Tricyclic compound, preparation method therefor, and use thereof in medicine

Abstract

The present disclosure relates to a tricyclic compound, a preparation method therefor, and the use thereof in medicine. In particular, the present disclosure relates to a tricyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the tricyclic compound, and the use thereof as a therapeutic agent, in particular the use as a VAV1 inhibitor or degradation agent, and the use in the preparation of a medicament for treating and / or preventing VAV1-mediated or -dependent diseases or conditions. The groups in general formula (I) are as defined in the description.

Description

Tricyclic compounds, their preparation methods and their pharmaceutical applications Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a tricyclic compound of general formula (I), a method for its preparation, a pharmaceutical composition containing the heterocyclic compound, and its use as a therapeutic agent, particularly as a VAV1 inhibitor or degrader, and in the preparation of medicaments for the treatment and / or prevention of VAV1-mediated or dependent diseases or conditions. Background Technology

[0002] The VAV family is a group of signal transduction proteins that act as nucleation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. In vertebrates, this family consists of three members: Vav1, Vav2, and Vav3. Vav1 primarily encodes and expresses GEFs in human hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells, while family members VAV2 and VAV3 are more commonly expressed. The multi-domain structure of VAV1 is crucial for its activation and function; different domains regulate both GEF-dependent and GEF-independent VAV1 activity and subsequent downstream signal transduction. Regarding the function of VAV1, researchers first discovered Vav1… - / - Mice exhibited severe T cell developmental defects, including a significant reduction in the number of thymic and peripheral T cells; conversely, Vav2... – / – Vav3 – / – and Vav2 – / – / 3 – / – The mouse model showed normal T cell development, indicating the crucial role of Vav1 in T cell development; secondly, Vav1 also affects signal transduction in T / B cells, for example: Vav1 - / - CD4 +Th cells exhibited a deficiency in IL-4 expression. Furthermore, CRISPR screening further validated the crucial role of VAV1 in TCR-mediated activation and T cell effector function. When the TCR, BCR, and other cytokine receptors are activated, Vav1 is rapidly phosphorylated, activating Rac GTPases. Vav1 plays a role in various cellular functions, including actin remodeling, F-actin polymerization, TCR aggregation, integrin-mediated cell adhesion activation, immune synapse formation between T cells and antigen-presenting cells (APCs), and chemokine-mediated cell migration. VAV1 also regulates B cell cytoskeleton remodeling. In addition, Vav1 functions as a scaffold protein in GEF-independent pathways. T cells derived from GEF-inactivated VAV1 mice showed normal TCR-mediated calcium release and NFAT pathway activation in vitro. Conversely, transfection of human VAV1-deficient J.Vav1 T cells with a GEF-retaining N-terminal truncated mutant resulted in incomplete Ca2+ release, calmodulin binding, and NFAT pathway activation in vitro due to the inability to interact with phospholipase C-γ (PLCγ)1. These findings demonstrate the scaffold function of VAV1. Although the exact role of VAV1 in human diseases remains to be clinically validated, multiple pieces of evidence suggest its association with autoimmune and chronic inflammatory diseases. VAV1-deficient mice antagonize MOG(5-55)-induced EAE, a model widely used to evaluate drug efficacy against multiple sclerosis. Genomic screening of primary human T cells using the CRISPRa and CRISPRi methods also revealed VAV1 as an important positive regulator of T cell function. These findings highlight VAV1's potential as a target in autoimmune and chronic diseases. Because VAV1 lacks a distinct binding pocket, it has long been considered an untreatable target. Molecular glue degraders (MGDs) are oral small molecules that induce ubiquitination and degradation of target proteins by binding to the surface of E3 ligase complexes, representing a novel class of molecules targeting proteins without a clear binding pocket. Monte Rosa Therapeutics has designed a molecular glue, MRT-6160, targeting VAV1. Through MGD, it degrades VAV1 protein, modulates TCR and BCR-mediated activation, and inhibits T cell proliferation and cytokine production. MRT-6160 has shown excellent preclinical efficacy in animal models of arthritis and colitis, providing a solid foundation for future clinical trials. This disclosure describes a molecular glue that specifically degrades VAV1. Summary of the Invention

[0003] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0004] in:

[0005] R 1 The tricyclic cycloalkyl, tricyclic heterocyclic, tricyclic aryl, and tricyclic heteroaryl groups are each independently and optionally converted by one or more R groups. 1a replace;

[0006] R 1a Selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0007] Or, two Rs 1a Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0008] L is selected from bond, O, S, C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), S(alkylene), NR c(alkylene), C(O)(alkylene) and (alkylene)C(O), wherein the alkylene is optionally converted by one or more R 0 replace;

[0009] R c Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0010] R 2 Selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuteralkyl groups, cyano groups, and cycloalkyl groups;

[0011] X is N or CR 6a ;

[0012] Y is N or CR 6d ;

[0013] R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0014] R 7Selected from hydrogen atom, deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy and deuteralkyl;

[0015] R 16 R 17 and R 18 The same or different, and each independently selected from hydrogen atoms, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0016] R 19 Selected from hydrogen atoms, alkyl groups, deuterated alkyl groups, and cycloalkyl groups;

[0017] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, and cycloalkyl; or, R 20 and R 21 Together with the attached carbon atom, they form cycloalkyl groups;

[0018] R 0 Selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0019] Or, two Rs 0 Together with the atoms attached thereto, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, deuteralkoxy and oxo.

[0020] v can be 0, 1, or 2.

[0021] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0022] in:

[0023] R 1 The tricyclic cycloalkyl, tricyclic heterocyclic, tricyclic aryl, and tricyclic heteroaryl groups are each independently and optionally converted by one or more R groups. 1a replace;

[0024] R 1a Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0025] Or, two Rs 1a Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0026] L is selected from bond, O, S, C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), S(alkylene), NR c(alkylene), C(O)(alkylene) and (alkylene)C(O), wherein the alkylene is optionally converted by one or more R 0 replace;

[0027] R c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0028] R 2 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, and cycloalkyl groups;

[0029] X is N or CR 6a ;

[0030] Y is N or CR 6d ;

[0031] R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0032] R 7 Selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups;

[0033] R 16 R 17 and R 18 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0034] R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0035] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, hydroxyl groups, and cycloalkyl groups; or, R 20 and R 21 Together with the atoms they are attached, they form cycloalkyl groups;

[0036] R 0 Selected from halogens, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0037] Or, two Rs 0 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and oxo.

[0038] v can be 0, 1, or 2.

[0039] In some embodiments of this disclosure, X is CR 6a ;R 6a As defined in general formula (I); in some implementations, X is CH; in some implementations, X is N.

[0040] In some embodiments disclosed herein, Y represents CR 6d ;R 6d As defined in general formula (I); in some implementations, Y is CH; in some implementations, Y is N.

[0041] In some embodiments of this disclosure, X is CR 6a Y is CR 6d ;R 6a and R 6d As defined in general formula (I); in some implementations, X is CH; Y is CH.

[0042] In some embodiments disclosed herein, R 7 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, hydroxyl and C 1-6 Deuterated alkyl; in some embodiments of this disclosure, R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and hydroxyl; in some embodiments, R 7 It is a hydrogen atom or a deuterium atom; in some embodiments, R 7 It is a hydrogen atom.

[0043] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof.

[0044] in:

[0045] R 1 -R 5 R 6a R 6b R 6c R 6d And L is as defined by general formula (I).

[0046] In some embodiments disclosed herein, R 3 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 3 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3 It is a hydrogen atom or a deuterium atom; in some embodiments, R 3 It is a hydrogen atom.

[0047] In some embodiments disclosed herein, R 4 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 4 It is a hydrogen atom or a deuterium atom; in some embodiments, R 4 It is a hydrogen atom.

[0048] In some embodiments disclosed herein, R 5 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5 It is a hydrogen atom or a deuterium atom; in some embodiments, R 5 It is a hydrogen atom.

[0049] In some embodiments disclosed herein, R 3 It is a hydrogen atom or a deuterium atom; and / or R 4 It is a hydrogen atom or a deuterium atom; and / or R 5 It is a hydrogen atom or a deuterium atom; in some embodiments, R 3 It is a hydrogen atom; and / or R 4 It is a hydrogen atom; and / or R 5 It is a hydrogen atom.

[0050] In some embodiments disclosed herein, R 6a Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 6a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6a It is a hydrogen atom or a deuterium atom; in some embodiments, R 6a It is a hydrogen atom.

[0051] In some embodiments disclosed herein, R 6b Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 6b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6b It is a hydrogen atom or a deuterium atom; in some embodiments, R6b It is a hydrogen atom.

[0052] In some embodiments disclosed herein, R 6c Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 6c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6c It is a hydrogen atom or a deuterium atom; in some embodiments, R 6c It is a hydrogen atom.

[0053] In some embodiments disclosed herein, R 6d Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 6d Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6d It is a hydrogen atom or a deuterium atom; in some embodiments, R 6d It is a hydrogen atom.

[0054] In some embodiments disclosed herein, R 6a It is a hydrogen atom or a deuterium atom; and / or R 6b It is a hydrogen atom or a deuterium atom; and / or R 6c It is a hydrogen atom or a deuterium atom; and / or R 6d It is a hydrogen atom or a deuterium atom; in some embodiments, R 6a It is a hydrogen atom; and / or R 6b It is a hydrogen atom; and / or R 6c It is a hydrogen atom; and / or R 6d It is a hydrogen atom.

[0055] In some embodiments disclosed herein, R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; R 6d It is a hydrogen atom.

[0056] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.

[0057] in:

[0058] L, R 1 and R2 As defined in general formula (I).

[0059] In some embodiments disclosed herein, L is selected from key, O, C 1-3 Alkylene and OC 1-3 Alkylene; in some embodiments, L is selected from bond, O, CH2 and OCH2; in some embodiments, L is bond; in some embodiments, L is O; in some embodiments, L is CH2, CH2 and CH2CH2CH2; in some embodiments, L is CH2; in some embodiments, L is OCH2.

[0060] In some embodiments disclosed herein, R 1 It is a 9- to 16-membered tricyclic heterocyclic group or a 9- to 16-membered tricyclic heteroaryl group, wherein each of the 9- to 16-membered tricyclic heterocyclic group and the 9- to 16-membered tricyclic heteroaryl group is independently and optionally converted by one or more R 1a Replace; R 1a As defined in general formula (I);

[0061] In some implementation schemes, R 1 It is a 9- to 16-membered tricyclic heterocyclic group or a 9- to 16-membered tricyclic heteroaryl group, wherein each of the 9- to 16-membered tricyclic heterocyclic group and the 9- to 16-membered tricyclic heteroaryl group is independently and optionally converted by one or more R 1a Replace; R 1a Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl and oxo group; or, two R groups. 1a Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups;

[0062] In some implementation schemes, R 1 It is an 11- to 15-membered tricyclic heterocyclic group or an 11- to 15-membered tricyclic heteroaryl group, wherein each of the 11- to 15-membered tricyclic heterocyclic group and the 11- to 15-membered tricyclic heteroaryl group is independently and optionally converted by one or more R 1a Replace; R 1a C 1-6 Alkyl or oxo group.

[0063] In some implementation schemes, R 1 It is an 11- to 13-membered tricyclic heterocyclic group or an 11- to 13-membered tricyclic heteroaryl group, wherein each of the 11- to 13-membered tricyclic heterocyclic group and the 11- to 13-membered tricyclic heteroaryl group is independently and optionally converted by one or more R 1a Replace; R 1a Selected from deuterium atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups, oxoalkyl groups, and 3- to 6-membered cycloalkyl groups.

[0064] In some embodiments of this disclosure, R 1 Selected from In some implementation schemes, R 1 Selected from B is selected from CH2, O, S, and NR. 1m B 1 For N or CR 1b B 2 For N or CR 1c B 3 For N or CR 1d B 4 For N or CR 1e B 5 For N or CR 1h B 6 For N or CR 1f B 7 For N or CR 1g B 8 For N or CR 1n G is selected from O, S, and NR. 1k ; d is 0, 1, 2, or 3; d1 is 0, 1, 2, or 3; k is 0, 1, 2, or 3; a1, a, and b are each independently 1, 2, 3, 4, or 5; the condition is that when d1 is 0, a1 is selected from 2, 3, 4, or 5; when k is 0, b is selected from 2, 3, 4, or 5; R 1k and R 1m Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, and heterocyclic alkyl groups; R 1b R 1c R 1d R 1e R 1f R 1g R 1h and R 1n Each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 Replace; or, R 1b and R 1c Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1e Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1h Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1e and R 1k Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1h and R 1k Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1g Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1n Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 Replace; R 0 R 16 -R 19 And v is as defined in general formula (I).

[0065] In some implementation schemes, R 1 Selected from

[0066] R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups and 3- to 6-membered cycloalkyl groups; R 1k Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl groups and 3- to 6-membered cycloalkyl groups; or, R 1b and R 1c Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl groups or 3- to 6-membered heterocyclic groups, or, R 1d and R 1e Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl groups or 3- to 6-membered heterocyclic groups, or, R 1d and R 1h Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl groups or 3- to 6-membered heterocyclic groups, or, R 1f and R 1g Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; or, R 1e and R 1k Together with their respective connected atoms, they form 3 to 6-membered heterocyclic groups; a is 1 or 2; a1 is 1 or 2; b is 1 or 2; d is 0, 1 or 2; d1 is 1, 2 or 3; k is 1 or 2;

[0067] In some implementation schemes, R 1 Selected from

[0068] In some implementation schemes, R 1 Selected from

[0069] In some embodiments of this disclosure, R 1 Selected from In some implementation schemes, R 1 Selected from Where a1, a, and b are each independently 1, 2, 3, 4, or 5; d1 is 0, 1, 2, or 3; d is 0, 1, 2, or 3; k is 0, 1, 2, or 3; the condition is that when d1 is 0, a1 is selected from 2, 3, 4, or 5; when k is 0, b is selected from 2, 3, 4, or 5; R 1k Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, and heterocyclic alkyl groups; R1b R 1c R 1d R 1e R 1f R 1g and R 1h Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 Replace; or, R 1b and R 1c Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1e Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1h Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1g Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1e and R 1k Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 Replace; R 0 R 16 -R 19And v is as defined in general formula (I); in some embodiments, a1, a, and b are each independently 1, 2, 3, 4, or 5; d1 is 0, 1, 2, or 3; d is 0, 1, 2, or 3; k is 0, 1, 2, or 3; the condition is that when d1 is 0, a1 is selected from 2, 3, 4, or 5; when k is 0, b is selected from 2, 3, 4, or 5; R 1k Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, and heterocyclic alkyl groups; R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 Replace; or, R 1b and R 1c Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1e Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1h Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1gTogether with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1e and R 1k Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 Replace; R 0 R 16 -R 19 And v is as defined in general formula (I).

