Heterocyclic carbonyl derivative modulator, preparation method therefor and use thereof

Abstract

The present invention relates to a heterocyclic carbonyl derivative modulator, a preparation method therefor and a use thereof. In particular, the present invention relates to a compound represented by general formula (VIII-1A), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the compound as a modulator in the treatment of Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders. Each substituent in general formula (VIII-1A) is the same as defined in the description.

Description

Heterocyclic carbonyl derivative modifiers, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a heterocyclic carbonyl derivative regulator, its preparation method, and its application. Background Technology

[0002] The purpose of this invention is to provide compounds that help treat or prevent such diseases and improve therapeutic properties.

[0003] Schizophrenia is a severe, complex, and debilitating mental health disorder characterized by a range of symptoms, including delusions, hallucinations, speech or behavioral disturbances, slowed speech, and emotional blunting. Schizophrenia is also frequently accompanied by severe cognitive impairment, which further limits the patient's ability to work and maintain interpersonal relationships. According to the World Health Organization, schizophrenia affects more than 23 million people worldwide, with a lifetime prevalence of 3.8‰-8.4‰. Onset is most common in late adolescence, and the main challenges in treatment are low medication adherence and high relapse rates. Only 20% of patients report good treatment outcomes; medication adherence is poor, with an 18-month adherence rate of approximately 60%, a discontinuation rate of 74%, and a 1-year relapse rate of 77% and a 2-year relapse rate of 90% for patients who discontinue medication. Compared to the general population, the life expectancy of people with schizophrenia is shortened by 10 to 25 years.

[0004] Muscarinic receptors belong to the acetylcholine receptor family and are typical GPCRs, with five subtypes: M1-5. Among them, M4, which is coupled to a G protein, is mainly expressed in the cerebral cortex, striatum, hypothalamus, and hippocampus. A 2018 genome-wide association study in Nature Genetics on schizophrenia (11,260 cases and 24,542 controls) showed a significant association between M4 gene mutations and the disease.

[0005] Cholinergic neuronal transmission is crucial for cognitive function, and its receptor antagonists can lead to severe memory impairment. In schizophrenia, excessive dopamine levels in the striatum and nucleus accumbens are considered disease-associated, thus blocking dopamine D2 receptors is currently an effective treatment strategy. Some newly developed M4-specific positive isomeric modulators (PAMs) enhance the effects of the endogenous agonist acetylcholine, revealing that muscarinic acetylcholine receptors are involved in controlling dopamine release from key synapses in the hippocampus and striatum that are involved in cognition.

[0006] In recent studies, M4 PAMs have reduced striatal dopamine release in wild-type mice after amphetamine treatment, and further in vivo studies have shown that M4 PAM VU0467154 improved learning impairment induced by the NMDA receptor antagonist MK-801.

[0007] PAM CVL-231, which targets the M4 receptor, is currently in Phase II clinical trials. Its Phase Ib clinical trial showed good overall tolerability. After six weeks of administration, both the 30 mg / day once a day and 20 mg / day twice a day doses showed significant antipsychotic activity. Compared with the placebo group, the total score of the Positive and Negative Syndrome Scale (PANSS) in the 30 mg / day once a day group decreased by an average of 19.5 points from baseline, and the total score of the PANSS in the 20 mg / day twice a day group decreased by an average of 17.9 points from baseline, which were statistically and clinically significant.

[0008] By specifically activating M4 receptors in the striatum and hippocampus using PAM, the hyperdopamine state in the striatum and the hyperstimulation state in the hippocampus can be significantly improved, providing a therapeutic approach for the psychotic symptoms and cognitive impairment of schizophrenia. Therefore, modulating M4 receptor activity is an effective strategy for treating or preventing M4 dysregulation-mediated schizophrenia. Summary of the Invention

[0009] The object of this invention is to provide a compound of general formula (VIII-A), its stereoisomers, or a pharmaceutically acceptable salt thereof:

[0010] in:

[0011] It is a cycloalkyl, heterocyclic, aromatic, or heteroaryl group;

[0012] X1 is selected from CR 11 Or N;

[0013] X2 is selected from CR 22 Or N;

[0014] X3 is selected from CR 33 Or N;

[0015] X4 is selected from CR 44 Or N;

[0016] L4 or L5 are each independently selected from bonds, C (R5R6), N (R5), O or S;

[0017] R0, R 11 R 22 R 33 R 44R1, R2, R3, R4, R5, or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0018] Or, R1, R2, R3, R4, R 11 R 22 R 33 Or R 44 Any two groups in the group are linked to the adjacent atoms to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0019] Cyclone F or cyclone G may or may not be present, and when present, each is independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further subjected to R. 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0020] R 55 R7, R8, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -O(CR) aa R bb ) n1 R 31 -N(CR) aa R bb ) n1 R 31 -S(CR) aa R bb ) n1 R 31 -OCR 31 R32 R 33 、-(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) n1 C(O)NR 31 R 32 -(CH2) n1 P(O)R 31 R 32 -(CH2) n1 P(O)2R 31 R 32 、-(CR aa R bb ) n1 (NR 31 )C(O)R 32 、-(CR aa R bb ) n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups.

[0021] R 31 R 32 R 33 R aa R bb Or R cc Each of the following is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0022] m1 is 0, 1, or 2;

[0023] n1 is 0, 1, or 2;

[0024] w can be 0, 1, 2, 3, or 4;

[0025] The condition is that R3 or R4 is the same as R. 11 R1 or R2 and R 44 Or R 22 With R 33 They are linked to the adjacent atoms to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0026] In some embodiments of the present invention, wherein:

[0027] It is a cycloalkyl, heterocyclic, aromatic, or heteroaryl group;

[0028] X1 is selected from CR 11 Or N;

[0029] X2 is selected from CR 22 Or N;

[0030] X3 is selected from CR 33 Or N;

[0031] X4 is selected from CR 44 Or N;

[0032] L4 or L5 are each independently selected from bonds, C (R5R6), N (R5), O or S;

[0033] R0, R 11 R 22 R 33 R 44 R1, R2, R3, R4, R5, or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0034] Furthermore, R1, R2, R3, R4, R 11 R 22 R 33 Or R 44 Any two groups in the group are linked to the adjacent atoms to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0035] Cyclone F or cyclone G may or may not be present, and when present, each is independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further subjected to R. 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0036] R 55 R7, R8, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -O(CR) aa R bb ) n1 R 31 -N(CR) aa Rbb ) n1 R 31 、 -S(CR aa R bb ) n1 R 31 、 -OCR 31 R 32 R 33 、 -(CR aa R bb ) n1 C(O)R 31 、 N=S=OR 31 R 32 、 N(R 31 )=S=OR 32 -、 -(CH2) n1 C(O)NR 31 R 32 、 -(CH2) n1 P(O)R 31 R 32 、 -(CH2) n1 P(O)2R 31 R 32 、 -(CR aa R bb ) n1 (NR 31 )C(O)R 32 、 -(CR aa R bb ) n1 C(O)NR 31 R 32 、 -(CR aa R bb ) n1 (NR 31 )S(O)<0000(此处可能有误,推测应为 m1 )R 32 、 -(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、 -(CR aa R bb ) n1 S(O)(=NR cc )R 32 或 -(CR aa R bb ) n1 S(O) m1 R 32 请注意原文中可能存在一些格式或内容上的不规范之处(如 31 后面突然变成<0000(此处可能有误,推测应为正确格式) m1 ),翻译时尽量按照原文呈现。The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups.

[0037] R 31 R 32 R 33 R aa R bb Or R cc Each of the following is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0038] m1 is 0, 1, or 2;

[0039] n1 is 0, 1, or 2;

[0040] w can be 0, 1, 2, 3, or 4.

[0041] In a preferred embodiment of the invention, general formula (VIII-A) is further shown as general formula (VIII-1A), (VIII-1B), or (VIII-1C):

[0042] in:

[0043] X1 is selected from CR 11 Or N;

[0044] X2 is selected from CR 22 Or N;

[0045] X3 is selected from CR 33 Or N;

[0046] X4 is selected from CR 44 Or N;

[0047] L4 or L5 are each independently selected from bonds, C (R5R6), N (R5), O or S;

[0048] X5 is selected from CR 55 Or N;

[0049] M1, M2, M3, or M4 are each independently selected from C or N;

[0050] When M1, M2, M3, or M4 is N, R7, R8, R9, or R 10 It does not exist;

[0051] Ring F or ring G are each independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0052] R0, R 11 R 22 R 33 R 44 R1, R2, R3, R4, R5, or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkyl group is substituted by one or more substituents;

[0053] R 55 R7, R8, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, -O(CR) aa R bb ) n1 R 31 -N(CR) aa R bb ) n1 R 31 -S(CR) aa R bb ) n1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 -(CH2) n1 C(O)NR 31 R 32 -(CH2) n1 P(O)R 31 R 32 -(CH2)n1 P(O)2R 31 R 32 、-(CR aa R bb ) n1 (NR 31 )C(O)R 32 、-(CR aa R bb ) n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0054] R 31 R 32 R 33 R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0055] m1 is 0, 1, or 2; and

[0056] n1 is 0, 1, or 2;

[0057] The conditions are:

[0058] (1) R1 and R 44 , or R2 and R 44 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0059] Or, (2) R3 and R 11 , or R4 and R 11 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0060] Or, (3)R 22 With R 33 Linked with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0061] Or, (4)R 33 With R 44 Linked with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0062] Or, (5)R 11 With R 22 Linked with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0063] In a further preferred embodiment of the present invention, Each independently

[0064] Rings C1, C2, C3, C4, or C5 are each independently 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 or containing 1 to 3 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1 to 3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1 to 3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0065] Preferably, rings C1, C2, C3, C4, or C5 are each independently selected from C1. 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 heteroaryl containing 1-3 N, O, or S atoms, wherein the C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10A aryl group or a 5-10 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with a deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0066] More preferably, rings C1, C2, C3, C4, or C5 are each independently selected from C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A aryl group or a 5-6 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with a deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0067] More preferably, rings C1, C2, C3, C4, or C5 are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Optionally substituted with one or more of the following substituents: hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl;

[0068] Ring F, Ring G, L4, L5, R0, R1, R2, R3, R4, R7, R8, R9, R 10 X1, X2, X3, X4, X5, M1, M2, M3, M4 or w as defined in general formulas (VIII-1A), (VIII-1B) or (VIII-1C).

[0069] In a further preferred embodiment of the present invention,

[0070] Each independently

[0071] Each independently

[0072] Each independently

[0073] Each independently

[0074] X6, X7, or X8 are each independently selected from bonds, C(O), (CR) 66 R 77 ) n2 NR 88 、(CR 66 R 77 ) n2 NR 88 NR 88 (CR 66 R 77 ) n2 O, (CR) 66 R 77 ) n2 O、O(CR 66 R 77 ) n2 Or S;

[0075] R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1 to 3 5-10 heteroaryl groups selected from N, O or S atoms;

[0076] Preferably, R 66 R 77 Or R88 Each is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 membered heteroaryl groups selected from N, O or S atoms;

[0077] More preferably, R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-6 heteroaryl groups selected from N, O or S atoms;

[0078] More preferably, R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, ethyl epoxy, propyl epoxy, or butyl epoxy.

[0079] p, q, or t are each independently 0, 1, 2, 3, or 4; and

[0080] n2 can be 0, 1, 2 or 3 independently;

[0081] Ring F, Ring G, L4, L5, R0, R1, R2, R3, R4, R7, R8, R9, R 10X1, X2, X3, X4, X5, M1, M2, M3, M4 or w as defined in general formula (VIII-1A), (VIII-1B) or (VIII-1C);

[0082] Ring C5 Defined in Chinese.

[0083] In a further preferred embodiment of the present invention,

[0084] Each independently

[0085] Each independently

[0086] Each independently

[0087] Each independently

[0088] Ring F, Ring G, L4, L5, R0, R1, R2, R3, R4, R7, R8, R9, R 10 X1, X2, X3, X4, X5, M1, M2, M3, M4 or w as defined in general formula (VIII-1A), (VIII-1B) or (VIII-1C);

[0089] R 66 Or R 77 As defined above.

[0090] In a further preferred embodiment of the present invention,

[0091] General formula (VIII-A) is further shown as general formulas (VIII-2A), (VIII-2B), (VIII-2C), or (VIII-2D):

[0092] It is aryl or aryl heterol.

[0093] In some embodiments of the present invention, general formula (VIII-A) is further shown as in general formula (VIII):

[0094] in:

[0095] It is an aromatic ring or a heterocyclic aromatic ring;

[0096] X1 is selected from CR 11 Or N;

[0097] X2 is selected from CR 22 Or N;

[0098] X3 is selected from CR 33 Or N;

[0099] X4 is selected from CR 44 Or N;

[0100] L4 or L5 are each independently selected from bonds, C (R5R6), N (R5), O or S;

[0101] R 11 R 22 R 33 R 44 R1, R2, R3, R4, R5, or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0102] Furthermore, R1, R2, R3, R4, R 11 R 22 R 33 Or R 44 Any two groups in the group are linked to the adjacent atoms to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0103] Cyclone F or cyclone G are each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further selected by R. 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0104] R 55 R7, R8, R9 or R 10Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -O(CR) aa R bb ) n1 R 31 -N(CR) aa R bb ) n1 R 31 -S(CR) aa R bb ) n1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) n1 C(O)NR 31 R 32 -(CH2) n1 P(O)R 31 R 32 -(CH2) n1 P(O)2R 31 R 32 、-(CR aa R bb ) n1 (NR 31 )C(O)R 32 、-(CR aa R bb ) n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups.

[0105] R 31 R 32 R 33 R aa R bb Or R cc Each of the following is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0106] m1 is 0, 1, or 2;

[0107] n1 can be 0, 1, or 2.

[0108] In a preferred embodiment of the invention, general formula (VIII) or (VIII-A) is further shown as general formula (VIII-1):

[0109] in:

[0110] X1 is selected from CR 11 Or N;

[0111] X2 is selected from CR 22 Or N;

[0112] X3 is selected from CR 33 Or N;

[0113] X4 is selected from CR 44 Or N;

[0114] L4 or L5 are each independently selected from bonds, C (R5R6), N (R5), O or S;

[0115] X5 is selected from CR 55 Or N;

[0116] M1, M2, M3, or M4 are each independently selected from C or N;

[0117] When M1, M2, M3, or M4 is N, R7, R8, R9, or R 10 It does not exist;

[0118] Ring F is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0119] R 11 R 22 R 33 R 44 R1, R2, R3, R4, R5, or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkyl group is substituted by one or more substituents;

[0120] R 55 R7, R8, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, -O(CR) aa R bb ) n1 R 31 -N(CR) aa R bb ) n1 R 31 -S(CR) aa R bb ) n1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 -(CH2) n1 C(O)NR 31 R 32 -(CH2)n1 P(O)R 31 R 32 -(CH2) n1 P(O)2R 31 R 32 、-(CR aa R bb ) n1 (NR 31 )C(O)R 32 、-(CR aa R bb ) n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0121] R 31 R 32 R 33 R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0122] m1 is 0, 1, or 2; and

[0123] n1 is 0, 1, or 2;

[0124] The conditions are:

[0125] (1) R1 and R 44 , or R2 and R 44 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0126] Or, (2) R3 and R 11 , or R4 and R 11 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0127] Or, (3)R 22 With R 33Linked with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0128] Or, (4)R 33 With R 44 Linked with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0129] In a further preferred embodiment of the invention, general formula (VIII) or (VIII-A) is further shown as general formulas (VIII-2), (VIII-3), (VIII-4), or (VIII-5):

[0130] Rings F, C1, C2, C3, or C4 are each independently selected from C. 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or containing 1 to 3 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1 to 3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1 to 3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0131] Preferably, rings F, C1, C2, C3, or C4 are each independently selected from C. 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 heteroaryl containing 1-3 N, O, or S atoms, wherein the C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A aryl group or a 5-10 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with a deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0132] More preferably, rings F, C1, C2, C3, or C4 are each independently selected from C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, wherein the C3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A aryl group or a 5-6 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with a deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0133] More preferably, rings F, C1, C2, C3, or C4 are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Optionally substituted with one or more of the following substituents: hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl;

[0134] Rings F, L4, L5, R1, R2, R3, R4, R7, R8, R9, R 10 X1, X2, X3, X4, X5, M1, M2, M3 or M4 as defined in general formula (VIII-1).

[0135] In a further preferred embodiment of the invention, general formula (VIII) or (VIII-A) is further shown as general formulas (VIII-6), (VIII-7), (VIII-8), or (VIII-9):

[0136] X6, X7, or X8 are each independently selected from bonds, C(O), (CR) 66 R 77 ) n2 NR 88 、(CR 66 R 77 ) n2 NR 88 NR 88 (CR 66 R 77 ) n2 O, (CR) 66 R 77 ) n2 O、O(CR 66 R77 ) n2 Or S;

[0137] R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1 to 3 5-10 heteroaryl groups selected from N, O or S atoms;

[0138] Preferably, R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 membered heteroaryl groups selected from N, O or S atoms;

[0139] More preferably, R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-6 heteroaryl groups selected from N, O or S atoms;

[0140] More preferably, R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, ethyl epoxy, propyl epoxy, or butyl epoxy.

[0141] p, q, or t are each independently 0, 1, 2, 3, or 4; and

[0142] n2 can be 0, 1, 2 or 3 independently;

[0143] L4, L5, R1, R2, R3, R4, R7, R8, R9, R 10 X1, X2, X3, X4, X5, M1, M2, M3 or M4 as defined by general formula (VIII-2), (VIII-3), (VIII-4) or (VIII-5).

