) and ethyl 4-oxazolyl carboxylate (1.11 g, 7.87 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL), and palladium acetate (58.9 mg, 262.26 μmol), tributylphosphine (530.6 mg, 2.62 mmol), and cesium carbonate (2.56 g, 7.87 mmol) were added sequentially. The mixture was purged with nitrogen three times, and then the mixture was heated to 120 °C and stirred for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, and insoluble matter was removed by diatomaceous earth filtration. The solution was washed with ethyl acetate, and the filtrate was collected and concentrated under reduced pressure to obtain product 2-[(12R)-12-ethyl-7-{[(2-methylprop-2-yl)oxy]carbonyl}-7,10-diazatricyclo[8.2.1.05,13]tetrazol-1(13),2,4-trien-2-yl]-1,3-oxazacyclopentan-4-carboxylic acid ethyl ester 202b (2.6 g, crude product).

[0810] MS m / z(ESI): 442.2 [M+1]

[0811] Step 2

[0812] 2-[(12R)-7-[(benzyloxy)carbonyl]-12-ethyl-7,10-diazatricyclo[8.2.1.05,13]tetrazol-1(13),2,4-trien-2-yl]-1,3-oxazacyclopentane-4-carboxylic acid ethyl ester

[0813] Compound 202b (2.6 g, 5.89 mmol) was dissolved in anhydrous dichloromethane (13 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 13 mL) was added. The mixture was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, and anhydrous dichloromethane (26 mL) was added to the residue. The reaction mixture was cooled to 0 °C, and triethylamine (1.79 g, 17.67 mmol, 2.46 mL) and benzyl chloroformate (1.51 g, 8.83 mmol, 1.24 mL) were added slowly in sequence. The mixture was then naturally heated to 20 °C and stirred for another hour. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to obtain the product 2-[(12R)-7-[(benzyloxy)carbonyl]-12-ethyl-7,10-diazatricyclo[8.2.1.05,13]tetrazol-1(13),2,4-trien-2-yl]-1,3-oxazacyclopentan-4-carboxylic acid ethyl ester 202c (1.3 g, yield: 46.4%).

[0814] MS m / z(ESI): 476.2 [M+1]

[0815] Step 3

[0816] (3R)-3-ethyl-5-[4-(hydroxycyclopropyl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid benzyl ester

[0817] Compound 202c (2.6 g, 2.10 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL). Tetraisopropyl titanate (597.7 mg, 2.10 mmol, 622 μL) was added under nitrogen protection at 20 °C and stirred for 0.5 hours. Then, ethyl magnesium bromide (3 M, 3.5 mL) was added over approximately three minutes, and the reaction was continued at 20 °C with stirring for 1 hour. The reaction solution was cooled to 0°C, and the reaction was quenched and diluted by slowly adding saturated ammonium chloride solution (35 mL). The mixture was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain product (3R)-3-ethyl-5-[4-(hydroxycyclopropyl)-1,3-oxazacyclopentanyl-2-yl]-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-10-carboxylic acid benzyl ester 202d (160 mg, yield: 16.6%).

[0818] MS m / z(ESI): 460.2 [M+1]

[0819] Step 4

[0820] 1-{2-[(3R)-3-ethyl-1,10-diazatricyclo[6.4.1.04,13]tetrazol-4(13),5,7-trien-5-yl]-1,3-oxazacyclopentanol-4-yl}cyclopropane-1-ol

[0821] Compound 202d (160 mg, 348.18 μmol) was dissolved in anhydrous methanol (5 mL), and wet palladium on carbon (30 mg, 10%) was added under nitrogen protection. The mixture was purged three times with hydrogen, and then stirred at 20 °C for 1 hour under a hydrogen balloon atmosphere (~15 psi). Diatomaceous earth was used as a filter aid, the filter cake was washed with methanol, the filtrate was collected and concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). The residue was then purified by high performance liquid chromatography (0.1% ammonia / acetonitrile / water) and lyophilized under vacuum to give product 1-{2-[(3R)-3-ethyl-1,10-diazatricyclo[6.4.1.04,13]tridecyl-4(13),5,7-trien-5-yl]-1,3-oxazacyclopentan-4-yl}cycloprop-1-ol 202 (82.8 mg, yield: 73.1%).

[0822] MS m / z(ESI): 326.2 [M+1]

[0823] 1 H NMR (400MHz, DMSO) δ7.90(s,1H),7.16(d,1H),6.95(d,1H),6.13(s,1H),3.91(d,1H),3.69–3.63(m,1H),3.57(d,1 H),3.22–3.07(m,4H),2.70(dd,12.1Hz,2H),1.46(ddd,1H),1.30(ddd,6.9Hz,1H),1.07–0.98(m,4H),0.88(t,3H).

[0824] The preparation of the following examples is based on Example 202:

[0825] Example 242

[0826] 2,2,2-Trifluoro-1-(2-(10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)ethanol-1-ol

[0827] The synthesis of Example 242 was obtained by referring to the method of Example 194.

[0828] MS m / z(ESI): 372.1 [M+1]

[0829] Example 243

[0830] 2-(5-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)isoxazol-3-yl)prop-2-ol

[0831] The synthesis of Example 243 was obtained by referring to the method of Example 195.

[0832] MS m / z(ESI): 346.2 [M+1]

[0833] Example 244

[0834] 2-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)-5-fluoropyrimidin-4-yl)prop-2-ol

[0835] The synthesis of Example 244 was obtained by referring to the method of Example 193.

[0836] MS m / z (ESI): 357.2 [M+1]

[0837] Example 245

[0838] The synthesis of Example 245 was obtained by referring to the method of Example 98.

[0839] MS m / z(ESI): 347.2 [M+1]

[0840] or,

[0841] first step

[0842] tert-Butyl(R)-8-cyano-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester

[0843] 0.5 g (1.25 mmol) of tert-butyl(R)-8-bromo-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptanno[6,7,1-hi]indole-2(1H)-carboxylic acid intermediate 5-P1 and zinc cyanide (0.18 g, 1.5 mmol) were dissolved in 10 mL of N,N-dimethylformamide. 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.18 g, 0.25 mmol) was added, and nitrogen was purged. The reaction was stirred at 140 °C for 5 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the product tert-butyl(R)-8-cyano-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245b (0.3 g, yield: 69%).

[0844] MS m / z(ESI): 346.2 [M+1]

[0845] Step 2

[0846] tert-Butyl(R,Z)-7-ethyl-10-fluoro-8-(N'-hydroxyaminomethyleneimino)-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester

[0847] 0.3 g (0.87 mmol) of tert-butyl(R)-8-cyano-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazo-heptanno[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245b was dissolved in 10 mL of ethanol, and potassium carbonate (0.36 g, 2.6 mmol) and 50% hydroxylamine aqueous solution (3 mL) were added. The reaction was stirred at 90 °C for 18 hours. Add 50 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain tert-butyl(R,Z)-7-ethyl-10-fluoro-8-(N'-hydroxyaminomethyliminoyl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245c (200 mg, yield: 60%).

[0848] MS m / z(ESI): 379.2 [M+1]

[0849] Step 3

[0850] tert-Butyl(R)-8-(5-(2-acetoxypropane-2-yl)-1,2,4-oxadiazol-3-yl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester

[0851] 245c of tert-butyl(R,Z)-7-ethyl-10-fluoro-8-(N'-hydroxyaminomethyleneimino)-3,4,6,7-tetrahydro-[1,4]diazo-heptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245c (0.16 g, 0.42 mmol) and (2-chloro-1,1-dimethyl-2-carbonyl-ethyl)acetate (0.1 mg, 0.6 mmol) were dissolved in pyridine (5 mL), and the reaction was stirred at 120 °C for 1 hour. Add 50 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to give tert-butyl(R)-8-(5-(2-acetoxypropane-2-yl)-1,2,4-oxadiazol-3-yl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245d (0.2 g, yield: 96%).

[0852] MS m / z(ESI): 489.2 [M+1]

[0853] Step 4

[0854] tert-Butyl(R)-7-ethyl-10-fluoro-8-(5-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-3-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester

[0855] 245d (0.2 g, 0.4 mmol) of tert-butyl(R)-8-(5-(2-acetoxypropane-2-yl)-1,2,4-oxadiazol-3-yl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazolyptono[6,7,1-hi]indole-2(1H)-carboxylic acid ester was dissolved in 10 mL of methanol, and potassium carbonate (0.56 g, 4.1 mmol) was added. The reaction was stirred at 20 °C for 1 hour. Add 50 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to give tert-butyl(R)-7-ethyl-10-fluoro-8-(5-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-3-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245e (0.18 g, yield: 98%).

[0856] MS m / z(ESI): 447.2 [M+1]

[0857] Step 5

[0858] (R)-2-(3-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-5-yl)propane-2-ol

[0859] 0.18 g (0.37 mmol) of tert-butyl(R)-7-ethyl-10-fluoro-8-(5-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-3-yl)-3,4,6,7-tetrahydro-[1,4]diazolyptono[6,7,1-hi]indole-2(1H)-carboxylic acid ester 245e was dissolved in 1 mL of dichloromethane, and 4M hydrochloric acid / dioxane (5 mL) was added. The reaction was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give product (R)-2-(3-(7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-5-yl)propane-2-ol 245 (86 mg, yield: 61%).

[0860] MS m / z(ESI): 347.2 [M+1]

[0861] 1H NMR (400MHz, DMSO-d6) δ7.00(d,J=11.1Hz,1H),6.07(s,1H),4.22(d,J=15.8Hz,1H),3.66–3.57(m,1H),3.49–3.42(m ,2H),3.26–3.06(m,3H),2.84–2.73(m,2H),1.61(s,6H),1.51–1.42(m,1H),1.40–1.30(m,1H),0.87(t,J=7.3Hz,3H).

[0862] Example 246

[0863] 8-(4-Cyclopropyl-1H-imidazol-2-yl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indole

[0864] The synthesis of Example 246 was obtained by referring to the method of Example 71.

[0865] MS m / z(ESI): 327.2 [M+1]

[0866] or,

[0867] first step

[0868] 2-Bromo-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium

[0869] Under ice bath conditions, sodium hydride (32.1 mg, 801.98 μmol, 60% purity) was added to a solution of 2-bromo-4-cyclopropyl-1H-imidazolium 246A (100 mg, 534.65 μmol) in N,N-dimethylformamide (1 mL). After stirring at room temperature for 0.5 hours, 2-(trimethylsilyl)ethoxymethyl chloride (98.1 mg, 588.12 μmol, 104.09 μL) was added under ice bath conditions, and the mixture was stirred at 20 degrees Celsius for 2 hours. The reaction solution was added to a saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (8 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the product 2-bromo-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium 246B (121 mg, yield: 71.3%).

[0870] MS m / z(ESI): 317.0 / 319.0 [M+1]

[0871] Step 2

[0872] (R)-8-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazolium [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0873] 2-bromo-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium 246B (120 mg, 378.20 μmol) and (R)-(2-(tert-butoxycarbonyl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazolium [6,7,1-hi]indol-8-yl)boronic acid (220.4 mg, 605.11 μmol) and potassium carbonate (104.5 mg, 756.39 μmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (30.9 mg, 37.82 μmol) was added. The mixture was stirred at 100°C for 12 hours. After cooling to room temperature, the reaction solution was diluted with water (6 mL), extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give (R)-8-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazolium [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 246C (78 mg, yield: 37.0%).

[0874] MS m / z (ESI): 557.2 [M+1]

[0875] Step 3

[0876] (R)-8-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazolium [6,7,1-hi]indole

[0877] The (R)-8-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-ethyl-10-fluoro-3,4,6,7-tetrahydro-[1,4]diazolium [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 246C (78 mg, 140.09 μmol) was dissolved in 1 mL of methanol, and 0.1 mL (0.4 mmol) of 4 M dioxane chloride solution was added. The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (R)-8-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazo [6,7,1-hi]indole 246D (63.9 mg, yield: 99.9%).