[0070] In some embodiments of this disclosure, R 1 Selected from In some implementation schemes, R 1 Selected from In some implementation schemes, R 1 for In some implementation schemes, R 1 for in,

[0071] a and b are each independently 1, 2, 3, 4, or 5; R 1b R 1c R 1d R 1e R 1f and R 1g Each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0072] Or, R 1b and R 1c Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1e Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1g Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 Replace; R 0 R 16 -R 19 And v is as defined in general formula (I).

[0073] In some implementation schemes, R 1 Selected from

[0074] In some embodiments disclosed herein, R 1 Selected from In some implementation schemes, R 1 Selected from

[0075] In some implementation schemes, R 1 Selected from In some implementation schemes, R 1 Selected from In some implementation schemes, R 1 Selected from

[0076] In some implementation schemes, R 1 Selected from

[0077] In some implementation schemes, R 1 for

[0078] In some implementation schemes, R 1 for

[0079] In some implementation schemes, R 1 for

[0080] In some implementation schemes, R 1 for

[0081] In some implementation schemes, R 1 Selected from

[0082] In some embodiments of this disclosure, a is 1 or 2; in some embodiments, a is 1; in some embodiments, a is 2.

[0083] In some embodiments of this disclosure, a1 is 1 or 2; in some embodiments, a1 is 1; and in some embodiments, a1 is 2.

[0084] In some embodiments of this disclosure, b is 1 or 2; in some embodiments, b is 1; and in some embodiments, b is 2.

[0085] In some embodiments of this disclosure, d is 0, 1, or 2; in some embodiments, d is 0 or 1; in some embodiments, d is 0; and in some embodiments, d is 1.

[0086] In some embodiments of this disclosure, d1 is 0, 1, or 2; in some embodiments, d1 is 1 or 2; in some embodiments, d1 is 0; and in some embodiments, d1 is 1.

[0087] In some embodiments of this disclosure, d1 is 0 and a1 is 2; in some embodiments, d1 is 1 and a1 is 1 or 2; in some embodiments, d1 is 1 and a1 is 1.

[0088] In some embodiments of this disclosure, k is 0, 1, or 2; in some embodiments, k is 1 or 2; in some embodiments, k is 0; and in some embodiments, k is 1.

[0089] In some embodiments of this disclosure, k is 0 and b is 2; in some embodiments, k is 1 and b is 1 or 2; in some embodiments, k is 1 and b is 1.

[0090] In some embodiments of this disclosure, B is O and CH2; in other embodiments, B is O.

[0091] In some embodiments disclosed herein, B 1For CR 1b ;R 1b As defined above; in some implementations, B 1 For CH.

[0092] In some embodiments disclosed herein, B 2 For CR 1c ;R 1c As defined above; in some implementations, B 2 For CH.

[0093] In some embodiments disclosed herein, B 3 For CR 1d ;R 1d As defined above.

[0094] In some embodiments disclosed herein, B 4 It can be N or CH.

[0095] In some embodiments disclosed herein, B 5 It can be N or CH.

[0096] In some embodiments disclosed herein, B 6 For CR 1f ;R 1f As defined above.

[0097] In some embodiments disclosed herein, B 7 For CR 1g ;R 1g As defined above; in some implementations, B 7 For CH.

[0098] In some embodiments disclosed herein, B 8 For N or CH; in some implementations, B 8 Let N be the number of elements in the array.

[0099] In some embodiments of this disclosure, G is NR 1k ;R 1k As defined above; in some implementations, G is N-methyl.

[0100] In some embodiments disclosed herein, R 1a They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy and oxo groups; or, two R groups. 1a Together with the attached atoms, they form a 3- to 8-membered cycloalkyl group; in some embodiments, R 1aThey may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl and oxo group; or, two R groups. 1a Together with the attached atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 1a Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and oxo groups; in some embodiments, R 1a Selected from deuterium atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups, oxoyl groups, and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1a Selected from C 1-6 Alkyl, oxo, and 3- to 6-membered cycloalkyl; in some embodiments, R 1a C 1-6 Alkyl or oxo group; in some embodiments, R 1a It is a methyl or oxo group; in some embodiments, R 1a For oxygen groups; in some embodiments, the two R groups are... 1a Together with the adjacent atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, two R atoms on the same carbon atom 1a Together with the atoms attached to it, they form a cyclopropyl group.

[0101] In some embodiments disclosed herein, R 1b R 1c R 1d R 1e R 1f and R 1g Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and 3 to 6-membered cycloalkyl; or, R 1b and R 1c Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl groups, or, R 1d and R 1e Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl groups, or, R 1f and R 1g Together with their respective attached atoms, they form 3- to 6-membered cycloalkyl groups; in some embodiments, R 1b R 1c R 1d R 1e R 1f and R 1gEach is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1b R 1c R 1d R 1e R 1f and R 1g Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1b R 1c R 1d R 1e R 1f and R 1g Each is independently selected from hydrogen atoms, methyl, isopropyl, and cyclopropyl; in some embodiments, R 1b and R 1c Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 1b and R 1c Each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 1b and R 1c Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Deuterated alkyl; in some embodiments, R 1b and R 1c Each is independently selected from hydrogen atoms, deuterium atoms, and deuterated methyl groups; in some embodiments, R 1b and R 1c For hydrogen atoms; in some implementations, R 1e For hydrogen atoms; in some implementations, R 1g For hydrogen atoms; in some implementations, R 1e For hydrogen atoms; R 1d Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1g For hydrogen atoms; R 1f Selected from hydrogen atoms, C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups.

[0102] In some embodiments disclosed herein, R 1b It is a hydrogen atom.

[0103] In some embodiments disclosed herein, R 1c It is a hydrogen atom.

[0104] In some implementation schemes, R 1d Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1d Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1d Selected from hydrogen atoms, deuterium atoms, methyl groups, deuterated methyl groups, isopropyl groups, and cyclopropyl groups; in some embodiments, R 1d Selected from hydrogen atom, methyl, isopropyl and cyclopropyl.

[0105] In some implementation schemes, R 1e Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 1e Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1e It is a hydrogen atom.

[0106] In some implementation schemes, R 1f Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 1f It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 1f It can be a hydrogen atom or a methyl group.

[0107] In some embodiments disclosed herein, R 1g Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 1g It is a hydrogen atom.

[0108] In some embodiments disclosed herein, R 1h Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1h Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1h Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 1h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 1h It is a hydrogen atom.

[0109] In some embodiments disclosed herein, R 1n Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 1n Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1n It is a hydrogen atom.

[0110] In some embodiments disclosed herein, R 1k Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1k Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 1k C 1-6 Alkyl; in some embodiments, R 1k It is a methyl group.

[0111] In some embodiments disclosed herein, R 1m Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 1m It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0112] In some implementation schemes disclosed herein, for In some implementation schemes, for In some implementation schemes, for

[0113] In some embodiments disclosed herein, R 16 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 16 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 16 C 1-6 alkyl.

[0114] In some embodiments disclosed herein, R 17 and R 18 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Deuterated alkyl; in some embodiments, R 17 and R 18 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0115] In some embodiments disclosed herein, R 19 It is a hydrogen atom.

[0116] In some embodiments disclosed herein, R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 20 and R 21 It is F.

[0117] In some embodiments of this disclosure, v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0118] In some embodiments disclosed herein, R 0 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy and oxo groups; or two R groups 0 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl group; in some embodiments, R 0 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy and oxo groups; in some embodiments, R0 Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 0 It is an oxo group.

[0119] In some embodiments disclosed herein, R t Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl and oxo group; in some embodiments, R t Selected from halogens, C 1- 6-alkyl and C 1-6 Halogenated alkyl groups.

[0120] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; R 3 It is a hydrogen atom or a deuterium atom; R 4 It is a hydrogen atom or a deuterium atom; R 5 It is a hydrogen atom or a deuterium atom; X is a CR atom. 6a ;R 6a It is a hydrogen atom or a deuterium atom; R 6b It is a hydrogen atom or a deuterium atom; R 6c It consists of hydrogen or deuterium atoms; Y is CR 6d ;R 6d It is a hydrogen atom or a deuterium atom; R 7 It consists of hydrogen or deuterium atoms; L represents a bond; R represents a hydrogen atom or deuterium atom. 1 Selected from a is 1 or 2; a1 is 1; b is 1; d is 1; d1 is 1; k is 1; R 1b and R 1c Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Deuterated alkyl; R 1d Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; R 1e For hydrogen atoms; R 1h It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 1f It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 1g For hydrogen atoms; R 1k C 1- 6-alkyl group.

[0121] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; L is selected from bond, O, CH2 and OCH2; R 1 It is an 11- to 15-membered tricyclic heterocyclic group or an 11- to 15-membered tricyclic heteroaryl group, wherein each of the 11- to 15-membered tricyclic heterocyclic group and the 11- to 15-membered tricyclic heteroaryl group is independently and optionally converted by one or more R 1a Replace; R 1a C 1-6 Alkyl or oxo group.

[0122] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; L is selected from bond, O, CH2 and OCH2; R 1 It is an 11- to 13-membered tricyclic heterocyclic group or an 11- to 13-membered tricyclic heteroaryl group, wherein each of the 11- to 13-membered tricyclic heterocyclic group and the 11- to 13-membered tricyclic heteroaryl group is independently and optionally converted by one or more R 1a Replace; R 1a Selected from deuterium atoms, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups, oxoalkyl groups, and 3- to 6-membered cycloalkyl groups.

[0123] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; L is selected from bond, O, CH2 and OCH2; R 1 Selected from

[0124] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 Selected from a is 1 or 2; a1 is 1 or 2; b is 1 or 2; d is 0 or 1; d1 is 1 or 2; k is 1; R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; R 1k Selected from hydrogen atoms, C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups.

[0125] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 Selected from a is 1 or 2; b is 1; R 1b R 1c R 1d R 1e R 1f and R 1g Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups.

[0126] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 Selected from a = 2; b = 1; R 1b R 1c R 1d R 1e R 1f and R 1g Each is independently selected from hydrogen atoms, halogens, and C atoms. 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups.

[0127] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 Selected from

[0128] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 Selected from

[0129] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 for a is 1 or 2; R 1b and R 1c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups.

[0130] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 for b is 1; R 1e For hydrogen atoms; R 1d Selected from hydrogen atoms, C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups.

[0131] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen; L is a bond; R 1 for a1 is 1 or 2; d1 is 1 or 2; R 1b and R 1c Each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 alkyl.

[0132] This disclosure also relates to the following specific implementation plans:

[0133] 1. A pharmaceutical composition, based on the total weight of the composition, comprising 3%-97% of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0134] in:

[0135] R 1 The tricyclic cycloalkyl, tricyclic heterocyclic, tricyclic aryl, and tricyclic heteroaryl groups are each independently and optionally converted by one or more R groups. 1a replace;

[0136] R 1aSelected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0137] Or, two Rs 1a Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0138] L is selected from bond, O, S, C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), S(alkylene), NR c (alkylene), C(O)(alkylene) and (alkylene)C(O), wherein the alkylene is optionally converted by one or more R 0 replace;

[0139] R c Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0140] R 2Selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuteralkyl groups, cyano groups, and cycloalkyl groups;

[0141] X is N or CR 6a ;

[0142] Y is N or CR 6d ;

[0143] R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0144] R 7 Selected from hydrogen atom, deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy and deuteralkyl;

[0145] R 16 R 17 and R 18The same or different, and each independently selected from hydrogen atoms, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0146] R 19 Selected from hydrogen atoms, alkyl groups, deuterated alkyl groups, and cycloalkyl groups;

[0147] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, and cycloalkyl; or, R 20 and R 21 Together with the attached carbon atom, they form cycloalkyl groups;

[0148] R 0 Selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0149] Or, two Rs 0 Together with the atoms attached thereto, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, deuteralkoxy and oxo.

[0150] v can be 0, 1, or 2.

[0151] 2. A pharmaceutical composition, based on the total weight of the composition, comprising 3%-97% of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0152] in:

[0153] R 1 The tricyclic cycloalkyl, tricyclic heterocyclic, tricyclic aryl, and tricyclic heteroaryl groups are each independently and optionally converted by one or more R groups. 1a replace;

[0154] R 1a Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0155] Or, two Rs 1a Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0156] L is selected from bond, O, S, C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), S(alkylene), NR c (alkylene), C(O)(alkylene) and (alkylene)C(O), wherein the alkylene is optionally converted by one or more R 0 replace;

[0157] Rc Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0158] R 2 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, and cycloalkyl groups;

[0159] X is N or CR 6a ;

[0160] Y is N or CR 6d ;

[0161] R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0162] R 7 Selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups;

[0163] R 16 R 17 and R 18The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0164] R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0165] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, hydroxyl groups, and cycloalkyl groups; or, R 20 and R 21 Together with the atoms they are attached, they form cycloalkyl groups;

[0166] R 0 Selected from halogens, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0167] Or, two Rs 0 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and oxo.

[0168] v can be 0, 1, or 2.

[0169] 3. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the unit dose of the pharmaceutical composition is 0.15 mg to 900 mg.

[0170] in:

[0171] R 1The tricyclic cycloalkyl, tricyclic heterocyclic, tricyclic aryl, and tricyclic heteroaryl groups are each independently and optionally converted by one or more R groups. 1a replace;

[0172] R 1a Selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0173] Or, two Rs 1a Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0174] L is selected from bond, O, S, C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), S(alkylene), NR c (alkylene), C(O)(alkylene) and (alkylene)C(O), wherein the alkylene is optionally converted by one or more R 0 replace;

[0175] R cSelected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0176] R 2 Selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuteralkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, deuteralkyl groups, cyano groups, and cycloalkyl groups;

[0177] X is N or CR 6a ;

[0178] Y is N or CR 6d ;

[0179] R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0180] R 7 Selected from hydrogen atom, deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy and deuteralkyl;

[0181] R 16 R17 and R 18 The same or different, and each independently selected from hydrogen atoms, alkyl, deuterated alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0182] R 19 Selected from hydrogen atoms, alkyl groups, deuterated alkyl groups, and cycloalkyl groups;

[0183] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, hydroxyl, and cycloalkyl; or, R 20 and R 21 Together with the attached carbon atom, they form cycloalkyl groups;

[0184] R 0 Selected from deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteryl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0185] Or, two Rs 0 Together with the atoms attached thereto, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from deuterium, halogen, alkyl, haloalkyl, deuteralkyl, alkoxy, haloalkoxy, deuteralkoxy and oxo.

[0186] v can be 0, 1, or 2.

[0187] 4. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the unit dose of the pharmaceutical composition is 0.15 mg to 900 mg.