[0144] In a further preferred embodiment of the invention, general formula (VIII) or (VIII-A) is further shown as general formulas (VIII-a1), (VIII-a2), (VIII-a3), or (VIII-a4):

[0145] L4, L5, R 66 R 77 , R1, R2, R3, R4, R7, R8, R9, R 10 X1, X2, X3, X4, X5, M1, M2, M3 or M4 as defined in general formulas (VIII-6), (VIII-7), (VIII-8) or (VIII-9).

[0146] In a further preferred embodiment of the invention, the compound of general formula (VIII) or (VIII-A) is further shown as of general formula (VIII-4A) or (VIII-4B):

[0147] In the general formulas described above in this invention, the compounds do not contain the following structures:

[0148] In the above general formulas described in this invention, wherein:

[0149] R 11 R 22 R 33 Or R 44 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0150] Preferably, R 11 R 22 R 33 Or R 44 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, optionally by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 It is substituted by one or more substituents of a deuterated alkyl group.

[0151] In the above general formulas described in this invention, wherein:

[0152] R 55 Alternatively, each of the R8 groups can be independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl or containing 1-3 5-10 heteroaryl groups selected from N, O or S atoms, -O(CR aa R bb ) n1 R 31 -N(CR) aa R bb ) n1 R 31 -S(CR) aa R bb ) n1 R 31 、-(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 -(CH2) n1 C(O)NR 31 R 32 -(CH2) n1 P(O)R 31 R 32 -(CH2) n1 P(O)2R 31 、-(CR aa R bb ) n1 (NR 31 )C(O)R 32 、-(CR aa R bb ) n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally prefixed with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0153] R 31 R 32 Or R 33 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 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, wherein the amino group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3Haloalkyl, C 1- 3-alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0154] Preferably, R 31 R 32 Or R 33 Each of the following is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy. The amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy groups are optionally selected from deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0155] R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, the amino groups, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1- 3-alkoxy group, C1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally deuterated, hydroxyl, halogenated, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0156] Preferably, R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0157] In a further preferred embodiment of the present invention,

[0158] R 55 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl or containing 1-3 5-10 heteroaryl groups selected from N, O or S atoms, -(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 -(CH2) n1 C(O)NR 31 R 32 -(CH2) n1 P(O)R 31 R 32 -(CH2) n1 P(O)2R 31 、-(CR aa R bb ) n1 (NR 31 )C(O)R 32 、-(CR aa R bb )n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally prefixed with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0159] R 31 R 32 Or R 33Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0160] Preferably, R 31 R 32 Or R 33 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0161] R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally deuterated, hydroxyl, halogenated, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0162] Preferably, R aa R bb Or R ccEach is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0163] In the above general formulas described in this invention, wherein:

[0164] R1 or R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0165] Preferably, R1 or R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0166] Alternatively, R1 and R2 can link with the adjacent carbon atoms to form C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0167] Preferably, R1 and R2 are linked with the adjacent carbon atoms to form C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in an alkyl group are substituted.

[0168] In the above general formulas described in this invention, wherein:

[0169] R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0170] Preferably, R3 or R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0171] Alternatively, R3 and R4 can link with the adjacent carbon atoms to form C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0172] Preferably, R3 and R4 are linked with the adjacent carbon atoms to form C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in an alkyl group are substituted.

[0173] In the above general formulas described in this invention, wherein:

[0174] R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0175] Preferably, R5 or R6 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0176] Alternatively, R5 and R6 can link with the adjacent carbon atoms to form C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0177] Preferably, R5 and R6 are linked with the adjacent carbon atoms to form C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0178] More preferably, R5 and R6 are linked with the adjacent carbon atom to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0179] In the above general formulas described in this invention, wherein:

[0180] R7, R8, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 atoms selected from N, O or S atoms, -O(CR aa R bb ) n1 R 31 -N(CR) aa R bb ) n1 R 31 -S(CR) aa R bb ) n1 R 31 、-(CR aa R bb ) n1 C(O)R 31 N = S = OR 31 R 32 -(CH2) n1 C(O)NR 31 R 32 -(CH2) n1 P(O)R 31 R 32 -(CH2) n1 P(O)2R 31 、-(CR aa R bb ) n1 (NR31 )C(O)R 32 、-(CR aa R bb ) n1 C(O)NR 31 R 32 、-(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally prefixed with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0181] R 31 R 32 Or R 33 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 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, wherein the amino group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1- 3-alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0182] Preferably, R 31 R 32 Or R 33 Each of the following is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy. The amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy groups are optionally selected from deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, amino, C1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0183] R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, the amino groups, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1- 3-alkoxy group, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally deuterated, hydroxyl, halogenated, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0184] Preferably, R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0185] In the above general formulas described in this invention, wherein:

[0186] R7, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0187] Preferably, R7, R9 or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0188] More preferably, R7, R9 or R 10Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, vinyl, allyl, propenyl, ethynyl, propynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, fluorinated methoxy, fluorinated ethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0189] In the above general formulas described in this invention, wherein:

[0190] R 11 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0191] Preferably, R 11 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0192] More preferably, R 11 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, vinyl, allyl, propenyl, ethynyl, propynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, fluorinated methoxy, fluorinated ethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0193] In the above general formulas described in this invention, wherein:

[0194] R0 is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0195] Preferably, each of R0 is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0196] More preferably, R0 is independently selected from one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0197] In the above general formulas described in this invention, wherein:

[0198] R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents;

[0199] Preferably, R 66 R 77 Or R 88 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, optionally by deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 It is substituted by one or more substituents of a deuterated alkyl group.

[0200] In the above general formulas described in this invention, ring F is selected from C. 3-8Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 heteroaryl containing 1-3 N, O, or S atoms, wherein the C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A aryl group or a 5-10 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0201] Preferably, ring F is selected from C. 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A aryl group or a 5-6 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0202] More preferably, cycloF is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Optionally substituted with one or more of the following substituents: hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl;

[0203] In some embodiments of the present invention, cycloF is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Optionally substituted with one or more of the following substituents: hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl;

[0204] More preferably, ring F is selected from Optionally substituted with one or more of the following substituents: hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl;

[0205] This indicates the site connected to L4 or L5. When L4 or L5 is a bond, it indicates the site connected to a carbonyl group or ring G.

[0206] In some embodiments of the present invention, ring F is selected from... It may optionally be substituted with one or more of the following substituents: hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0207] In some embodiments of the present invention, ring F is selected from... Optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl;

[0208] This indicates the site connected to L4. When L4 is a bond, it indicates the site connected to the carbonyl group.

[0209] * indicates a site connected to L5. When L5 is a bond, it indicates a site connected to ring G.

[0210] In the above general formulas described in this invention, the ring G is selected from C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 heteroaryl containing 1-3 N, O, or S atoms, wherein the C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 heteroaryl groups containing 1-3 N, O or S atoms, optionally bonded by R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0211] Preferably, ring G is selected from C.3-8 Cycloalkyl groups, 5-6 membered monocyclic heterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused-ring heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, 5-6 membered monocyclic heteroaryl containing 1-3 N, O or S atoms, or 8-10 membered fused-ring heteroaryl containing 1-3 N, O or S atoms, optionally coated with R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0212] More preferably, ring G is selected from benzene ring, naphthalene ring, pyridine, Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0213] More preferably, ring G is selected from Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0214] The symbol indicates the site connected to L5. When L5 is a bond, it indicates the site connected to ring F; when ring F is absent, it indicates the site connected to L4; when L4 is a bond, it indicates the site connected to C(O). In some embodiments of the present invention, ring G is selected from benzene rings, naphthalene rings, pyridine, etc. Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0215] In some embodiments of the present invention, ring G is selected from... Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0216] The symbol represents the site connected to L5. When L5 is a bond, it represents the site connected to ring F. When ring F does not exist, it represents the site connected to L4. When L4 is a bond, it represents the site connected to C(O).

[0217] In some embodiments of the present invention, ring G is selected from benzene ring, naphthalene ring, pyridine, etc. Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0218] In some embodiments of the present invention, ring G is selected from benzene ring, naphthalene ring, pyridine, etc. Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0219] In some embodiments of the present invention, ring G is selected from... Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0220] This indicates the site connected to L5. When L5 is a bond, it indicates the site connected to ring F.

[0221] In some embodiments of the present invention, ring G is selected from benzene ring, naphthalene ring, pyridine, etc. Optionally, it can be further optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample;

[0222] In some embodiments of the present invention, ring G is selected from... Optionally R 55 R7, R8, R9 or R 10 One or more substituents are substituted in the sample.

[0223] The present invention also provides a compound of general formula (IX), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0224] in:

[0225] It is aryl or heteroaryl;

[0226] X1 is selected from CR 11 Or N;

[0227] X2 is selected from CR 22 Or N;

[0228] X3 is selected from CR 33 Or N;

[0229] X4 is selected from CR 44 Or N;

[0230] R L1 The protecting group is selected from hydrogen, deuterium or amino groups, preferably, the amino protecting group is selected from benzyl protecting group, carboxylic acid ester protecting group, acyl protecting group or silyl protecting group;

[0231] More preferably, the benzyl protecting group is selected from benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl or 2,4,6-trimethoxybenzyl; the carboxylic acid ester protecting group is selected from allyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxyformyl, 9-fluorenmethoxycarbonyl, methoxycarbonyl or ethoxycarbonyl; the acyl protecting group is selected from acetyl, benzoyl, p-methoxybenzylcarbonyl, acetyl, toluenesulfonyl, p-nitrobenzenesulfonyl, phthaloyl, p-toluenesulfonyl or trifluoroacetyl; the silyl protecting group is selected from tert-butyldimethylsilyl or (trimethylsilyl)ethoxymethyl;

[0232] R 11 R 22 R 33 R 44 R1, R2, R3, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12Aryl or 5-12 heteroaryl groups, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkyl group is substituted by one or more substituents;

[0233] Alternatively, R1 may link with R2 or R3 may link with R4 to form an oxo group;

[0234] Or, R 11 R 22 R 33 R 44 Any two groups from R1, R2, R3, or R4 are linked to the adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0235] The conditions are:

[0236] (1) R3 and R 11 , or R4 and R 11 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0237] Or, (2) R1 and R 44 , or R2 and R 44 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0238] Or, (3)R 22 With R 33 Linked with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution;

[0239] R 22 With R 33 It cannot form a cyclopentyl group when linked to the adjacent atom.

[0240] In a preferred embodiment of the present invention, general formula (IX) is further shown as general formulas (IX-1), (IX-2), (IX-3), or (IX-4):

[0241] Rings C1, C3, C4, or C5 are as defined above.

[0242] In a further preferred embodiment of the invention, the general formula (IX) is further shown as in general formulas (IX-1A), (IX-1B), (IX-1C), or (IX-1D):

[0243] T1, T2, or T3 are each independently selected from bonds, C(O), and CR. 66 、N、(CR 66 R 77 ) n2 NR 88 、(CR 66 R 77 ) n2 NR 88 NR 88 (CR 66 R 77 ) n2 O, (CR) 66 R 77 ) n2 O、O(CR 66 R 77 ) n2 Or S;

[0244] R 66 R 77 R 88 Or n2 as defined above.

[0245] In a further preferred embodiment of the invention, the general formula (IX) is further as shown in general formulas (IX-2A), (IX-2B), (IX-2C), (IX-2D), or (IX-2E):

[0246] T1, T2, or T3 are each independently selected from CR 66 Or N.

[0247] This invention also provides a method for preparing compounds of general formula (VIII-9), their stereoisomers, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0248] Compounds of general formula (IX-a) and general formula (IX-b), their stereoisomers or pharmaceutically acceptable salts thereof are prepared by condensation reactions to give general formula (VIII-9).

[0249] In a preferred embodiment of the present invention, the reaction is carried out in a condensation reagent selected from N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-propylphosphonic anhydride, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, N,N'-carbonyldiimazole, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1H-benzotriazol-1-yloxytripyrrolidinylhexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, (2-oxime-cyanoethyl acetate)-N,N- One or more of the following: dimethylmorpholinourea hexafluorophosphate, N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate, 2-hydroxypyridine-N-oxide, tripyrrolylphosphonium bromide hexafluorophosphate, bis(2-oxo-3-oxazolyl)phosphine chloride, 2-chloro-1-methylpyridine iodide, diethyl cyanophosphate, 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-chloro-4,6-dimethoxy-1,3,5-triazine, ethyl 2-oxime cyanoacetate, diphenyl azidophosphate, bis(pentafluorophenyl) carbonate, and 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazin-4-one.

[0250] In a further preferred embodiment of the present invention, the reaction is carried out under the action of a base, the base being selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, N-methylimidazolium, pyridine, 4-dimethylaminopyridine, 2,6-dimethylpyridine, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, trimethylamine, pyridine, piperidine, morpholine, lithium diisopropylamino, lithium diethylamino, lithium di(trimethylsilyl)amino, sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, lithium isopropylcyclohexylamino, potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide, or 2-tert-butyl-1,1,3,3-tetramethylguanidine and mixtures thereof.

[0251] In a further preferred embodiment of the present invention, the reaction solvent is selected from one or more of N,N-dimethylformamide, 1,4-dioxane, methanol, ethanol, trifluoroethanol, propanol, hexafluoroisopropanol, butanol, acetone, tetrahydrofuran, diethyl ether, propyl ether, ethylene glycol monoethyl ether, ethyl acetate, dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, butanone, acetonitrile, or toluene.

[0252] This invention also provides a method for preparing a compound of general formula (IX-a), its stereoisomer, or a pharmaceutically acceptable salt thereof, which is obtained by deprotection of a compound of general formula (IX-c):

[0253] R L1 The protecting group is selected from hydrogen, deuterium or amino groups. Preferably, the amino protecting group is selected from benzyl protecting groups, carboxylic acid ester protecting groups, acyl protecting groups or silyl protecting groups.

[0254] In a preferred embodiment of the present invention, the benzyl protecting group is selected from benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl or 2,4,6-trimethoxybenzyl; the carboxylic acid ester protecting group is selected from allyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxyformyl, 9-fluorenmethoxycarbonyl, methoxycarbonyl or ethoxycarbonyl; the acyl protecting group is selected from acetyl, benzoyl, p-methoxybenzylcarbonyl, acetyl, toluenesulfonyl, p-nitrobenzenesulfonyl, p-toluenesulfonyl or trifluoroacetyl; and the silyl protecting group is selected from tert-butyldimethylsilyl or (trimethylsilyl)ethoxymethyl.

[0255] In a further preferred embodiment of the present invention, the deprotecting agent is selected from one or a combination of hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoroacetic acid, p-toluenesulfonic acid, 2,3-dichloro-5,6-dicyanobenzoquinone, cerium ammonium nitrate, tetra(triphenylphosphine)palladium / phenylsilane, mercaptoacetic acid, pyrrolidine, palladium on carbon, palladium hydroxide, ethylamine, triethylamine, N,N-diisopropylethylamine, piperidine, triisopropylamine, pyridine, tetrabutylammonium fluoride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, or sodium carbonate.

[0256] In a further preferred embodiment of the present invention, the reaction is carried out in water or an organic solvent selected from one or more of 1,4-dioxane, methanol, ethanol, propanol, butanol, acetone, tetrahydrofuran, diethyl ether, propyl ether, ethylene glycol monoethyl ether, ethyl acetate, dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, butanone, acetonitrile, or toluene.

[0257] This invention also provides a method for preparing a compound of general formula (IX-c), its stereoisomer, or a pharmaceutically acceptable salt thereof, which is prepared from a compound of general formula (IX-d) by a reduction reaction:

[0258] In a preferred embodiment of the present invention, the reducing agent is selected from one or a combination of the following: boran dimethyl sulfide, boran tetrahydrofuran, boran N,N-diethylaniline, catechol borane, 9-boronbicyclo[3.3.1]nonane, lithium aluminum hydride, trimethoxy lithium aluminum hydride, tritert-butoxy lithium aluminum hydride, triethylaluminum / sodium hydride, sodium borohydride, aluminum isopropoxide, diisobutylaluminum hydride, methyldimethoxysilane, n-butyldimethylsilane, triisopropylsilane, phenylmethylsilane, triethylsilane, or trimethoxysilane, sodium cyanoborohydride, or sodium triacetoxyborohydride.

[0259] In a further preferred embodiment of the invention, the reaction is carried out under an amino-protecting agent selected from di-tert-butyl dicarbonate, p-toluenesulfonyl chloride, benzyl chloroformate, benzyloxycarbonyl chloride, allyloxycarbonyl chloride, trifluoroacetic anhydride, benzyl bromide, 2,4-dimethoxybenzyl chloride, fluorenemethoxycarbonyl chloride, acetic anhydride, acetyl chloride, benzoyl chloride, methanesulfonyl chloride, o-nitrobenzenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride. The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0260] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0261] 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.

[0262] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0263] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0264] In some embodiments of the invention, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof may be administered by any convenient method, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0265] In some embodiments of the invention, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0266] The present invention further relates to any of the compounds of the general formula shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical compositions thereof in the preparation of medicaments for treating diseases related to M4.

[0267] The present invention further relates to the use of compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, Parkinson's disease or symptoms, Parkinson's disease-levodopa-induced motor disorders, Huntington's disease, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down syndrome, cerebral amyloid angiopathy, dementia, hereditary Dutch amyloid hemorrhage, Creutzfeldt-Jakob disease, prions, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis, more preferably in the preparation of medicaments for treating Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders.

[0268] The present invention further relates to compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in methods for preparing medicaments for treating M4-related and related diseases.

[0269] This invention also relates to a method for treating, preventing, and / or treating diseases associated with M4, comprising administering to a patient a therapeutically effective dose of a compound of the general formula, its stereoisomers, 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, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1... mg / day, 2mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 80mg / day, 100mg / day, 125mg / day, 150mg / day, 160mg / day, 200mg / day, 300mg / day, 320mg / day, 400mg / day, 480mg / day, 600mg / day, 640mg / day, 800mg / day, 1000mg / day.

[0270] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to M4.