[0878] MS m / z (ESI): 457.2 [M+1]

[0879] Step 4

[0880] (R)-8-(4-cyclopropyl-1H-imidazol-2-yl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazolium [6,7,1-hi]indole

[0881] The (R)-8-(4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4]diazide [6,7,1-hi]indole 246D (63.9 mg, 139.93 μmol) was dissolved in tetrahydrofuran (1 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.7 mL, 0.7 mmol) was added. The mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (R)-8-(4-cyclopropyl-1H-imidazol-2-yl)-7-ethyl-10-fluoro-1,2,3,4,6,7-hexahydro-[1,4-diazolidinyl] [6,7,1-hi]indole 246 (9.4 mg, yield: 20.2%).

[0882] MS m / z(ESI): 327.2 [M+1]

[0883] 1H NMR (400MHz, DMSO-d6) δ=9.61-9.21(m,1H),7.17-7.12(m,1H),7.55-7.09(m,1H),7.00(d,J=11.4Hz,1H),4.45(br d,J=15.3Hz,1H),4.09(br d,J=15.3Hz,1H),3.88-3.74(m,1H),3.60-3.51(m,1H),3.44(br d,J=5.0Hz,4H),3.29-3.23(m,1H),3.22-3.10(m,1H),2.04-1.88(m,1H),1.36-1.10(m,2H),1.05-0.87(m,2H),0.86-0.54(m,5H).

[0884] Example 247

[0885] 1-(2-(10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)oxazol-4-yl)prop-1-ol

[0886] The synthesis of Example 247 was obtained by referring to the method of Example 194.

[0887] MS m / z(ESI): 332.2 [M+1]

[0888] or,

[0889] first step

[0890] (R)-8-bromo-10-fluoro-7-methyl-3,4,6,7-tetrahydro-[1,4]diazide [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester intermediate 4-P1 (500 mg, 1.30 mmol), oxazol-4-carboxaldehyde (377.9 mg, 3.89 mmol), tributylphosphine (525.1 mg, 2.60 mmol), and cesium carbonate (845.7 mg, 2.60 mmol) were dissolved in 1,4-dioxane (10 mL), and palladium acetate (14.6 mg, 64.9 μmol) was added. The mixture was stirred at 120°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the product (R)-10-fluoro-8-(4-formyloxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazide. [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247A (50 mg, yield: 9.6%).

[0891] MS m / z(ESI): 402.2 [M+1]

[0892] Step 2

[0893] (R)-10-fluoro-8-(4-formyloxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247A (50 mg, 124.55 μmol) was dissolved in tetrahydrofuran (1 mL), and ethyl magnesium bromide (1 M in THF, 374 μL) was added under ice bath. The mixture was stirred at 20°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was separated. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (7R)-10-fluoro-8-(4-(1-hydroxypropyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazide [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247B (53 mg, yield: 98.6%).

[0894] MS m / z(ESI): 432.2 [M+1]

[0895] Step 3

[0896] Compound (7R)-10-fluoro-8-(4-(1-hydroxypropyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247B (60 mg, 139.76 μmol) was separated by a chiral column (column: CHIRALCEL IG, 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:EtOH:MeOH:DEA = 70:15:15:0.1; runtime (min): 12; linear mode: isocratic), yielding the product (R)-10-fluoro-8-(4-((R)-1-hydroxypropyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazide. [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247B-P1 (17.0 mg, RT (retention time) = 3.657 min, yield: 32.1%); product (R)-10-fluoro-8-(4-((S)-1-hydroxypropyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazide [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247B-P2 (25.0 mg, RT (retention time) = 4.770 min, yield: 47.2%).

[0897] 247B-P1 / P2:MS m / z(ESI):432.2[M+1]

[0898] Step 4

[0899] (R)-10-fluoro-8-(4-((R)-1-hydroxypropyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazide [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247B-P1 (17.0 mg, 39.4 μmol) was dissolved in 21 mL of methanol, and 4 M dioxane hydrochloride solution (1 mL, 4.0 mmol) was added. The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (R)-1-(2-((R)-10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazide). [6,7,1-hi]indol-8-yl)oxazol-4-yl)propane-1-ol 247-P1 (6.2 mg, yield: 47.5%).

[0900] MS m / z(ESI): 332.2 [M+1]

[0901] 1H NMR (400MHz, DMSO-d6) δ = 7.95 (s, 1H), 6.97-6.91 (m, 1H), 5.19 (d, J = 5.0Hz, 1H), 4.46 (q, J = 5.6 Hz,1H),4.20(d,J=15.8Hz,1H),3.86(quin,J=7.2Hz,1H),3.44(d,J=15.6Hz,1H),3.41-3.35(m ,2H),3.28-3.24(m,J=9.5Hz,1H),3.21-3.14(m,1H),3.14-3.05(m,1H),2.83-2.69(m,2H),1. 87-1.73(m,1H),1.66(quind,J=7.2,13.9Hz,1H),1.11(d,J=6.9Hz,3H),0.88(t,J=7.4Hz,3H).

[0902] Step 5

[0903] (R)-10-fluoro-8-(4-((S)-1-hydroxypropyl)oxazol-2-yl)-7-methyl-3,4,6,7-tetrahydro-[1,4]diazine [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 247B-P2 (25.0 mg, 57.94 μmol) was dissolved in 1 mL of methanol, and 4 M dioxane hydrochloride solution (1 mL, 4.0 mmol) was added. The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (S)-1-(2-((R)-10-fluoro-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazide). [6,7,1-hi]indol-8-yl)oxazol-4-yl)propane-1-ol 247-P2 (7.5 mg, yield: 39.0%).

[0904] MS m / z(ESI): 332.2 [M+1]

[0905] 1H NMR (400 MHz, DMSO-d6) δ = 7.93 (d, J = 0.8 Hz, 1H), 6.93 (d, J = 11.3 Hz, 1H), 5.22 (d, J = 5.1 Hz, 1H), 4.48 (q, J = 5.4 Hz, 1H), 4.20 (d, J = 15.8 Hz,1H),3.92-3.80(m,1H),3.44(d,J=15.8 Hz,1H),3.41-3.35(m,2H),3.26(dd,J=1.1,9.5 Hz,1H),3.19(dd,J=4.1,9.9 Hz,1H),3.14-3.05(m,1H),2.82-2.71(m,2H),1.87-1.74(m,1H),1.66(quind,J=7.2,14.0 Hz,1H),1.11(d,J=6.8 Hz,3H),0.89(t,J=7.4 Hz,3H).

[0906] Example 248

[0907] 2-(2-(7-(ethyl-d5)-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)-5-fluoropyrimidin-4-yl)prop-2-ol

[0908] The synthesis of Example 248 was obtained by referring to the method of Example 193.

[0909] MS m / z(ESI): 362.2 [M+1]

[0910] Example 249

[0911] (R)-1-(3-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-5-yl)cyclopropane-1-ol

[0912] Following the synthetic method of Example 245, (R)-1-(3-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazol-5-yl)cyclopropane-1-ol 249 was obtained.

[0913] MS m / z(ESI): 327.2 [M+1]

[0914] 1H NMR (400 MHz, DMSO-d6) δ7.22 (d, J = 7.8 Hz, 1H), 7.01–6.95 (m, 2H), 3.93 (d, J = 15.3 Hz,1H),3.66–3.56(m,2H),3.44–3.37(m,1H),3.21–3.07(m,3H),2.81–2.65(m,2H),2.03–1.94(m,1H),1.50–1.29(m,6H),0.87(t,J=7.3 Hz,3H).

[0915] Example 250

[0916] (2R)-12-(5-cyclopropyl-1,2,4-oxadiazacyclopentan-3-yl)-2-ethyl-10-fluoro-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0917] The synthesis of Example 250 can be carried out with reference to Example 92, using intermediate 5-P1 as the raw material.

[0918] MS m / z(ESI): 329.2 [M+1]

[0919] 1 H NMR (400MHz, DMSO) δ6.95(d,1H),4.21(d,1H),3.60–3.53(m,1H),3.47–3.41(m,2H),3.29(s,1H),3.21–3.17(m,1H),3.10( dd,1H),2.81–2.71(m,2H),2.39(tt,1H),1.44(ddt,1H),1.39–1.31(m,1H),1.29(dd,2H),1.20–1.11(m,2H),0.86(t,3H).

[0920] Example 251

[0921] (3R)-5-(5-cyclopropyl-1,2,4-oxadiazonocyclopentan-3-yl)-7-fluoro-3-methyl-1,10-diazatricyclo[6.4.1.04,13]deca-4(13),5,7-triene

[0922] The synthesis of Example 251 can be referred to Example 92, using intermediate 4-P1 as the raw material.

[0923] MS m / z(ESI): 315.2 [M+1]

[0924] 1 H NMR(400MHz,DMSO)δ6.96(d,1H),4.22(d,1H),3.78–3.68(m,1H),3.45(d,1H),3.38(d,1H),3.26(dd,1H),3.2 2–3.17(m,1H),3.11(dd,1H),2.82–2.73(m,2H),2.39(tt,1H),1.28(tq,2H),1.21–1.15(m,2H),1.09(d,3H).

[0925] Example 252

[0926] (R)-3-Cyclopropyl-5-(7-Ethyl-1,2,3,4,6,7-Hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole

[0927] Referring to the synthesis method of Example 201, using intermediate 8-P2 as a starting material, (R)-3-cyclopropyl-5-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)-1,2,4-oxadiazole 252 was obtained.

[0928] MS m / z(ESI): 311.2 [M+1]

[0929] 1H NMR (400MHz, DMSO-d6) δ7.30(d,J=8.0Hz,1H),7.10(d,J=7.9Hz,1H),4.08(d,J=15.8Hz,1H),3.73–3.61(m,2H),3.24–3.20(m,2H),2 .86–2.73(m,2H),2.24–2.16(m,2H),1.48–1.42(m,2H),1.32–1.29(m,2H),1.16–1.10(m,2H),1.02–0.95(m,2H),0.88–0.84(m,3H).

[0930] Example 253

[0931] 3-Cyclopropyl-5-[(3R)-3-methyl-7-fluoro-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-5-yl]-1,2,4-oxadiazole

[0932] first step

[0933] Intermediate 6-P2 (200 mg, 548.83 μmol), tetrahydrofuran (0.8 mL), methanol (0.2 mL), and water (0.2 mL) were added to a single-necked flask. Lithium hydroxide monohydrate (115.14 mg, 2.74 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, methanol and tetrahydrofuran were removed by rotary evaporation. The pH was adjusted to 6 with dilute hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, and concentrated to give compound 253a (189 mg, 539.41 μmol), which was used directly in the next step.

[0934] MS m / z(ESI): 351.0 [M+H] +

[0935] Step 2

[0936] Compound 253a (179 mg, 510.87 μmol), N'-hydroxycyclopropaneformamide (76.72 mg, 766.30 μmol), and N,N-diisopropylethylamine (198.07 mg, 1.53 mmol, 266.95 μL) were dissolved in DMF (5 mL). HATU (289.10 mg, 766.30 μmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 253b (200 mg, yield: 90.52%).

[0937] MS m / z(ESI): 433.2 [M+H] +

[0938] Step 3

[0939] Compound 253b (200 mg, 462.44 μmol) was dissolved in DMF (5 mL) and heated to 120 °C with stirring for 6 hours. The mixture was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 253c (190 mg, yield: 99.13%).

[0940] MS m / z (ESI): 415.2 [M+H] +

[0941] Step 4

[0942] Compound 253c (190 mg, 458.41 μmol) was dissolved in 5 mL of dioxane hydrochloride solution and stirred at room temperature for 1 hour. The reaction solution was concentrated and reversed to prepare compound 253 (46.6 mg, yield: 32.33%).