[0188] in:

[0189] R 1 The tricyclic cycloalkyl, tricyclic heterocyclic, tricyclic aryl, and tricyclic heteroaryl groups are each independently and optionally converted by one or more R groups. 1a replace;

[0190] R 1a Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0191] Or, two Rs 1a Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0192] L is selected from bond, O, S, C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), S(alkylene), NR c (alkylene), C(O)(alkylene) and (alkylene)C(O), wherein the alkylene is optionally converted by one or more R 0 replace;

[0193] R c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0194] R 2 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, and cycloalkyl groups;

[0195] X is N or CR 6a ;

[0196] Y is N or CR 6d ;

[0197] R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0198] R 7 Selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups;

[0199] R 16 R 17 and R 18The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are each independently optionally selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0200] R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0201] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, hydroxyl groups, and cycloalkyl groups; or, R 20 and R 21 Together with the atoms they are attached, they form cycloalkyl groups;

[0202] R 0 Selected from halogens, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0203] Or, two Rs 0 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and oxo.

[0204] v can be 0, 1, or 2.

[0205] 5. The pharmaceutical composition according to any one of embodiments 1 to 4, wherein the compound of general formula (I) or a pharmaceutically acceptable salt thereof is the compound of general formula (II) or a pharmaceutically acceptable salt thereof.

[0206] in:

[0207] R 1 -R 5 R 6a R6b R 6c R 6d And L as defined in implementation schemes 1, 2, 3 or 4.

[0208] 6. The pharmaceutical composition according to any one of embodiments 1 to 5, wherein R 3 It is a hydrogen atom or a deuterium atom; and / or R 4 It is a hydrogen atom or a deuterium atom; and / or R 5 It consists of hydrogen or deuterium atoms;

[0209] Furthermore, R 3 It is a hydrogen atom; and / or R 4 It is a hydrogen atom; and / or R 5 It is a hydrogen atom.

[0210] 7. The pharmaceutical composition according to any one of embodiments 1 to 6, wherein R 6a It is a hydrogen atom or a deuterium atom; and / or R 6b It is a hydrogen atom or a deuterium atom; and / or R 6c It is a hydrogen atom or a deuterium atom; and / or R 6d It consists of hydrogen or deuterium atoms;

[0211] Furthermore, R 6a It is a hydrogen atom; and / or R 6b It is a hydrogen atom; and / or R 6c It is a hydrogen atom; and / or R 6d It is a hydrogen atom.

[0212] 8. The pharmaceutical composition according to any one of embodiments 1 to 7, wherein the compound of general formula (I) or a pharmaceutically acceptable salt thereof is the compound of general formula (III) or a pharmaceutically acceptable salt thereof.

[0213] in:

[0214] L, R 1 and R 2 As defined in implementation schemes 1, 2, 3 or 4.

[0215] 9. The pharmaceutical composition according to any one of embodiments 1 to 8, wherein L is selected from bond, O, CH2 and OCH2; further, L is bond.

[0216] 10. The pharmaceutical composition according to any one of embodiments 1 to 9, wherein R 1 Selected from a1, a, and b are each independently 1, 2, 3, 4, or 5; d1 is 0, 1, 2, or 3; d is 0, 1, 2, or 3; k is 0, 1, 2, or 3; the condition is that when d1 is 0, a1 is selected from 2, 3, 4, or 5; when k is 0, b is selected from 2, 3, 4, or 5; R 1k Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, and heterocyclic alkyl groups; R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0217] Or, R 1b and R 1c Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1e Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1h Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1gTogether with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1e and R 1k Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 Replace; R 0 R 16 -R 19 and v as defined in implementation scheme 1;

[0218] Furthermore, R 1 Selected from

[0219] 11. The pharmaceutical composition according to any one of embodiments 1 to 10, wherein R 2 For halogen; further, R 2 It is Cl.

[0220] 12. The pharmaceutical composition according to any one of embodiments 1 to 11, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is selected from the compounds shown in Table A or pharmaceutically acceptable salts thereof.

[0221] 13. The pharmaceutical composition according to any one of embodiments 1 to 12, wherein the pharmaceutical composition is a tablet, capsule, powder, granule, drop pill, film or injection.

[0222] 14. The pharmaceutical composition according to any one of embodiments 1 to 13, wherein the pharmaceutically acceptable excipient is selected from carriers, excipients, fillers, disintegrants, lubricants, binders, coating agents, flow aids, sweeteners, diluents, preservatives, dyes / coloring agents, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers;

[0223] Further, the pharmaceutically acceptable excipients are selected from starch, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, powdered cellulose, sugar alcohols, inorganic salts, micronized silica gel, magnesium oxide, distilled water, ethanol, starch paste, cellulose derivatives, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, povidone, gelatin, gum arabic, sucrose, alginate, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose, effervescent disintegrants, surfactants, agar, magnesium stearate, talc, micronized silica gel, polyethylene glycol, sodium lauryl sulfate, boric acid, magnesium lauryl sulfate, leucine, sodium oleate, sodium benzoate, and sodium acetate.

[0224] 15. A method for preparing a pharmaceutical composition according to any one of embodiments 1 to 14, the method comprising the following steps:

[0225] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0226] in:

[0227] R w Selected from Bpin and -B(OH)2;

[0228] R L For leaving groups; further, R L For halogens; furthermore, R L For Br;

[0229] R 1 -R 5 R 7 X, Y, L, R 6b and R 6c As defined in any one of Implementation Schemes 1 to 11.

[0230] 16. A kit comprising a pharmaceutical composition according to any one of embodiments 1 to 14.

[0231] 17. Use of the pharmaceutical composition according to any one of embodiments 1 to 14, or the kit according to embodiment 16, in the preparation of a medicament for inhibiting or degrading VAV1.

[0232] 18. Use of the pharmaceutical composition according to any one of embodiments 1 to 14, or the kit according to embodiment 16, in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on VAV1.

[0233] 19. Use of the pharmaceutical composition according to any one of embodiments 1 to 14, or the kit according to embodiment 16, in the preparation of a medicament for treating and / or preventing tumors, autoimmune diseases, and inflammatory diseases; wherein said autoimmune or inflammatory diseases are further selected from autoimmune encephalomyelitis (EAE), multiple sclerosis, arthritis, rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, Graves' disease, alopecia areata, allergic diseases, asthma, allergic asthma, atopic dermatitis, and allergic skin diseases. Inflammation, rhinitis, conjunctivitis, allergic contact dermatitis, colitis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphine scleroderma, chronic inflammatory demyelinating polyradiculoneuropathy, Alzheimer's disease, autoimmune liver disease, hepatitis, amyloidosis, macular degeneration, lupus nephritis, pulmonary hypertension, chronic graft-versus-host disease, acute graft-versus-host disease, cholecystitis, sclerosing cholangitis, and axial spondyloarthritis.

[0234] Table A lists typical compounds disclosed herein, including but not limited to:

[0235] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0236] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0237] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0238] in:

[0239] R w Selected from Bpin and -B(OH)2;

[0240] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0241] R 1 -R 5 R 7 X, Y, L, R 6b and R 6c As defined in general formula (I).

[0242] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0243] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIB) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0244] in:

[0245] R w Selected from Bpin and -B(OH)2;

[0246] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0247] R 1 -R 5 R 6a R 6b R 6c R 6d And L is as defined in general formula (II).

[0248] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0249] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0250] in:

[0251] R w Selected from Bpin and -B(OH)2;

[0252] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0253] R 1 R 2 And L is as defined in general formula (III).

[0254] In some implementation schemes, R w for

[0255] In some embodiments of this disclosure, the preparation methods of the compounds represented by general formulas (I), (II), or (III) or their pharmaceutically acceptable salts, wherein the coupling reaction is carried out under alkaline conditions and with the action of a metal catalyst; the metal catalyst includes, but is not limited to, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; the reagent providing the alkaline conditions includes organic and inorganic bases, wherein the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, the reagent providing the alkaline conditions is potassium phosphate.

[0256] In some embodiments of this disclosure, the preparation method of the compound represented by general formula (I), (II) or (III) or its pharmaceutically acceptable salt thereof, wherein the coupling reaction is carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0257] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III) or Table A of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0258] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for inhibiting or degrading VAV1.

[0259] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating the ubiquitination and degradation of VAV1 protein in a subject.

[0260] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on VAV1.

[0261] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of tumors, autoimmune diseases, and inflammatory diseases.

[0262] This disclosure also relates to a method for regulating the ubiquitination and degradation of VAV1 protein in a subject, comprising administering to a desired patient a compound of the above general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0263] This disclosure also relates to a method of inhibiting or degrading VAV1 in a subject, comprising administering to a desired patient a compound of the above general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0264] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on VAV1, comprising administering to a desired patient a compound of the above general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0265] This disclosure also relates to a method of treating and / or preventing tumors, autoimmune diseases and inflammatory diseases, comprising administering to a desired patient a compound of the above general formula (I), (II), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0266] This disclosure further relates to a compound of the above general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0267] This disclosure further relates to a compound of the above general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a drug for regulating the ubiquitination and degradation of VAV1 protein in a subject.

[0268] This disclosure further relates to a compound of the above general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on VAV1.

[0269] This disclosure further relates to compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for regulating VAV1 protein ubiquitination and degradation in a subject.

[0270] This disclosure further relates to compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading VAV1 in a subject.

[0271] This disclosure further relates to compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on VAV1.

[0272] This disclosure further relates to compounds of the above general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of tumors, autoimmune diseases and inflammatory diseases.

[0273] In some embodiments, the VAV1-mediated or dependent diseases or conditions described in this disclosure are selected from tumors, autoimmune diseases, and inflammatory diseases; in some embodiments, the VAV1-mediated or dependent diseases or conditions described in this disclosure are autoimmune diseases or inflammatory diseases; in some embodiments, the VAV1-mediated or dependent diseases or conditions described in this disclosure are tumors.

[0274] In some embodiments, the autoimmune or inflammatory diseases described in this disclosure are selected from autoimmune encephalomyelitis (EAE), multiple sclerosis, arthritis, rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, Graves' disease, alopecia areata, allergic diseases, asthma, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, allergic contact dermatitis, colitis, inflammatory bowel disease (IBD), Crohn's disease, and other related conditions. Engel's disease, ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, chronic inflammatory demyelinating polyradiculoneuropathy, Alzheimer's disease, autoimmune liver disease, hepatitis, amyloidosis, macular degeneration, lupus nephritis, pulmonary hypertension, chronic graft-versus-host disease, acute graft-versus-host disease, cholesclerosis, sclerosing cholangitis, and axial spondyloarthritis.

[0275] In some embodiments, the autoimmune or inflammatory diseases described in this disclosure are selected from systemic lupus erythematosus (SLE), ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, and Kawasaki disease. Diseases, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis (IC), mixed connective tissue disease (MCTD), morphine scleroderma, multiple sclerosis, chronic spontaneous urticaria (CSU), neuromuscular rigidity, psoriasis, psoriatic arthritis, psoriasis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiffness syndrome, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis. Atosis), atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease; in some embodiments, the autoimmune diseases described in this disclosure are selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and Guillain-Barré syndrome (GBS); in some embodiments, the autoimmune diseases described in this disclosure are selected from atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease.

[0276] In some embodiments, the tumors described in this disclosure are selected from lymphoma, leukemia, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, melanoma, sarcoma, Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, and peripheral neuroepithelial tumor. Neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, glioblastoma, neuroblastoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma, prostate cancer, endometrial cancer, testicular cancer, thyroid cancer, astrocytoma, carcinosarcoma, Hodgkin's disease, nephroblastoma and teratoma; in some embodiments, the tumors described in this disclosure are selected from leukemia, lymphoma, breast cancer and lung cancer; in some embodiments, the tumors described in this disclosure are leukemia or lymphoma; in some embodiments, the tumors described in this disclosure are lymphoma.

[0277] In some implementations, the tumor described in this disclosure is cancer.

[0278] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0279] In some implementations, the lung cancer described in this disclosure is non-small cell lung cancer (NSCLC).

[0280] In some embodiments, the lymphoma described in this disclosure is selected from non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DIBCLs), Burkitt lymphoma, T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, lymphoblastic lymphoma, Pre-B lymphoma, B-cell lymphoma, B-cell ALL, follicular lymphoma, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, and Waldenström macroglobulinemia (WM); in some embodiments, the lymphoma described in this disclosure is B-cell lymphoma; in some embodiments, the lymphoma described in this disclosure is diffuse large B-cell lymphoma; in some embodiments, the lymphoma described in this disclosure is non-Hodgkin lymphoma (NHL); in some embodiments, the lymphoma described in this disclosure is relapsed / refractory non-Hodgkin lymphoma.

[0281] In some embodiments, the leukemia described in this disclosure is selected from T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, precursor B-cell acute lymphoblastic leukemia (Pre-B ALL), B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia (CLL), B-cell leukemia, and chronic myeloid leukemia.

[0282] The active compounds can be formulated into forms suitable for administration via any appropriate route. As a general guideline, the active compounds of this disclosure are, in some embodiments, in a unit dose manner or in a manner that a patient can self-administer as a single dose. The unit dose of the disclosed compounds or compositions can be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg. In some embodiments, a suitable unit dose may be 0.1 mg to 1000 mg.

[0283] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0284] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0285] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0286] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0287] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0288] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0289] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0290] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0291] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0292] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0293] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0294] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0295] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0296] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0297] Terminology Explanation

[0298] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0299] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments, having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). 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. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. In some embodiments, the substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0300] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point; in some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0301] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker; in some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0302] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments, alkylenes having 1 to 8 carbon atoms (i.e., C1646-C ... 1-8 Alkylenes), in some embodiments, are selected to have 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylene; in some embodiments, alkylene having 1, 2, or 3 carbon atoms (i.e., C14) 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable link. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0303] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable link. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0304] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group) or a cycloalkyl group having 4 to 11 ring atoms (i.e., a 4 to 11-membered cycloalkyl group); in some embodiments, a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group); in some embodiments, a cycloalkyl group having 4 to 8 ring atoms (i.e., a 4 to 8-membered cycloalkyl group); in some embodiments, a cycloalkyl group having 4 to 6 ring atoms (i.e., a 4 to 6-membered cycloalkyl group); and in some embodiments, a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group).

[0305] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0306] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0307] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.). In some embodiments, it is a monospirocyclic alkyl or a bispirocyclic alkyl. In some embodiments, the spirocyclic alkyl group is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0308] Its connection point can be anywhere;

[0309] wait.