[0271] The present invention also relates to a method for treating M4-related diseases in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0272] The compounds prepared by this invention have high M4 agonist activity and selectivity, high solubility and permeability, and Ks can reach more than 250 μM in PBS solution at pH 7.4. Furthermore, they have higher plasma freeness and brain exposure.

[0273] Detailed description of the invention

[0274] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0275] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0276] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0277] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0278] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0279] wait;

[0280] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0281] wait.

[0282] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0283] wait.

[0284] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0285] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0286] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; even more preferably, it contains a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0287] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0288] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include: wait.

[0289] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the 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 selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include: wait.

[0290] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m(where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: wait.

[0291] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0292] wait.

[0293] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0294] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0295] The ring connected to the parent structure is an aryl ring, and non-limiting examples include: wait.

[0296] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0297] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: wait.

[0298] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0299] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0300] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0301] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0302] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0303] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, which is a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located anywhere within the alkenyl group. Alkenyl groups have a carbon density of 2 to 20 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkenyl groups include: The alkenyl group described therein may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0304] "Alynyl" refers to (CH≡C-) that contains at least one carbon-carbon triple bond, which can be located anywhere within the alkynyl group, and at least one carbon-carbon double bond, which can be located anywhere within the alkenyl group. The alkynyl group has 2 to 20 carbon atoms. 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 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkynyl groups include: The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0305] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0306] "Hydroxy" refers to the -OH group.

[0307] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0308] "Amino" refers to -NH2.

[0309] “Cyano” refers to -CN.

[0310] "Nitro" refers to -NO2.

[0311] "Carbonyl" refers to -C(O)-.

[0312] "Carboxyl group" refers to -C(O)OH.

[0313] "THF" refers to tetrahydrofuran.

[0314] “MeOH” refers to methanol.

[0315] "DMF" refers to N,N-dimethylformamide.

[0316] "TFA" refers to trifluoroacetic acid.

[0317] 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.

[0318] 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.

[0319] "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.

[0320] 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.

[0321] "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, unless otherwise specified. The type and number of substituents can be arbitrary on a chemically feasible basis, for example, five, or one to three hydrogen atoms independently replaced by the corresponding number of substituents. 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).

[0322] 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.

[0323] "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.

[0324] "Pharmaceutical acceptable salt" or "medicinal salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0325] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers".

[0326] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers and compounds enriched with enantiomers / non-corresponding isomers / stereoisomers.

[0327] "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.

[0328] "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%.

[0329] "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.

[0330] "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.

[0331] 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

[0332] Example

[0333] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0334] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0335] HPLC determinations were 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 C18 150×4.6mm column).

[0336] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0337] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0338] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0339] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0340] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0341] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0342] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0343] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0344] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0345] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0346] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0347] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0348] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0349] The eluent systems for column chromatography and the developing solvent systems for thin-layer chromatography used to purify the compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0350] Reference example 1

[0351] 1-(2-chloro-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0352] first step

[0353] 1-(2-chloro-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0354] 2-Chloro-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine 1A (50 mg, 0.29 mmol) was dissolved in 2.0 mL of N,N-dimethylformamide. Then, 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)acetic acid (77 mg, 0.29 mmol, prepared by the known method "Patent WO2018002760"), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (168 mg, 0.44 mmol), and diisopropylethylamine (114 mg, 0.88 mmol) were added sequentially to the reaction system. The reaction was carried out at 25°C for 2 hours. Add 10 mL of water to the reaction solution, extract with ethyl acetate (10 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (10 mL × 2), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high-performance liquid chromatography to give title product 1 (35 mg, yield: 28.9%). MS m / z (ESI): 412.2 [M+1]

[0355] Reference example 2

[0356] 1-(5,6-dimethyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0357] first step

[0358] 6,7-Dimethyl-4-oxo-1,3,4,5-tetrahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester

[0359] Polyphosphate (100 g) was added to a mixture of 2a (5 g, 23.8 mmol) and 2-butanone (20 mL) at 100 °C, and the mixture was then heated to 120 °C and stirred for 4 hours. After the reaction mixture was cooled to 15 °C, it was quenched with water (1.5 L), and the pH of the mixture was adjusted to 10-11 with the addition of solid sodium hydroxide. Di-tert-butyl dicarbonate (10 g, 45.8 mmol) was added, and the reaction mixture was stirred overnight at 15 °C. After the reaction was complete, the mixture was filtered. The collected solid was washed successively with water (7 x 50 mL), and a mixture of tert-butyl methyl ether and petroleum ether (1:1, 7 x 40 mL) to give crude product 2b. MS m / z (ESI): 265.3 [M+1].

[0360] Step 2

[0361] 6,7-Dimethyl-4-((trifluoromethyl)sulfonyl)oxy-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester

[0362] Triethylamine (25 g, 25 mmol) and trifluoromethanesulfonic anhydride (5.9 g, 21 mmol) were added separately to a solution of 2b (5 g, 19 mmol) in dichloromethane (200 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours, then quenched with water (5 mL) and extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Compound 2c (4 g, yield: 58%) was given by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5:1). MS m / z (ESI): 397.4.

[0363] Step 3

[0364] 4-(diphenylmethylene)amino)-6,7-dimethyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester was added to a 2c (9.2 g, 23.2 mmol) solution of toluene (100 mL) containing 1,1-diphenylmethyleneimine (6.31 g, 34.8 mmol), palladium acetate (521 mg, 2.32 mmol), 1,1'-binaphthyl-2,2'-dimethylbis(diphenylphosphine) (BINAP; 1.45 g, 2.33 mmol) and cesium carbonate (11.3 g, 34.7 mmol). The mixture was heated at 100 °C for 16 hours, then filtered, and the filtrate was concentrated under vacuum to obtain crude product 2d, which was directly used in the next reaction. MS m / z (ESI): 428.6.

[0365] Step 4

[0366] 4-Amino-6,7-dimethyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester

[0367] Sodium acetate (4.0 g, 48.8 mmol) and hydroxylamine hydrochloride (3.39 g, 48.8 mmol) were added to a methanol (100 mL) solution of crude product 2d. The reaction mixture was stirred at room temperature for 72 hours. It was then filtered and the filtrate was concentrated under reduced pressure. Recrystallization from ethyl acetate gave 2e (5 g, yield: 82%). MS m / z (ESI): 264.3.

[0368] Step 5

[0369] (E)-4-(((dimethylamino)methylene)amino)-6,7-dimethyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester

[0370] At room temperature, 1,1-dimethoxy-N,N-dimethylimine (1.63 g, 13.68 mmol) was added to a 10 mL solution of toluene in product 2e. The reaction mixture was heated under reflux for 2 h and then cooled to room temperature. The crude product 2f was directly concentrated and used directly in the next step. MS m / z (ESI): 319.4.

[0371] Step 6

[0372] (E)-4-(N'-hydroxyformamido)-6,7-dimethyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester was prepared by adding 6.6 g (94.3 mmol) of hydroxylamine hydrochloride to a 20 mL methanol solution at room temperature, refluxing the reaction mixture for 1 h, and then cooling to room temperature. The reaction mixture was quenched with 15 mL of water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then directly concentrated to give 2 g of crude product, which could be used directly in the next step. MS m / z (ESI): 307.4.

[0373] Step 7

[0374] 5,6-Dimethyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid tert-butyl ester

[0375] At 0 °C, trifluoroacetic anhydride (0.83 g, 3.93 mmol) was added to 2 g of THF (20 mL), and the reaction mixture was stirred overnight at room temperature, then concentrated. The product was purified by silica gel chromatography (gradient: 33% to 100% ethyl acetate / petroleum ether) to give 2 h (450 mg, yield 42%), MS m / z (ESI): 289.

[0376] Step 8

[0377] 5,6-Dimethyl-8,9-dihydro-7H-pyrrolo[3,4-c][1,2,4]triazolo[1,5-a]pyridine

[0378] At 0 °C, a solution of ethyl acetate (4 M, 10 mL) containing hydrogen chloride was added to a 142 h (450 mg, 1.56 mmol) solution of ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure to give product 2i (300 mg, 85% yield), MS m / z (ESI): 189.2.

[0379] Step 9

[0380] 1-(5,6-dimethyl-7,9-dihydro-8H-pyrrolo[3,4-c][1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0381] Reference Example 2 was obtained by referring to the synthesis method of Reference Example 1. MS m / z(ESI): 431.4.

[0382] See Example 3

[0383] 1-(8-methyl-1,2,3,5,6,7-hexahydrocyclopentano[1,2-e]pyrrolo[4,3-b]pyridin-2-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azacyclobut-3-yl}ethyl-1-one

[0384] first step

[0385] 2-Hydroxy-4-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-3-carboxynitrile

[0386] Compound 3a (5 g, 39.63 mmol) was dissolved in 100 mL of ethanol, followed by the addition of cyanoacetamide (3.33 g, 39.63 mmol) and piperidine (3.37 g, 39.63 mmol). The mixture was then refluxed at 80 °C with stirring for 12 hours. The reaction solution was cooled to room temperature, resulting in the precipitation of a large amount of solid. The solid was filtered under reduced pressure, and the filter cake was washed with ice-cold ethanol (10 mL × 3). The filter cake was collected and dried under reduced pressure to give the title product 3b (3.4 g, yield: 49.2%). MS m / z (ESI): 175.1 [M+1]

[0387] Step 2

[0388] 2-Bromo-4-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-3-carboxylonitrile

[0389] Compound 3b (1 g, 5.74 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL), and phosphorus tribromooxy (1.62 g, 9.69 mmol, 1.46 mL) was added under nitrogen protection. The mixture was then heated to 90 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (20 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 using eluent system B to give the title product 3c (700 mg, yield: 51.4%). MS m / z (ESI): 237.0 [M+1]

[0390] Step 3

[0391] methyl 3-cyano-4-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-2-carboxylate

[0392] Compound 3c (700 mg, 2.95 mmol) was dissolved in a mixed solvent of methanol (7 mL) and N,N-dimethylformamide (7 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (241 mg, 0.30 mmol) and triethylamine (596 mg, 5.90 mmol) were added sequentially. The mixture was purged three times with carbon monoxide gas, and then stirred at 100 °C for 12 hours under a carbon monoxide balloon atmosphere (~15 psi). The reaction solution was cooled to room temperature, and saturated ammonium chloride solution (70 mL) and ethyl acetate (40 mL) were added. Insoluble matter was removed by diatomaceous earth filtration. The mixture was separated, and the organic phase 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 using eluent system B to give the title product 3d (400 mg, yield: 62.7%). MS m / z(ESI): 217.1 [M+1]

[0393] Step 4

[0394] 8-Methyl-1,2,3,5,6,7-hexahydrocyclopentano[1,2-e]pyrrolo[4,3-b]pyridin-3-one

[0395] Compound 3d (400 mg, 2.95 mmol) was dissolved in anhydrous methanol (8 mL). Nickel dichloride hexahydrate (1.40 g, 5.90 mmol) and sodium borohydride (1.12 g, 29.50 mmol) were added sequentially under ice bath conditions. The mixture was then stirred at 25 °C for 1 hour. Triethylamine (894 mg, 8.85 mmol, 1.23 mL) was added, and the mixture was heated to 50 °C and stirred for another 12 hours. The reaction mixture was cooled to room temperature, and saturated ammonium chloride solution (80 mL) and ethyl acetate (40 mL) were added. Insoluble matter was removed by diatomaceous earth filtration. The mixture was separated, and the organic phase 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 using eluent system B to give the title product 3e (200 mg, yield: 57.5%).

[0396] MS m / z(ESI): 189.1 [M+1]

[0397] Step 5

[0398] 8-Methyl-1,2,3,5,6,7-hexahydrocyclopentano[1,2-e]pyrrolo[4,3-b]pyridine

[0399] Compound 3e (200 mg, 1.91 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL). A dimethyl sulfide solution of borane (2 M, 4 mL) was added under nitrogen protection. The mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooled to 0 °C, and the reaction was quenched by adding anhydrous methanol (4 mL). Concentrated hydrochloric acid (12 M, 2 mL) was added, and the mixture was heated to 70 °C and stirred for 12 hours. The reaction mixture was cooled again to 20 °C, and sodium hydroxide solution (2 M, 12 mL) was slowly added to adjust the pH to >8. The mixture was diluted with water (40 mL), extracted with ethyl acetate (20 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 using eluent system B to give the title product 3f (100 mg, yield: 54.1%). MS m / z (ESI): 175.1 [M+1]

[0400] Step 6

[0401] 1-(8-methyl-1,2,3,5,6,7-hexahydrocyclopentano[1,2-e]pyrrolo[4,3-b]pyridin-2-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azacyclobut-3-yl}ethyl-1-one

[0402] Compound 3f (100 mg) and compound {1-[2-(trifluoromethyl)pyridin-4-yl]azacyclobut-3-yl}acetic acid (100 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL). Triethylamine (100 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (100 mg) were added sequentially at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (0.1% formic acid / acetonitrile / water) to give the title product Reference Example 3 (20 mg). MS m / z (ESI): 417.2 [M+1];

[0403] 1 H NMR(400MHz, CDCl3)δ8.26(d,1H),6.58(t,1H),6.35(dd,1H),4.80(d,2H),4.74(d,2H),4.29(td,2H ),3.78(dt,2H),3.33(q,1H),3.05(q,2H),2.90(t,2H),2.83(t,2H),2.23(d,3H),2.20–2.13(m,2H).

[0404] Example 1

[0405] 1-(6,7-dimethyl-2,3,3a,5-tetrahydropyrrolo[2,3,4-de][1,8]naphthylpyridin-4(1H)-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0406] Example 1 was obtained by referring to the synthesis method of Reference Example 2. MS m / z (ESI): 432.5.

[0407] Example 2

[0408] 1-(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)ethyl-1-one

[0409] first step

[0410] 2-(azacyclobutane-3-yl)methyl acetate hydrochloride

[0411] 5 g (21.81 mmol) of tert-butyl 3-(2-methoxy-2-oxoethyl)azacyclobutane-1-carboxylate 2A was dissolved in 50 mL of 1,4-dioxane, and 21.8 mL of 4 M dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 2B (3.61 g, yield: 100%). MS m / z (ESI): 130.1 [M+1].

[0412] Step 2

[0413] 2-[1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl]methyl acetate

[0414] 2-Chloro-5-(trifluoromethyl)pyrimidine (300 mg, 1.64 mmol) and 2B (561.7 mg, 2.14 mmol) were dissolved in 7 mL of 1-methylpyrrolidone, and potassium carbonate (681.4 mg, 4.93 mmol) was added. The mixture was stirred at 70°C for 16 hours. After cooling to room temperature, 70 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (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 the title product 2C (380 mg, yield: 84.0%). MS m / z (ESI): 276.2 [M+1].

[0415] Step 3

[0416] 2-[1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl]acetic acid

[0417] 2C (380 mg, 1.38 mmol) was dissolved in 14 mL of tetrahydrofuran, and potassium trimethylsilanolate (531.4 mg, 4.14 mmol) was added. The mixture was stirred at 25°C for 2 hours. The pH of the reaction solution was adjusted to 4 with 1N dilute hydrochloric acid, and the extract was obtained with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2D (300 mg, yield: 29.7%). MS m / z (ESI): 262.0 [M+1].

[0418] Step 4

[0419] 2-Hydroxy-4-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-3-carboxynitrile

[0420] Compound 2E (5 g, 39.63 mmol) was dissolved in 100 mL of ethanol, and cyanoacetamide (3.33 g, 39.63 mmol) and piperidine (3.37 g, 39.63 mmol) were added sequentially. The mixture was stirred at 80°C for 12 hours. After cooling the reaction solution to room temperature, a large amount of solid precipitated. The mixture was filtered under reduced pressure, and the filter cake was washed with ice-cold ethanol (10 mL × 3). The filter cake was dried under reduced pressure to give the title product 2F (3.4 g, yield: 49.2%). MS m / z (ESI): 175.1 [M+1].

[0421] Step 5

[0422] 2-Bromo-4-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-3-carboxylonitrile

[0423] Compound 2F (1 g, 5.74 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL), and phosphorus tribromooxy (1.62 g, 9.69 mmol) was added under nitrogen protection. The mixture was heated to 90 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 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 2G (700 mg, yield: 51.4%). MS m / z (ESI): 237.0 / 239.0 [M+1].

[0424] Step 6

[0425] methyl 3-cyano-4-methyl-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-2-carboxylate

[0426] Compound 2G (700 mg, 2.95 mmol) was dissolved in a mixed solvent of methanol (7 mL) and N,N-dimethylformamide (7 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (241 mg, 0.3 mmol) and triethylamine (821 μL, 5.9 mmol) were added sequentially. The mixture was purged three times with carbon monoxide gas, and the reaction mixture was stirred at 100°C for 12 hours under a carbon monoxide balloon. After cooling to room temperature, a saturated ammonium chloride solution (70 mL) and ethyl acetate (40 mL) were added. Insoluble matter was removed by diatomaceous earth filtration. The mixture was separated, and the organic phase was washed with a saturated sodium chloride solution (30 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 2H (400 mg, yield: 62.7%). MS m / z (ESI): 217.1 [M+1].

[0427] Step 7

[0428] 8-Methyl-1,2,3,5,6,7-hexahydrocyclopentano[1,2-e]pyrrolo[4,3-b]pyridin-3-one

[0429] Compound 2H (400 mg, 2.95 mmol) was dissolved in anhydrous methanol (8 mL). Nickel dichloride hexahydrate (1.40 g, 5.9 mmol) and sodium borohydride (1.12 g, 29.5 mmol) were added sequentially under ice bath conditions. The mixture was stirred at 25°C for 1 hour. Triethylamine (1.23 mL, 8.85 mmol) was then added, and the mixture was heated to 50°C and stirred for another 12 hours. After cooling to room temperature, a saturated ammonium chloride solution (80 mL) and ethyl acetate (40 mL) were added. Insoluble matter was removed by diatomaceous earth filtration. The mixture was separated, and the organic phase 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 using eluent system B to give the title product 2I (200 mg, yield: 57.5%). MS m / z (ESI): 189.1 [M+1].