[0943] MS m / z (ESI): 315.2 [M+H] +

[0944] 1 H NMR (400MHz, DMSO-d6) δ7.15(d,J=10.8Hz,1H),4.54(d,J=15.6Hz,1H),4.14(d,J=15.5Hz,1H),3.88–3.79(m,1H),3.58(t,J=8.8Hz,2H),3. 46–3.33(m,3H),3.25(d,J=12.8Hz,1H),2.27–2.14(m,1H),1.18(d,J=6.9Hz,3H),1.14(dd,J=8.3,4.1Hz,2H),1.00(dd,J=7.9,4.4Hz,2H).

[0945] Example 254

[0946] (3R)-5-(4-cyclopropyl-1,3-oxazacyclopentanyl-2-yl)-7-fluoro-3-methyl-1,10-diazatricyclo[6.4.1.04,13]deca-4(13),5,7-triene

[0947] The synthesis of Example 254 can be carried out with reference to Example 88, using intermediate 4-P1 as the raw material.

[0948] MS m / z(ESI): 314.2 [M+1]

[0949] 1 H NMR(400MHz,DMSO)δ9.01(s,2H),8.02(s,1H),7.07(d,1H),4.54(d,1H),4.07(d,1H),3.86(p,1H),3.57(d,1H), 3.49–3.41(m,2H),3.38(t,2H),3.15–3.06(m,1H),1.91(tt,1H),1.15(d,3H),0.90(dd,2H),0.81–0.70(m,2H).

[0950] Example 255

[0951] (R)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)-4-(methoxymethyl)oxazole

[0952] first step

[0953] (R)-7-ethyl-8-(4-(hydroxymethyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0954] Compound 202b (250 mg, 566.20 μmol) was dissolved in THF (8 mL), and lithium aluminum hydride (38 mg, 1.13 mmol) was added. Nitrogen was then introduced to replace the nitrogen atmosphere, and the reaction was stirred at 25 °C for 1 hour. LC-MS showed product formation. Water (30 mL) was added, and the aqueous phase was extracted with EA (30 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1–3 / 1) to give compound 255-2 (150 mg, yield: 66%).

[0955] MS m / z(ESI): 400.2 [M+1]

[0956] Step 2

[0957] (R)-7-ethyl-8-(4-(methoxymethyl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0958] Compound 255-2 (0.15 g, 0.38 mmol) was dissolved in 5 mL of tetrahydrofuran, and sodium hydride (30 mg, 0.76 mmol) and methyl iodoform (106 mg, 0.76 mmol) were added. The reaction was stirred at 20 °C for 1 hour. Water (30 mL) was added, and the aqueous phase was extracted with EA (30 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 3 / 1) to give compound 255-3 (80 mg, yield: 52%).

[0959] MS m / z(ESI): 414.2 [M+1]

[0960] Step 3

[0961] (R)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hi]indol-8-yl)-4-(methoxymethyl)oxazole

[0962] Compound 199-2 (0.08 g, 0.19 mmol) was dissolved in 5 mL of dioxane, and 4 M HCl / dioxane (5 mL) was added. The reaction mixture was stirred at 20 °C for 0.5 h. The reaction solution was concentrated under reduced pressure to give compound 255 (40 mg, yield: 66%).

[0963] MS m / z(ESI): 314.2 [M+1]

[0964] 1 H NMR(400MHz, DMSO)δ8.04(t,J=0.9Hz,1H),7.59(d,J=9.0Hz,1H),7.18–7.12(m,1H),4.42 (d,J=1.0Hz,2H),3.94–3.86(m,3H),3.67(dd,J=10.8,5.3Hz,1H),3.63–3.51(m,2H),3.50 (dddt,J=7.7,6.2,3.5,1.5Hz,1H),3.41(s,2H),3.18(tt,J=6.0,4.4Hz,1H),3.07–2.98( m,3H),1.80(dtd,J=19.6,7.3,6.4Hz,1H),1.61–1.50(m,1H),0.83(td,J=7.3,1.5Hz,3H).

[0965] Example 256

[0966] (2R)-2-ethyl-12-(5-methoxybenzo[d][1,3]oxazacyclopentan-2-yl)-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0967] first step

[0968] (2R)-2-ethyl-12-(5-methoxybenzo[d][1,3]oxazacyclopentan-2-yl)-4,7-diazatricyclo[7.3.1.04,13]tridecyl-1(13),9(10),11-trien-7-carboxylic acid-2-methylpropyl-2-yl ester

[0969] Intermediate 8-P2 (100 mg, 262.26 μmol, synthesized via patent CN107873030A) and compound 256a (47 mg, 314.71 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL). Palladium acetate (3 mg, 13.11 μmol), tricyclohexylphosphine fluoroborate (5 mg, 13.11 μmol), bromo(o-phenanthroline)(triphenyl)copper (8 mg, 13.11 μmol), and DBU (80 mg, 524.51 μmol, 78 μL) were added sequentially. The mixture was bubbled under nitrogen for 30 seconds, then the reaction mixture was sealed in a tube and stirred for 12 hours at 120 °C. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain product 256b (300 mg, crude product).

[0970] MS m / z (ESI): 450.2 [M+1]

[0971] Step 2

[0972] (2R)-2-ethyl-12-(5-methoxybenzo[d][1,3]oxazacyclopentan-2-yl)-4,7-diazatricyclo[7.3.1.04,13]deca-1(13),9(10),11-triene

[0973] Compound 256b (300 mg) was dissolved in anhydrous dichloromethane (3 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 3 mL) was added. The mixture was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure, and methanol (2 mL) was added to the residue. A small amount of triethylamine was then added to alkalize the mixture. The mixture was filtered, and the filtrate was purified by high-performance liquid chromatography (0.1% formic acid / acetonitrile / water) and then lyophilized under vacuum to obtain product 256 (8.5 mg).

[0974] MS m / z (ESI): 350.2 [M+1]

[0975] 1 H NMR (400MHz, DMSO) δ7.66(d,1H),7.44(d,1H),7.33(d,1H),7.08(d,1H),7.00(dd,1H),4.02(d,1H),3.93( d,1H),3.84(s,3H),3.69(s,1H),3.48(s,1H),3.23(d,3H),2.79(dd,2H),1.57–1.41(m,2H),0.92(t,3H).

[0976] The preparation of the following examples is based on Example 256:

[0977] The preparation of the following examples is based on Example 209:

[0978] Example 282

[0979] (R)-2-(5-chloro-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazol-4-yl)prop-2-ol

[0980] Following the synthesis method of Example 245, Example 282 was obtained, with MS m / z (ESI): 362.2 [M+1].

[0981] 1 H NMR (400MHz, DMSO-d6)δ=6.96-6.83(m,2H),5.04(s,1H),3.90-3.79(m,1H),3.77-3.66(m,1H),3.24-3.14(m,2H),3.03(br d,J=10.8Hz,3H),2.92-2.76(m,2H),1.40(s,3H),1.30(s,3H),1.24-1.19(m,2H),0.74(t,J=7.4Hz,3H).

[0982] Example 283

[0983] 1-(2-(7,7-dimethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazol-4-yl)cyclopropane-1-ol

[0984] first step

[0985] Under ice bath conditions, a 2.5 M lithium aluminum hydride tetrahydrofuran solution (11.5 mL, 28.74 mmol) was added dropwise to a tetrahydrofuran solution of 4-bromo-3,3-dimethyl-dihydroindole-2-one 283A (4.6 g, 19.16 mmol) in 80 mL of bromo-3,3-dimethyl-2-dihydroindole 283A, and the mixture was stirred at 70°C for 1 hour. Under ice bath conditions, water (1.2 mL), 15% sodium hydroxide aqueous solution (1.2 mL), and water (3.6 mL) were added dropwise to the reaction mixture. Finally, anhydrous sodium sulfate was added and the mixture was dried. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the product 4-bromo-3,3-dimethyl-2-dihydroindole 283B (4.1 g, yield: 94.7%).

[0986] MS m / z(ESI): 226.0 / 228.0 [M+1]

[0987] Steps 2 through 7

[0988] Following the synthesis method of Example 202, Example 283 was obtained, with MS m / z (ESI): 326.1 [M+1].

[0989] Example 284

[0990] 2-(2-(7,7-dimethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazol-4-yl)propane-2-ol

[0991] Following the synthesis method of Example 245, Example 284 was obtained, with MS m / z (ESI): 328.1 [M+1].

[0992] Example 285

[0993] (R)-1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indol-8-yl)oxazol-4-yl)cyclopropane-1-amine

[0994] first step

[0995] (R)-8-(4-(1-aminocyclopropyl)oxazol-2-yl)-7-ethyl-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[0996] (R)-8-(4-cyanoxazol-2-yl)-7-ethyl-3,4,6,7-tetrahydro-[1,4]diaza[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 285a (318.0 mg, 806.2 μmol) was dissolved in 5 mL of diethyl ether, and tetraisopropyl titanate (252.0 mg, 1.7 mmol) was added. The reaction mixture was stirred at room temperature for 10 min. Then, ethyl magnesium bromide (564 μL, 3.0 M in Et₂O, 886.8 μmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, boron trifluoride diethyl ether (228.8 mg, 1.6 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. 10 mL of saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The residue was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give title compound 285b (122.4 mg, yield: 36%).

[0997] MS m / z(ESI): 425.2 [M+1]

[0998] Step 2

[0999] (R)-1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indol-8-yl)oxazol-4-yl)cyclopropane-1-amine

[1000] 285b (78.2 mg, 184.2 μmol) was dissolved in 3 mL of 4.0 M dioxane hydrochloride solution, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the crude product was purified by reverse acidic preparative HPLC to obtain product 285 (13.6 mg, yield 23%).

[1001] MS m / z(ESI): 325.2 [M+1]

[1002] 1 H NMR (400MHz, DMSO) δ7.94(d,J=13.6Hz,2H),7.08(dd,J=77.0,7.9Hz,1H),5.75(s,2H),4.03(q,J=7.2Hz,1H),3.71–3.60(m,1H),3.17(s,4H ),2.89(s,3H),2.73(s,3H),1.99(s,1H),1.57–1.40(m,1H),1.38–1.2 1(m,2H),1.18(t,J=7.1Hz,1H),1.08–0.97(m,1H),0.94–0.80(m,2H).

[1003] Example 286

[1004] 1-(2-(1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)cycloprop-1-ol

[1005] The synthesis of Example 286 can be referred to Example 283.

[1006] MS m / z(ESI): 298.2 [M+1]

[1007] Example 287

[1008] 2-(2-(1,2,3,4,6,7-hexahydro-[1,4]diazazo[6,7,1-hydro]indol-8-yl)oxazol-4-yl)prop-2-ol

[1009] The synthesis of Example 287 can be referred to Example 284.

[1010] MS m / z(ESI): 300.2 [M+1]

[1011] Example 288

[1012] 2-(1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)-4-(1-methoxycyclopropyl)oxazole

[1013] The synthesis of Example 288 can be referred to Example 276.

[1014] MS m / z(ESI): 312.2 [M+1]

[1015] Example 289

[1016] (R)-N-(isopropyl)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazol-4-carboxamide

[1017] first step

[1018] (R)-8-bromo-7-ethyl-3,4,6,7-tetrahydro-[1,4]diazide The intermediates 8-P2 (1.25 g, 3.28 mmol) of [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester, oxazol-4-carboxylic acid ethyl ester (555.2 mg, 3.93 mmol), tricyclohexylphosphine tetrafluoroborate (120.7 mg, 327.8 μmol), (1,10-o-phenanthroline)(triphenylphosphine)copper bromide (I) (192.7 mg, 327.8 μmol), and 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (1.47 mL, 9.83 mmol) were dissolved in N,N-dimethylformamide (10 mL), and palladium acetate (73.6 mg, 327.8 μmol) was added. The mixture was stirred at 120 °C for 12 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the product (R)-2-(2-(tert-butoxycarbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide). [6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid methyl ester 289A (1.32 g, yield: 91.2%).