[0310] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a ternary / quadrivalent, ternary / quinary, ternary / six-membered, quadrivalent / quadrivalent, quadrivalent / five-membered, quadrivalent / six-membered, quadrivalent / quadrivalent, quadrivalent / six-membered, 5-member / tertiary, 5-member / quadrivalent, 5-member / five-membered, 5-member / six-membered, 5-member / seven-membered, 6-member / tertiary, 6-member / quadrivalent, 6-member / four-membered, 6-member / five-membered, 6-member / six-membered, 6-member / seven-membered, 7-member / five-membered, or 7-member / six-member bicyclic fused cyclic alkyl group. Non-limiting examples include: Its connection point can be anywhere; wait.

[0311] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl with 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl with 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be anywhere.

[0312] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0313] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group is a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 11 to 13 ring atoms (i.e., an 11 to 13-membered heterocyclic group); in some embodiments, a heterocyclic group having 11 ring atoms (i.e., an 11-membered heterocyclic group); and in some embodiments, a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group).

[0314] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0315] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0316] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups). In some embodiments, it is a monospirocyclic or bispirocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include:

[0317] wait.

[0318] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group); in some embodiments, it is a fused heterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered fused heterocyclic group); and in some embodiments, it is a fused heterocyclic group having 9 ring atoms (i.e., a 9-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.). In some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include: wait.

[0319] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds, and the system contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and in some embodiments, it has 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include: wait.

[0320] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0321] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl group further includes fusion of the phenyl group with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl group with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including: wait.

[0322] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0323] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl group is, in some embodiments, a heteroaryl group with 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), in some embodiments a heteroaryl group with 11 to 13 ring atoms (i.e., an 11 to 13-membered heteroaryl group), in some embodiments a heteroaryl group with 11 ring atoms (i.e., an 11-membered heteroaryl group), and in some embodiments a heteroaryl group with 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0324] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0325] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples of polycyclic heteroaryl groups include: wait.

[0326] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0327] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0328] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0329] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0330] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0331] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0332] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0333] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0334] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0335] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0336] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0337] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0338] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0339] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0340] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0341] The term "deuterated alkoxy" refers to an alkoxy group that is replaced by one or more deuterium atoms, where the alkoxy group is as defined above.

[0342] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0343] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0344] The term "hydroxyl group" refers to -OH.

[0345] The term "thiol" refers to -SH.

[0346] The term "amino" refers to -NH2.

[0347] The term "cyano" refers to -CN.

[0348] The term "nitro" refers to -NO2.

[0349] The term "oxo" or "oxo group" refers to "=O".

[0350] The term "carbonyl" refers to C=O.

[0351] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0352] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0353] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0354] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0355] “TBS” refers to tert-butyldimethylsilyl substituent.

[0356] “Boc” refers to the tert-butyloxycarbonyl substituent.

[0357] “SEM” refers to (trimethylsilyl)ethoxymethyl substituent.

[0358] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, -OTs, or -OH.

[0359] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography. In the chemical structure of the compound described in this disclosure, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0360] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0361] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0362] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0363] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of steric interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0364] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I,124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0365] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0366] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0367] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0368] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). 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).

[0369] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically 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 its biological activity.

[0370] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0371] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0372] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0373] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0374] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Attached Figure Description

[0375] Figure 1. Disease severity scores for mice in each group. Detailed Implementation

[0376] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0377] Example

[0378] 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 determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0379] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS);

[0380] Waters ACQuity UPLC-QD / SQD (Manufacturer: Waters, MS model: waters ACQuity Qda Detector / waters SQ Detector);

[0381] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).

[0382] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0383] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0384] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0385] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0386] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0387] 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.

[0388] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0389] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0390] The known starting materials disclosed herein can be synthesized using or in accordance with 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.

[0391] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0392] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0393] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0394] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0395] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0396] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0397] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0398] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0399] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0400] Example 1

[0401] 3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0402] first step

[0403] 1-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid 1b

[0404] Sodium hydroxide (1.63 g, 40.72 mmol) was dissolved in water (75 mL), and 1-aminocyclopropanecarboxylic acid (4.11 g, 40.72 mmol, Shanghai Titan) and 4-hydroxy-6-methyl-2-pyranone 1a (5.13 g, 40.7 mmol, Shanghai Bide) were added. The mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to <7 with 1M hydrochloric acid. The mixture was filtered, and the filter cake was washed with methanol and dried to obtain the crude title compound 1b (3.79 g). The product was used directly in the next reaction without purification.

[0405] MS m / z(ESI):210.2[M+1].

[0406] Step 2

[0407] 1-(4-(benzyloxy)-6-methyl-2-oxopyridine-1(2H)-yl)cyclopropane-1-carboxylic acid benzyl ester 1c

[0408] Compound 1b (9.2 g, 43.97 mmol) was dissolved in N,N-dimethylformamide (120 mL), potassium carbonate (22.27 g, 16.1 mmol) and benzyl bromide (18.9 g, 110.5 mmol) were added, and the mixture was heated to 60 °C and reacted for 6 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, filtered, and the filtrate was washed three times with water and once with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1c (8.5 g, yield: 49.4%). MS m / z (ESI): 390.2 [M+1].

[0409] Step 3

[0410] 4-(benzyloxy)-1-(1-(hydroxymethyl)cyclopropyl)-6-methylpyridin-2(1H)-one 1d

[0411] Compound 1c (4 g, 10.27 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and 1 M tetrahydrofuran solution of lithium aluminum hydride (10.3 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour. Then, 0.4 mL of water, 0.4 mL of 15% sodium hydroxide aqueous solution, and 1.2 mL of water were added to the reaction solution in sequence. Anhydrous sodium sulfate was then added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain the crude title compound 1d (3.75 g). The product was used directly in the next reaction without purification.

[0412] MS m / z(ESI):286.2[M+1].

[0413] Step 4

[0414] 4-(benzyloxy)-1-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-6-methylpyridin-2(1H)-one 1e

[0415] The crude compound 1d (8.82 g, 30.91 mmol) was dissolved in dichloromethane (120 mL), and tert-butyldimethylchlorosilane (9.32 g, 61.83 mmol) and imidazole (7.3 g, 108.1 mmol) were added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (7 g, yield: 56.6%).

[0416] MS m / z(ESI): 400.2 [M+1].

[0417] Step 5

[0418] 4-(benzyloxy)-1-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde 1f

[0419] Compound 1e (5.57 g, 14 mmol) was dissolved in 1,4-dioxane (120 mL), and selenium dioxide (2.32 g, 20.9 mmol) was added. The tube was sealed and the mixture was stirred at 120 °C for 16 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1f (5.8 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 414.1 [M+1].

[0420] Step 6

[0421] 4-(benzyloxy)-1-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-6-(hydroxymethyl)pyridin-2(1H)-one 1g

[0422] The crude compound 1f (8.85 g, 21.4 mmol) was dissolved in tetrahydrofuran (50 mL) and methanol (10 mL), cooled to 0 °C, and sodium borohydride (528 mg, 14 mmol) was added in portions. After the addition was complete, the mixture was stirred at the temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1 g (3.85 g, yield: 43.2%).

[0423] MS m / z(ESI):416.1[M+1].

[0424] Step 7 (4-(benzyloxy)-1-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-6-oxo-1,6-dihydropyridin-2-yl)methylmethanesulfonate 1h

[0425] 1 g (3.85 g, 9.26 mmol) of compound was dissolved in dichloromethane (70 mL), cooled to 0 °C, and then triethylamine (7.29 g, 72 mmol) and methanesulfonic anhydride (4.84 g, 27.78 mmol) were added. The mixture was stirred for 0.5 h, and the reaction solution was quenched with saturated sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1h (4.5 g). The product was used directly in the next reaction without purification.

[0426] MS m / z(ESI):494.2[M+1].

[0427] Step 8

[0428] 8'-(benzyloxy)-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-6'(1'H)-one 1i

[0429] The crude title compound 1h (5.37 g, 108.7 mmol) was dissolved in tetrahydrofuran (50 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (9.3 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed three times with water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (1.33 g, yield: 43.1%).

[0430] MS m / z(ESI):284.2[M+1].

[0431] Step 9

[0432] 8'-Hydroxy-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-6'(1'H)-one

[0433] Compound 1i (2.6 g, 9.17 mmol) was dissolved in methanol (45 mL), and 10% palladium on carbon hydrogenation catalyst (327 mg) was added. The mixture was purged with hydrogen and stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1j (1.58 g). The product was used directly in the next reaction without purification.

[0434] MS m / z(ESI):194.2[M+1].

[0435] Step 10

[0436] 6'-oxo-1',6'-dihydro-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-8'-yltrifluoromethanesulfonate 1k

[0437] The crude compound 1j (1.58 g, 8.17 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (4.95 g, 49 mmol) and trifluoromethanesulfonic anhydride (4.65 g, 16.48 mmol) were added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 1k (1.3 g, yield: 48.8%).

[0438] MS m / z(ESI): 325.9 [M+1].

[0439] Step 11

[0440] 3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-6'(1'H)-one 1l

[0441] Compound 1k (1 g, 3.07 mmol) was dissolved in tetrahydrofuran (60 mL), and triethylamine (3.28 g, 32.42 mmol), formic acid (1.41 g, 30.74 mmol), and tetra(triphenylphosphine)palladium (355 mg, 307.21 μmol) were added. The mixture was purged with nitrogen and heated to 60 °C for 16 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to give the title compound 1l (362 mg, yield: 66.5%).

[0442] MS m / z(ESI): 178.2 [M+1].

[0443] Step Twelve

[0444] 7'-Bromo-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-6'(1'H)-one 1m

[0445] Compound 1l (711 mg, 4.01 mmol) was dissolved in acetonitrile (30 mL), cooled to 0 °C, and N-bromosuccinimide (600 mg, 3.37 mmol) was added in portions. The mixture was stirred for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution and saturated sodium sulfite aqueous solution. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1m (617 mg, yield: 60%).

[0446] MS m / z(ESI):255.9[M+1].

[0447] Step Thirteen

[0448] 7'-(4-bromophenyl)-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-6'(1'H)-one 1n

[0449] Compound 1m (80 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (3 mL, Adamas), and 4-bromophenylboronic acid (76 mg, 0.37 mmol, Shaoyuan), potassium phosphate (198 mg, 0.93 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 6 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 1n (18 mg, yield: 17.3%). MS m / z (ESI): 331.9 [M+1].

[0450] Step Fourteen

[0451] 3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0452] Compound 1n (18 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL, Adamas) and water (0.2 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (37 mg, 0.10 mmol, prepared by the method disclosed in intermediate A on page 184 of patent application WO2024151547A1), potassium carbonate (22 mg, 0.15 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5 mg, 6.83 μmol, Adamas) were added. The mixture was purged with nitrogen three times and heated to 80 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system B to give title compound 1 (2.2 mg, yield: 8.5%).

[0453] MS m / z(ESI): 475.4 [M+1].

[0454] 1H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.73-7.71(m,1H),7.62-7.61(m,1H),7.62-7.61(m,1H),7.44-7.31(m,3H),7.21-7.1 8(m,1H),6.66(s,1H),6.39-6.37(m,1H),5.34-5.30(m,1H),4.80(s,1H),3.79(s,1H),2.08-1.95(m,6H),0.88-0.84(m,4H).

[0455] Examples 1-1 and 1-2

[0456] (S)-3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 1-1

[0457] (R)-3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclopropane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 1-2

[0458] Compound 1 (44 mg, 92.64 μmol) was prepared chirally (separation conditions: chiral preparation column ChiralArt Cellulose-C, 10 μm, 40 mm * 250 mm (YMC, in-house packed); mobile phase 1: acetonitrile (60%); mobile phase 2: ethanol (40%), flow rate: 60 mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to obtain title compounds 1-1 and 1-2.

[0459] Single configuration compound (longer retention time): 19 mg, yield: 43%.

[0460] MS m / z(ESI): 475.4 [M+1].

[0461] Chiral HPLC analysis: retention time 4.885 min, chiral purity: 100% (column: CHIRALCEL OD-H, 150*4, 6 mm (Phenomenex, 5 μm); mobile phase 1: ethanol (90%); mobile phase 2: dichloromethane (10%), flow rate: 1 mL / min).

[0462] 1H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.71-7.69(m,2H),7.60-7.59(m,1H),7.41-7.32(m,5H),6.38-6.36(m,1H),4.79(s,2H),4.37-4. 33(m,1H),3.78(s,2H),2.83-2.78(m,1H),2.76-2.59(m,1H),2.38-2 .30(m,1H),2.07-2.05(m,1H),1.95-1.94(m,2H),1.09-1.07(m,2H).

[0463] Single configuration compound (shorter retention time): 18 mg, yield: 41%.

[0464] MS m / z(ESI): 475.5 [M+1].

[0465] Chiral HPLC analysis: retention time 3.771 min, chiral purity: 100% (column: CHIRALCEL OD-H, 150*4, 6 mm (Phenomenex, 5 μm); mobile phase 1: ethanol (90%); mobile phase 2: dichloromethane (10%), flow rate: 1 mL / min).

[0466] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.71-7.69(m,2H),7.60-7.59(m,1H),7.41-7.32(m,5H),6.38-6.36(m,1H),4.79(s,2H),4.37-4. 33(m,1H),3.78(s,2H),2.83-2.77(m,1H),2.63-2.56(m,1H),2.38-2 .30(m,1H),2.07-2.04(m,1H),1.95-1.94(m,2H),1.09-1.07(m,2H).

[0467] Example 2

[0468] 3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0469] Using the synthetic route of Example 1, the first step of 1-aminocyclopropanecarboxylic acid was replaced with 1-aminocyclobutanecarboxylic acid (Shanghai Titan) to obtain title compound 2 (39 mg, yield: 39.4%).

[0470] MS m / z(ESI):489.4[M+1].

[0471] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.78-7.76(m,2H),7.63-7.61(m,1H),7.44-7.34(m,5H),6.16-6.15(m,1H),4.81(s,2H),4.34-4. 30(m,1H),4.02(s,2H),3.37-3.35(m,2H),2.78-2.74(m,1H),2.58-2 .52(m,1H),2.45-2.33(m,1H),2.09-2.07(m,2H),1.87-1.85(m,3H).

[0472] Examples 2-1 and 2-2

[0473] (S)-3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 2-1

[0474] (R)-3-(2-chloro-4'-(6'-oxo-1',6'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrido[2,1-c][1,4]oxazine]-7'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 2-2

[0475] Compound 2 was chiralized to obtain compounds 2-1 and 2-2.