[0430] Step 8

[0431] 8-Methyl-1,2,3,5,6,7-hexahydrocyclopentano[1,2-e]pyrrolo[4,3-b]pyridine

[0432] Compound 2I (200 mg, 1.91 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL). A dimethyl sulfide solution of borane (2 M, 4 mL) was added under nitrogen protection, and the mixture was stirred at 70°C for 12 hours. The reaction mixture was cooled to 0°C, and the reaction was quenched by adding anhydrous methanol (4 mL). Concentrated hydrochloric acid (12 M, 2 mL) was then added, and the mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to 0°C again, and sodium hydroxide solution (2 M, 12 mL) was slowly added to adjust the pH to >8. The mixture was diluted with water (40 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 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 2J (100 mg, yield: 54.1%). MS m / z (ESI): 175.1 [M+1].

[0433] Step 9

[0434] 1-(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane)

[0435] -3-yl)ethyl-1-one

[0436] Compounds 2J (100 mg, 573.9 μmol) and 2D (149.9 mg, 573.9 μmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL), followed by the sequential addition of N,N-diisopropylethylamine (300 μL, 1.72 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (261.9 mg, 688.7 μmol). The mixture was stirred at 25°C for 1 h. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give title product 2 (55.6 mg, yield: 23.2%). MS m / z (ESI): 418.2 [M+1].

[0437] Example 3

[0438] 1-(5-methyl-3,6,7,8-tetrahydrocyclopentan[d]pyrrolo[3,4-b]pyridin-2(1H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)ethyl-1-one

[0439] Example 3 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 393.5.

[0440] Example 4

[0441] 1-(3,4-Dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0442] first step

[0443] Methyl 3-chloro-2,4-dioxolane

[0444] Methyl 2,4-dioxolane 4A (40 g, 277.5 mmol) was dissolved in 320 mL of dichloromethane, and sulfonyl chloride (29.2 mL, 360.8 mmol) was added dropwise. The mixture was stirred at 25°C for 2 hours. The reaction solution was washed with water (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 4B (32 g, yield: 64.6%). MS m / z (ESI): 179.0 [M+1].

[0445] 1H NMR (400MHz, CDCl3) δ14.43 (s, 1H), 5.36 (d, J = 54.4Hz, 1H), 3.95–3.88 (m, 6H), 2.50–2.24 (m, 6H).

[0446] Step 2

[0447] methyl 3-chloro-2-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylate

[0448] 4B (32 g, 179.2 mmol) was dissolved in 500 mL of acetic acid, and 3-amino-2-cyclohexen-1-one (19.92 g, 179.2 mmol) was added. The mixture was stirred at 120 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to greater than 7 by adding 300 mL of saturated sodium bicarbonate aqueous solution. The residue was extracted with dichloromethane (150 mL × 2), and the organic phases were combined. The residue was washed with saturated brine (400 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 4C (20.32 g, yield: 44.7%). MS m / z (ESI): 254.1 [M+1].

[0449] Step 3

[0450] 2,3-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acid methyl ester

[0451] A mixture of 4C (20.32 g, 80.1 mmol), 3.5 M trimethylcyclotriboroxane tetrahydrofuran solution (68.66 mL, 240.3 mmol), potassium carbonate (33.21 g, 240.30 mmol), 100 mL of 1,4-dioxane, and 100 mL of water was added to [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (2.59 g, 4.0 mmol). The mixture was stirred at 110 °C for 16 hours. 500 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine (1000 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 4D (18.6 g, yield: 99.6%). MS m / z(ESI): 234.1 [M+1].

[0452] Step 4

[0453] 3,4-Dimethyl-6,7-dihydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0454] 4D (18.6 g, 79.74 mmol) and ammonium acetate (18.44 g, 239.22 mmol) were dissolved in 160 mL of tetrahydrofuran, and ethyl titanate (72.76 g, 318.95 mmol) was added. The mixture was stirred at 80°C for 16 hours. 74 g of N,N,N',N'-tetra(2-hydroxyethyl)ethylenediamine was added to the reaction mixture, and the mixture was stirred at 65°C for 0.5 hours. Then, 500 mL of water and 300 mL of ethyl acetate were added to dilute the mixture, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filter cake was dried under reduced pressure to give the title product 4E (6.81 g, yield: 42.7%).

[0455] MS m / z(ESI): 201.1 [M+1].

[0456] Step 5

[0457] 3,4-Dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0458] 4E (6 g, 29.96 mmol) was dissolved in 300 mL of methanol, and 10% palladium on carbon (637.8 mg, 599.3 μmol) was added. After purging with hydrogen three times, the mixture was stirred for 2 hours in a hydrogen balloon at 25°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 4F (6.06 g, yield: 100%). MS m / z (ESI): 203.1 [M+1].

[0459] Step 6

[0460] 3,4-Dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0461] 4F (6.06 g, 29.96 mmol) was dissolved in 20 mL of tetrahydrofuran. 2M boron dimethyl sulfide solution (75 mL, 150 mmol) was added under ice bath conditions, and the mixture was stirred at 80°C for 12 hours. The reaction was quenched by adding 20 mL of methanol under ice bath conditions. 40 mL of 6 mol / L hydrochloric acid was added, and the mixture was stirred at 70°C for 0.5 hours. After cooling to room temperature, the pH was adjusted to greater than 10 with 6 mol / L sodium hydroxide (50 mL). Di-tert-butyl dicarbonate (13.8 mL, 59.93 mmol) was added, and the mixture was stirred at 25°C for 1 hour. 100 mL of water was added to the reaction mixture, 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 A to give the title product 4G (3.92 g, yield: 45.4%). MS m / z(ESI): 289.2 [M+1].

[0462] Step 7

[0463] 3,4-Dimethyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0464] 4 g (60 mg, 208.1 μmol) was dissolved in 2 mL of 1,4-dioxane, and 0.5 mL (2.1 mmol) of 4 M dioxane chloride solution was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to give the title product 4H (50.0 mg, yield: 92.0%). MS m / z (ESI): 189.1 [M+1].

[0465] Step 8

[0466] 1-(3,4-Dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0467] 2-[1-[2-(trifluoromethyl)-4-pyridyl]azacyclobutan-3-yl]acetic acid (59.8 mg, 229.7 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (87.4 mg, 229.7 μmol) were dissolved in 2 mL of N,N-dimethylformamide. Triethylamine (102 μL, 574.3 μmol) and 4H (50.0 mg, 191.4 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give title product 4 (26.5 mg, yield: 32.2%).

[0468] MS m / z(ESI): 431.2 [M+1]. 1 H NMR(400MHz,d6)δ8.23(d,J=5.9Hz,1H),6.80(s,1H),6.61–6.53(m,1H),5.19–4.89(m,2H),4.83–4.67(m,1H),4.23(q,J=8.2Hz,2H),3.7 6–3.74(m,2H),3.16–3.04(m,2H),2.95–2.82(m,3H),2.64(s,3H),2.28(s,3H),2.19–2.05(m,1H),2.00–1.82(m,1H),1.41–1.10(m,2H).

[0469] Example 5

[0470] 1-(6-methyl-1,2a,3,4-tetrahydro-2H-2,7-diazacyclopentadien[cd]inden-2-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0471] first step

[0472] 1-Methoxy-3-methyl-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one

[0473] 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (1.72 g, 2.35 mmol) was added to a mixture of 80 mL of 1,4-dioxane and 20 mL of water in a solution of 3-chloro-1-methoxy-5,6-dihydro-7H-cyclopentadienzo[c]pyridin-7-one 5A (4.64 g, 23.48 mmol), 3.5 M trimethylcyclotriboroxane tetrahydrofuran solution (8.05 mL, 28.18 mmol), potassium carbonate (6.49 g, 46.96 mmol), and potassium carbonate. The mixture was stirred at 110°C for 16 hours. Add 100 mL of water to the reaction solution, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated brine (250 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 the title product 5B (3.8 g, yield: 91.3%).

[0474] MS m / z(ESI): 178.1 [M+1].

[0475] Step 2

[0476] 4-Methyl-6,7-dihydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0477] 5B (3.8 g, 21.44 mmol) and sodium iodide (9.64 g, 64.33 mmol) were dissolved in 50 mL of acetonitrile, and trimethylchlorosilane (8.2 mL, 64.33 mmol) was added. The mixture was stirred at 80°C for 16 hours. After adding 50 mL of saturated sodium sulfite aqueous solution to the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give the title product 5C (2.5 g, yield: 71.4%). MS m / z (ESI): 164.1 [M+1].

[0478] Step 3

[0479] 1-Chloro-3-methyl-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one

[0480] 5C (2.5 g, 15.32 mmol) was dissolved in 30 mL of phosphorus oxychloride and stirred at 90 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) were added to the residue. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (250 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 5D (2.2 g, yield: 79.1%). MS m / z (ESI): 182.1 [M+1]

[0481] Step 4

[0482] N-(1-Chloro-3-methyl-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-2-methylpropane-2-sulfinamide

[0483] 5D (2.2 g, 12.11 mmol) and tert-butylsulfonamide (2.2 g, 18.17 mmol) were dissolved in 60 mL of tetrahydrofuran, and ethyl titanate (10.1 mL, 48.45 mmol) was added. The mixture was stirred at 80°C for 16 hours. Under ice bath conditions, sodium borohydride (916.5 mg, 24.23 mmol) and 10 mL of methanol were added sequentially, and the mixture was stirred at 25°C for 1 hour. 100 mL of saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (250 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 5E (2.8 g, yield: 80.6%). MS m / z (ESI): 287.1 [M+1].

[0484] Step 5

[0485] 1-Chloro-3-methyl-6,7-dihydro-5H-cyclopentadieno[c]pyridine-7-amine dihydrochloride

[0486] 5E (2.8 g, 9.76 mmol) was dissolved in 25 mL of methanol and added to a 4 M dioxane chloride solution (25 mL, 100 mmol). The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to give the title product 5F (2.49 g, yield: 99.8%).

[0487] MS m / z(ESI): 183.1 [M+1].

[0488] Step 6

[0489] N-(1-Chloro-3-methyl-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-4-nitrobenzenesulfonamide

[0490] 5F (2.49 g, 9.74 mmol) and pyridine (2.36 mL, 29.23 mmol) were dissolved in 50 mL of dichloromethane, and 4-nitrobenzenesulfonyl chloride (2.59 g, 11.69 mmol) was added. The mixture was stirred at 25°C for 12 hours. 50 mL of water was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (150 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 5G (2.6 g, yield: 72.6%). MS m / z (ESI): 368.1 [M+1].

[0491] Step 7

[0492] N-(1-Cyano-3-methyl-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-4-nitrobenzenesulfonamide

[0493] 5g (2.6g, 7.07mmol), zinc cyanide (1.66g, 14.14mmol), and 1,1'-bis(diphenylphosphine)ferrocene (1.57g, 2.83mmol) were dissolved in 50mL of N,N-dimethylformamide solution. Tris(dibenzylacetone)dipalladium (647.3mg, 706.9μmol) was added, and the mixture was stirred at 90°C for 16 hours. 500mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200mL × 3). The organic phases were combined, washed with saturated brine (500mL), 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 5H (1.7g, yield: 67.1%). MS m / z (ESI): 359.1 [M+1].

[0494] Step 8

[0495] 3-Methyl-7-((4-nitrophenyl)sulfonylamino)-6,7-dihydro-5H-cyclopentadien[c]pyridine-1-carboxylic acid ethyl ester

[0496] 5H (1.7 g, 4.74 mmol) was dissolved in 20 mL of ethanol, and 12 mL (2.1 mmol) of 4 M dioxane chloride solution was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give the title product 5I (1.2 g, yield: 62.4%).

[0497] MS m / z(ESI): 406.1 [M+1].

[0498] Step 9

[0499] 3-Bromo-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0500] 5I (1.2 g, 2.96 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.77 mL, 11.84 mmol) were dissolved in 20 mL of acetonitrile, and mercaptoacetic acid (0.41 mL, 5.92 mmol) was added. The mixture was stirred at 25°C for 2 hours. 50 mL of saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was 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. The residue was purified by silica gel column chromatography using eluent system A to give the title product 5J (475 mg, yield: 92.1%). MS m / z (ESI): 175.1 [M+1].

[0501] Step 10

[0502] 6-Methyl-1,2a,3,4-tetrahydro-2H-2,7-diazacyclopentadien[cd]indene-2-carboxylic acid tert-butyl ester

[0503] 5 J (400 mg, 2.3 mmol) was dissolved in 10 mL of tetrahydrofuran, and 2 M borane dimethyl sulfide solution (2.3 mL, 4.59 mmol) was added. The mixture was stirred at 70°C for 2 hours. The reaction was quenched by adding 1 mL of methanol to the reaction solution under ice bath conditions. Then, 1 mL of 1 mol / L dilute hydrochloric acid was added, and the mixture was stirred for 0.5 hours. Next, 2 mL of 1 mol / L sodium hydroxide and 791 μL of ditert-butyl dicarbonate (3.44 mmol) were added sequentially, and the mixture was stirred at 25°C for 2 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (40 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 5K (356 mg, yield: 59.6%).

[0504] MS m / z(ESI): 261.1 [M+1].

[0505] Step 11

[0506] 6-Methyl-2,2a,3,4-tetrahydro-1H-2,7-diazacyclopentadien[cd]indene dihydrochloride

[0507] 5 K (50 mg, 192.1 μmol) was dissolved in 2 mL of 1,4-dioxane, and 0.48 mL (1.92 mmol) of 4 M dioxane chloride solution was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to give 5 L (44.0 mg, yield: 98.3%) of the title product. MS m / z (ESI): 161.1 [M+1].

[0508] Step Twelve

[0509] 1-(6-methyl-1,2a,3,4-tetrahydro-2H-2,7-diazacyclopentadien[cd]inden-2-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0510] 2-[1-[2-(trifluoromethyl)-4-pyridyl]azacyclobutan-3-yl]acetic acid (40.2 mg, 154.4 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (58.7 mg, 154.4 μmol) were dissolved in 1.5 mL of N,N-dimethylformamide. Triethylamine (69 μL, 386.0 μmol) and 5 L (30.0 mg, 128.7 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. 15 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give title product 5 (15.2 mg, yield: 29.4%). MS m / z(ESI): 403.1 [M+1]

[0511] Example 6

[0512] (S)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one and (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0513] first step

[0514] (S)-3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester and (R)-3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0515] Compound 4G (670 mg, 2.32 mmol) was resolved 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:DEA = 70:30:0.1%; run time (min): 12; linear mode: isocratic) to give title product 6A-P1 (257 mg, RT (retention time) = 5.413 min, yield: 38.4%) and title product 6A-P2 (252 mg, RT (retention time) = 6.010 min, yield: 37.6%). MS m / z (ESI): 289.1 [M+1]

[0516] Step 2

[0517] (S)-3,4-dimethyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride and

[0518] (R)-3,4-Dimethyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0519] 6A-P1 (257 mg, 891.2 μmol) was dissolved in 5 mL of methanol, and 4 M 1,4-dioxane hydrochloride solution (4 M, 5.14 mL) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 6B-P1 (232 mg, yield: 99.7%). MS m / z (ESI): 189.1 [M+1]

[0520] 6A-P2 (252 mg, 873.8 μmol) was dissolved in 5 mL of methanol, and 4 M 1,4-dioxane hydrochloride solution (4 M, 5.04 mL) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 6B-P2 (228 mg, yield: 99.9%). MS m / z (ESI): 189.1 [M+1]

[0521] Step 3

[0522] (S)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)ethane-1-one and

[0523] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)ethane-1-one

[0524] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (232 mg, 888.2 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (402.1 mg, 1.07 mmol) were dissolved in 8 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (464 μL, 2.66 mmol) and 6B-P1 (232 mg, 888.2 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 20 mL of water to the reaction solution, extract with dichloromethane (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high-performance liquid chromatography to give the title product 6-P1 (326.4 mg, yield: 84.4%). MS m / z (ESI): 432.2 [M+1]

[0525] 1 H NMR(400MHz, DMSO-d6)δ8.67(s,2H),5.18–4.90(m,2H),4.83–4.68(m,1H),4.36–4.21(m,2H),3.93–3.80(m,2H),3.16–3. 05(m,2H),3.01–2.75(m,4H),2.64(s,3H),2.29(d,J=3.6Hz,3H),2.20–2.07(m,1H),2.00–1.80(m,1H),1.43–1.11(m,1H).

[0526] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (228 mg, 872.9 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (395.2 mg, 1.05 mmol) were dissolved in 8 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (456 μL, 2.62 mmol) and 6B-P2 (228 mg, 872.9 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 20 mL of water to the reaction solution, extract with dichloromethane (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high-performance liquid chromatography to give the title product 6-P2 (311.2 mg, yield: 80.5%). MS m / z (ESI): 432.2 [M+1]

[0527] 1 H NMR(400MHz,DMSO-d6)δ8.67(s,2H),5.14–4.86(m,2H),4.80–4.67(m,1H),4.34–4.18(m,2H),3.94–3.76(m,2H),3.1 5–3.04(m,2H),3.02–2.77(m,4H),2.63(s,3H),2.28(s,3H),2.19–2.04(m,1H),2.00–1.81(m,1H),1.33–1.22(m,1H).

[0528] Example 7

[0529] 1-(6-methyl-1,2a,3,4-tetrahydro-2H-2,7-diazacyclopentane[cd]inden-2-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acetoone

[0530] Example 7 was obtained by referring to the synthesis method of Example 5. MS m / z (ESI): 404.4.