[1019] MS m / z(ESI): 442.0 [M+1]

[1020] Step 2

[1021] (R)-2-(2-(tert-butoxycarbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide Methyl 289A of [6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid (1.32 g, 2.99 mmol) was dissolved in tetrahydrofuran (20 mL), and potassium trimethylsilanolate (767.1 mg, 5.98 mmol) was added. The mixture was stirred at 20°C for 2 hours. 20 mL of water was added to the reaction mixture, and the pH was adjusted to 5 with 1 N dilute hydrochloric acid. The mixture was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (R)-2-(2-(tert-butoxycarbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazolium [6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid 289B (1.02 g, yield: 82.5%).

[1022] MS m / z(ESI): 414.1 [M+1]

[1023] Step 3

[1024] (R)-2-(2-(tert-butoxycarbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide [6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid 289B (100 mg, 241.86 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (109.5 mg, 290.23 μmol) were dissolved in N,N-dimethylformamide (8 mL), and then difluoroethylamine (21.4 mg, 362.8 μmol) and N,N-diisopropylethylamine (126 μL, 725.5 μmol) were added sequentially. The mixture was stirred at 25 degrees Celsius for 1 hour. Add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (80 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the product (R)-8-(4-((2-isopropyl)carbamoyl)oxazol-2-yl)-7-ethyl-3,4,6,7-tetrahydro-[1,4]diazide. [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 289C (109.9 mg, yield: 99.9%).

[1025] MS m / z(ESI): 455.1 [M+1]

[1026] Step 4

[1027] The (R)-8-(4-((2-isopropyl)carbamoyl)oxazol-2-yl)-7-ethyl-3,4,6,7-tetrahydro-[1,4]diazide [6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester 289C (109.9 mg, 241.77 μmol) was dissolved in 1,4-dioxane (1 mL), and 4M dioxane chloride solution (0.3 mL, 1.2 mmol) was added. The mixture was stirred at 20°C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (R)-N-(isopropyl)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide). [6,7,1-hi]indol-8-yl)oxazol-4-carboxamide 289 (47.8 mg, yield: 55.8%).

[1028] MS m / z (ESI): 355.2 [M+1]

[1029] 1 H NMR (400MHz, CDCl3) δ = 8.32-8.11 (m, 1H), 7.36 (d, J = 7.9Hz, 1H), 6.97 (d, J = 8.0Hz, 1H), 6.86 (br d,J=7.8Hz,1H),4.36-4.17(m,1H),4.14-4.01(m,1H),3.87-3.72(m,2H),3.56-3.44(m,1H),3.36-3.18(m,3H),3. 08-2.93(m,1H),2.84-2.66(m,1H),1.71-1.59(m,1H),1.55-1.42(m,1H),1.33-1.21(m,6H),0.99(t,J=7.4Hz,3H).

[1030] The preparation of the following examples is based on Example 289:

[1031] Example 308

[1032] (3R)-3-ethyl-5-([1,3]oxazapyrrocyclopentano[4,5-b]pyridin-2-yl)-1,10-diazatricyclo[6.4.1.04,13]deca-4(13),5,7-triene

[1033] The synthesis of Example 308 can be referred to Example 90.

[1034] MS m / z(ESI): 321.2 [M+1]

[1035] Example 309

[1036] (R)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)-5-fluorooxazolo[4,5-b]pyridine

[1037] first step

[1038] 6-Fluoro-2-nitropyridine-3-ol

[1039] Potassium nitrate (4.47 g, 44.21 mmol) was slowly added to concentrated sulfuric acid (50 mL) at 0 °C, followed by the slow addition of 2-fluoro-5-hydroxypyridine 309-1 (5 g, 44.21 mmol). The reaction was carried out at 25 °C for 5 hours. The reaction solution was slowly poured into ice water (250 mL), and a yellow solid precipitated. The solid was filtered, and the filter cake was dried to give 6-fluoro-2-nitropyridine-3-ol 309-2 (3 g, yield: 42.9%).

[1040] MS m / z (ESI): 159.1 [M+1]

[1041] 1 H NMR (400MHz, CDCl3) δ10.22(s,1H),7.79(dd,J=8.8,6.0Hz,1H),7.34(dd,J=8.8,3.7Hz,1H).

[1042] Step 2

[1043] 2-Amino-6-fluoropyridine-3-ol

[1044] 309-2 (3 g, 18.98 mmol) was dissolved in 30 mL of tetrahydrofuran, and a solution of ammonium chloride (6.09 g, 113.86 mmol) in water (30 mL) was added. Zinc powder (6.20 g, 94.88 mmol) was added in portions at 0 °C, and the reaction was carried out for 0.5 h. Then, the reaction was carried out at 25 °C for 12 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 309-3 (1.2 g, yield: 49.36%).

[1045] MS m / z(ESI): 129.1 [M+1]

[1046] Step 3

[1047] 5-Fluoroxazolo[4,5-b]pyridine-2-thiol

[1048] 309-3 (1.2 g, 9.37 mmol) was dissolved in 12 mL of N,N-dimethylformamide, and 1,1'-thiocarbonyldiimidazole (1.92 g, 10.77 mmol) was added at 0 °C. The reaction mixture was reacted at 25 °C for 12 hours. The reaction mixture was slowly poured into water (100 mL), the pH was adjusted to 5-6 with 1 N HCl, filtered, and the filtrate was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 309-4 (1 g, yield: 62.74%).

[1049] MS m / z(ESI): 171.1 [M+1]

[1050] Step 4

[1051] 2-Chloro-5-Fluoroxazolo[4,5-b]pyridine

[1052] A mixture of 309-4 (400 mg, 2.35 mmol) and dimethylformamide (10 mL) was added to oxalyl chloride (5.0 mL, 2.35 mmol) and stirred at 20 °C for 3 hours. The mixture was concentrated, and the residue was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 309-5 (375 mg, yield: 62.74%).

[1053] MS m / z(ESI): 173.0 [M+1]

[1054] Step 5

[1055] (R)-7-ethyl-8-(5-fluorooxazolo[4,5-b]pyridin-2-yl)-3,4,6,7-tetrahydro-[1,4]diazazo[6,7,1-hi]indole-2(1H)-carboxylic acid tert-butyl ester

[1056] Add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (81 mg, 0.1 mmol) to a mixed solution of 309-5 (375 mg, 2.17 mmol), (R)-(2-(tert-butoxycarbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indol-8-yl)boronic acid (750.82 mg, 2.17 mmol) and potassium carbonate (700 mg, 5 mmol) in 5 mL of 1,4-dioxane and 1 mL of water, and stir at 85 °C for 2 hours. Add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to give 309-6 (400 mg, yield: 70%).

[1057] MS m / z(ESI): 439.2 [M+1]

[1058] Step 6

[1059] (R)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)-5-fluorooxazolo[4,5-b]pyridine

[1060] 309-6 (400 mg, 0.91 mmol) was dissolved in dioxane (2 mL), and 4N HCl / dioxane (4 mL) was added at 0 °C. The reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 309 (200 mg, yield: 62.74%).

[1061] MS m / z(ESI): 339.2 [M+1]

[1062] Example 310

[1063] (R)-2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazide) [6,7,1-hi]indol-8-yl)oxazolo[4,5-c]pyridine-4-amine

[1064] Following the synthesis method of Example 309, Example 310 was obtained, with MS m / z (ESI): 336.1 [M+1].

[1065] Example 311

[1066] (R)-1-(2-(10-methyl-1,2,3,4,5,6,10,11-octahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-13-yl)oxazol-4-yl)cyclopropane-1-ol

[1067] first step

[1068] 4-Bromo-3-formyl-1H-indole-6-carboxylic acid methyl ester

[1069] Methyl 4-bromo-1H-indole-6-carboxylic acid ester (5 g, 19.8 mmol) was dissolved in 50 mL of water and 25 mL of acetic acid. Hexamethylenetetramine (5.5 g, 39.4 mmol) was added, and the reaction was stirred at 110 °C for 18 hours. The reaction solution was poured into 200 mL of sodium carbonate aqueous solution, stirred for half an hour, filtered, and the solid was collected and evaporated to dryness to give product 311b (5.0 g, yield: 90%).

[1070] MS m / z(ESI):282.2,284.2[M+1]

[1071] Step 2

[1072] 4-Bromo-3-methyldihydroindole-6-carboxylic acid methyl ester

[1073] 311b (5 g, 17.7 mmol) was dissolved in 25 mL of trifluoroacetic acid, and 25 mL of triethylsilane was added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into 200 mL of sodium carbonate aqueous solution and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 311c (1.9 g, yield: 39%).

[1074] MS m / z(ESI):270.2,272.2[M+1]

[1075] Step 3

[1076] 4-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-methyldihydroindole-6-carboxylic acid methyl ester

[1077] 311c (1.9 g, 7 mmol) and tert-butyl(2-bromoethyl)carbamate (1.9 g, 8.4 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and cesium carbonate (6.8 g, 21 mmol) was added. The reaction mixture was stirred at 120 °C for 18 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give product 311d (2 g, yield: 69%).

[1078] MS m / z (ESI): 413.2, 415.2 [M+1]

[1079] Step 4

[1080] tert-Butyl(2-(4-bromo-6-formyl-3-methyldihydroindole-1-yl)ethyl)carbamate

[1081] 311d (2 g, 4.8 mmol) was dissolved in 20 mL of tetrahydrofuran and cooled to -78 °C. A tetrahydrofuran solution of diisobutylaluminum hydride (5.8 mL, 5.8 mmol) was added, and the reaction was stirred at this temperature for 1 hour. 50 mL of ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 311e (1.2 g, yield: 65%).

[1082] MS m / z (ESI): 383.2, 385.2 [M+1]

[1083] Step 5

[1084] (Z)-3-(4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-methyldihydroindol-6-yl)acryloyl ethyl ester

[1085] 311e (1.2 g, 3.1 mmol) was dissolved in 20 mL of dichloromethane, and ethoxyformylmethylenetriphenylphosphine (1.3 g, 3.7 mmol) was added. The reaction mixture was stirred at 40 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give product 311f (1.2 g, yield: 85%).

[1086] MS m / z (ESI): 453.2, 455.2 [M+1]

[1087] Step 6

[1088] (Z)-13-bromo-10-methyl-2,3,10,11-tetrahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-4(1H)-one

[1089] 311f (1.2 g, 2.6 mmol) was dissolved in 10 mL of 1,4-dioxane, and 20 mL of 4M hydrochloric acid / dioxane was added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of sodium carbonate aqueous solution was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give product 311 g (0.7 g, yield: 86%).

[1090] MS m / z (ESI): 307.2, 309.2 [M+1]

[1091] Step 7

[1092] (Z)-13-bromo-10-methyl-1,2,3,4,10,11-hexahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecanoin

[1093] 311 g (0.7 g, 2.3 mmol) was dissolved in 5 mL of tetrahydrofuran, and 10 mL of 1 M borane / tetrahydrofuran solution was added. The reaction was stirred at 80 °C for 2 hours. The reaction was quenched with methanol, and the reaction solution was concentrated under reduced pressure to obtain product 311h (0.67 g, yield: 100%), which was directly used in the next reaction.

[1094] MS m / z(ESI): 293.2, 295.2 [M+1]

[1095] Step 8

[1096] (Z)-13-bromo-10-methyl-1,2,10,11-tetrahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-3(4H)-carboxylic acid methyl ester

[1097] 311h (0.67 g, 2.3 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (1.2 g, 11.5 mmol) was added, followed by benzylformyl chloride (0.6 g, 3.5 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give product 311i (0.7 g, yield: 72%).