[0476] Example 3

[0477] 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0478] first step

[0479] 3-Bromo-1-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclopropyl)-1H-pyrazole-5-carboxylic acid ethyl ester 3b

[0480] Ethyl 3-bromo-1H-pyrazole-5-carboxylate 3a (10 g, 45.65 mmol, Bide) was dissolved in tetrahydrofuran (200 mL), and tert-butyl (1-hydroxycyclopropyl)methylcarbamate (9.4 g, 50.20 mmol, Shaoyuan) and triphenylphosphine (15.56 g, 59.32 mmol, Titan) were added. The mixture was cooled to 0 °C, and diisopropyl azodicarboxylate (12.00 g, 59.34 mmol, Titan) was added dropwise. The mixture was allowed to return to room temperature for 3 hours, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3b (17.7 g, yield: 99.8%).

[0481] MS m / z(ESI): 388.2 [M+1].

[0482] Step 2

[0483] 2'-Bromo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 3c

[0484] Compound 3b (17.7 g, 45.59 mmol) was dissolved in dichloromethane (50 mL), and dioxane hydrochloride solution (20 mL, 80.00 mmol, 4 M, Adamas) was added. The mixture was reacted at room temperature for 3 hours, concentrated under reduced pressure, and the residue was dissolved in methanol (90 mL). Sodium methoxide (3.7 g, 68.49 mmol, Titan) was added, and the mixture was heated to 70 °C and reacted for 6 hours. The mixture was then allowed to return to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 3c (11 g, yield: 99.7%).

[0485] MS m / z(ESI):242.0[M+1].

[0486] Step 3

[0487] 7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 3d

[0488] Compound 3c (2.5 g, 10.33 mmol) was dissolved in methanol (50 mL), and palladium on carbon (1.1 g, 1.03 mmol, 10% purity, BIDE) was added. The mixture was purged with hydrogen three times and reacted at 50 °C for 12 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3d (740 mg, yield: 43.9%). MS m / z (ESI): 164.1 [M+1].

[0489] Step 4

[0490] 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 3e

[0491] Compound 3d (740 mg, 4.54 mmol) was dissolved in N,N-dimethylformamide (25 mL, Adamas), and 1-bromo-4-iodobenzene (1.94 g, 6.86 mmol, Shaoyuan), potassium phosphate (1.94 g, 9.14 mmol, Sinopharm), N,N-dimethylethylenediamine (82 mg, 0.93 mmol, Bide), and cuprous iodide (175 mg, 0.92 mmol, Bailingwei) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 3e (610 mg, yield: 42.3%).

[0492] MS m / z(ESI):318.1[M+1].

[0493] Step 5

[0494] 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-

[0495] (3-)piperidine-2,6-dione

[0496] Compound 3e (610 mg, 1.92 mmol) was dissolved in 1,4-dioxane (12 mL, Adamas) and water (2 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (874 mg, 2.50 mmol, prepared by the method disclosed in intermediate A on page 184 of patent application WO2024151547A1), potassium phosphate (815 mg, 3.84 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (142 mg, 0.19 mol, Bide) were added. The mixture was purged with nitrogen three times and heated to 90 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give title compound 3 (350 mg, yield: 39.6%).

[0497] MS m / z(ESI):461.4[M+1].

[0498] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.66-7.65(m,1H),7.51-7.49(m,2H),7.49-7.37(m,5H),6.91(s,1H),4.58(s, 2H),4.39-4.36(m,1H),2.59-2.54(m,1H),2.38-2.35(m,1H),2.08-1.98(m,2H),1.06-1.04(m,2H),0.77-0.74(m,2H).

[0499] Examples 3-1 and 3-2

[0500] (S)-3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 3-1

[0501] (R)-3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 3-2

[0502] Compound 3 was separated by chiral column chromatography to obtain compounds 3-1 and 3-2.

[0503] Example 4

[0504] 3-(2-chloro-4'-(2'-methyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0505] first step

[0506] 3-Bromo-1-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclopropyl)-1H-pyrazole-5-carboxylic acid ethyl ester 3b

[0507] Ethyl 3-bromo-1H-pyrazole-5-carboxylate 3a (10 g, 45.65 mmol, Bide) was dissolved in tetrahydrofuran (200 mL), and tert-butyl (1-hydroxycyclopropyl)methylcarbamate (9.4 g, 50.20 mmol, Shaoyuan) and triphenylphosphine (15.56 g, 59.32 mmol, Titan) were added. The mixture was cooled to 0 °C, and diisopropyl azodicarboxylate (12.00 g, 59.34 mmol, Titan) was added dropwise. The mixture was allowed to return to room temperature for 3 hours, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3b (17.7 g, yield: 99.8%).

[0508] MS m / z(ESI): 388.2 [M+1].

[0509] Step 2

[0510] 2'-Bromo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 3c

[0511] Compound 3b (17.7 g, 45.59 mmol) was dissolved in dichloromethane (50 mL), and dioxane hydrochloride solution (20 mL, 80.00 mmol, 4 M, Adamas) was added. The mixture was reacted at room temperature for 3 hours, concentrated under reduced pressure, and the residue was dissolved in methanol (90 mL). Sodium methoxide (3.7 g, 68.49 mmol, Titan) was added, and the mixture was heated to 70 °C and reacted for 6 hours. The mixture was then allowed to return to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 3c (11 g, yield: 99.7%).

[0512] MS m / z(ESI):242.0[M+1].

[0513] Step 3

[0514] 2'-Methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 4a

[0515] Compound 3c (5 g, 20.66 mmol) was dissolved in 1,4-dioxane (60 mL, Adamas) and water (12 mL), followed by the addition of methylboric acid (3.73 g, 62.31 mmol, Shaoyuan), potassium carbonate (5.73 g, 41.46 mmol, Sinopharm), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.53 g, 2.09 mmol, Bide). The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 4a (2 g, yield: 54.6%). MS m / z (ESI): 178.2 [M+1].

[0516] Step 4

[0517] 5'-(4-bromophenyl)-2'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 4b

[0518] Compound 4a (2 g, 11.29 mmol) was dissolved in toluene (100 mL, Adamas), and 1-bromo-4-iodobenzene (4.14 g, 14.63 mmol, Shaoyuan), potassium phosphate (4.8 g, 22.61 mmol, Sinopharm), N,N-dimethylethylenediamine (200 mg, 2.27 mmol, Bide), and cuprous iodide (431 mg, 2.26 mmol, Bailingwei) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give title compound 4b (1.56 g, yield: 41.6%). MS m / z (ESI): 332.1 [M+1].

[0519] Step 5

[0520] 3-(2-chloro-4'-(2'-methyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0521] Compound 4b (700 mg, 2.11 mmol) was dissolved in 1,4-dioxane (20 mL, Adamas) and water (4 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (885 mg, 2.53 mmol, prepared by the method disclosed in intermediate A on page 184 of patent application WO2024151547A1), potassium phosphate (895 mg, 4.22 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (155 mg, 0.21 mol, Bide) were added. The mixture was purged with nitrogen three times and heated to 90 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give title compound 4 (360 mg, yield: 36.0%).

[0522] MS m / z(ESI): 475.4 [M+1].

[0523] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.50-7.48(m,2H),7.43-7.36(m,5H),6.67(s,1H),4.47(s,2H),4. 39-4.36(m,1H),2.58-2.54(m,2H),2.27(s,3H),2.02-2.00(m,2H),1.05-1.02(m,2H),0.75-0.72(m,2H).

[0524] Examples 4-1 and 4-2

[0525] (S)-3-(2-chloro-4'-(2'-methyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 4-1

[0526] (R)-3-(2-chloro-4'-(2'-methyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 4-2

[0527] Compound 4 (50 mg) was purified by high performance liquid chromatography (Agilent 1290DAD, column: CHIRALPAK IE, 4.6 mm * 150 mm, 5 μm; mobile phase: ethanol and acetonitrile, gradient ratio: acetonitrile 10%, flow rate: 1 mL / min) to obtain title compound 4-1 (10 mg, 40%) and compound 4-2 (10 mg, 40%).

[0528] Single-configuration compounds (shorter retention time) 4-2:

[0529] MS m / z(ESI): 475.2 [M+1].

[0530] HPLC analysis: retention time 8.59 min, purity: 99% (column: CHIRALPAK IE, 4.6 mm * 150 mm, 5 μm; mobile phase: ethanol and acetonitrile, gradient ratio: acetonitrile 10%).

[0531] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.51-7.47(m,2H),7.45-7.35(m,5H),6.68(s,1H),4.47(s,2H),4.41-4.34(m,1H),2. 86-2.76(m,1H),2.60-2.53(m,1H),2.41-2.30(m,1H),2.27(s,3H),2.10-2.04(m,1H),1.05-1.02(m,2H),0.75-0.72(m,2H).

[0532] Single-configuration compounds (longer retention time) 4-1:

[0533] MS m / z(ESI): 475.2 [M+1].

[0534] HPLC analysis: retention time 14.18 min, purity: 99% (column: CHIRALPAK IE, 4.6 mm * 150 mm, 5 μm; mobile phase: ethanol and acetonitrile, gradient ratio: acetonitrile 10%).

[0535] 1H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.52-7.47(m,2H),7.47-7.34(m,5H),6.68(s,1H),4.47(s,2H),4.41-4.35(m,1H),2. 87-2.77(m,1H),2.66-2.62(m,1H),2.39-2.35(m,1H),2.27(s,3H),2.11-2.06(m,1H),1.05-1.02(m,2H),0.75-0.72(m,2H).

[0536] Example 5

[0537] 3-(2-chloro-4'-(2'-cyclopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0538] Using the synthetic route from step 3 to step 5 in Example 4, the starting compound methylboronic acid in step 3 was replaced with cyclopropylboronic acid to obtain title compound 5 (70 mg, yield: 33.4%).

[0539] MS m / z(ESI): 501.2 [M+1].

[0540] 1 H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.49-7.47(m,2H),7.43-7.34(m,5H),6.61(s,1H),4.45(s,2H),4.38-4.35(m, 1H),2.83-2.77(m,1H),2.38-2.33(m,1H),2.08-1.93(m,3H),1.04-1.01(m,2H),0.92-0.90(m,2H),0.75-0.71(m,4H).

[0541] Examples 5-1 and 5-2

[0542] (S)-3-(2-chloro-4'-(2'-cyclopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 5-1

[0543] (R)-3-(2-chloro-4'-(2'-cyclopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 5-2

[0544] Compound 5 was chirally separated to obtain compounds 5-1 and 5-2.

[0545] Example 6

[0546] 3-(2-chloro-4'-(2'-isopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0547] first step

[0548] 2'-(prop-1-en-2-yl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 6a

[0549] Compound 3c (0.3 g, 1.24 mmol) was dissolved in 1,4-dioxane (4 mL, Adamas) and water (0.8 mL), and potassium isopropenyl trifluoride borate (0.367 g, 2.48 mmol, Adamas), potassium carbonate (0.34 g, 2.48 mmol, Sinopharm), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (90.7 mg, 0.12 mmol, Bide) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give title compound 6a (250 mg, yield: 99.3%).

[0550] MS m / z(ESI):204.4[M+1].

[0551] Step 2

[0552] 2'-Isopropyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 6b

[0553] Compound 6a (315 mg, 1.5 mmol) was dissolved in methanol (20 mL, Adamas), and palladium / carbon (330 mg, 0.15 mmol, 5% purity, Shaoyuan) was added. The mixture was purged with hydrogen three times and reacted overnight at room temperature under a hydrogen system. The mixture was filtered, and the filtrate was evaporated to dryness to give the title compound 6b (318 mg, yield: 99.96%).

[0554] MS m / z(ESI):206.2[M+1].

[0555] Step 3

[0556] 3-(2-chloro-4'-(2'-isopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0557] Using the synthetic route of steps four and five in Example 4, the starting compound 4a in step four was replaced with compound 6b to obtain title compound 6 (87 mg, yield: 41.5%).

[0558] MS m / z(ESI): 503.2 [M+1].

[0559] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.51-7.48(m,2H),7.45-7.35(m,5H),6.74(s,1H),4.49(s,2H),4.39-4.36(m, 1H),3.00-2.95(m,1H),2.85-2.78(m,2H),2.09-2.05(m,2H),1.27-1.25(m,6H),1.05-1.02(m,2H),0.75-0.72(m,2H).

[0560] Examples 6-1 and 6-2

[0561] (S)-3-(2-chloro-4'-(2'-isopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 6-1

[0562] (R)-3-(2-chloro-4'-(2'-isopropyl-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 6-2

[0563] Compound 6 was chirally separated to obtain compounds 6-1 and 6-2.

[0564] Example 7

[0565] 3-(2-chloro-4'-(6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0566] first step

[0567] 3-Bromo-1H-pyrazole-5-carboxamide 7b

[0568] Methyl 3-bromo-1H-pyrazole-5-carboxylic acid ester 7a (20 g, 97.6 mmol, Adamas) was dissolved in methanol (300 mL), and ammonia water (136.8 g, 975.9 mmol, 25%, Sinopharm) was added. The reaction mixture was reacted at 60 °C for 3 days. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, title compound 7b, which was used directly in the next step without purification.

[0569] MS m / z(ESI):191.9[M+2].

[0570] Step 2

[0571] 3-Bromo-1H-pyrazole-5-carboxynitrile 7c

[0572] Compound 7b (18.5 g, 97.4 mmol) was dissolved in pyridine (300 mL), and trifluoroacetic anhydride (81.8 g, 389.5 mmol, Sinopharm) was added at 0 °C, and the mixture was stirred for 40 minutes. The reaction solution was diluted with 400 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (400 mL × 2), washed with 1 M hydrochloric acid solution (200 mL × 2), washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 7c (6.3 g, yield: 37.7%).

[0573] MS m / z(ESI):171.5[M+1].

[0574] Step 3

[0575] 2-(3-bromo-5-cyano-1H-pyrazole-1-yl)methyl acetate 7d

[0576] Compound 7c (6.3 g, 36.7 mmol) was dissolved in N,N-dimethylformamide (70 mL), and potassium carbonate (10.14 g, 73.4 mmol, Sinopharm) and methyl chloroacetate (5.97 g, 55 mmol, Adamas) were added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 7d (8.3 g, yield: 92.7%).

[0577] MS m / z(ESI):244.1[M+1].

[0578] Step 4

[0579] 2'-Bromo-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-6'(7'H)-one 7e

[0580] Compound 7d (4 g, 16.4 mmol) was dissolved in tetrahydrofuran (120 mL), and tetraisopropyl titanate (5.12 g, 18 mmol, Adamas) and ethyl magnesium bromide (4.37 g, 32.8 mmol, Adamas) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with 100 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (120 mL × 3). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 7e (2.6 g, yield: 65.5%).

[0581] MS m / z(ESI):242.0[M+1].

[0582] Step 5

[0583] 3-(2-chloro-4'-(6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0584] Using the synthetic route from step 3 to step 5 in Example 3, the starting compound 3c in step 3 was replaced with compound 7e to obtain title compound 7 (4.5 mg, yield: 15.53%).