[0531] Example 8

[0532] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(6-ethoxypyridin-3-yl)azacyclobutane-3-yl)ethyl-1-one

[0533] Following the synthesis method of Example 6-P2, Example 8 was obtained using 6A-P2 as the starting material. MS m / z (ESI): 407.5.

[0534] Example 9

[0535] 2-(1-(6-ethoxypyridin-3-yl)azacyclobutane-3-yl)-1-(6-methyl-1,2a,3,4-tetrahydro-2H-2,7-diazacyclopentane[cd]inden-2-yl)acetoone

[0536] Example 9 was obtained by referring to the synthesis method of Example 5. MS m / z (ESI): 379.5.

[0537] Example 10

[0538] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(1-methyl-1H-indazol-5-yl)azacyclobutane-3-yl)acet-1-one

[0539] Following the synthesis method of Example 6-P2, Example 10 was obtained using 6A-P2 as the starting material. MS m / z (ESI): 416.2.

[0540] Example 11

[0541] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)azacyclobutane-3-yl)acet-1-one

[0542] Following the synthesis method of Example 6-P2, Example 11 was obtained using 6A-P2 as the raw material. MS m / z (ESI): 417.2.

[0543] Example 12

[0544] (R)-2-(1-(6-cyclopropoxypyridin-3-yl)azacyclobutane-3-yl)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)acet-1-one

[0545] Following the synthesis method of Example 6-P2, Example 12 was obtained using 6A-P2 as the starting material. MS m / z (ESI): 419.2.

[0546] Example 13

[0547] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-(ethylamino)pyrimidin-4-yl)azacyclobutane-3-yl)ethyl-1-one

[0548] Following the synthesis method of Example 6-P2, Example 13 was obtained using 6A-P2 as the raw material. MS m / z (ESI): 407.2.

[0549] Example 14

[0550] (R)-2-(1-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)azacyclobutane-3-yl)-1-(3,4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)acet-1-one

[0551] Following the synthesis method of Example 6-P2, Example 14 was obtained using 6A-P2 as the starting material. MS m / z (ESI): 419.2.

[0552] Example 15

[0553] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-fluoropyrimidin-2-yl)azacyclobutane-3-yl)ethyl-1-one

[0554] Following the synthesis method of Example 6-P2, Example 15 was obtained using 6A-P2 as the starting material. MS m / z (ESI): 382.2.

[0555] Example 16

[0556] (R)-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)(1-(trifluoromethyl)-1H-pyrazol-4-yl)methyl ketone

[0557] Following the synthesis method of Example 6-P2, Example 16 was obtained using 6A-P2 as the starting material. MS m / z (ESI): 351.1.

[0558] Example 17

[0559] (8-Methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)(1-(trifluoromethyl)-1H-pyrazol-4-yl)methyl ketone

[0560] Example 17 was obtained by referring to the synthesis method of Reference Example 2. MS m / z (ESI): 337.1.

[0561] Example 18

[0562] 1-(5-chloro-1,2a,3,4-tetrahydro-2H-2,6,8,8a-tetraazacyclopentadien[cd]-s-inden-2-yl)-2-(1-(2-(trifluoromethyl)pyrimidin-5-yl)azacyclobutan-3-yl)ethane-1-one

[0563] first step

[0564] 3-Chloro-1-hydroxy-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one

[0565] 3-Chloro-1-methoxy-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one 18A (5 g, 25.4 mmol) and sodium iodide (10.8 g, 76.1 mmol) were dissolved in 150 mL of acetonitrile, cooled to 0 °C, and chloro(trimethyl)silane (11.3 g, 76.1 mmol) was added. The mixture was heated to 80 °C and reacted for 18 hours. After cooling the reaction solution to room temperature, 300 mL of water was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 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 the title product 18B (4.5 g, yield: 96%). MS m / z (ESI): 184.2 [M+1].

[0566] Step 2

[0567] 3-Amino-1-hydroxy-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one

[0568] 18B (4.5 g, 24.5 mmol) and 100 mL of 7 M amine / methanol were added to a sealed container, and the reaction was stirred at 110 °C for 18 hours. The reaction solution was concentrated under reduced pressure to give the title product 18C (4.0 g, yield: 99%). MS m / z (ESI): 165.2 [M+1]

[0569] Step 3

[0570] 3-Amino-1-chloro-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one

[0571] 18C (4.0 g, 24.5 mmol) was dissolved in 40 mL of phosphorus oxychloride and heated to 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched in 1000 mL of water. The mixture was extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The solutions were washed with saturated sodium chloride solution (200 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 the title product 18D (3.5 g, yield: 78%). MS m / z (ESI): 183.2 [M+1].

[0572] Step 4

[0573] 3-Amino-7-carbonyl-6,7-dihydro-5H-cyclopentadieno[c]pyridine-1-carboxylic acid ethyl ester

[0574] 18D (3.5 g, 19.2 mmol) was dissolved in 30 mL of ethanol, and tetrakis(triphenylphosphine)palladium (2.2 g, 1.9 mmol) and triethylamine (5.8 g, 57.6 mmol) were added to replace carbon monoxide. The reaction was stirred at 100 °C for 18 hours. The solution was added to 300 mL of water, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (200 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 the title product 18E (3.0 g, yield: 71%). MS m / z (ESI): 221.2 [M+1].

[0575] Step 5 to Step 6

[0576] 6-Amino-2,2a,3,4-Tetrahydro-1H-2,7-diazacyclopentadien[cd]inden-1-one

[0577] Following the synthesis method described in steps four and five of Example 4, using 18E as the starting material, product 18G was obtained. MS m / z (ESI): 176.2 [M+1]

[0578] Step 7

[0579] 6-Amino-5-chloro-2,2a,3,4-tetrahydro-1H-2,7-diazacyclopentadien[cd]inden-1-one

[0580] 18G (1.5 g, 8.5 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and N-chlorosuccinimide (1.4 g, 10.4 mmol) was added. The reaction was stirred at 25 °C for 2 hours. The solution was added to 100 mL of water, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 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 the title product 18H (1.2 g, yield: 67%).

[0581] MS m / z(ESI): 210.2 [M+1].

[0582] Step 8

[0583] (Z)-N-(5-chloro-1-carbonyl-2,2a,3,4-tetrahydro-1H-2,7-diazacyclopentadien[cd]inden-6-yl)-N'-hydroxymethylammonium

[0584] 18H (1.2 g, 5.7 mmol) and N,N-dimethylformamide dimethyl acetal (1.0 g, 8.6 mmol) were dissolved in 20 mL of isopropanol, and the reaction was stirred at 90 °C for 2 h. The mixture was cooled to 50 °C, and hydroxylamine hydrochloride (0.6 g, 8.6 mmol) was added. The reaction was stirred at 50 °C for 18 h. The reaction mixture was filtered while hot, the filtrate was concentrated, 10 mL of ethanol was added, and the mixture was stirred for half an hour. A solid precipitated; this solid was filtered, collected, and dried under vacuum to give the title product 18I (0.8 g, yield: 55%). MS m / z (ESI): 253.2 [M+1].

[0585] Step 9

[0586] 5-Chloro-2,2a,3,4-Tetrahydro-1H-2,6,8,8a-Tetraazacyclopentadien[cd]-s-inden-1-one

[0587] 18I (0.8 g, 3.2 mmol) was dissolved in 10 mL of tetrahydrofuran, and trifluoroacetic anhydride (1.3 g, 6.4 mmol) was added. The reaction was stirred at 100 °C for 18 hours. The reaction was quenched with 30 mL of ice water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 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 the title product 18J (0.7 g, yield: 93%). MS m / z (ESI): 235.2 [M+1].

[0588] Step 10

[0589] 5-Chloro-2,2a,3,4-Tetrahydro-1H-2,6,8,8a-Tetraazacyclopentane[cd]-S-indenadiene

[0590] 18J (700 mg, 3.0 mmol) was dissolved in 10 mL of tetrahydrofuran, and 2 M borane dimethyl sulfide solution (3.0 mL, 6 mmol) was added. The mixture was stirred at 70 °C for 2 hours. The reaction was quenched by adding 1 mL of methanol to the reaction solution under ice bath conditions, followed by the addition of 1 mL of 1 mol / L dilute hydrochloric acid. The mixture was stirred for 0.5 hours, then added to 30 mL of sodium carbonate aqueous solution. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was 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 the title product 18K (0.4 g, yield: 60%).

[0591] MS m / z(ESI): 221.2 [M+1].

[0592] Step 11

[0593] 1-(5-chloro-1,2a,3,4-tetrahydro-2H-2,6,8,8a-tetraazacyclopentadien[cd]-s-inden-2-yl)-2-(1-(2-(trifluoromethyl)pyrimidin-5-yl)azacyclobutan-3-yl)ethane-1-one

[0594] Referring to the synthesis method in step 8 of Example 4, using 18K as the starting material, the title product 18 was obtained.

[0595] MS m / z(ESI): 464.2 [M+1].

[0596] Example 19

[0597] 1-(6-chloro-2a,3,4,5-tetrahydropyrrolo[2,3,4-ij][1,2,4]triazolo[1,5-b]isoquinoline-2(1H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)ethyl-1-one

[0598] Example 19 was obtained by referring to the synthesis method of Example 18. MS m / z (ESI): 478.2.

[0599] Example 20

[0600] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)ethane-1-one

[0601] first step

[0602] 2-(azacyclobutane-3-yl)methyl acetate 2,2,2-trifluoroacetate

[0603] 20 g (87.23 mmol) of tert-butyl 3-(2-methoxy-2-oxoethyl)azacyclobutane-1-carboxylate 20A was dissolved in 150 mL of dichloromethane, and 50 mL of trifluoroacetic acid was added. The mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure to give the title product 20B (21.21 g, yield: 99.9%). MS m / z (ESI): 130.1 [M+1].

[0604] Step 2

[0605] 2-[1-(2-methoxypyrimidin-4-yl)azacyclobutane-3-yl]methyl acetate

[0606] 4-Chloro-2-methoxypyrimidine (560 mg, 3.87 mmol) and N,N-diisopropylethylamine (3.4 mL, 19.37 mmol) were dissolved in 7 mL of isopropanol, and 20B (1.13 g, 4.65 mmol) was added. The mixture was stirred at 90°C for 1 hour. After cooling to room temperature, 40 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 20C (1.2 g, yield: 99.9%).

[0607] MS m / z(ESI): 238.1 [M+1].

[0608] Step 3

[0609] 2-[1-(2-methoxypyrimidin-4-yl)azacyclobutane-3-yl]potassium acetate

[0610] 20C (918 mg, 3.87 mmol) was dissolved in 10 mL of tetrahydrofuran, and potassium trimethylsilanolate (992.8 mg, 7.74 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was filtered, and the filter cake was dried under reduced pressure to give the title product 20D (300 mg, yield: 29.7%). MS m / z (ESI): 224.1 [M+1+HK].

[0611] Step 4

[0612] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0613] Compound 20D (50 mg, 191.3 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (86.6 mg, 229.6 μmol) were dissolved in 3 mL of N,N-dimethylformamide. 6B-P2 (50 mg, 191.3 μmol) and N,N-diisopropylethylamine (167 μL, 956.7 μmol) were added, and the mixture was stirred at 25 °C for 1 h. 40 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give the title product 20 (42.6 mg, yield: 56.4%). MS m / z (ESI): 394.2 [M+1].

[0614] 1 H NMR (400MHz, DMSO-d6) δ7.94 (dd, J=5.8, 1.0Hz, 1H), 6.02 (t, J=5.4Hz, 1H), 4.82 (d,J=15.0Hz,1H),4.74–4.40(m,2H),4.14(dt,J=14.5,8.1Hz,2H),3.76(s,3H), 3.69(ddd,J=15.6,8.9,5.9Hz,2H),3.07(h,J=7.2Hz,1H),2.93–2.57(m,4H),2. 39(s,3H),2.13(s,3H),2.09–1.95(m,1H),1.90–1.73(m,1H),1.45–0.70(m,2H).

[0615] Example 21

[0616] 2-(1-(5-fluoro-2-methoxypyridin-4-yl)azacyclobutane-3-yl)-1-(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)ethyl-1-one

[0617] Example 21 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 397.2.

[0618] 1H NMR(400MHz,DMSO-d6)δ7.73(d,1H),5.75(d,1H),4.78(d,2H),4.54(d,2H),4.19(t,2H),3 .75(d,2H),3.73(s,3H),3.07(d,1H),2.88(t,2H),2.83(dt,4H),2.16(d,3H),2.06(p,2H).

[0619] Example 22

[0620] (R)-(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)(1-(pyrimidin-4-yl)pyrrolidin-3-yl)methyl ketone

[0621] Example 22 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 350.2.

[0622] 1 H NMR (400MHz, DMSO-d6) δ8.59(t,J=1.6Hz,1H),8.37(dd,J=4.9,1.6Hz,1H),6.51(dd,J=4.9,1.5Hz,1H),4.85–4.59(m, 4H),3.81–3.71(m,2H),3.65–3.51(m,2H),3.42–3.19(m,3H),3.04–2.98(m,2H),2.29–2.20(m,5H),2.24–1.98(m,2H).

[0623] Example 23

[0624] (1-Cyclopropyl-1H-pyrazole-4-yl)(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl) methyl ketone

[0625] Example 23 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 309.2. 1 H NMR(400MHz,DMSO-d6)δ8.39(d,1H),7.92(d,1H),5.01(d,2H),4.72(d,2H),3.83(tt,1H ),2.90(t,2H),2.84(t,2H),2.21(d,3H),2.07(p,2H),1.17–1.09(m,2H),1.01(dq,2H).

[0626] Example 24

[0627] (8-Methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)-3-((2-(trifluoromethyl)pyridin-4-yl)amino)cyclobutyl) ketone

[0628] Example 24 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 417.5.

[0629] Example 25

[0630] (S)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one and (R)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0631] first step

[0632] 4-Ethoxy-3-methyl-2-carbonyl-3-enbutyric acid methyl ester

[0633] Under ice bath conditions, oxaloyl chloride monomethyl ester (3.32 mL, 36.13 mmol) was slowly added dropwise to a 12 mL solution of 1-ethoxyprop-1-ene 25A (10 mL, 90.33 mmol) and triethylamine (7.56 mL, 54.20 mmol). The mixture was slowly heated to 20 °C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) and methyl tert-butyl ether (50 mL) were added, and the mixture was stirred until clear. The organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (30 mL). The combined organic phases were 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 the title product 25B (4.55 g, yield: 29.3%). MS m / z (ESI): 173.1 [M+1].

[0634] 1 H NMR (400MHz, CDCl3) δ7.59 (d, J = 1.1Hz, 1H), 4.17 (q, J = 7.1Hz, 2H), 3.86 (s, 3H), 1.76 (d, J = 1.1Hz, 3H), 1.38 (t, J = 7.1Hz, 3H).

[0635] Step 2

[0636] 3-Methyl-5-carbonyl-5,6,7,8-tetrahydroquinoline-4-carboxylic acid methyl ester

[0637] 25B (4.55 g, 26.4 mmol) was dissolved in 50 mL of acetic acid, and 3-amino-2-cyclohexen-1-one (2.93 g, 26.4 mmol) was added. The mixture was stirred at 120 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and 150 mL of saturated sodium bicarbonate aqueous solution was added to the residue. The mixture was extracted with dichloromethane (100 mL × 2), and the organic phases were combined. The residue was 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 title product 25C (515 mg, yield: 8.9%). MS m / z (ESI): 220.1 [M+1].

[0638] Step 3

[0639] 3-Methyl-6,7-dihydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0640] 25C (515 mg, 2.35 mmol) and ammonium acetate (543.2 mg, 7.05 mmol) were dissolved in 5 mL of tetrahydrofuran, and ethyl titanate (2.1 g, 9.40 mmol) was added. The mixture was stirred at 80°C for 16 hours. 2.5 g of N,N,N',N'-tetra(2-hydroxyethyl)ethylenediamine was added to the reaction mixture, and the mixture was stirred at 65°C for 0.5 hours. Then, 50 mL of water was added, and the mixture was extracted with a mixture of dichloromethane and methanol (v / v 5:1, 30 mL × 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 25D (437 mg, yield: 99.9%). MS m / z (ESI): 187.1 [M+1].

[0641] Step 4

[0642] 3-Methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0643] 25D (437 mg, 2.35 mmol) was dissolved in 20 mL of methanol, and 50 mg of 10% palladium on carbon was added. After purging with hydrogen three times, the mixture was stirred for 1 hour in a hydrogen balloon at 25°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 25E (440 mg, yield: 99.6%). MS m / z (ESI): 189.1 [M+1].

[0644] Step 5

[0645] 3-Methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0646] 25E (440 mg, 2.34 mmol) was dissolved in 10 mL of tetrahydrofuran. 2M boron dimethyl sulfide solution (5.84 mL, 11.68 mmol) was added under ice bath conditions, and the mixture was stirred at 80°C for 12 hours. Under ice bath conditions, 1.6 mL of methanol was added to quench the reaction mixture, followed by 3.2 mL of 6 mol / L dilute hydrochloric acid. The mixture was stirred at 70°C for 0.5 hours, then cooled to room temperature. The pH was adjusted to greater than 10 using 6 mol / L sodium hydroxide (3.9 mL), and di-tert-butyl dicarbonate (1.07 mL, 4.68 mmol) was added. The mixture was stirred at 25°C for 1 hour. Add 20 mL of water to the reaction mixture, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated brine (100 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 A to give the title product 25F (235 mg, yield: 36.6%). MS m / z (ESI): 275.2 [M+1].

[0647] Step 6

[0648] (S)-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester and (R)-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0649] Compound 25F (235 mg, 856.55 μmol) was resolved by a chiral column (column: CHIRALCEL OD, 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:MeOH:EtOH:DEA = 70:15:15:0.1%; run time (min): 12; linear mode: isocratic), yielding the title product 25F-P1 (99 mg, RT (retention time) = 3.073 min, yield: 43.1%) and the title product 25F-P2 (69 mg, RT (retention time) = 3.730 min, yield: 29.4%). MS m / z (ESI): 275.2 [M+1].