[1098] MS m / z (ESI): 427.2, 429.2 [M+1]

[1099] Steps 9 to 12

[1100] (R)-1-(2-(10-methyl-1,2,3,4,5,6,10,11-octahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-13-yl)oxazol-4-yl)cyclopropane-1-ol

[1101] 311 was obtained by referring to the synthesis method of Example 95.

[1102] MS m / z(ESI): 340.2 [M+1]

[1103] Example 312

[1104] (R)-2-(2-(10-methyl-1,2,3,4,5,6,10,11-octahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-13-yl)oxazol-4-yl)propane-2-ol

[1105] 312 was obtained by referring to the synthesis method of Example 311.

[1106] MS m / z(ESI): 342.2 [M+1]

[1107] Example 313

[1108] (R)-1-(2-(10-ethyl-1,2,3,4,5,6,10,11-octahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-13-yl)oxazol-4-yl)cyclopropane-1-ol

[1109] 313 was obtained by referring to the synthesis method of Example 311.

[1110] MS m / z(ESI): 354.2 [M+1]

[1111] Example 314

[1112] (R)-2-(2-(10-ethyl-1,2,3,4,5,6,10,11-octahydro-7,9-(cyclohexane[1,2]diethylene)pyrrolo[1,2-d][1,4]diazodecano-13-yl)oxazol-4-yl)propane-2-ol

[1113] 314 was obtained by referring to the synthesis method of Example 311.

[1114] MS m / z(ESI): 356.2 [M+1]

[1115] Example 315

[1116] (3R)-3-ethyl-5-(5-methoxy-1H-benzimidazol-2-yl)-1,10-diazabicyclo[6.4.1.04,13]tetadeca-4(13),5,7-triene

[1117] first step

[1118] 6-Methoxy-1H-benzimidazole-2-thiol 315A (1 g, 5.55 mmol) was dissolved in acetic acid (20.8 mL), followed by the addition of 48% hydrobromic acid aqueous solution (0.74 mL) and methanol (9.26 mL). Bromine diluted in acetic acid (20.8 mL) was then slowly added dropwise (1.06 mL) under ice bath conditions. The mixture was stirred for 2 hours under ice bath conditions, followed by stirring at room temperature for 6 hours. After the reaction was complete, the mixture was directly filtered and dried to obtain the product 2-bromo-6-methoxy-1H-benzimidazole 315B (1.48 g, yield: 85.0%).

[1119] MS m / z(ESI): 226.9 / 228.9 [M+1]

[1120] Step 2

[1121] Under ice bath conditions, sodium hydride (176.17 mg, 4.40 mmol, 60% purity) was added to a tetrahydrofuran (5 mL) solution of 2-bromo-4-cyclopropyl-1H-imidazolium 315B (500 mg, 2.20 mmol). After stirring at room temperature for 0.5 hours, 2-(trimethylsilyl)ethoxymethyl chloride (440.56 mg, 2.64 mmol) was added under ice bath conditions, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was then extracted with 10 mL of saturated ammonium chloride aqueous solution and ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the product 2-[(2-bromo-6-methoxybenzimidazol-1-yl)methoxy]ethyltrimethylsilane 315C (515 mg, yield: 65.4%).

[1122] MS m / z(ESI): 357.0 / 359.0 [M+1]

[1123] Step 3

[1124] 2-[(2-bromo-6-methoxybenzimidazol-1-yl)methoxy]ethyltrimethylsilane 315C (309.61 mg, 866.48 μmol), (3R)-10-tert-butoxycarbonyl-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-5-yl]boronic acid (200 mg, 577.65 μmol) and sodium carbonate (183.68 mg, 1.73 mmol) were dissolved in a mixed solvent of isopropanol (4 mL) and water (0.8 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (40.55 mg, 57.77 μmol) was added. The mixture was stirred at 80 degrees Celsius for 48 hours. After cooling to room temperature, the reaction solution was diluted with water (8 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give (3R)-3-ethyl-5-[5-methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,10-diazacyclic[6.4.1.04,13]tridecane-4(13),5,7-trien-10-carboxylic acid tert-butyl ester 315D (101 mg, yield: 30.2%).

[1125] MS m / z (ESI): 579.3 [M+1]

[1126] Step 4

[1127] (3R)-3-ethyl-5-[5-methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-10-carboxylic acid tert-butyl ester 315D (101 mg, 174.49 μmol) was dissolved in 2 mL of trifluoroacetic acid and stirred at 80°C for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (3R)-3-ethyl-5-(5-methoxy-1H-benzimidazol-2-yl)-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien 315 (13.1 mg, yield: 21.5%).

[1128] MS m / z(ESI): 349.2 [M+1]

[1129] 1H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.03 (s, 1H), 7.58 (d, J = 8.8Hz, 1H), 7.30 (s, 2H), 7.14 (d, J = 2 .4Hz,1H),6.96(dd,J=9.0,2.4Hz,1H),4.43(dd,J=15.0,4.5Hz,1H),4.21–4.16(m,1H),4.08(s,1H ),3.84(s,3H),3.58(d,J=13.0Hz,1H),3.48(dd,J=9.9,2.2Hz,1H),3.43–3.33(m,3H),3.08(dd,J= 13.9,10.5Hz,1H),1.40(d,J=4.5Hz,1H),1.30(ddd,J=13.7,6.8,2.2Hz,1H),0.76(t,J=7.3Hz,3H).

[1130] Example 316

[1131] 2-[(3R)-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tetadeca-4(13),5,7-trien-5-yl]-1H-benzimidazol-5-nitrile

[1132] first step

[1133] 3,4-Diaminobenzonitrile 316A (2 g, 15.02 mmol) was dissolved in tetrahydrofuran (100 mL), and N,N'-carbonyldiimidazole (3.17 g, 19.53 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 18 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-oxo-1,3-dihydrobenzimidazole-5-nitrile 316B (1.98 g, yield: 82.8%).

[1134] MS m / z(ESI): 160.0 [M+1]

[1135] Step 2

[1136] 2-O-1,3-dihydrobenzimidazole-5-onitrile 316B (500 mg, 3.14 mmol) was dissolved in phosphorus tribromooxy (5 mL) and reacted with stirring at 70°C for 16 hours. The reaction solution was slowly poured into ice water (50 mL) to quench the reaction, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-bromo-1H-benzimidazole-5-onitrile 316C (500 mg, yield: 71.6%).

[1137] MS m / z(ESI): 221.9 / 223.9 [M+1]

[1138] Step 3

[1139] Under ice bath conditions, sodium hydride (193.64 mg, 4.84 mmol, 60% purity) was added to a tetrahydrofuran (5 mL) solution of 2-bromo-1H-benzimidazole-5-onitrile 316C (430 mg, 1.94 mmol). After stirring at room temperature for 0.5 hours, 2-(trimethylsilyl)ethoxymethyl chloride (484.30 mg, 2.90 mmol) was added under ice bath conditions, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was then extracted with 10 mL of saturated ammonium chloride aqueous solution and ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the product 2-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-onitrile 316D (330 mg, yield: 48.3%).

[1140] MS m / z(ESI): 352.0 / 354.0 [M+1]

[1141] Step 4

[1142] 2-Bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-onitrile 316D (244.21 mg, 693.19 μmol), (3R)-10-tert-butoxycarbonyl-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-5-yl]boronic acid (200 mg, 577.65 μmol) and potassium carbonate (239.50 mg, 1.73 mmol) were dissolved in a mixed solvent of toluene (4 mL) and water (0.8 mL), and tetrakis(triphenylphosphine)palladium (66.75 mg, 57.77 μmol) was added. The mixture was stirred at 110°C for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (8 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain (3R)-5-[6-cyano-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4,6,8(13)-trien-10-carboxylic acid tert-butyl ester 316E (231 mg, yield: 69.6%).

[1143] MS m / z (ESI): 574.3 [M+1]

[1144] Step 5

[1145] (3R)-5-[6-cyano-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4,6,8(13)-trien-10-carboxylic acid tert-butyl ester 316E (210 mg, 365.98 μmol) was dissolved in 2 mL of trifluoroacetic acid and stirred at 80°C for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product 2-[(3R)-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-5-yl]-1H-benzimidazol-5-nitrile 316 (24.0 mg, yield: 19.1%).

[1146] MS m / z(ESI): 344.2 [M+1]

[1147] 1H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.98 (s, 1H), 8.14 (s, 1H), 7.76 (d, J = 8.4Hz, 1 H),7.62(dd,J=8.3,1.5Hz,1H),7.39(d,J=7.9Hz,1H),7.30(d,J=8.0Hz,1H),4.44( d,J=13.0Hz,1H),4.24–4.13(m,2H),3.59–3.51(m,2H),3.39(q,J=9.2,8.3Hz,3H), 3.06(t,J=12.1Hz,1H),1.59–1.43(m,1H),1.41–1.29(m,1H),0.82(t,J=7.4Hz,3H).

[1148] Example 317

[1149] (3R)-3-ethyl-5-pyrazolo[1,5-a]pyridin-2-yl-1,10-diazabicyclo[6.4.1.04,13]tetadeca-4(13),5,7-triene

[1150] first step

[1151] 2-bromopyrazolo[1,5-A]pyridine 317A (128.04 mg, 649.86 μmol), (3R)-10-tert-butoxycarbonyl-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-5-yl]boronic acid (150 mg, 433.24 μmol) and sodium carbonate (137.76 mg, 1.30 mmol) were dissolved in a mixed solvent of isopropanol (4 mL) and water (0.8 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (30.41 mg, 43.32 μmol) was added. The mixture was stirred at 80 degrees Celsius for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (8 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain (3R)-3-ethyl-5-pyrazolo[1,5-a]pyridin-2-yl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-10-carboxylic acid tert-butyl ester 317B (160 mg, yield: 88.2%).

[1152] MS m / z(ESI): 419.2 [M+1]

[1153] Step 2

[1154] (3R)-3-ethyl-5-pyrazolo[1,5-a]pyridin-2-yl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-triene-10-carboxylic acid tert-butyl ester 317B (160 mg, 382.29 μmol) was dissolved in 2 mL of trifluoroacetic acid and stirred at 80°C for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product (3R)-3-ethyl-5-pyrazolo[1,5-a]pyridin-2-yl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-triene 317 (20.0 mg, yield: 13.1%).

[1155] MS m / z(ESI): 319.2 [M+1]

[1156] 1 H NMR (400MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.68–8.57 (m, 1H), 7.69 (ddd, J = 9.0, 3.0, 1.5Hz, 1H), 7.28 (dt ,J=7.9,2.5Hz,1H),7.26–7.21(m,1H),7.16(dt,J=8.0,2.5Hz,1H),6.94–6.84(m,2H),4.38(dd,J=1 4.9,3.0Hz,1H),4.16(dd,J=14.8,3.0Hz,1H),3.93(ddd,J=9.0,5.9,3.1Hz,1H),3.56(dd,J=13.2,5 .2Hz,1H),3.52–3.21(m,5H),1.59–1.47(m,1H),1.38(d,J=6.5Hz,1H),0.86(td,J=7.4,2.9Hz,3H).

[1157] Example 318

[1158] (R)-7-ethyl-8-(1H-imidazol[4,5-c]pyridin-2-yl)1,2,3,4,6,7-hexahydro-[1,4]diazolium [6,7,1-hi]indole

[1159] Following the synthesis method of Example 316, Example 318 was obtained, with MS m / z (ESI): 320.2 [M+1].