[0585] MS m / z(ESI): 461.4 [M+1]

[0586] 1H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.54-7.51(m,3H),7.46-7.37(m,3H),7.31-7.29(m,2H),6. 11(s,1H),5.11(s,2H),4.39-4.36(m,1H),2.08-1.97(m,4H),1.15-1.12(m,2H),0.87-0.85(m,2H).

[0587] Examples 7-1 and 7-2

[0588] (S)-3-(2-chloro-4'-(6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 7-1

[0589] (R)-3-(2-chloro-4'-(6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 7-2

[0590] Compound 7 was chirally separated to obtain compounds 7-1 and 7-2.

[0591] Example 8

[0592] 3-(2-chloro-4'-(2'-methyl-6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0593] Using the synthetic route from step 3 to step 5 in Example 4, the starting material compound 3c acid in step 3 was replaced with compound 7e to obtain title compound 8 (9 mg, yield: 12.6%).

[0594] MS m / z(ESI): 475.4 [M+1].

[0595] 1H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.52-7.51(m,2H),7.45-7.37(m,3H),7.30-7.28(m,2H),5.88(s,1H),5.01(s,2H),4. 39-4.36(m,1H),2.85-2.78(m,1H),2.38-2.34(m,1H),2.17(s,3H),2.09-1.99(m,2H),1.21-1.18(m,2H),1.12-1.09(m,2H).

[0596] Examples 8-1 and 8-2

[0597] (S)-3-(2-chloro-4'-(2'-methyl-6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 8-1

[0598] (R)-3-(2-chloro-4'-(2'-methyl-6'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]-5'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 8-2

[0599] Compound 8 was chirally separated to obtain compounds 8-1 and 8-2.

[0600] Example 9

[0601] 3-(2-chloro-4'-(5'-oxo-1',5'-dihydro-2'H-spiro[cyclopropane-1,3'-indoleazine]-6'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 9

[0602] first step

[0603] 2-(But-3-yn-1-yl)-6-methoxypyridine 9b

[0604] 2-Methoxy-6-methylpyridine 9a (10 g, 81.20 mmol, BID) was dissolved in tetrahydrofuran (200 mL), and n-butyllithium (50.8 mL, 81.33 mmol, 1.6 M, Shaoyuan) was added at -78 °C. The mixture was stirred for 30 minutes, and 3-bromoprop-1-yne (9.7 g, 81.54 mmol, Titan) was added dropwise at -78 °C. The reaction was maintained at -78 °C for 1 hour. The mixture was then brought to room temperature, quenched with saturated ammonium chloride solution, and 100 mL of water was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give the title compound 9b (2.2 g, yield: 16.8%).

[0605] MS m / z(ESI): 162.3 [M+1].

[0606] Step 2

[0607] 6-(But-3-yn-1-yl)pyridine-2-phenol 9c

[0608] Compound 9b (2.2 g, 13.65 mmol) was dissolved in N,N-dimethylformamide (40 mL), p-toluenesulfonic acid monohydrate (4.7 g, 27.29 mmol, Adamas) and lithium chloride (1.2 g, 27.36 mmol, Adamas) were added, the mixture was heated to 110 °C and reacted for 3 hours, then returned to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 9c (1.52 g, yield: 75.7%).

[0609] MS m / z(ESI):148.3[M+1].

[0610] Step 3

[0611] 3-Methylene-2,3-dihydroindoleazine-5(1H)-one 9d

[0612] Compound 9c (1.4 g, 9.51 mmol) was dissolved in toluene (40 mL), and silver trifluoromethanesulfonate (123 mg, 0.48 mmol, BIDE) was added. The mixture was purged with nitrogen three times and reacted at 80 °C for 0.5 h. After returning to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 9d (1.0 g, yield: 71.4%). MS m / z (ESI): 148.2 [M+1].

[0613] Step 4

[0614] 1',2'-Dihydro-5'H-spiro[cyclopropane-1,3'-indoleazine]-5'-one 9e

[0615] Diethylzinc (13.0 mL, 25.91 mmol, 2 M, Shaoyuan) was dissolved in dichloromethane (15 mL, Adamas), and trifluoroacetic acid (3 g, 26.31 mmol, Shaoyuan) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour, and diiodomethane (7 g, 26.14 mmol, Sinopharm) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hours, and compound 9d (950 mg, 6.46 mmol) was added at 0 °C. The reaction was carried out at room temperature for 12 hours. 5 mL of water was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 9e (1.1 g, yield: 48.1%).

[0616] MS m / z(ESI): 162.2 [M+1].

[0617] Step 5

[0618] 6'-(4-bromophenyl)-1',2'-dihydro-5'H-spiro[cyclopropane-1,3'-indoleazine]-5'-one 9f

[0619] Compound 9e (300 mg, 1.86 mmol) was dissolved in acetonitrile (40 mL, Adamas), and 4-bromophenylhydrazine hydrochloride (832 mg, 3.72 mmol), potassium carbonate (515 mg, 3.73 mmol, Sinopharm), and potassium permanganate (883 mg, 5.58 mol, Bio-D) were added. The mixture was heated to 80 °C and reacted for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 9f (50 mg, yield: 8.5%).

[0620] MS m / z(ESI): 316.2 [M+1].

[0621] Step 6

[0622] 3-(2-chloro-4'-(5'-oxo-1',5'-dihydro-2'H-spiro[cyclopropane-1,3'-indoleazine]-6'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 9

[0623] Using the synthetic route in step fourteen of Example 1, the starting compound 1n was replaced with the starting compound 9f to obtain title compound 9 (40 mg, yield: 45.9%).

[0624] MS m / z(ESI):459.4[M+1].

[0625] 1H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.71-7.69(m,2H),7.62-7.60(m,1H),7.43-7.33(m,5H),6.35-6.33(m,1H),4.38-4. 35(m,1H),3.12-3.09(m,2H),2.80-2.78(m,1H),2.65-2.63(m,1H),2.37-2.34(m,2H),2.25-2.20(m,4H),0.77-0.76(m,2H).

[0626] Examples 9-1 and 9-2

[0627] (S)-3-(2-chloro-4'-(5'-oxo-1',5'-dihydro-2'H-spiro[cyclopropane-1,3'-indoleazine]-6'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 9-1

[0628] (R)-3-(2-chloro-4'-(5'-oxo-1',5'-dihydro-2'H-spiro[cyclopropane-1,3'-indoleazine]-6'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 9-2

[0629] Compound 9 (250 mg) was purified by high performance liquid chromatography (Gilson-281 Prep system, column: CHIRALPAK IE, 20 mm * 250 mm, 5 μm; mobile phase: ethanol and acetonitrile, gradient ratio: acetonitrile 18%, flow rate: 20 mL / min) to obtain title compounds 9-1 and 9-2.

[0630] Single configuration compound (shorter retention time): 83 mg, yield: 33.2%.

[0631] MS m / z(ESI): 459.5 [M+1].

[0632] HPLC analysis: retention time 8.93 min, purity: 100% (column: CHIRALPAK IE, 20 mm * 250 mm, 5 μm; mobile phase: ethanol and acetonitrile, gradient ratio: acetonitrile 18%).

[0633] 1¹H NMR (500MHz, DMSO-d6): δ 10.93 (s, 1H), 7.71–7.69 (m, 2H), 7.62–7.60 (m, 1H), 7.43–7.33 (m, 5H), 6.35–6.33 (m, 1H), 4.38–4.35 (m, 1H), 3.12–3.09 (m, 2H), 2.80–2.78 (m, 1H), 2.65–2.63 (m, 1H), 2.37–2.34 (m, 2H), 2.25–2.20 (m, 4H), 0.77–0.76 (m, 2H). Single configuration compound (longer retention time): 81 mg, yield: 32.4%.

[0634] MS m / z(ESI): 459.5 [M+1].

[0635] HPLC analysis: retention time 15.77 min, purity: 99% (column: CHIRALPAK IE, 20 mm * 250 mm, 5 μm; mobile phase: ethanol and acetonitrile, gradient ratio: acetonitrile 18%).

[0636] 1 H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.71-7.69(m,2H),7.62-7.60(m,1H),7.43-7.33(m,5H),6.35-6.33(m,1H),4.38-4. 35(m,1H),3.12-3.09(m,2H),2.80-2.78(m,1H),2.65-2.63(m,1H),2.37-2.34(m,2H),2.25-2.20(m,4H),0.77-0.76(m,2H).

[0637] Example 10

[0638] 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 10

[0639] first step

[0640] 1-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclopropyl)-1H-imidazol-2-carboxylic acid methyl ester 10b

[0641] 1H-imidazolium-2-carboxylate methyl ester 10a (1 g, 7.93 mmol, Leyan) was dissolved in tetrahydrofuran (20 mL), and (1-hydroxycyclopropyl)methyl)carbamate tert-butyl ester (1.64 g, 8.76 mmol, Shaoyuan) and triphenylphosphine (2.71 g, 10.33 mmol, Titan) were added dropwise after cooling to 0 °C. The reaction was allowed to proceed at room temperature for 3 hours, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 10b (2 g, yield: 85.4%).

[0642] MS m / z(ESI):296.3[M+1].

[0643] Step 2

[0644] 5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one 10c

[0645] Compound 10b (1 g, 3.23 mmol) was dissolved in dichloromethane (10 mL), and dioxane hydrochloride solution (4 mL, 16.00 mmol, 4 M, Adamas) was added. The mixture was reacted at room temperature for 3 hours, concentrated under reduced pressure, and the residue was dissolved in methanol (9 mL). Sodium methoxide (262 mg, 4.85 mmol, Titan) was added, and the mixture was heated to 70 °C and reacted for 6 hours. The mixture was then allowed to return to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 10c (170 mg, yield: 32.2%).

[0646] MS m / z(ESI): 164.2 [M+1].

[0647] Step 3

[0648] 7'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one 10d

[0649] Compound 10c (170 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (5 mL, Adamas), and 1-bromo-4-iodobenzene (384 g, 1.36 mmol, Shaoyuan), potassium phosphate (443 mg, 2.09 mmol, Sinopharm), N,N-dimethylethylenediamine (18.4 mg, 0.21 mmol, Bide), and cuprous iodide (40 mg, 0.21 mmol, Bailingwei) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, and 10 mL of water was added. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 10d (170 mg, yield: 51.3%).

[0650] MS m / z(ESI):318.1[M+1].

[0651] Step 4

[0652] 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-

[0653] 10-Piperidine-2,6-dione

[0654] Compound 10d (170 mg, 0.53 mmol) was dissolved in 1,4-dioxane (5 mL, Adamas) and water (1 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (225 mg, 0.64 mmol, prepared by the method disclosed in intermediate A on page 184 of patent application WO2024151547A1), potassium phosphate (227 mg, 1.07 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.05 mol, Bide) were added. The mixture was purged with nitrogen three times and heated to 90 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give title compound 10 (130 mg, yield: 52.8%).

[0655] MS m / z(ESI):461.3[M+1].

[0656] 1H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.50-7.48(m,2H),7.45-7.37(m,6H),7.22(s,1H),4.45(s,2H),4.38 -4.36(m,1H),2.58-2.55(m,1H),2.38-2.35(m,1H),2.08-1.98(m,2H),1.03-1.00(m,2H),0.75-0.73(m,2H).

[0657] Examples 10-1 and 10-2

[0658] (S)-3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 10-1

[0659] (R)-3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 10-2

[0660] Compound 10 was separated by chiral column chromatography to obtain compounds 10-1 and 10-2.

[0661] Example 11

[0662] 3-(2-chloro-4'-(2'-methyl-4'-oxo-2',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione 11

[0663] first step

[0664] (E)-6-((dimethylamino)methylene)-4-azaspiro[2.5]octane-5,7-dione 11b

[0665] 4-azaspiro[2.5]octane-5,7-dione 11a (140 mg, 1.0 mmol, Icon) was dissolved in N,N-dimethylformamide (4.5 mL), and 1,1-dimethoxy-N,N-dimethylmethylamine (131.9 g, 1.1 mmol, Adamas) was added. The mixture was heated to 90 °C and stirred for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, title compound 11b, which was used directly in the next step without purification.

[0666] Step 2

[0667] 2'-Methyl-2',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-4'(5'H)-one 11c

[0668] Compound 11b (195 mg, 1.0 mmol) was dissolved in ethanol (7 mL), cooled to -30 °C, and N,N-diisopropylethylamine (129.8 mg, 1.0 mmol, Sinopharm) and methylhydrazine sulfate (144.7 mg, 1.0 mmol, Adamas) were added sequentially. The mixture was heated to room temperature and stirred for 30 minutes, then heated to reflux and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give title compound 11c (70 mg, yield: 39.35%).

[0669] MS m / z(ESI): 178.2 [M+1].

[0670] Step 3

[0671] 3-(2-chloro-4'-(2'-methyl-4'-oxo-2',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(4'H)-yl)-

[0672] [1,1'-Biphenyl]-3-yl)piperidin-2,6-dione

[0673] Using the synthetic route from step four to step five in Example 4, the starting compound 4a in step four was replaced with starting compound 11c to obtain title compound 11 (17 mg, yield: 19.82%).

[0674] MS m / z(ESI): 475.2 [M+1].

[0675] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),8.23(s,1H),7.45-7.43(m,3H),7.41-7.37(m,2H),7.36-7.2 8(m,2H),4.39-4.35(m,1H),3.89(s,3H),3.00(s,2H),2.03-1.98(m,4H),0.82(s,2H),0.60(s,2H).

[0676] Examples 11-1 and 11-2

[0677] (S)-3-(2-chloro-4'-(2'-methyl-4'-oxo-2',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 11-1

[0678] (R)-3-(2-chloro-4'-(2'-methyl-4'-oxo-2',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 11-2

[0679] Compound 11 was separated by chiral column chromatography to obtain compounds 11-1 and 11-2.

[0680] Example 12

[0681] 3-(2-chloro-4'-(1'-methyl-4'-oxo-4',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione 12

[0682] first step

[0683] 1'-Methyl-1',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-4'(5'H)-one 12a

[0684] Compound 11b (195 mg, 1.0 mmol) was dissolved in ethanol (7 mL), cooled to -30 °C, and N,N-diisopropylethylamine (129.8 mg, 1.0 mmol, Sinopharm) and methylhydrazine sulfate (144.7 mg, 1.0 mmol, Adamas) were added sequentially. The mixture was heated to room temperature and stirred for 30 minutes, then refluxed and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give title compound 12a (100 mg, yield: 56.21%).

[0685] MS m / z(ESI): 178.2 [M+1].