[0650] Step 7

[0651] (S)-3-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0652] 25F-P1 (49 mg, 178.6 μmol) was dissolved in 3 mL of methanol, and 1 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 25G-P1 (44 mg, yield: 99.7%).

[0653] MS m / z(ESI): 175.1 [M+1].

[0654] Step 8

[0655] (S)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0656] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (46.5 mg, 178.0 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (80.6 mg, 213.6 μmol) were dissolved in 1.8 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (93 μL, 534.1 μmol) and 25G-P1 (44 mg, 178.0 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 5 mL of water to the reaction mixture, extract with dichloromethane (2 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (6 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high performance liquid chromatography to give the title product 25-P1 (34.8 mg, yield: 43.0%). MS m / z (ESI): 418.2 [M+1].

[0657] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,2H),8.21(s,1H),4.90–4.78(m,1H),4.77 –4.46(m,2H),4.33–4.18(m,2H),3.92–3.74(m,2H),3.07(dq,J=15.0,7.5 Hz,1H),2.88(dtd,J=17.9,10.8,4.3Hz,4H),2.69–2.54(m,1H),2.21(d,J =2.7Hz,3H),2.11–1.97(m,1H),1.86(q,J=10.6Hz,1H),1.27–1.06(m,1H).

[0658] Step 9

[0659] (R)-3-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0660] 25F-P2 (69 mg, 251.5 μmol) was dissolved in 4.5 mL of methanol, and 1.5 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 25G-P2 (62 mg, yield: 99.7%). MS m / z (ESI): 175.1 [M+1].

[0661] Step 10

[0662] (R)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0663] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (65 mg, 248.9 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (112.7 mg, 298.6 μmol) were dissolved in 2.5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (130 μL, 746.6 μmol) and 25G-P2 (61.5 mg, 248.9 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 5 mL of water to the reaction mixture, extract with dichloromethane (2 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (6 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high performance liquid chromatography to give the title product 25-P2 (44.3 mg, yield: 40.3%). MS m / z (ESI): 418.2 [M+1].

[0664] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,2H),8.21(s,1H),4.91–4.78(m,1H),4.77–4.44(m,2H),4.32–4.18(m,2H),3.93–3.71(m,2H), 3.17–3.01(m,1H),2.99–2.78(m,4H),2.70–2.52(m,1H),2.20(s,3H),2.10–1.97(m,1H),1.93–1.75(m,1H),1.28–1.02(m,1H).

[0665] Example 26

[0666] Imidazolo[1,5-a]pyridin-6-yl(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl) methyl ketone

[0667] Example 26 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 319.1.

[0668] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=13.7Hz,2H),7.76(d,J=10.3Hz,2H),7.16(t,J=12.2Hz,1H),4.92( d,J=5.5Hz,2H),4.83(d,J=17.1Hz,2H),2.97–2.80(m,4H),2.28–2.10(m,3H),2.07(q,J=7.5Hz,2H).

[0669] Example 27

[0670] Benz[d]thiazolyl-6-yl(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl) methyl ketone

[0671] Example 27 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 336.1.

[0672] 1 H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 8.51 (dd, J=10.9, 1.7Hz, 1H), 8.18 (dd, J=8.5, 4.5Hz, 1H), 7.79 (ddd, J= 8.4, 3.8, 1.7Hz, 1H), 4.91–4.75 (m, 4H), 2.85 (ddt, J=20.5, 14.2, 7.6Hz, 4H), 2.22 (s, 1H), 2.11–2.00 (m, 4H).

[0673] Example 28

[0674] (R)-(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)(1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)methyl ketone

[0675] Example 28 was obtained by referring to the synthesis method of Reference Example 2. MS m / z (ESI): 417.2.

[0676] 1 H NMR (400MHz, DMSO-d6) δ8.40(d,J=4.1Hz,1H),7.09(d,J=0.8Hz,1H),6.57(dd,J=4.2,2.2Hz,1H),4.85–4.74(m,2H),4.70–4.59( m,2H),3.74(t,J=7.8Hz,2H),3.65–3.53(m,2H),3.39–3.20(m,3H),3.01(t,J=6.1Hz,2H),2.29–2.20(m,5H),1.93–1.85(m,2H).

[0677] Example 29

[0678] 1-(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)-2-(trans-2-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)ethyl-1-one

[0679] Example 29 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 402.2.

[0680] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=5.0Hz,1H),7.63(s,1H),7.41(d,J=3.5Hz,1H),4.76(d,J=17.4Hz,2H),4.54(d,J=19.7Hz,2H),2.88(t,J=7 .7Hz,2H),2.82(t,J=7.5Hz,2H),2.68–2.52(m,2H),2.15(s,3H),2.10 –1.94(m,3H),1.64–1.52(m,1H),1.25–1.18(m,1H),1.17–1.07(m,1H).

[0681] Example 30

[0682] (8-Methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)(1,3,4-thiadiazol-2-yl)methyl ketone

[0683] Example 30 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 287.1.

[0684] Example 31

[0685] (1-(difluoromethyl)-1H-pyrazol-4-yl)(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl) methyl ketone

[0686] Example 31 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 319.1.

[0687] 1 H NMR (400MHz, DMSO-d6) δ8.85(d,J=6.0Hz,1H),8.25(d,J=11.4Hz,1H),7.87(td,J=58.6,7.3Hz,1H) ,5.10-4.99(m,2H),4.80-4.67(m,2H),2.96-2.78(m,4H),2.21(d,J=3.9Hz,3H),2.12-2.02(m,2H).

[0688] Example 32

[0689] (2-(difluoromethyl)thiazolyl-5-yl)(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl) methyl ketone

[0690] Example 32 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 336.1.

[0691] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,1H),7.41(td,1H),5.16(d,2H),4.80(d,2H),2.90(t,2H),2.88–2.81(m,2H),2.21(s,3H),2.08(p,2H).

[0692] Example 33

[0693] (8-Methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)(2-methylthiazolyl)methyl ketone

[0694] Example 33 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 300.1.

[0695] Example 34

[0696] (2-Cyclopropylthiazolyl-5-yl)(8-Methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)methyl ketone

[0697] Example 34 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 326.1.

[0698] Example 35

[0699] (2-(cyclopropylmethyl)thiazolyl-5-yl)(8-methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl) methyl ketone

[0700] Example 35 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 340.1.

[0701] Example 36

[0702] (8-Methyl-3,5,6,7-tetrahydrocyclopentan[b]pyrrolo[3,4-e]pyridin-2(1H)-yl)(1-methyl-5-(trifluoromethyl)-1H-pyrrolo-3-yl) methyl ketone

[0703] Example 36 was obtained by referring to the synthesis method of Example 2. MS m / z (ESI): 350.1.

[0704] Example 37

[0705] (S)-1-(4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one and (R)-1-(4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0706] first step

[0707] 1-(tert-Butoxycarbonyl)-3-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline-5-oxide

[0708] 3-Methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester 25F (900 mg, 3.28 mmol) was dissolved in 27 mL of dichloromethane, and m-chloroperoxybenzoic acid (849.13 mg, 4.92 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was quenched with saturated sodium sulfite aqueous solution (25 mL) and saturated sodium bicarbonate aqueous solution (25 mL), extracted with dichloromethane (50 mL × 2), and the organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 37A (950 mg, yield: 99.7%). MS m / z (ESI): 291.2 [M+1]

[0709] Step 2

[0710] 4-Chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0711] 37A (950 mg, 3.27 mmol) was dissolved in 100 mL of N,N-dimethylformamide, and oxaloyl chloride (6.37 mL, 75.25 mmol) was added under ice bath conditions. The mixture was stirred at 25°C for 16 hours. 800 mL of saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated brine (500 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 37B (268 mg, yield: 26.5%). MS m / z (ESI): 309.1 [M+1]

[0712] Step 3

[0713] (S)-4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester and (R)-4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0714] Compound 37B (268 mg, 867.87 μmol) was resolved by a chiral column (column: CHIRALCEL OJ, 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; run time (min): 12; linear mode: isocratic), yielding the title product 37B-P1 (135 mg, RT (retention time) = 2.783 min, yield: 50.4%) and the title product 37B-P2 (123 mg, RT (retention time) = 3.267 min, yield: 45.9%). MS m / z (ESI): 309.1 [M+1]

[0715] Step 4

[0716] (S)-4-chloro-3-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0717] 37B-P1 (50.4 mg, 163.21 μmol) was dissolved in 3 mL of methanol, and 1 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give the title product 37C-P1 (45.6 mg, yield: 99.2%). MS m / z (ESI): 209.1 [M+1]

[0718] Step 5

[0719] (S)-1-(4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0720] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (42 mg, 160.80 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (72.8 mg, 192.96 μmol) were dissolved in 1.6 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (84 μL, 482.39 μmol) and 37C-P1 (45.3 mg, 160.80 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 5 mL of water to the reaction solution, extract with ethyl acetate (2 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (6 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high-performance liquid chromatography to give the title product 37-P1 (42.0 mg, yield: 57.3%). MS m / z (ESI): 452.1 [M+1]

[0721] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,2H),4.88(d,J=15.5Hz,1H),4.81–4.46(m,2H),4.34–4.19(m,2H),3.91–3.77(m,2H),3.08(q,J=7 .9Hz,1H),2.86(td,J=18.8,7.6Hz,4H),2.68–2.53(m,1H),2.22(s,3H),2.10–1.97(m,1H),1.93–1.72(m,1H),1.31–1.05(m,1H).

[0722] Step 6

[0723] (R)-4-chloro-3-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0724] 37B-P2 (50.4 mg, 163.21 μmol) was dissolved in 3 mL of methanol, and 1 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 0.5 h. The reaction solution was concentrated under reduced pressure to give the title product 37C-P2 (45.6 mg, yield: 99.2%). MS m / z (ESI): 209.1 [M+1]

[0725] Step 7

[0726] (R)-1-(4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0727] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (42 mg, 160.80 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (72.80 mg, 192.96 μmol) were dissolved in 1.6 mL N,N-dimethylformamide was mixed with N,N-diisopropylethylamine (84 μL, 482.39 μmol) and 37C-P2 (45.3 mg, 160.80 μmol), and the mixture was stirred at 25 °C for 1 hour. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give the title product 37-P2 (41.8 mg, yield: 57.3%). MS m / z (ESI): 452.1 [M+1]

[0728] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,2H),4.92–4.47(m,3H),4.33–4.18(m,2H),3.93–3.77(m,2H),3.16–3.02(m,1H) ),2.96–2.77(m,4H),2.69–2.53(m,1H),2.22(s,3H),2.10–1.94(m,1H),1.92–1.73(m,1H),1.30–1.03(m,1H).

[0729] Example 38

[0730] 1-((R)-3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(trans-2-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)ethyl-1-one

[0731] first step

[0732] tert-Butyldimethyl(2-(trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)cyclopropyl)ethoxy)silane

[0733] Under a nitrogen atmosphere, diethylzinc (1.0 M, 19.21 mL) was added to a 125 mL double-necked flask containing DCM (50 mL). The reaction solution was stirred in a -40 °C cold bath. Then, a DCM (5 mL) solution containing TFA (1.47 mL, 19.21 mmol) was slowly added dropwise. After stirring the reaction solution at -40 °C for half an hour, a DCM (5 mL) solution containing diiodomethane (1.55 mL, 19.21 mmol) was added. The reaction solution was stirred in an ice-water bath at 0 °C for 1 hour. Then, a DCM (5 mL) solution containing trans-4-(tert-butyldimethylsiloxy)-1-buten-1-ylboronic acid pinacol ester 38A (2.25 mL, 6.40 mmol) was added. The reaction solution was stirred at room temperature for 12 hours. Under ice-water bath stirring conditions, a saturated ammonium chloride solution (40 mL) was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (40 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried with anhydrous sodium sulfate, filtered and evaporated to dryness to obtain the title product 38B (1.7 g, yield: 81%).

[0734] 1 H NMR (400MHz, CDCl3) δ3.69–3.63(m,2H),1.50–1.43(m,2H),1.21(s,12H),1.01–0.94(m,1H), 0.89(s,9H),0.70–0.63(m,1H),0.44–0.37(m,1H),0.05(s,6H),-0.40(dt,J=9.5,5.8Hz,1H).

[0735] Step 2

[0736] 4-(trans-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl)-2-(trifluoromethyl)pyridine

[0737] Weigh 120.85 mg (337.06 μmol) of n-butyldi(1-adamantyl)phosphine and 75.67 mg (337.06 μmol) of palladium acetate into a 100 mL round-bottom flask. Add 18 mL of tert-amyl alcohol. After purging with nitrogen three times, stir the reaction mixture at room temperature for 1 hour. Then add 3 mL of H₂O, 5.49 g (16.85 mmol) of cesium carbonate, 38B (1.17 g (3.37 mmol) of 38B, and 4-bromo-2-trifluoromethylpyridine (446 μL (3.37 mmol)). After purging with nitrogen three times again, stir the reaction mixture in an oil bath at 75 °C for 12 hours. Concentrate the reaction mixture under reduced pressure and purify the residue by silica gel column chromatography using eluent system A to give the title product 38C (883.1 mg, yield: 76%). MS m / z (ESI): 346.1 [M+1].

[0738] Step 3

[0739] 2-(trans-2-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)acetic acid

[0740] Weigh 1.5 g (4.34 mmol) of 38C into a 100 mL round-bottom flask, add 15 mL of acetonitrile and 90.1 mg (434.2 μmol) of ruthenium trichloride, and then add dropwise a 3 mL solution of sodium periodate (2.79 g, 13.0 mmol). Stir the reaction mixture at room temperature for 5 hours. Remove the solvent by rotary evaporation, add 50 mL of acetonitrile to the crude product, stir thoroughly, filter through a diatomaceous earth short column, and wash with 200 mL of acetonitrile. Reduce the filtrate by rotary evaporation to obtain the title product 38D (909.2 mg, yield: 85%). MS m / z (ESI): 246.1 [M+1].

[0741] Step 4

[0742] 1-((R)-3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(trans-2-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)acetoone

[0743] 38D (54.6 mg, 222.5 μmol), 6B-P2 (50 mg, 222.5 μmol), and HATU (125.9 mg, 333.7 μmol) were dissolved in 3 mL of DMF. DIEA (194 μL, 1.1 mmol) was added dropwise under ice bath conditions, and the reaction mixture was stirred at room temperature for 1 hour. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give the title product 38 (28.5 mg, yield: 31%). MS m / z (ESI): 416.2 [M+1].

[0744] 1H NMR(400MHz,DMSO-d6)δ8.55(dd,J=5.3,2.2Hz,1H),7.61(d,J=1.7Hz,1H),7 .41(d,J=5.1Hz,1H),4.80(dd,J=15.0,7.8Hz,1H),4.71–4.41(m,2H),2.92– 2.76(m,2H),2.71–2.52(m,2H),2.39(s,3H),2.13(s,3H),2.05–1.93(m,2H) ,1.91–1.72(m,1H),1.63–1.50(m,1H),1.30–1.19(m,2H),1.18–0.98(m,2H).

[0745] Example 39

[0746] (R)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-methylimidazo[1,2-b]pyridazin-6-yl)azacyclobutane-3-yl)acet-1-one

[0747] Following the synthesis method of Example 25-P2, Example 39 was obtained using 25F-P2 as the key intermediate. MS m / z (ESI): 403.2 [M+1].

[0748] 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.68(d,J=9.6Hz,1H),7.64(s,1H),6.55(dd,J =9.7,2.9Hz,1H),4.84(d,J=15.1Hz,1H),4.78–4.62(m,2H),4.15(p,J=7.5Hz,2H),3 .72(dq,J=14.2,7.1Hz,2H),3.15–3.00(m,2H),2.86(qt,J=17.0,7.4Hz,4H),2.60–2 .53(m,1H),2.27(s,3H),2.21(d,J=4.9Hz,3H),2.03(s,1H),1.86(d,J=12.6Hz,1H).

[0749] Example 40

[0750] (R)-2-(1-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)azacyclobutane-3-yl)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)acet-1-one

[0751] Following the synthesis method of Example 25-P2, Example 40 was obtained using 25F-P2 as the key intermediate. MS m / z (ESI): 405.2 [M+1].

[0752] 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),7.22(d,J=2.9Hz,1H),6.67(d,J=2.8Hz,1H),4. 83(d,J=15.2Hz,1H),4.77–4.60(m,2H),4.18–4.09(m,2H),3.94(q,J=7.2Hz,2H),3.5 1–3.39(m,2H),3.03(h,J=7.1Hz,1H),2.95–2.76(m,4H),2.71(t,J=6.5Hz,2H),2.58 (dd,J=17.6,8.3Hz,2H),2.21(d,J=3.6Hz,3H),2.10–1.97(m,1H),1.93–1.76(m,3H).

[0753] Example 41

[0754] (R)-1-(4-chloro-3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-methoxypyrimidin-4-yl)azacyclobutane-3-yl)ethyl-1-one

[0755] Following the synthesis method of Example 37-P2, Example 41 was obtained using 37C-P2 as the key intermediate. MS m / z (ESI): 414.1 [M+1].

[0756] 1 H NMR (400MHz, DMSO-d6) δ8.05 (dd, J=7.1, 2.4Hz, 1H), 6.41 (d, J=7.1Hz, 1H), 4. 98–4.86(m,1H),4.83–4.74(m,1H),4.72–4.65(m,1H),4.52–4.36(m,2H),4.0 3(s,5H),3.16(td,J=8.2,4.2Hz,1H),3.01–2.80(m,4H),2.71–2.58(m,1H),2 .26(d,J=3.4Hz,3H),2.08–1.98(m,1H),1.93–1.77(m,1H),1.23–1.06(m,1H).