[1160] Example 319

[1161] (R)-1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazo-heptan[6,7,1-hi]indol-8-yl)oxazol-4-yl)cyclopentan-1-ol

[1162] first step

[1163] Ethyl(R)-2-(2-((benzyloxy)carbonyl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indol-8-yl)oxazol-4-carboxylic acid ester (0.5 g, 1.05 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to 0 °C, and then allyl magnesium bromide (4.2 mL, 4.2 mmol) was added. The reaction was stirred at 20 °C for 1 hour. Add 20 mL of saturated ammonium chloride aqueous solution to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography with eluent system B to obtain the product benzyl(R)-7-ethyl-8-(4-(4-hydroxyhept-1,6-dien-4-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 319b (0.25 g, yield: 46%).

[1164] MS m / z (ESI): 514.2 [M+1]

[1165] Step 2

[1166] Benzyl(R)-7-ethyl-8-(4-(4-hydroxyhept-1,6-dien-4-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 319b (0.25 g, 0.49 mmol) was dissolved in 25 mL of 1,2-dichloroethane, and 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinediyl)(dichlorobenzylmethyl)(tricyclohexylphosphine)ruthenium (85 mg, 0.1 mmol) was added. The reaction was stirred at 20 °C for 2 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the product benzyl(R)-7-ethyl-8-(4-(1-hydroxycyclopent-3-en-1-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 319c (0.17 g, yield: 71.5%).

[1167] MS m / z (ESI): 486.2 [M+1]

[1168] Step 3

[1169] Benzyl(R)-7-ethyl-8-(4-(1-hydroxycyclopent-3-en-1-yl)oxazol-2-yl)-3,4,6,7-tetrahydro-[1,4]diazoylheptan[6,7,1-hi]indole-2(1H)-carboxylic acid ester 319c (0.17 g, 0.35 mmol) was dissolved in 5 mL of tetrahydrofuran, and palladium on carbon (0.1 g) was added to replace hydrogen gas. The reaction was stirred at 20 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to obtain product (R)-1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diazoylheptan[6,7,1-hi]indole-8-yl)oxazol-4-yl)cyclopentan-1-ol 319 (33 mg, yield: 27%).

[1170] MS m / z(ESI): 354.2 [M+1]

[1171] 1H NMR (400MHz, DMSO-d6) δ7.84(s,1H),7.18(d,J=7.8Hz,1H),6.96(d,J=7.9Hz,1 H),4.98(s,1H),3.92(d,J=15.3Hz,1H),3.78–3.71(m,1H),3.58(d,J=15.3Hz,1 H),3.41–3.38(m,2H),3.22–3.10(m,3H),2.80–2.64(m,2H),2.03–1.94(m,2H), 1.85–1.66(m,6H),1.53–1.42(m,1H),1.37–1.27(m,1H),0.89(t,J=7.3Hz,3H).

[1172] Example 320

[1173] (R)-8-(5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)-7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hi]indole

[1174] Product 320 was obtained by referring to the synthesis method of Example 316.

[1175] MS m / z(ESI): 379.2 [M+1]

[1176] Example 321

[1177] (R)-1-(2-(7-ethyl-1,2,3,4,6,7-hexahydro-[1,4]diaza[6,7,1-hydro]indol-8-yl)oxazol-4-yl)cyclopropane-1-nitrile

[1178] first step

[1179] 2-(1,3-oxazol-4-yl)acetonitrile 321A (200 mg, 1.85 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of cesium carbonate (2.41 g, 7.40 mmol) and 1,2-dibromoethane (695.15 mg, 3.70 mmol). The mixture was stirred at 50°C for 12 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the product 1-oxazol-4-ylcyclopropanenitrile 321B (214 mg, yield: 86.2%).

[1180] MS m / z(ESI): 135.0 [M+1]

[1181] Step 2

[1182] 1-Oxazol-4-ylcyclopropanenitrile 321B (105.53 mg, 786.77 μmol), (3R)-10-tert-butoxycarbonyl-3-ethyl-1,10-diazabicyclo[6.4.1.04,13]tridecane-4(13),5,7-trien-...

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ###0001### (I) ​ wherein: represents a single or double bond; M1, M3 or M6 are each independently selected from a bond, N, O, C, S(O) m , S(O)NR a , (CR a R b m , (CR a m , NR a , C=O, C=S or C=NR a ;​​ M2, M4or M5are each independently selected from N, C or CR a ; M7or M8are each independently selected from the group consisting of a bond, N, S(O) m NR b , CR b , NR b or C(R b )2; L1 is selected from key, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-14 4-14 membered heterocyclic alkyl groups, C 6-14 Metaaryl, 5-14 metaaryl, C 3-14 4-14 membered heterocyclic amino groups, C 6-14 5-14-membered heteroarylamines, C 3-14 4-14 cycloalkoxide, cycloalkoxide, C 6-14 5-14-membered heteroaryloxy, C 3-14 4-14 membered heterocyclic thiol group, C 6-14 5-14-membered heteroaryl mercapto, C 3-14 4-14 member heterocyclic methyl groups, C 6-14 5-14-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=NR4)-,-NR4C=S-,-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -, (CH2) m1 S(O)NR4(CH2) m1 -, (CH2) m2 -, -S(=O)(=NR4)R4or -(CH2) m1 NR4CO(CH2) m2 -, -S(=O)(=NR4)R4or -(CH2) O-, wherein said C 1-6 alkylene, C 1-6 alkenylene, C 1-6 alkynylene, C 3-14 cycloalkylene, 4-14 membered heterocyclyl ene, C 6-14 arylene, 5-14 membered heteroarylene, C 3-14 cycloalkyl eneamino, 4-14 membered heterocyclyl eneamino, C 6-14 aryleneamino, 5-14 membered heteroaryleneamino, C 3-14 cycloalkyleneoxy, 4-14 membered heterocyclyl eneoxy, C 6-14 aryleneoxy, 5-14 membered heteroaryleneoxy, C 3-14 cycloalkyl enesulfido, 4-14 membered heterocyclyl enesulfido, C 6-14 arylenesulfido, 5-14 membered heteroarylenesulfido, C 3-14 cycloalkyl enemethyl, 4-14 membered heterocyclyl enemethyl, C 6-14 arylenemethyl, 5-14 membered heteroarylenemethyl, -(CH2) m1 O(CH2) m2 -, -(CH2) m1 S(CH2) m2 -, -(CH2) m1 C=O(CH2) m2 -, -(CH2) m1 C=S(CH2) m2 -, -(CH2) m1 C(=O)O(CH2) m2 -, -(CH2) m1 OC(=O)(CH2) m2 -, -(CH2) m1 C(=O)S(CH2) m2 -, -(CH2) m1 C(=S)O(CH2) m2 -, -(CH2) m1 NR4(CH2) m2 -, -(CH2) m1 CONR4(CH2) m2 m1 NR4CO(CH2) m2 -, -(CH2) m1 S(O) m NR4(CH) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents of 5-14 heteroaryl groups are substituted, preferably the bond, -CONR4 or -NR4-; Preferably, L1 is selected from bonds, C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-10 4-10 membered heterocyclic alkyl groups, C 6-10 Metaaryl, 5-10 metaaryl, C 3-10 4-10 membered heterocyclic amino groups, C 6-10 5-10 methylamine, 5-10 methylamine, C 3-10 4-10 member cycloalkoxide, cycloalkoxide, C 6-10 5-10 arylene oxides, 5-10 heteroarylene oxides, C 3-10 4-10 membered heterocyclic thiol group, C 6-10 5-10 methyl aryl thiol, 5-10 methyl aryl thiol, C 3-10 4-10 member heterocyclic methyl groups, C 6-10 5-10-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=NR4)-,-NR4C=S-,-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -、(CH2) m1 S(O)NR4(CH2) m2 -or -S(=O)(=NR4)R4, wherein the C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-10 4-10 membered heterocyclic alkyl groups, C 6-10 Metaaryl, 5-10 metaaryl, C 3-10 4-10 membered heterocyclic amino groups, C 6-10 5-10 methylamine, 5-10 methylamine, C 3-10 4-10 member cycloalkoxide, cycloalkoxide, C 6-10 5-10 arylene oxides, 5-10 heteroarylene oxides, C 3-10 4-10 membered heterocyclic thiol group, C 6-10 5-10 methyl aryl thiol, 5-10 methyl aryl thiol, C 3-10 4-10 member heterocyclic methyl groups, C 6-10 5-10-membered heteroarylene methyl groups, -(CH2) m1 O(CH2) m2 -、-(CH2) m1 S(CH2) m2 -、-(CH2) m1 C=O(CH2) m2 -、-(CH2) m1 C = S(CH2) m2 -、-(CH2) m1 C(=O)O(CH2) m2 -、-(CH2) m1 OC(=O)(CH2) m2 -、-(CH2) m1 C(=O)S(CH2) m2 -、-(CH2) m1 C(=S)O(CH2) m2 -、-(CH2) m1 NR4(CH2) m2 -、-(CH2) m1 CONR4(CH2) m2 -、-(CH2) m1 NR4CO(CH2) m2 -、-(CH2) m1 S(O) m NR4(CH2) m2 -、-(CH2) m1 NR4S(O) m (CH2) m2 -, (CH2) m1 S(O)NR4(CH2) 1-6 - or -S(=O)(=NR4)R4, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 2-6 haloalkoxy, C 2-6 alkenyl, C 3-14 alkynyl, C 6-12 cycloalkyl, 3-14 membered heterocyclyl, C 1-6 aryl, or 5-14 membered heteroaryl, preferably a bond, -CONR4, or -NR4-; L2is selected from the group consisting of a bond, NH, O, S, C 1-6 alkylene, C(O), C(O)O, -(CH2) m1 CONR4(CH2) m2 -(CH2) m1 NR4CO(CH2) m2 -; R1, R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, wherein the amino, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-14 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 substituted with one or more substituents selected from the group consisting of halo, oxo, cyano, hydroxy, -C(=O)R', -C(=O)OR', -C(=O)NRR', -NR'R", -OR', -SR', R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl mercapto, 5-14 heteroaryl mercapto, optionally further divided by one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted; or R a , R b , R2, L1or L2form a C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6- 12 aryl or 5-14 membered heteroaryl, said C 3-14 cycloalkyl, 3-14 membered heterocyclyl, and C 6-12 aryl and 5-14 membered heteroaryl, optionally further substituted by one or more R3substituents; or, any two R a or R2and the atom to which it is attached form C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 aryl or 5-14 membered heteroaryl, said C 3-14 cycloalkyl, 3-14 membered heterocyclyl, and C 6-12 aryl and 5-14 membered heteroaryl, optionally further substituted by one or more R3substituents; R3is each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6hydroxyalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C2-C6hydroxyalkynyl, C3-C10cycloalkyl, 3-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, C3-C10cycloalkoxy, 3-10 membered heterocycloxy, C6-C10aryloxy, 5-10 membered heteroaryloxy, C3-C10cycloalkamino, 3-10 membered heterocycloamino, C6-C10arlamino, 5-10 membered heteroarlamino, C3-C10cycloalkanoyl, 3-10 membered heterocycloanoyl, C6-C10aroyl, 5-10 membered heteroaroyl, C3-C10cycloalkylsulfanyl, 3-10 membered heterocycloalkylsulfanyl, C6-C10aryl sulfanyl, or 5-10 membered heteroaryl sulfanyl, wherein the hydroxyl, cyano, thiol, oxo, thioxo, C1- C6alkyl, C1-C6deuteroalkyl, C1-C6halogenalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, and C1-C6haloalkoxy groups are optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, or thiol; 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocycloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-10 cycloalkamino, 3-10 membered heterocycloamino, 6-12 arlamino, 5-10 membered heteroarlamino, C 3-10 cycloalkanoyl, 3-10 membered heterocycloanonyl, C 6-12 aroyl, 5-10 membered heteroaroyl, C 3-10 cycloalkylsulfanyl, 3-10 membered heterocyclo alkylsulfanyl, C 6-12 arylsulfanyl, or 5-10 membered heteroarylsulfanyl, wherein the hydroxyl, cyano, thiol, oxo, thiox, C1-C6alkyl, C1-C6deuteroalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3- 10 cycloalkoxy, 3-10 membered heterocycloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C C 3-10 cycloalkamino, 3-10 membered heterocycloamimo, C 6- 12 arlamino, 5-10 membered heteroarlamino, C C 3-10 cycloalkanoyl, 3-10 membered heterocycloanoyi, C 6-12 aroyl, 5-10 membered heteroaroyl, C C 3-10 cycloalkylsulfanyl, 3-10 membered heterocyc loalkylsulfanyl, C 6-12 arylsulfanyl, or 5-10 membered heteroarylsulfanyl optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl; R4 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, cyano, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents on the aryl or 5-10 membered heteroaryl group; each of m1or m2independently is 0, 1, 2 or 3; m is 0, 1 or 2; s is 1, 2 or 3; each of r or t independently is 0, 1 or 2.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compounds are further illustrated by the general formula (II): wherein: M1, M3 or M6 are each independently selected from a bond, N, O, S, C or CR a , preferably at most one of M1, M3 or M6 is a bond; M7or M8are each independently selected from the group consisting of a bond, O, S(O) m , S(O) m NR b , NR b or C(R b )2; L1is selected from a bond, -CONR4-, -S(O) m NR4-, -NR4-, 4-6 membered heterocyclylene containing 1-3 atoms selected from N, O or S, 5-6 membered heteroarylene containing 1-3 atoms selected from N, O or S, 4-6 membered heterocycloamino containing 1-3 atoms selected from N, O or S, or 5-6 membered heteroarylamino containing 1-3 atoms selected from N, O or S; L2is selected from a bond, C(O), O, S, or C 1-3 alkylene; R1, R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents on the aryl or 5-10 membered heteroaryl group; R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1- 3-alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents selected from alkenyl, C alkynyl, C cycloalkyl, 3-10 membered heterocyclyl, C or R a , R b , R2, L1or L2any two of which can form, with the atoms to which they are attached, a C 3-14 cycloalkyl, 4-14 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-12 aryl, or 5-14 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said C 3-14 cycloalkyl, 4-14 membered heterocyclyl containing1-3 atoms selected from N, O, or S, C 6-12 aryl, and 5-14 membered heteroaryl containing 1-3 atoms selected from N, 0, or S, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 aryl, and 5-14 membered heteroaryl, one or more substituents of which are selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, R4is each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylamino, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6alkylcarbonyl, C1-C6alkoxycarbonyl, C1-C6alkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6hydroxyalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C2-C6hydroxyalkynyl, C3-C10cycloalkyl, 3-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, C3-C10cycloalkoxy, 3-10 membered heterocycloxy, C6-C10aryloxy, C6-C10arylamino, 5-10 membered heteroarylamino, C3-C10cycloalkanamino, C6-C10aroyl, 5-10 membered heteroaroyl, C3-C10cycloalkylsulfanyl, 3-10 membered heterocyclylsulfanyl, C6-C10arylsulfanyl, or 5-10 membered heteroarylsulfanyl, wherein the C1-C6alkyl, C1-C6haloalkyl, C1-C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocycloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkanamino, 3-10 membered heterocycloamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-8 cycloalkanoyl, 3-10 membered heterocyclooyl, C 6-12 aroyl, 5-10 membered heteroaroyl, C 3-8 cycloalkylsulfanyl, 3-10 membered heterocyclyl sulfanyl, C 6-12 arylsulfanyl, or 5-10 membered heteroarylsulfanyl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, C1-C6alkyl, C1-C6alkylamino, C1-C6alkylsulfanyl, 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocycloxy, 5-10 membered heteroaryloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C C 3-8 cycloalkanamino, 3-10 membered heterocycloamin, C 6-12 arylamino, 5-10 membered heteroarylamino, C C 3-8 cycloalkanoyl, 3-10 membered heterocycloanoyl, 5-10 membered heteroaroyl, 5-10 membered heteroarylamino, C 6-12 aroyl, 5-10 membered heteroaroyl, 5-10 3-8 cycloalkylsulfanyl, 3-10 membered heterocycloalkylsulfanyl, C 6-12 arylsulfanyl, or 5-10 membered heteroarylsulfanyl, 1- alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, The compounds are further illustrated by the general formula (III): wherein, Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S(O) m atoms; more preferably C 3-7 monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, C 6-10 aryl, 7-10 membered bicyclic heterocyclyl or 7-10 membered bicyclic heteroaryl, which heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from N, O or S(O) m ; optionally, ring A is further substituted with one or more R3; R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl acyl, 3-14 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-14 member heteroaromatic acyl group, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aromatic thiol, 5-14 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl, 5-14 heteroaryl, C 3-14 Cycloalkoxy, 3-14 member heterocyclic alkyl group, C 6-12 Aryloxy group, 5-14 member heteroaryloxy group, C 3-14 Cycloalkylamino, 3-14 membered heterocyclic amino, C 6-12 Aromatic amino, 5-14 membered heteroaromatic amino, C 3-14 Cycloalkyl thiol, 3-14 membered heterocyclic thiol, C 6-12 Aryl mercapto, 5-14 heteroaryl mercapto, optionally further divided by one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted; R3 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-10 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-10 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, hydroxy, -NRaRa, -C(O)NRaRa, -NRaC(O) or R3and the atom to which L1or L2, respectively, is attached form C 5-14 cycloalkyl or 5-14 membered heterocyclyl, said C 5-14 cycloalkyl or 5-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl; or R3and R2, together with the atoms to which they are attached, form a C 5-14 cycloalkyl or 5-14 membered heterocyclyl, said C 5-14 cycloalkyl or 5-14 membered heterocyclyl is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl; each of m1or m2independently is 0, 1 or 2; m is 1 or 2; s is 1, 2 or 3; each of t independently is 0, 1 or 2.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, L1is selected from 4-6 membered heterocyclylene containing 1-3 atoms selected from N, O or S or 5-6 membered heteroarylene containing 1-3 atoms selected from N, O or S; L2is selected from a bond, O, S, or C 1-3 alkylene; R1is selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1- hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkylamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-8 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, wherein said C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2- alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, or C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocyclyloxy, 6-12 aryloxy, 5-10 membered heteroaryloxy, C C 3-8 cycloalkylamino, 3-10 membered heterocyclylamin 6-12 C 3-8 cycloalkylthiol, 3-10 membered heterocyclythiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cy 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1- haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-12 aryl, or 5-10 membered heteroaryl.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein, M7or M8are each independently selected from the group consisting of a bond, S(O) m NR b , NR b or C(R b )2; Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally, C 3-10 C1-C6alkyl, C3-C10cycloalkyl, 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, or S(O)p, C6-C10aryl, or 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S(O)p; 6-10 C6-C10aryl, or 5-10 membered heteroaryl containing 1- 3 heteroatoms selected from N, O, or S(O)p; m C6-C10aryl, or 5-10 membered heteroaryl containing More preferably C 3-7 monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, C 6-10 aryl, 7-10 membered bicyclic heterocyclyl or 7-10 membered bicyclic heteroaryl, which heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from N, O or S(O) m ; optionally, ring A is further substituted with one or more R3; R3is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-10 cycloalkamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-10 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted with one or more substituents selected from halogen, amino, nitro, hydroxyl, cyano, thiol, ox 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 6-12 aryl or 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy or C 6-12 aryloxy, 5-10 membered heteroaryloxy or C 3-10 cycloalkamino, 3-10 membered heterocyclylamido or C 6-12 arylamino, 5-10 membered heteroarylamino or C 3-10 cycloalkylthiol, 3-10 membered heterocyclythiol or C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl or C 6-12 aryl or 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from halogen, amino, nit R2is each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-8 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, thiol, ox 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1- haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, or C 6-12 aryl or 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocyclyloxy or C 6-12 aryloxy or 5-10 membered heteroaryloxy, C 3-8 cycloalkamino, 3-10 membered heterocyclylamido, C 6-12 arylamino or 5-10 membered heteroarylamino, C 3-8 cycloalkylthiol, 3-10 membered heterocyclythiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl or C 6-12 aryl or 5-10 membered heteroaryl, C each of r or t independently is 0, 1 or 2.