[0686] Step 2

[0687] 3-(2-chloro-4'-(1'-methyl-4'-oxo-4',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione 12

[0688] Using the synthetic route from step four to step five in Example 4, the starting compound 4a in step four was replaced with starting compound 12a to obtain title compound 12 (28 mg, yield: 35.61%).

[0689] MS m / z(ESI): 475.2 [M+1].

[0690] 1 H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.81(s,1H),7.45-7.42(m,3H),7.41-7.37(m,2H),7.36-7.2 8(m,2H),4.38-4.35(m,1H),3.81(s,3H),3.17(s,2H),2.03-1.98(m,4H),0.87(s,2H),0.60(s,2H).

[0691] Examples 12-1 and 12-2

[0692] (S)-3-(2-chloro-4'-(1'-methyl-4'-oxo-4',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 12-1

[0693] (R)-3-(2-chloro-4'-(1'-methyl-4'-oxo-4',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[4,3-c]pyridine]-5'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 12-2

[0694] Compound 12 was separated by chiral column chromatography to obtain compounds 12-1 and 12-2.

[0695] Example 13

[0696] 3-(2-chloro-4'-(2'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 13

[0697] first step

[0698] 1-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclopropyl)-4-methyl-1H-imidazol-2-carboxylic acid ethyl ester 13b

[0699] 4-Methyl-1H-imidazolium-2-carboxylate ethyl 13a (1 g, 6.48 mmol, Leyan) was dissolved in tetrahydrofuran (20 mL), and (1-hydroxycyclopropyl)methyl)carbamate tert-butyl ester (1.34 g, 7.16 mmol, Shaoyuan) and triphenylphosphine (2.22 g, 8.46 mmol, Titan) were added. The mixture was cooled to 0 °C and diisopropyl azodicarboxylate (1.71 g, 8.46 mmol, Titan) was added dropwise. The mixture was allowed to return to room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 13b (1.41 g, yield: 67.2%).

[0700] MS m / z(ESI): 324.6 [M+1].

[0701] Step 2

[0702] 2'-Methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one 13c

[0703] Compound 13b (1.41 g, 4.36 mmol) was dissolved in dichloromethane (15 mL), and dioxane hydrochloride solution (6 mL, 24.00 mmol, 4 M, Adamas) was added. The mixture was reacted at room temperature for 3 hours, concentrated under reduced pressure, and the residue was dissolved in methanol (12 mL). Sodium methoxide (354 mg, 6.55 mmol, Titan) was added, and the mixture was heated to 70 °C and reacted for 6 hours. The mixture was then allowed to return to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 13c (400 mg, yield: 51.8%).

[0704] MS m / z(ESI):178.4[M+1].

[0705] Step 3

[0706] 7'-(4-bromophenyl)-2'-methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one 13d

[0707] Compound 13c (200 mg, 1.13 mmol) was dissolved in toluene (6 mL, Adamas), and 1-bromo-4-iodobenzene (416 g, 1.47 mmol, Shaoyuan), potassium phosphate (480 g, 2.26 mmol, Sinopharm), N,N-dimethylethylenediamine (20 mg, 0.23 mmol, Bide), and cuprous iodide (43 mg, 0.23 mmol, Bailingwei) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 13d (90 mg, yield: 24.0%).

[0708] MS m / z(ESI): 332.1 [M+1].

[0709] Step 4

[0710] 3-(2-chloro-4'-(2'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-

[0711] [Biphenyl]-3-yl)piperidine-2,6-dione 13

[0712] Compound 13d (90 mg, 2.11 mmol) was dissolved in 1,4-dioxane (3 mL, Adamas) and water (0.6 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (114 mg, 0.33 mmol, prepared by the method disclosed in intermediate A on page 184 of patent application WO2024151547A1), potassium phosphate (116 mg, 0.55 mmol, Sinopharm), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, 0.03 mol, Bide) were added. The mixture was purged with nitrogen three times and heated to 90 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give title compound 13 (50 mg, yield: 38.9%).

[0713] MS m / z(ESI): 475.5 [M+1].

[0714] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.49-7.34(m,7H),7.15(s,1H),4.37(s,3H),2.81-2.76(m,1H),2. 58-2.55(m,1H),2.37-2.34(m,1H),2.21(s,3H),2.09-2.06(m,1H),1.01-0.98(m,2H),0.74-0.71(m,2H).

[0715] Examples 13-1 and 13-2

[0716] (S)-3-(2-chloro-4'-(2'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 13-1

[0717] (R)-3-(2-chloro-4'-(2'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 13-2

[0718] Compound 13 was separated by chiral column chromatography to obtain compounds 13-1 and 13-2.

[0719] Example 14

[0720] 3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 14

[0721] first step

[0722] 1-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclopropyl)-5-methyl-1H-imidazol-2-carboxylic acid ethyl ester 14a

[0723] Compound 13a (1 g, 6.48 mmol, Leyan) was dissolved in tetrahydrofuran (20 mL), and tert-butyl (1-hydroxycyclopropyl)methyl)carbamate (1.34 g, 7.16 mmol, Shaoyuan) and triphenylphosphine (2.22 g, 8.46 mmol, Titan) were added. The mixture was cooled to 0 °C and diisopropyl azodicarboxylate (1.71 g, 8.46 mmol, Titan) was added dropwise. The mixture was allowed to return to room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 14a (400 mg, yield: 19.1%).

[0724] MS m / z(ESI): 324.6 [M+1].

[0725] Step 2

[0726] 3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 14

[0727] Using the synthetic route from step 2 to step 4 in Example 13, the starting compound 13b in step 2 was replaced with 14a to obtain title compound 14 (13 mg, yield: 10.1%).

[0728] MS m / z(ESI): 475.5 [M+1].

[0729] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.49-7.34(m,7H),7.15(s,1H),4.39-4.36(m,1H),4.30(s,2H),2.81-2.76( m,1H),2.58-2.55(m,1H),2.37-2.34(m,1H),2.21(s,3H),2.09-2.06(m,1H),1.01-0.98(m,2H),0.74-0.71(m,2H).

[0730] Examples 14-1 and 14-2

[0731] (S)-3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 14-1

[0732] (R)-3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 14-2

[0733] Compound 14 was separated by chiral column chromatography to obtain compounds 14-1 and 14-2.

[0734] Example 15

[0735] 3-(2-chloro-4'-(2'-(methyl-d3)-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione)15

[0736] first step

[0737] 2'-(methyl-d3)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one 15a

[0738] Compound 3c (12 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL, Adamas) and water (0.2 mL), and 4,4,5,5-tetramethyl-2-(methyl-d3)-1,3,2-dioxoboronylcyclopentane (20 mg, 0.14 mmol, Acon), potassium carbonate (14 mg, 0.10 mmol, Sinopharm), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (3.7 mg, 0.005 mmol, Bide) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give title compound 15a (3 mg, yield: 33.3%).

[0739] MS m / z(ESI): 181.2 [M+1].

[0740] Step 2

[0741] 3-(2-chloro-4'-(2'-(methyl-d3)-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione)15

[0742] Using the synthetic route from step four to step five in Example 4, compound 4a in step four was replaced with compound 15a to obtain title compound 15.

[0743] Examples 15-1 and 15-2

[0744] (S)-3-(2-chloro-4'-(2'-(methyl-d3)-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 15-1

[0745] (R)-3-(2-chloro-4'-(2'-(methyl-d3)-4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 15-2

[0746] Compound 15 was chirally resolved to give compounds 15-1 and 15-2.

[0747] Biological evaluation

[0748] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0749] Test Example 1: VAV1 Degradation Experiment in T Cells

[0750] The degradation rate of VAV1 protein in compound-treated T cells (Jurkat) was detected using Meso Scale Discovery (MSD) to assess the degradation activity of the compound on intracellular VAV1.

[0751] Experimental steps:

[0752] Electrochemiluminescence (ECL) is a specific chemiluminescent reaction initiated by electrochemistry on an electrode surface, offering higher sensitivity and a wider linear range for the detection of target proteins. In this experiment, Jurkat cells (ATCC, catalog number TIB-152) resuspended in RPMI 1640 medium containing 10% FBS were seeded into 96-well plates and cultured at 37°C with 5% CO2. Then, compounds of different concentration gradients were added, and the plates were treated at 37°C with 5% CO2 for 24 hours, after which lysed cells were collected. VAV1 was labeled using a VAV1-specific antibody sandwich method (Thermo, MA5-17198, Proteintech, 16364-1-AP), and the VAV1-antibody complex was tagged with a SULFO tag using Anti-Rabbit Antibody Goat SULFO-TAG Labeled (MSD, R32AB-1). Using a MESO SECTOR S 600 instrument, the electrochemical excitation of the SULFO-TAG™ label to emit a strong light signal was detected, allowing for the determination of VAV1. The content of VAV1 recombinant protein was calculated using a standard curve. DMSO-treated wells were used as negative controls, and blank cell lysates were used as positive controls. Concentration-response curves of compound concentration versus VAV1 degradation rate were obtained using four-parameter nonlinear fitting with GraphPad PRISM software (version 9.00; GraphPad San Diego, CA), and the relative DC content was calculated. 50 The value reflects the degradation activity of different compounds on VAV1.

[0753] Table 1. Degradation activity of the compounds disclosed herein against VAV1.

[0754] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1.

[0755] Test Example 2: VAV1 Degradation Experiment in Human PBMC Cells

[0756] The degradation rate of VAV1 protein in human PBMC cells treated with the compound was detected using Meso Scale Discovery (MSD) to evaluate the degradation activity of the compound on VAV1 in human PBMC cells.

[0757] Experimental steps:

[0758] Electrochemiluminescence (ECL) is a specific chemiluminescent reaction initiated by electrochemistry on an electrode surface, offering higher sensitivity and a wider linear range for the detection of target proteins. In this experiment, cryopreserved human PBMC cells (Xuanfeng, #SLB-HP050B) were revived and resuspended in RPMI 1640 medium containing 10% FBS. The cells were seeded at a density of 500,000 viable cells per well in 90 μL of 96-well round-bottom plates (Corning #3788). Then, 10 μL of compounds diluted 4-fold with culture medium at different concentrations were added, and the plates were treated at 37°C with 5% CO2 for 24 hours. After lysing the cells with HTRF lysis buffer (Revvity, #64KL1FDF), the cells were stored at -80°C. VAV1 was labeled using a VAV1-specific antibody sandwich method (Thermo, MA5-17198, Proteintech, #16364-1-AP), and the VAV1-antibody complex was tagged with a SULFO tag using Anti-Rabbit Antibody Goat SULFO-TAG Labeled (MSD, #R32AB-1). In a MESO SECTOR S 600 instrument, the SULFO-TAG™ label was excited by electrochemical reaction to emit a strong light signal, and VAV1 was measured. The content of recombinant VAV1 protein was calculated using a standard curve. DMSO-treated wells were used as positive controls, and blank cell lysate was used as a negative control. A concentration-response curve of compound concentration versus VAV1 degradation rate was obtained using four-parameter nonlinear fitting with GraphPad PRISM software (version 10.00; GraphPad San Diego, CA), and the absolute DC-DC ratio was calculated. 50 The value reflects the degradation activity of different compounds on VAV1.

[0759] Table 2. Degradation activity of the disclosed compounds against VAV1 in human PBMC cells.

[0760] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1 in human PBMC cells.

[0761] Test Example 3: Degradation Experiment of VAV1 in Human Whole Blood Cells

[0762] The ability of the compound to degrade VAV1 protein in human whole blood was evaluated by flow cytometry.

[0763] Experimental steps:

[0764] Fresh whole blood (Xuanfeng, #XFB-HWB-10A) was seeded at 90 μL per well into 96-well round-bottom plates (Corning, #3788). 10 μL of compounds diluted 4-fold with culture medium at different concentration gradients were added and thoroughly mixed. The plates were incubated at 37°C with 5% CO2 for 24 hours. APC-anti-CD45 antibody (Biolegend, #304037) (final concentration 0.2 μg / mL) was added to the human whole blood sample. The mixture was stirred at 900 rpm for 2 min and stained at 4°C for 1 hour. Red blood cells were then lysed. Each whole blood sample was added to 1.8 mL of red blood cell lysis buffer (Thermal, #00-4333-54), and the mixture was shaken at room temperature for 10-15 min until the red blood cells were fully lysed. The cells were then centrifuged at 500g for 5 minutes, and the supernatant was discarded. Add 1.2 mL of pre-chilled FACS buffer (PBS buffer containing 2% heat-inactivated FBS), centrifuge at 500 g for 5 minutes at 4°C and discard the supernatant. Resuspend the cell pellet in 200 μL of pre-chilled FACS buffer, centrifuge at 500 g for 5 minutes and discard the supernatant, washing the cells twice. Then add 100 μL of cell fixation and permeabilization buffer (BD, #554714) to each well and incubate at room temperature for 20 minutes. Centrifuge the fixed and permeabilized cell samples and discard the supernatant, washing twice with BD Perm / Wash Buffer (BD, #554714), 200 μL per well. Prepare VAV1 antibody (Proteintech, #16364-1-AP) to 1 μg / mL with BD Perm / Wash Buffer, resuspend the cells in 50 μL, and incubate overnight at 4°C. Wash the cells three times with BD Perm / Wash Buffer, 200 μL per well, and centrifuge at 500 g for 5 minutes. Using 1 μg / mL PE-labeled anti-rabbit antibody (Biolegend,

[0765] Cells were resuspended in 50 μL of BD Perm / Wash Buffer (#406421) and incubated at 4°C for 1 hour. Cells were washed three times with BD Perm / Wash Buffer, 200 μL per well, and centrifuged at 500g for 5 min. Flow cytometry analysis was performed using FACS. FlowJo software (version 10.9.0; Becton, Dickinson and Company; 2023) was used to process the flow cytometry data. The detection value for each well was calculated as the mean VAV1 fluorescence signal multiplied by the VAV1 positivity rate. Positive control wells were DMSO-treated blood sample wells, and negative control wells were DMSO-treated blood sample wells, but only stained with secondary antibody, not primary antibody for VAV1. Concentration-response curves of compound concentration versus VAV1 degradation rate were obtained using GraphPad PRISM software (version 10.00; GraphPad San Diego, CA) with four-parameter nonlinear fitting, and the absolute DC-DC ratio was calculated. 50 The value reflects the degradation activity of different compounds on VAV1.

[0766] Table 3. Degradation activity of the compounds disclosed herein against VAV1.

[0767] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1 in human whole blood cells.