[0757] Example 42

[0758] (R)-2-(1-(2-methoxypyrimidin-4-yl)azacyclobutane-3-yl)-1-(3-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)acet-1-one

[0759] Referring to the synthesis method of Example 25-P2, Example 42 was obtained using 25F-P2 as the key intermediate.

[0760] MS m / z(ESI): 380.2 [M+1].

[0761] 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 1H), 8.02 (dd, J = 7.2, 2.4Hz, 1H), 6.39 (d, J = 7.1 Hz,1H),5.14–4.89(m,2H),4.85–4.69(m,1H),4.49–4.36(m,2H),4.03–3.93(m, 5H),3.13–3.09(m,1H),2.88(ddd,J=18.0,7.8,3.6Hz,4H),2.71(dt,J=16.8,6. 1Hz,1H),2.37(s,3H),2.14–2.05(m,1H),1.98–1.85(m,1H),1.41–1.17(m,1H).

[0762] Example 43

[0763] (S)-1-(3-chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one and (R)-1-(3-chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0764] first step

[0765] Methyl 3-chloro-2,4-dioxolane

[0766] Methyl 2,4-dioxolane 43A (15 g, 104.1 mmol) was dissolved in 80 mL of dichloromethane, and sulfonyl chloride (11 mL, 135.3 mmol) was added dropwise. The mixture was stirred at 25°C for 2 hours. The reaction solution was washed with water (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 43B (12.6 g, yield: 67.8%). MS m / z (ESI): 179.0 [M+1].

[0767] 1 H NMR (400MHz, CDCl3) δ14.43 (s, 1H), 5.36 (d, J = 54.4Hz, 1H), 3.95–3.88 (m, 6H), 2.50–2.24 (m, 6H) for a 1:1 mixture of tautomers.

[0768] Step 2

[0769] methyl 3-chloro-2-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylate

[0770] 43B (12.6 g, 70.56 mmol) was dissolved in 120 mL of acetic acid, and 3-amino-2-cyclohexen-1-one (7.84 g, 70.56 mmol) was added. The mixture was stirred at 120 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to greater than 7 by adding 300 mL of saturated sodium bicarbonate aqueous solution. The residue was extracted with dichloromethane (150 mL × 2), and the organic phases were combined. The residue was washed with saturated brine (300 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 43C (5.95 g, yield: 33.2%). MS m / z (ESI): 254.1 [M+1].

[0771] Step 3

[0772] 3-Chloro-4-methyl-6,7-dihydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0773] 43C (1.22 g, 4.81 mmol) and ammonium acetate (1.11 g, 14.43 mmol) were dissolved in 8 mL of tetrahydrofuran, and ethyl titanate (4.39 g, 19.24 mmol) was added. The mixture was stirred at 80°C for 16 hours. 4 g of N,N,N',N'-tetra(2-hydroxyethyl)ethylenediamine was added to the reaction mixture, and the mixture was stirred at 65°C for 0.5 hours. Then, 50 mL of water and 30 mL of ethyl acetate were added to dilute the mixture, and the mixture was stirred for 20 minutes. The mixture was filtered, and the filter cake was dried under reduced pressure to give the title product 43D (960 mg, yield: 90.5%). MS m / z (ESI): 221.1 [M+1].

[0774] Step 4

[0775] 3-Chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-2(1H)-one

[0776] 43D (900 mg, 4.08 mmol) was dissolved in 180 mL of methanol, and 10% palladium on carbon (217 mg) was added. After purging with hydrogen three times, the mixture was stirred for 1 hour in a hydrogen balloon at 25°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the title product 43E (908 mg, yield: 100%). MS m / z (ESI): 223.1 [M+1].

[0777] Step 5

[0778] 3-Chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0779] 43E (902 mg, 4.05 mmol) was dissolved in 20 mL of tetrahydrofuran. 2M boron dimethyl sulfide solution (10.1 mL, 20.26 mmol) was added under ice bath conditions, and the mixture was stirred at 80°C for 12 hours. Under ice bath conditions, 1.3 mL of methanol was added to quench the reaction mixture, followed by 5.4 mL of 6 mol / L dilute hydrochloric acid. The mixture was stirred at 70°C for 0.5 hours, then cooled to room temperature. The pH was adjusted to greater than 10 using 6 mol / L sodium hydroxide (6.75 mL), and di-tert-butyl dicarbonate (1.86 mL, 8.10 mmol) was added. The mixture was stirred at 25°C for 1 hour. Add 50 mL of water to the reaction mixture, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated brine (100 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 give the title product 43F (405.8 mg, yield: 32.4%). MS m / z (ESI): 309.2 [M+1].

[0780] Step 6

[0781] (S)-3-chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester and (R)-3-chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-carboxylic acid tert-butyl ester

[0782] Compound 43F (405 mg, 1.31 mmol) was resolved by a chiral column (column: CHIRALCEL IA, 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:EtOH:DEA = 70:30:0.1%; run time (min): 12; linear mode: isocratic) to give the title product 43F-P1 (163 mg, RT (retention time) = 3.007 min, yield: 40.3%) and the title product 43F-P2 (168 mg, RT (retention time) = 5.813 min, yield: 41.5%).

[0783] MS m / z(ESI): 309.2 [M+1].

[0784] Step 7

[0785] (S)-3-chloro-4-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0786] 43F-P1 (40 mg, 129.53 μmol) was dissolved in 3 mL of methanol, and 0.8 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 0.5 h. The reaction solution was concentrated under reduced pressure to give the title product 43G-P1 (36.4 mg, yield: 99.8%). MS m / z (ESI): 209.1 [M+1].

[0787] Step 8

[0788] (S)-1-(3-chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0789] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (33.6 mg, 128.64 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (58.24 mg, 154.36 μmol) were dissolved in 1.2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (67 μL, 385.91 μmol) and 43G-P1 (36.2 mg, 128.64 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 5 mL of water to the reaction mixture, extract with dichloromethane (2 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (6 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high performance liquid chromatography to give the title product 43-P1 (38.6 mg, yield: 65.9%). MS m / z (ESI): 452.1 [M+1].

[0790] 1 H NMR(400MHz, DMSO-d6)δ8.65(s,2H),4.92(d,J=15.5Hz,1H),4.82–4.41(m,2H),4.34–4.19(m,2H),3.92–3.76(m,2H),3.06(dq, J=14.4,7.5Hz,1H),2.99–2.61(m,4H),2.60–2.52(m,1H),2.51(s,3H),2.14–1.93(m,1H),1.93–1.76(m,1H),1.26–1.04(m,1H).

[0791] Step 9

[0792] (R)-3-chloro-4-methyl-1,2,6,7,8,8a-hexahydropyrrolo[4,3,2-de]quinoline dihydrochloride

[0793] 43F-P2 (40 mg, 129.53 μmol) was dissolved in 3 mL of methanol, and 0.8 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at 25°C for 0.5 h. The reaction solution was concentrated under reduced pressure to give the title product 43G-P2 (36.4 mg, yield: 99.8%). MS m / z (ESI): 209.1 [M+1]

[0794] Step 10

[0795] (R)-1-(3-chloro-4-methyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutane-3-yl)acet-1-one

[0796] 2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (33.6 mg, 128.64 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (58.2 mg, 154.36 μmol) were dissolved in 1.2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (67 μL, 385.91 μmol) and 43G-P2 (36.2 mg, 128.64 μmol) were added. The mixture was stirred at 25 °C for 1 hour. Add 5 mL of water to the reaction solution, extract with dichloromethane (2 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (6 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high-performance liquid chromatography to give the title product 43-P2 (32.7 mg, yield: 55.4%). MS m / z (ESI): 452.1 [M+1]

[0797] 1 H NMR(400MHz, DMSO-d6)δ8.65(s,2H),4.92(d,J=15.4Hz,1H),4.79–4.43(m,2H),4.32–4.19(m,2H),3.92–3.75(m,2H),3.12 –2.98(m,1H),2.96–2.62(m,4H),2.62–2.52(m,1H),2.51(s,3H),2.12–1.95(m,1H),1.92–1.75(m,1H),1.25–1.06(m,1H).

[0798] Example 44

[0799] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(4-ethoxypyrimidin-2-yl)azacyclobutane-3-yl)ethyl-1-one

[0800] Example 45

[0801] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-ethoxypyrimidin-4-yl)azacyclobutane-3-yl)ethyl-1-one

[0802] first step

[0803] 2-(1-(4-chloropyrimidin-2-yl)azacyclobutane-3-yl)methyl acetate and 2-(1-(2-chloropyrimidin-4-yl)azacyclobutane-3-yl)methyl acetate

[0804] 2,4-Dichloropyrimidine 44A (1.54 g, 10.34 mmol) and N,N-diisopropylethylamine (9 mL, 51.69 mmol) were dissolved in 16 mL of isopropanol, and 2-(azacyclobutane-3-yl)methyl acetate-2,2,2-trifluoroacetate (2.51 g, 10.34 mmol) was added. The mixture was stirred at 25°C for 2 hours. Add 100 mL of water to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (120 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 give the title product 45A (1.4 g, yield: 56.0%) and the byproduct methyl 2-(1-(4-chloropyrimidin-2-yl)azacyclobutane-3-yl)acetate 44B (180 mg, yield: 7.2%). MS m / z (ESI): 242.1 [M+1].

[0805] Step 2

[0806] 2-(1-(4-ethoxypyrimidin-2-yl)azacyclobutane-3-yl)acetic acid

[0807] 44B (180 mg, 744.8 μmol) was dissolved in 8 mL of ethanol, and 0.3 mL (1.5 mmol) of 20% sodium ethoxide ethanol solution was added. The mixture was stirred at 85°C for 16 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, diluted with water (2 mL), and the pH was adjusted to 5 with 1 N hydrochloric acid. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product 44C (170 mg, yield: 96.2%). MS m / z (ESI): 238.1 [M+1]

[0808] 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),8.04(d,J=5.6Hz,1H),6.06(d,J=5.7Hz,1H),4.28(q,J=7.0Hz,2H),4.11(t ,J=8.5Hz,2H),3.68(dd,J=8.9,5.7Hz,2H),2.92(tt,J=7.9,5.7Hz,1H),2.66–2.62(m,2H),1.28(t,J=7.1Hz,3H).

[0809] Step 3

[0810] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(4-ethoxypyrimidin-2-yl)azacyclobutane-3-yl)ethyl-1-one

[0811] 44C (40 mg, 168.6 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (76.3 mg, 202.3 μmol) were dissolved in 1.6 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (88 μL, 505.8 μmol) and 6B-P2 (45 mg, 172.3 μmol) were added, and the mixture was stirred at 25 °C for 1 h. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give the title product 44 (28.5 mg, yield: 41.4%). MS m / z (ESI): 408.1 [M+1].

[0812] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=5.6Hz,1H),6.03(dd,J=5.6,1.2Hz,1H),4.82(d,J=14 .9Hz,1H),4.74–4.43(m,2H),4.27(q,J=7.0Hz,2H),4.13(p,J=7.8Hz,2H),3.78–3.63(m, 2H),2.98(dq,J=16.5,8.5Hz,1H),2.91–2.58(m,4H),2.49–2.42(m,1H),2.39(s,3H),2.1 3(s,3H),2.09–1.96(m,1H),1.92–1.74(m,1H),1.28(t,J=7.1Hz,3H),1.25–1.00(m,1H).

[0813] Step 4

[0814] 2-(1-(2-ethoxypyrimidin-4-yl)azacyclobutane-3-yl)acetic acid

[0815] 45A (400 mg, 1.66 mmol) was dissolved in 15 mL of ethanol, and 1.66 mL of 20% sodium ethoxide ethanol solution (8.3 mmol) was added. The mixture was stirred at 85°C for 16 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, diluted with water (10 mL), and the pH was adjusted to 5 with 1 N hydrochloric acid. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product 45B (363 mg, yield: 92.4%). MS m / z (ESI): 238.1 [M+1].

[0816] Step 5

[0817] (R)-1-(3,4-dimethyl-6,7,8,8a-tetrahydropyrrolo[4,3,2-de]quinoline-1(2H)-yl)-2-(1-(2-ethoxypyrimidin-4-yl)azacyclobutane-3-yl)ethyl-1-one

[0818] 45B (40 mg, 168.6 μmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (76.3 mg, 202.3 μmol) were dissolved in 1.6 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (88 μL, 505.8 μmol) and 6B-P2 (45 mg, 172.3 μmol) were added, and the mixture was stirred at 25 °C for 1 h. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to give the title product 45 (52.1 mg, yield: 75.8%). MS m / z (ESI): 408.1 [M+1].

[0819] 1 H NMR (400MHz, DMSO-d6) δ7.92 (dd, J=5.8, 1.1Hz, 1H), 6.00 (t, J=5.3Hz, 1H), 4.81 (d, J=14. 9Hz,1H),4.73–4.41(m,2H),4.21(q,J=7.1Hz,2H),4.13(p,J=8.0Hz,2H),3.69(ddd,J=22 .1,10.9,6.4Hz,2H),3.11–3.00(m,1H),2.92–2.59(m,4H),2.45(d,J=8.7Hz,1H),2.39(s ,3H),2.13(s,3H),2.08–1.96(m,1H),1.91–1.73(m,1H),1.24(s,3H),1.23–0.98(m,1H).

[0820] Biological testing evaluation

[0821] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0822] I. Cell Function Experiments

[0823] Test Example 1: Determination of the effect of the compound of the present invention on calcium flux in cells stably expressing the M1-M5 receptor.

[0824] 1. Experimental objective:

[0825] The effect of the compound on enhancing calcium flow activity in CHO-K1 / human M1 / 3 / 5 and CHO-K1 / Gα15M2 / 4 cells was investigated.

[0826] 2. Experimental instruments and reagents:

[0827] 2.1 Instruments:

[0828] 384-well test plate (Corning: 3764), 384-well plate (PE: 6008590), FLIPR Tip (Molecular Device: 9000-0764)

[0829] FLIPR Penta (Molecular Device) plate reader, Dispendix I-DOT non-contact nano-level dispensing system (Dispendix: I-DOT) pipetting workstation, and Multidrop Combi (ThermoFisher) liquid pipette.

[0830] 2.2 Reagents:

[0831] Ham's F-12 Nutrient Mix (Gibco: 11765-054), fetal calf serum (Gibco: 1009148), P / S (Gibco: 15140122), HBSS (Gibco: 14025076), HEPES (Gibco: 15630080), FLIPR calcium 6assay kit (Molecular Devices: R8190), Probenecid (PBA) (Invitrogen: P36400), Acetylcholine chloride (Sigma: A6625-25G)

[0832] Complete culture medium: DMEM + 10% FBS + 1X P / S; Cell seeding medium: DMEM + 10% FBS + 1X PS; Experimental buffer 1: 1X HBSS + 20mM HEPES + 2.5mM Probenecid; Experimental buffer 2: 1X HBSS + 20mM HEPES; Cell lines: CHO-K1 / M1; CHO-K1 / M2 / Gα15; CHO-K1 / M3; CHO-K1 / M4 / Gα15; CHO-K1 / M5.

[0833] FLIPR calcium 6assay kit: Dissolve Component A in experimental buffer 1, shake for 1-2 min, aliquot and store at -20℃.

[0834] 3. Experimental methods:

[0835] 1) CHO-K1 / M1; CHO-K1 / M2 / Gα15; CHO-K1 / M3; CHO-K1 / M4 / Gα15; CHO-K1 / M5 cell lines were cultured separately in complete medium at 37°C and 5% CO2 until 70%–90% confluence.

[0836] 2) Digest and resuspend the cells in cell seeding medium, and seed 5,000 to 10,000 cells / well / 20 μL into a 384-well cell culture plate and incubate at 37°C and 5% CO2 for 24 hours.

[0837] 3) Remove the cell culture plate from the CO2 incubator and allow it to equilibrate at room temperature for 10 minutes.

[0838] 4) Remove the Component A solution and allow it to equilibrate to room temperature. Add 20 μL of Component A solution to each well of the cell culture plate and incubate at room temperature in the dark for 1–2 hours.

[0839] 5) Prepare muscarinic receptor agonist Acetylcholine chloride (ACh) using experimental buffer 2 (concentration: EC). 20 / EC 100Add 30 μL of the prepared muscarinic receptor agonist to a 384-well agonist plate (PE: 6008590) using Multidrop Combi; dilute the working solutions of the positive control compound and the test compound 3.16 times using a Dispendix pipetting workstation and pipette 450 nL to a 384-well compound plate (PE: 6008590); add 30 μL of experimental buffer 2 to a 384-well compound plate (PE: 6008590) using Multidrop Combi; dilute the positive control compound and the test compound to 6X, vortex to mix, and set aside at room temperature.

[0840] 6) Add 10 μL of the diluted 6X compound to the corresponding well of the 384-well cell plate using FLIPR Penta and incubate for 2–10 minutes.

[0841] 7) Add 10 μL of the prepared muscarinic receptor agonist to the corresponding well of the 384-well cell plate using FLIPR Penta, and collect the data at the same time.

[0842] 4. Experimental data processing methods:

[0843] The FLIPR Penta reads and collects fluorescence signal values ​​(RFU), taking the maximum RFU value, and then uses the Low control (DMSO control group) and High control (ACh EC) values. 100 The experimental group's readings were used to calculate the percentage activation data: {% activation rate = (RFUsample - RFUlow control) / (RFUhigh control - RFUlow control) × 100}. The concentrations of the test compound, after being diluted 3.16 times in the reaction system, ranged from 30 μM to 0.095 nM in 11 locations. The percentage activation rate and the 11 concentration data were fitted to a nonlinear logic formula using XLFit to calculate the EC50 of the compound. 50 value

[0844] 5. Experimental Results:

[0845] The results showed that the compound of the present invention exhibited a good synergistic effect on calcium flow in cells stably expressing the M4 receptor, and also showed an effect on ECG of the target M2. 50 The EC50 of the preferred compound for target M2 can reach over 3000 nM. 50 When the concentration reaches 30 μM or higher, the compounds of this invention exhibit better selectivity for M4.