6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein The compounds are further illustrated by the general formula (IV-9): where in: Ring F is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1-3 atoms selected from N, O or S or 5-6 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally further substituted by one or more R6; each R6is independently selected from the group consisting of deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C(O)NR c R d , C(O)R c , C(O)OR c , C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkoxy, C 3-6 cycloalkylamino, 4-6 membered heterocyclyloxy, 5-6 membered heteroaryloxy, 4-6 membered heterocyclylamino, or 5-6 membered heteroarylamino, optionally substituted with one or more deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 3-6 cycloalkoxy, C 3-6 cycloalkylamino, 4-6 membered heterocycloxy, 5-6 membered heteroaryloxy, 4-6 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, or C 3-6 cycloalkylamino R c or R d each independently is selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or =CR 1-3 R 1-3 R 1-3 R 1-3 R 1-3 R 2-4 R 2-4 R 3-8 R 6-12 R e R f one or more substituents independently selected from deuterium, halogen, amino, nitro; R e or R f Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic, or 5-6 heteroaryl groups, optionally, wherein the hydroxyl, amino, nitro, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4-6 heterocyclic or 5-6 heteroaryl groups are one-steply converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted; L1is a bond; preferably, ring F is 5-6 membered heteroaryl containing 1 or 2 atoms selected from N, O or S; More preferably, ring F is selected from or, Ring F is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1-3 atoms selected from N, O or S or 5-6 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally further substituted by one or more -L2-R1; preferably, ring F is 5-6 membered heteroaryl containing 1 or More preferably, ring F is selected from each L2is independently selected from a bond, C(O), O, S, or C 1-3 alkylene; R1 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C(O)NR c R d C(O)R c C(O)OR c C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3- 8-cycloalkanoyl group, 3-10-membered heterocyclic acyl group, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6- 12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the oxo group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl; R c or R d each independently is selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl; L1is selected from a bond.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein, M1or M6is each independently selected from a bond, N, O, S, C, or CR a M1or M6is each independently selected from a bond, N, O, S, or C; R a selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-8 cycloalkamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-8 cycloalkanoyl, 3-10 membered heterocyclylcarbonyl, C 6-12 aroyl, 5-10 membered heteroaroyl, C 3-8 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted by halogen, amino, nitro, hydroxyl, cyano, thiol, ox o, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkoxy, 3-10 membered heterocyclyloxy, 6-12 aryloxy, 5-10 membered heteroaryloxy, C C 3-8 cycloalkamino, 3-10 membered heterocyclylam ino, C 6-12 arylamino, C 3-8 cycloalkanoyl, 3-10 membered heterocyclycarbonyl, C 6-12 aroyl, 5-10 membered heteroaroyl, 5-10 membered heteroarylamino, C 3-8 cycloalkylthiol, 3-10 membered heterocyclythiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substi tuted by halogen, amino, nitro, hydroxyl, cyano, thiol, o xo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents selected from alkenyl, C alkynyl, C cycloalkyl, 3-10 membered heterocyclyl, C ring F is selected from 4-6 membered heterocyclyl containing 1-3 atoms selected from N, O or S or 5-6 member heteroaryl containing 1-3 atoms selected from N, O or S, further substituted with one or more R6; R6is each independently selected from the group consisting of halogen, hydroxyl, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, or C 3-6 cycloalkylamino, optionally, the hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, or C 3-6 cycloalkylamino is further substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, hydroxy, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, or C 3-6 cycloalkylamino L1is a bond; R3is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-10 cycloalkamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-10 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted with one or more substituents selected from halogen, amino, nitro, hydroxyl, cyano, thiol, ox 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 6-12 aryl or 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy or C 6-12 aryloxy, 5-10 membered heteroaryloxy or C 3-10 cycloalkamino, 3-10 membered heterocyclylamido or C 6-12 arylamino, 5-10 membered heteroarylamino or C 3-10 cycloalkylthiol, 3-10 membered heterocyclythiol or C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl or C 6-12 aryl or 5-10 membered heteroaryl, C 8. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein The compounds are further illustrated by the general formula (IV-16), (IV-16-a) or (IV-16-b): each L2is independently selected from a bond, C(O), O, S, or C 1-3 alkylene; R1 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C(O)NR c R d C(O)R c C(O)OR c C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3- 8-cycloalkanoyl group, 3-10-membered heterocyclic acyl group, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6- 12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the oxo group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aryl thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl; R c or R d each independently is selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl; R1' is hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy, wherein said C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy, optionally further substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, or thiol; or, R1' and L2 together with the attached carbon atom form C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, or 5-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, optionally further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted; R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; R7is each independently selected from hydrogen, deuterium, fluorine, chlorine or C 1-3 alkyl.

9. A compound as shown below: or a pharmaceutically acceptable salt thereof: ​ 10. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein The compounds are further illustrated by the general formula (IV-10): wherein: L1 is selected from C 3-8 4-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The C-arylene group or containing 1-3 5-8 heteroarylene groups selected from N, O, or S atoms, wherein the C-arylene group is... 3-8 4-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The aryl group or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 4-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The arylene group is substituted with one or more substituents selected from 1 to 3 5-8 heteroarylene groups chosen from N, O or S atoms; L2is selected from the group consisting of a bond, NH, O, S, C 1-6 alkylene, C(O), C(O)O, -(CH2) m1 CONR4(CH2) m2 -(CH2) m1 NR4CO(CH2) m2 L2is selected from the group consisting of a bond, NH, O, S, C M1or M6are each independently selected from N or CR a ; R a Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 4-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A 5-8 member heteroaryl group containing 1-3 N, O, or S atoms, wherein the amino, hydroxyl, or C atom is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 4-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The arylene group or containing 1-3 5-8 heteroarylene groups selected from N, O, or S atoms, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 4-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 It is substituted with one or more substituents of a 5-8 member heteroaryl group containing 1-3 N, O or S atoms.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein, -L1-L2- is selected from -CONHO-, -NHCOO-, -NHCONH-, -OCONH- or -CONH-; M1is CH; M6is CR a ; R a selected from halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1- 3hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; R1 is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, optionally further coated with halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents on the aryl or 5-10 membered heteroaryl group; R3is selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-10 cycloalkamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-10 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted with one or more substituents selected from halogen, amino, nitro, hydroxyl, cyano, thiol, ox 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 6-12 aryl or 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy or C 6-12 aryloxy, 5-10 membered heteroaryloxy or C 3-10 cycloalkamino, 3-10 membered heterocyclylamido or C 6-12 arylamino, 5-10 membered heteroarylamino or C 3-10 cycloalkylthiol, 3-10 membered heterocyclythiol or C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl or C 6-12 aryl or 5-10 membered heteroaryl, C 12. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein The compounds are further illustrated by the general formula (IV-12) or (IV-13): M7is selected from a bond, N, or CR b ; M8is selected from the group consisting of a bond, O, S(O) m , S(O) m NR b , NR b or C(R b )2; L1is selected from the group consisting of a bond, C 1-3 alkylene, -(CH2) m1 NR4CO(CH2) m2 -, -CONR4-, -S(O) m NR4-, -NR4-, -NR4C=S-, -(CH2) m1 C=O(CH2) m2 -, -(CH2) m1 C(=NR4)-, -S(=O)(=NR4)R4, 4-6 membered heterocyclylene containing 1-3 atoms selected from N, O, or S, 5-6 membered heteroarylene containing 1-3 atoms selected from N, O, or S, 4-6 membered heterocycloamino containing 1-3 atoms selected from N, O, or S, or 5-6 membered heteroarylamino containing 1-3 atoms selected from N, O, or S, wherein said C 1-3 alkylene, 4-6 membered heterocyclylene containing 1-3 atoms selected 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 one or more substituents on aryl or 5-14 membered heteroaryl; L2is selected from a bond, O, S, or C 1-3 alkylene; R1 or R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1- 3-alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3- 8-cycloalkanoyl group, 3-10-membered heterocyclic acyl group, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl; R2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatyl mercapto or 5-10 heteroaryl mercapto, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1- 3-alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl; or R b , R2, L1or L2any two of which can form, with the atoms to which they are attached, a C 3-14 cycloalkyl, 4-14 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-12 aryl, or 5-14 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said C 3-14 cycloalkyl, 4-14 membered heterocyclyl containing1-3 atoms selected from N, O, or S, C 6-12 aryl, and 5-14 membered heteroaryl containing 1-3 atoms selected from N, 0, or S, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 aryl, and 5-14 membered heteroaryl, one or more substituents of which are selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, or, any two R2may form, with the atoms to which they are attached, a C 3-14 cycloalkyl, 4-14 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-12 aryl or 5-14 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said C 3-14 cycloalkyl, 4-14 membered heterocyclyl containing1-3 atoms selected from N, O, or S, C 6-12 aryl and 5-14 membered heteroaryl containing 1-3 atoms selected from N, 0, or S, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 one or more substituents of aryl and 5-14 membered heteroaryl; R3is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy, C 6-12 aryloxy, 5-10 membered heteroaryloxy, C 3-10 cycloalkamino, 3-10 membered heterocyclylamino, C 6-12 arylamino, 5-10 membered heteroarylamino, C 3-10 cycloalkylthiol, 3-10 membered heterocyclylthiol, C 6-12 arylthiol or 5-10 membered heteroarylthiol, wherein said hydroxyl, amino, thiol, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or C 6-12 aryl or 5-10 membered heteroaryl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyloxy or C 6-12 aryloxy or 5-10 membered heteroaryloxy, C 3-10 cycloalkamino, 3-10 membered heterocyclylamido or C 6-12 arylamino or 5-10 membered heteroarylamino, C 3-10 cycloalkylthiol, 3-10 membered heterocyclythiol or C 6-12 arylthiol or 5-10 membered heteroarylthiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 alkyl, C 1- deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, aryl or 5-10 membered heteroaryl, C 6-12 one or more substituents of R3are substituted with deuterium, halogen, amino, nitro, hydroxyl, cy ano, thiol, oxo, thioxo, C or R3and the atom to which L1or L2, respectively, is attached form C 5-14 cycloalkyl or 5-14 membered heterocyclyl, said C 5-14 cycloalkyl or 5-14 membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl; or R3and R2, together with the atoms to which they are attached, form a C 5-14 cycloalkyl or 5-14 membered heterocyclyl, said C 5-14 cycloalkyl or 5-14 membered heterocyclyl is optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl; R4 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, 5-10 membered heteroaromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl group, 5-10 heteroaryl group, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, wherein the amino, hydroxyl, thiol, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkoxy, 3-10 heterocyclic alkyl groups, C 6-12 Aryloxy group, 5-10 member heteroaryloxy group, C 3-8 Cycloalkylamino, 3-10 membered heterocyclic amino, C 6-12 Aromatic amino, C 3-8 Cycloalkyl acyl, 3-10 membered heterocyclic acyl, C 6-12 Aromatic acyl, 5-10 heteroaryl, 5-10 heteroarylamine, C 3-8 Cycloalkyl thiol, 3-10 membered heterocyclic thiol, C 6-12 Aromatic thiol or 5-10 heteroaryl thiol, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-10 membered heteroaryl; each of m1or m2independently is 0, 1, 3 or 4; m is 1 or 2; x is 1, 2 or 3; s is 1, 2 or 3; p is 0, 1, 2 or 3; t is 0, 1 or 2.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein, M7is N; M8is NH; R3is C 1-3 alkyl.

14. The compound or pharmaceutically acceptable salt thereof according to claim 12 or 13, characterized in that, The compounds are further illustrated by the general formula (IV-15): L1is selected from methylene, -NHC=S-, -CONH-, -C(=NR4)-, -C=0-, -NHCO-, -S(=0)(=NH)-, Optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted; L2is selected from a bond or O; R1is selected from C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl or carbonyl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl or carbonyl, optionally further substituted with one or more substitutents selected from deuterium, halogen, amino, nitro, hydroxyl, cyan, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; R2is hydrogen; R3is selected from methyl or ethyl, said methyl or ethyl being optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl; R4is each independently selected from hydrogen or C 1-3 alkyl, said C 1-3 alkyl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl.

15. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, of the specific structure of the compound is as follows: ​ 16. The compound according to any one of claims 1-3 or 5, or a pharmaceutically acceptable salt thereof, wherein, each L1is independently C 3-6 monocyclyl, C 6-14 fused cycloalkyl, C 5-10 bridged cycloalkyl, C 5-10 spirocycloalkyl, 3-6 membered monocyclyl heteroalkyl containing 1-3 heteroatoms selected from N, O, or S, 6-14 membered fused heteroalkyl containing 1-3 heteroatoms selected from N, O, or 3-6 monocyclyl, C 6-10 fused cycloalkyl, C 5-10 bridged cycloalkyl, C 5-10 spirocycloalkyl, 3-6 membered monocyclyl, 6-10 membered fused heteroalkyl, 5-10 membered bridged heteroalkyl, 5-10 membered spiro heteroalkyl, phenyl, naphthyl, 5-6 membered monocyclyl heteroaryl containing 1-3 heteroatoms selected from N, O, or S, or 6-10 membered fused heteroaryl containing 1-3 heteroatoms selected from N, O, or S L1 can be further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

17. The compound according to claims 1-3 or 10, or a pharmaceutically acceptable salt thereof, wherein, L1is selected from a bond, O, S, NH, CH2, CO, CONH or NHCO; L2is selected from a bond, O, S, NH, CH2, CONH or NHCO; Alternatively, L1is selected from * indicates the site of attachment to L2; L2is selected from CONH or CONHCH2.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

19. Use of a compound according to any one of claims 1-17, or a pharmaceutically salt thereof, or a pharmaceutical composition according to claim 28, for the manufacture of a medicament for the treatment of a 5-HT2cagonist.

20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, for the manufacture of a medicament for the treatment of a mood disorder.

21. Use of a compound according to any one of claims 1 to 17, or a pharmaceutical acceptable salt thereof, or a pharmaceutical composition according to claim 28, for the manufacture of a medicine for the treatment of bipolar disorder, depression, atypical depression, mood episodes, adjustment disorders, anxiety, panic disorder, post-traumatic stress syndrome, psychosis, schizophrenia, cognitive deficits in schizophrenia, memory loss, senile dementia, Alzheimer's disease, neuropsychiatric symptoms of Alzheimer's disease, diseases related to dementia and behaviour, social phobia, childhood psychiatric disorders, attention deficit hyperactivity disorder, organic mental disorders, autism, mutism, disruptive behaviour disorders, impulse control disorders, borderline personality disorder, obsessive-compulsive disorder, migraine and other conditions associated with headache or other pain, increased intracranial pressure, epilepsy, drug abuse, alcoholism, cocaine abuse, tobacco abuse, smoking cessation, male sexual dysfunction / erectile dysfunction, female sexual dysfunction, premenstrual syndrome, post-luteal phase syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea, chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis in Parkinson's disease, neuropsychiatric symptoms of Parkinson's disease, Lewy body dementia, neuropsychiatric symptoms of Lewy body dementia, spinal cord injury, trauma, stroke, pain, bladder dysfunction / incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular hypertension, cardiovascular diseases, gastrointestinal diseases, diabetes insipidus, diabetes mellitus, type I diabetes mellitus, type II diabetes mellitus, type III diabetes mellitus, diabetes secondary to pancreatic disease, diabetes associated with steroid use, complications of diabetes mellitus, hyperglycaemia and insulin resistance.

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