[0846] II. Pharmacokinetic Determination in SD Rats

[0847] 1. Research Objective:

[0848] Using SD rats as test animals, this study investigated the pharmacokinetic behavior of the compound examples in rat plasma and brain after oral administration at a dose of 5 mg / kg.

[0849] 2. Test Plan

[0850] 2.1 Test Drugs:

[0851] This invention is a self-made product.

[0852] 2.2 Experimental animals:

[0853] SD Rat, male.

[0854] 2.3 Administration:

[0855] Twenty-four male SD Rat were administered orally after fasting overnight at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0856] 2.4 Drug Preparation:

[0857] Oral administration preparation: 0.5% CMC-Na (1% Tween 80)

[0858] Weigh 0.50g of sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200Cps), dissolve it in 99mL of purified water, add 1ml of Tween80, mix and stir until a clear solution is formed.

[0859] Weigh out the sample and add it to a 100mL glass bottle. Add 80mL of the solution and sonicate for 10 minutes to obtain a homogeneous suspension with a concentration of 0.5mg / mL.

[0860] 2.5 Sample Collection:

[0861] After CO2 euthanasia, blood was collected from the heart and brain tissue at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after drug administration. The blood was placed in EDTA-2K tubes and centrifuged at 6000rpm for 6min at 4℃ to separate the plasma. The brain tissue was rinsed with pre-cooled PBS, dried, weighed, and stored at -80℃. The animals were fed 4h after drug administration.

[0862] 2.6 Sample preparation:

[0863] 1) Add 40uL of plasma sample to 160uL of acetonitrile for precipitation, mix, and centrifuge at 3500×g for 5-20 minutes. Dilute and homogenize brain tissue and centrifuge.

[0864] 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[0865] 2.7 Liquid Chromatography Analysis

[0866] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0867] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0868] ● Column: phenomenex Gemiu 5um C18 50×4.6mm

[0869] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile.

[0870] ● Flow rate: 0.8 mL / min

[0871] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0872] 3. Experimental Results and Analysis

[0873] The main pharmacokinetic parameters were calculated using WinNonlin 8.1. The results of the rat pharmacokinetic experiment are shown in the table below:

[0874] Pharmacokinetic parameters of the compound of the present invention in rats after oral administration

[0875] 4. Experimental conclusions:

[0876] The data in the table show that, in the pharmacokinetic evaluation experiment in rats, the compounds of the present invention showed higher exposure levels after oral administration, and higher drug plasma protein ionization rate and brain exposure. The ratio of total concentration of the compound in the brain to total concentration of the compound in plasma could reach 0.2 or higher, with preferred compounds reaching 0.3 or higher, and even more preferred compounds reaching 0.5 or higher.

[0877] III. Pharmacokinetic Determination in Balb / c Mice

[0878] 1. Research Objective:

[0879] Using Balb / c mice as test animals, the pharmacokinetic behavior of the compound examples in plasma and brain in mice after oral administration at a dose of 5 mg / kg was studied.

[0880] 2. Test Plan

[0881] 2.1 Test Drugs:

[0882] The compounds used in this invention embodiment are self-made.

[0883] 2.2 Experimental animals:

[0884] Balb / c Mouse, male.

[0885] 2.3 Administration:

[0886] Twenty-four male Balb / c mice were administered oral medication (PO) at a dose of 5 mg / kg and a volume of 10 mL / kg after fasting overnight.

[0887] 2.4 Drug Preparation:

[0888] Oral administration preparation: 0.5% CMC-Na (1% Tween 80)

[0889] Weigh 0.50g of sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200Cps), dissolve it in 99mL of purified water, add 1ml of Tween80, mix and stir until a clear solution is formed.

[0890] Weigh out the compound from the example and add it to a 4-mL glass bottle. Add 2.4mL of the solution and sonicate for 10 minutes to obtain a clear solution with a concentration of 0.5mg / mL.

[0891] 2.5 Sample Collection:

[0892] After CO2 euthanasia, blood was collected from the heart and brain tissue at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after drug administration. The blood was placed in EDTA-2K tubes and centrifuged at 6000rpm for 6min at 4℃ to separate the plasma. The brain tissue was rinsed with pre-cooled PBS, dried, weighed, and stored at -80℃. The animals were fed 4h after drug administration.

[0893] 2.6 Sample preparation:

[0894] 3) Add 40uL of plasma sample to 160uL of acetonitrile for precipitation, mix, and centrifuge at 3500×g for 5-20 minutes. Dilute and homogenize brain tissue and centrifuge.

[0895] 4) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[0896] 2.7 Liquid Chromatography Analysis

[0897] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0898] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0899] ● Column: phenomenex Gemiu 5um C18 50×4.6mm

[0900] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile.

[0901] ● Flow rate: 0.8 mL / min

[0902] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0903] 3. Experimental Results and Analysis

[0904] Experimental results showed that, in the mouse pharmacokinetic evaluation experiment, the compound of the present invention exhibited a high exposure level after oral administration, with an AUC of [missing value]. 0-∞ Above 1500 ng / mL*h, C max Above 1000 ng / mL, the preferred compound AUC 0-∞ Above 2000 ng / mL*h, C max Above 1500 ng / mL, the AUC of the preferred compound is [missing value]. 0-∞ Above 2500 ng / mL*h, C max Above 2000 ng / mL.

[0905] IV. Pharmacokinetic Determination in Beagle Dogs

[0906] 1. Research Objective:

[0907] Using beagle dogs as test animals, the pharmacokinetic behavior of the compound of the present invention in beagle dogs (plasma) after oral administration at a dose of 2 mg / kg was studied.

[0908] 2. Experimental Design:

[0909] 2.1 Experimental reagents:

[0910] The compounds used in this invention embodiment are self-made.

[0911] 2.2 Laboratory animals:

[0912] Each group consists of 3 male Beagles.

[0913] 2.3 Formulation:

[0914] Oral administration drug preparation: 0.5% CMC-Na in water

[0915] Weigh 0.50g of sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200Cps), dissolve it in 100mL of purified water, and mix and stir until a clear solution is obtained.

[0916] Weigh out the compound from the example and add it to a 100 mL glass bottle. Add the solution, vortex and sonicate for 10 minutes to obtain a white suspension with a concentration of 0.4 mg / mL.

[0917] 2.4 Administration:

[0918] Three male beagle dogs were administered orally after fasting overnight; the dose was 2 mg / kg, and the administration volume was 5 mL / kg.

[0919] 2.5 Sample Collection:

[0920] Blood collection: 0.5 mL of blood was collected from the forelimb veins of beagles before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in EDTA-K2 anticoagulant tubes and centrifuged at 6000 rpm for 6 minutes at 4°C to separate the plasma. The plasma was then stored at -80°C. The dogs were fed 4 hours after administration.

[0921] 2.6 Sample preparation:

[0922] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[0923] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex API 4000Qtrap.

[0924] 2.7 Liquid Chromatography Analysis:

[0925] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0926] ● Column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile

[0927] ● Flow rate: 0.4 mL / min

[0928] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0929] 3. Experimental Results and Analysis

[0930] Experimental results showed that in the canine pharmacokinetic evaluation experiment, the compound of the present invention exhibited a high exposure level after oral administration, with an AUC of [missing value]. 0-∞ Above 4000 ng / mL*h, the preferred compound AUC 0-∞ Above 5000 ng / mL*h, the AUC of the preferred compound is [missing value]. 0-∞ The AUC of the further optimized compound is above 6000 ng / mL*h. 0-∞ The AUC of the compound is further optimized at 7000 ng / mL*h or higher. 0-∞ Above 8000 ng / mL*h.

Claims

a compound according to Formula (VIII-1A), (VIII-1B), or (VIII-1C), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: wherein: is cycloalkyl, heterocyclyl, aryl or heteroaryl; X1is selected from CR 11 or N; X2is selected from CR 22 or N; X3is selected from CR 33 or N; X4is selected from CR 44 or N; L4or L5are each independently selected from a bond, C(R5R6), N(R5), O or S; X5is selected from CR 55 or N; M1, M2, M3or M4are each independently selected from C or N; R7, R8, R9or R10are absent when M1, M2, M3or M4is N; 10 absent; each of Ring F or Ring G is independently selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 3- 12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 one or more substituents of aryl or 5-12 membered heteroaryl; R0, R 11 , R 22 , R 33 , R 44 , R1, R2, R3, R4, R5or R6are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 deuteroalkyl; R 55 , R7, R8, R9or R 10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterioC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -O(CR aa R bb ) n1 R 31 , -N(CR aa R bb ) n1 R 31 , -S(CR aa R bb ) n1 R 31 , -OCR 31 R 32 R 33 , -(CR aa R bb ) n1 C(O)R 31 , N=S=OR 31 R 32 , -(CH2) n1 C(O)NR 31 R 32 , -(CH2) n1 P(O)R 31 R 32 , -(CH2) n1 P(O)2R 31 R 32 , -(CR aa R bb ) n1 (NR 31 )C(O)R 32 , -(CR aa R bb ) n1 C(O)NR 31 R 32 , -(CR aa R bb ) n1 (NR 31 S(O) m1 R 32 、-(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted to deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; R 31 , R 32 , R 33 , R aa , R bb , or R cc is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl; m1is 0, 1 or 2; and n1is 0, 1 or 2; provided that: (1) R3 and R 11 , or R4 and R 11 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Or, (2) R1 and R 44 , or R2 and R 44 They link with adjacent atoms to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally covered by deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; or, (3) R 22 with the atom to which it is attached forming C 33 with the atom to which it is attached forming C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C w is 0, 1, 2, 3 or 4; and General Formula (VIII-1A) or (VIII-1B) is not the following compound: The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: each independently selected from the group consisting of C1, C3, C4, or C5is each independently selected from C 3-10 C1, C3, C4, or C5is each independently selected from C 6-10 C1, C3, C4, or C5is each independently selected from C 3-10 C1, C3, C4, or C5is each independently selected from C 6-10 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 2-6 C1, C3, C4, or C5is each independently selected from C 2-6 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 1-6 C1, C3, C4, or C5is each independently selected from C 3-10 C1, C3, C4, or C5is each independently selected from C 6-10 C1, C3, C4, or C5is each independently selected from C Preferably, each of rings C1, C3, C4, or C5 is independently selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, said C 3-8 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 one or more substituents of alkyl; More preferably, each of rings C1, C3, C4, or C5 is independently selected from C 3-6 cycloalkyl, 5-6 membered heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl or 5-6 membered heteroaryl containing 1-3 N, O, or S atoms, said C 3-6 cycloalkyl, 5-6 membered heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl or 5-6 membered heteroaryl containing 1-3 N, O, or S atoms, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 one or more substituents of alkyl; Further preferably, each of the rings C1, C3, C4 or C5 is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, is optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl; The compound according to claim 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: each independently is each independently is each independently is each independently is X6, X7or X8are each independently selected from the group consisting of a bond, C(O), (CR 66 R 77 ) n2 , NR 88 , (CR 66 R 77 ) n2 NR 88 , NR 88 (CR 66 R 77 ) n2 , O, (CR 66 R 77 ) n2 O, O(CR 66 R 77 ) n2 or S; R 66 , R 77 , or R 88 are each independently selected from hydrogen, deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S; R 66 , R 77 , or R 88 are each independently selected from hydrogen, deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1- 3hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-8 membered heteroaryl containing 1-3 atoms selected from N, O, or S; More preferably, R 66 , R 77 , or R 88 is each independently selected from hydrogen, deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-6 membered heteroaryl containing 1-3 atoms selected from N, O, or S; Further preferably, R 66 , R 77 or R 88 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl or oxetanyl; p, q or t are each independently 0, 1, 2, 3 or 4; and n2are each independently 0, 1, 2 or 3. The compound according to claim 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: each independently is each independently is each independently is each independently is The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to Claim 3, characterized in that, The compounds are further represented by formula (VIII-6), (VIII-8) or (VIII-9): L5is a bond; is aryl or heteroaryl. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 5, characterized in that, The compounds are further represented by formula (VIII-a1), (VIII-a3) or (VIII-a4): The compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 11 , R 22 , R 33 or R 44 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 deuteroalkyl; R 11 , R 22 , R 33 or R 44 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl or oxetanyl, said amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl or oxetanyl optionally substituted with one or more substituents selected from deuterium, hydroxyl, halogen, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 deuterated alkyl. The compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 55 or each R8is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, -O(CR aa R bb ) n1 R 31 , -N(CR aa R bb ) n1 R 31 , -S(CR aa R bb ) n1 R 31 , -(CR aa R bb ) n1 C(O)R 31 , N=S=OR 31 R 32 , -(CH2) n1 C(O)NR 31 R 32 , -(CH2) n1 P(O)R 31 R 32 , -(CH2) n1 P(O)2R 31 , -(CR aa R bb ) n1 (NR 31 )C(O)R 32 , -(CR aa R bb ) n1 C(O)NR 31 R 32 , -(CR aa R bb ) n1 (NR 31 )S(O) m1 R 32 , -(CR aa R bb ) n1 S(O) m1 NR 31 R 32 、-(CR aa R bb ) n1 S(O)(=NR cc )R 32 or -(CR) aa R bb ) n1 S(O) m1 R 32 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally prefixed with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. R 31 R 32 or R 33 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 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, wherein the amino group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1- 3-alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents; R 31 , R 32 , or R 33 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy, said amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, or propoxy optionally substituted with one or more substituents selected from deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 deuteroalkyl; R aa R bb Or R cc Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2- 3-acetylinyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, the amino groups, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1- 3-alkoxy group, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally deuterated, hydroxyl, halogenated, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkyl group is substituted by one or more substituents; Preferably, R aa , R bb or R cc are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy or propoxy. The compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3, R4, R5or R6are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2- 4alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, optionally substituted with deuterium, hydroxyl, halogen, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 deuteroalkyl; Preferably, R1, R2, R3, R4, R5or R6are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy or propoxy; or R1and R2, R3and R4, or R5and R6, respectively, together with the carbon atom to which they are attached, form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, one or more substituents of which are selected from the group consisting of deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C R1and R2, R3and R4, or R5and R6, respectively, are linked to form a C 3-8 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 Aryl or 5-8 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said C 3- 8Cycloalkyl, 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 Aryl or 5-8 membered heteroaryl containing 1-3 atoms selected from N, O, or S, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, haloC 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents of alkyl. The compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R7, R9or R 10 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2- alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1- alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O, or S. R7, R9or R 10 each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-8 membered heteroaryl containing 1-3 atoms selected from N, O, or S, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-10 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O, or S, C 6-10 aryl, or 5-8 membered heteroaryl containing 1-3 atoms selected from N, O, or S, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 one or more substituents of the alkyl group; More preferably, R7, R9or R 10 each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, ethenyl, allyl, propenyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, fluorosubstituted methoxy, fluorosubstituted ethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R0 is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, and C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted; Preferably, each of R0 is independently selected from hydrogen, deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted; More preferably, R0are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl. The compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring F is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, said C 3-8 cycloalkyl, 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, optionally substituted with deuterium, oxo, thioxo, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 one or more substituents of alkyl; Preferably, ring F is selected from C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Cycloalkyl groups, 5-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 A aryl group or a 5-6 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with a deuterium, oxo group, thio group, halogen, amino group, hydroxyl group, cyano group, nitro group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted; More preferably, ring F is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, is optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl; Further preferably, ring F is selected from is optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl; denotes the position to which L4or L5is attached, when L4or L5is a bond, then denotes the position to which the carbonyl group or ring G is attached. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein Ring G is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing from 1-3 N, O, or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing from 1-3 N, O, or S atoms, said C 3-8 cycloalkyl, 3-8 membered heterocyclyl containing from 1-3 N, O, or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing from 1-3 N, O, or S atoms, optionally substituted with one or more substituents selected from R 55 , R7, R8, R9, or R 10 ; Preferably, ring G is selected from C 3-8 cycloalkyl, 5-6 membered monocyclic heterocyclyl containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclyl containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic heterocyclyl containing 1-3 N, O, or S atoms, C 6-10 aryl, 5-6 membered monocyclic heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally substituted with one or more substituents selected from R 55 , R7, R8, R9, or R 10 ; More preferably, ring G is selected from a phenyl ring, a naphthyl ring, a pyridine, optionally substituted by one or more substituents selected from R 55 , R7, R8, R9or R 10 10; Further preferably, ring G is selected from optionally substituted by one or more substituents selected from R 55 , R7, R8, R9or R 10 10; represents the position connected to L5, when L5 is a bond, then represents the position connected to ring F, when ring F is absent, represents the position connected to L4, when L4 is a bond, represents the position connected to C(O). A compound as shown below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the structure of the compound is as follows: A compound as shown below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the structure of the compound is as follows: A pharmaceutical composition comprising a therapeutically effective amount of a compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1-14, and one or more pharmaceutically acceptable carriers or excipients. The use of a compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1-14, or the pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment of a disease associated with M4, preferably the disease associated with M4 is selected from the group consisting of Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, Parkinson's disease or conditions, levodopa-induced dyskinesia in Parkinson's disease, Huntington's disease, dry mouth, pulmonary arterial hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down's syndrome, cerebral amyloid angiopathy, dementia, hereditary Dutch-type amyloid cerebral hemorrhage, Creutzfeldt-Jakob disease, prion disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism and atherosclerosis, more preferably Alzheimer's disease, schizophrenia, pain, addiction and sleep disorders.

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