[0768] Test Example 4: Pharmacokinetic Evaluation

[0769] I. C57BL / 6N Mouse Experiment

[0770] 1. Abstract

[0771] Using C57BL / 6N mice as test animals, the plasma drug concentration at different time points after gavage (ig) administration of the compound of the present invention to C57BL / 6N mice was determined by LC / MS / MS method. The pharmacokinetic behavior of the compound of the present invention in C57BL / 6N mice was studied and its pharmacokinetic characteristics were evaluated.

[0772] 2. Test Plan

[0773] 2.1 Test Drugs

[0774] Compound 4-2;

[0775] Comparative Example 1 (Compound 185 from WO2024151547, prepared according to the method disclosed in WO2024151547), with the following structure:

[0776] 2.2 Experimental Animals

[0777] Eighteen female C57BL / 6N mice were randomly divided into two groups and fed overnight (Changzhou Cavens Laboratory Animal Co., Ltd., License No. SCXK(Su)2021-0013).

[0778] 2.3 Drug Preparation

[0779] Weigh out a certain amount of the test compound and add 10% SBE-β-CD pure aqueous solution to prepare a 3 mg / mL colorless and transparent solution.

[0780] 2.4. Administration

[0781] The dosage is 30 mg / kg, and the administration volume is 10 mL / kg.

[0782] 3. Operation

[0783] The drug was administered by gavage, and 0.1 mL of blood was collected from the orbital venous plexus at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 10,000 rpm for 1 minute at 4°C to separate the plasma. The process was completed within 1 hour and the plasma was stored at -20°C for analysis.

[0784] The levels of the target compounds in the plasma of C57BL / 6N mice after administration of different compounds were determined by LC / MS / MS.

[0785] 4. Pharmacokinetic Parameter Results

[0786] Table 4. Pharmacokinetic parameters of the compounds disclosed herein in C57BL / 6N mice.

[0787] Conclusion: Compared with Comparative Example 1, the compound disclosed herein exhibits higher blood concentrations, higher exposure, and lower clearance in C57BL / 6N mice, demonstrating pharmacokinetic advantages.

[0788] Test Example 5: Solubility of the Compounds Disclosed

[0789] 1. Experimental materials

[0790] Reagents: Dimethyl sulfoxide (chromatographic grade, Adamas-beta, catalog number 75927E), acetonitrile (chromatographic grade, Merck, catalog number 1.00030.4008), ammonium acetate (ACS) reagents (Sigma-Aldrich, catalog number 32301-100G), FaSSIF / FeSSIF / FaSSGF powder (Biorelevant, catalog number FFF02), FaSSIF buffer concentrate (Biorelevant, FASBUF), FeSSIF buffer concentrate (Biorelevant, FESBUF), sodium dihydrogen phosphate dihydrate (analytical grade, Sinopharm, 20040718), disodium hydrogen phosphate dodecahydrate (analytical grade, Sinopharm, 10020318), sodium chloride (analytical grade, Sinopharm, 10019318), sodium hydroxide (analytical grade, Sinopharm, 10019718), hydrochloric acid (analytical grade, Sinopharm, 10011018), and ultrapure water (made in-house using an ELGACHORUS laboratory ultrapure water system).

[0791] Instrument: Agilent 1200DAD high-performance liquid chromatograph (Agilent Technologies, Inc.)

[0792] 2. Material preparation

[0793] 2.1 Preparation of FassIF solution

[0794] Weigh 2.0825g of FaSSIF medium solution and 48.055g of ultrapure water into a 50mL beaker, then add 0.112g of FaSSIF / FeSSIF / FaSSGF powder. Stir to dissolve and let stand for equilibration for 2 hours before use (the solution should be used within 48 hours).

[0795] 2.2 Preparation of FessIF solution

[0796] Weigh 4.0705g of FeSSIF medium solution and 45.97g of ultrapure water into a 50mL beaker, then add 0.56g of FaSSIF / FeSSIF / FaSSGF powder and stir to dissolve (the solution should be used within 48 hours).

[0797] 2.3 Preparation of PBS solution

[0798] Weigh 0.57g NaH2PO4·2H2O, 5.55g Na2HPO4·12H2O, and 6.48g NaCl, add them to ultrapure water, adjust the pH to 7.4±0.05 with 1M NaOH or 1M HCl, and then add water to a final volume of 1L. Store at 4℃ (shelf life is 6 months).

[0799] 3. Experimental Procedure

[0800] 3.1 Solubility test in FassIF and FessIF solutions

[0801] 3.1.1 Weigh an appropriate amount of the analyte and prepare a 10 mM stock solution using DMSO as the solvent. Accurately measure 10 μL of the stock solution (10 mM concentration, dissolved in DMSO) and 990 μL of DMSO into a 1.5 mL PE tube, mix well, and obtain a clear 100 μM sample solution, which will serve as the reference solution.

[0802] 3.1.2 Dissolve 1 mg of the sample to be tested in 900 μL of FassIF solution (or FessIF solution), mix vigorously, and prepare two parallel solutions; shake in a constant temperature shaker at 37℃ for 24 hours, transfer the mixed solution to a 1.5 mL PE tube, centrifuge at 12000 rpm for 30 min, and use the supernatant as the sample solution, transfer it to a 2 mL vial for liquid chromatography analysis.

[0803] 3.2 Solubility test in PBS solution

[0804] 3.2.1 Weigh an appropriate amount of the analyte and prepare a 10 mM stock solution using DMSO as the solvent. Accurately measure 10 μL of the stock solution (10 mM concentration, dissolved in DMSO) and 990 μL of DMSO into a 1.5 mL PE tube, mix well, and obtain a clear 100 μM sample solution, which will serve as the reference solution.

[0805] 3.2.2 Accurately transfer 10 μL of the sample stock solution (10 mM concentration, dissolved in DMSO) and 990 μL of PBS solution into a 96-well deep-well plate (2 mL). Cover the plate with the silicone sealant and mix well. Prepare four parallel aliquots. Shake the plate at 1200 rpm at room temperature for 24 hours on a THERMO-SHAKER microplate shaker. Centrifuge the entire plate at 4000 rpm for 1 hour. Transfer 300 μL of the supernatant into a 96-well shallow-well plate (0.5 mL), cover with the 96-well plate sealant, and transfer to liquid chromatography for analysis.

[0806] 4. Experimental Results

[0807] Solubility (μM) = Peak area of ​​sample / Peak area of ​​reference × Concentration of reference solution (μM) × Dilution factor of sample solution × Injection volume of reference solution ÷ Injection volume of sample solution

[0808] The average of the two measurements was taken as the final solubility in FassIF, FessIF, and PBS solutions.

[0809] Table 5. Solubility of the compounds disclosed herein

[0810] Conclusion: Compared with Comparative Example 1, the compound disclosed herein exhibits excellent solubility in PBS, FastsIF, and FessIF solutions.

[0811] Test Example 6: Drug Efficacy Evaluation

[0812] 1. Experimental Objective

[0813] The efficacy of compound 4-2 in a mouse EAE model was evaluated.

[0814] 2. Experimental reagents

[0815] Compound 4-2

[0816] The volume of both the solvent and compound 4-2 was 10 mL / kg; the solvent was 10% SBE-β-CD.

[0817] 3. Experimental methods and materials

[0818] 3.1 Laboratory animals and their housing conditions

[0819] Female C57BL / 6J mice, aged 7-8 weeks, were purchased from Changzhou Cavens Laboratory Animal Co., Ltd., Production License No. SCXK(Su)2021-0013, Certificate No. 320730250100272224. Five mice were housed per cage, with a 12 / 12-hour light / dark cycle, a constant temperature of 23±1℃, and humidity of 50-60%. Free access to food and water was provided.

[0820] 3.2 Animal grouping

[0821] After acclimatization, the mice were grouped and administered medication as follows:

[0822] Table 6.1. Grouping and Dosing Regimens of Animals in In Vivo Efficacy Experiments

[0823] Note: po indicates oral administration.

[0824] 3.3 Experimental Methods:

[0825] After acclimatization, the mice were divided into 5 groups based on their body weight. Five mice were placed in the blank control group, and the remaining mice were placed in each group with 10 mice. An equal volume of 2 mg / mL MOG was drawn using a screw-type syringe. 35-55The solution was connected to a 6 mg / mL CFA solution via a three-way valve. The syringe was kept on ice and repeatedly pushed and pulled for approximately one hour to ensure thorough mixing and the formation of a stable emulsion. Mice were anesthetized with isoflurane, and the injection sites (skin on the back of both hind limbs and neck and shoulder) were disinfected with 75% alcohol. 150 μl of the emulsion was injected subcutaneously, followed by 50 μl at each of the three sites. Simultaneously, 200 μl (400 ng) of PTX solution was injected intraperitoneally, followed by another 200 μl of PTX intraperitoneally 48 hours later. Mice began to show symptoms 8-12 days post-immunization. Mouse weight was recorded daily, and clinical disease severity was assessed (Table 6.2 below). QD (quick-dose) administration began the day after onset of symptoms at a volume of 10 mL / kg for 9 consecutive days. Whole blood samples were collected before the last administration and at 2, 6, and 24 hours after the last administration for PK / PD analysis.

[0826] Table 6.2. Disease Severity Scores from the EAE Model

[0827] 3.4 Data Statistics

[0828] All data are expressed as mean ± standard error (Mean ± SEM) and plotted using GraphPad software.

[0829] 4. Results

[0830] As shown in Figure 1, the highest average score for disease progression in the solvent group mice in this experiment was approximately 3.7 points, with a disease incidence rate of 90%. Compound 4-2 showed strong therapeutic effects at high, medium, and low doses, with the high dose of 30 mpk completely inhibiting disease progression in the animals.

[0831] 5. Conclusion

[0832] This experiment used Rat MOG 35-55 A mouse EAE model was established using a peptide combined with PTX to evaluate the therapeutic potential of VAV1 molecular gel degrader compound 4-2 in treating MS. Compared with the model group, compound 4-2 showed a stronger pharmacodynamic response, demonstrating significant therapeutic effects at low doses and completely inhibiting disease progression at high doses.

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is a tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl, and tricyclic heteroaryl, each independently optionally substituted with one or more R 1a substituents; R 1a selected from deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterium- substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterium-substituted alkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 16 , -NR 17 R 18 , -C(O)R 16 , -C(O)OR 16 , -C(O)NR 17 R 18 , -OC(O)NR 17 R 18 , -OC(O)R 16 , -OC(O)OR 16 , -NR 19 C(O)R 16 , -NR 19 C(O)OR 16 , -S(O) v R 16 , -S(O) v NR 17 R 0 , oxo, =S, and =CR 20 R 21 ; each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 0 ; or two R 1a and the atoms to which they are attached, together form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is independently optionally substituted with one or more R 0 substituents; L is selected from the group consisting of a bond, O, S, C(O), NR c , C(O)NR c , NR c C(O), alkylene, O(alkylene), S(alkylene), NR c (alkylene), C(O)(alkylene), and (alkylene)C(O), said alkylene being optionally substituted with one or more R 0 ; R c is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R 2 selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cyano group, and a cycloalkyl group; X is N or CR 6a ; Y is N or CR 6d ; R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace; R 7 is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, and a deuterated alkoxy group; R 16 , R 17 , and R 18 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more R 0 ; or R 17 and R 18 , together with the nitrogen atom to which they are attached, form a heterocyclyl group optionally substituted with one or more R 0 ; R 19 selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, and a cycloalkyl group; R 20 and R 21 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, an alkoxy group, a hydroxyl group, and a cycloalkyl group; or, R 20 and R 21 together with the carbon atom to which they are attached form a cycloalkyl group; R 0 selected from the group consisting of a deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterium substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterium substituted alkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =0, =S, =CH2, =CHF, =CF2, -C(0)0alkyl, -C(0)OH, -C(0)NH2, -C(0)NHalkyl, -C(0)N(alkyl)2, -C(0)halogen, -C(0)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; or, two R 0 and the atoms attached thereto form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, each independently optionally substituted with one or more substituents selected from a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated-alkyl, an alkoxy, a haloalkoxy, a deuterated-alkoxy, and an oxo group; v is 0, 1 or 2. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is a tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl, and tricyclic heteroaryl, each independently optionally substituted with one or more R 1a substituents; R 1a Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 , oxo group, =S and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace; or two R 1a and the atoms to which each is attached together form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is independently optionally substituted with one or more R 0 substituents; L is selected from the group consisting of a bond, O, S, C(O), NR c , C(O)NR c , NR c C(O), alkylene, O(alkylene), S(alkylene), NR c (alkylene), C(O)(alkylene), and (alkylene)C(O), said alkylene being optionally substituted with one or more R 0 ; R c is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R 2 selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, and a cycloalkyl group; X is N or CR 6a ; Y is N or CR 6d ; R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace; R 7 selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group; R 16 , R 17 and R 18 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; wherein each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more R 0 ; or R 17 and R 18 together with the nitrogen atom to which they are attached form a heterocyclyl group optionally substituted with one or more R 0 ; R 19 selected from a hydrogen atom, an alkyl group and a cycloalkyl group; R 20 and R 21 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a hydroxy group, and a cycloalkyl group; or, R 20 and R 21 together with the atoms to which they are attached form a cycloalkyl group; R 0 selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =0, =S, =CH2, =CHF, =CF2, -C(0)0alkyl, -C(0)OH, -C(0)NH2, -C(0)NH(alkyl), -C(0)N(alkyl)2, -C(0)halogen, -C(0)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; or two R 0 and the atoms to which they are attached form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, each independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and oxo; v is 0, 1 or 2. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 is a compound of general formula (I) a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof, wherein: R 1 -R 5 , R 6a , R 6b , R 6c , R 6d and L are as defined in claim 1 or 2. The compound represented by General Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3 is a hydrogen atom or a deuterium atom; and / or R 4 is a hydrogen atom or a deuterium atom; and / or R 5 is a hydrogen atom or a deuterium atom. Preferably, R 3 is a hydrogen atom; and / or R 4 is a hydrogen atom; and / or R 5 is a hydrogen atom. The compound represented by General Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 6a is a hydrogen atom or a deuterium atom; and / or R 6b is a hydrogen atom or a deuterium atom; and / or R 6c is a hydrogen atom or a deuterium atom; and / or R 6d is a hydrogen atom or a deuterium atom. Preferably, R 6a is a hydrogen atom; and / or R 6b is a hydrogen atom; and / or R 6c is a hydrogen atom; and / or R 6d is a hydrogen atom. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein: L, R 1 and R 2 as defined in claim 1 or 2. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein L is selected from the group consisting of a bond, O, CH2and OCH2; preferably L is a bond. The compound of general formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is selected from a1, a, and b are each independently 1, 2, 3, 4, or 5; d1 is 0, 1, 2, or 3; d is 0, 1, 2, or 3; k is 0, 1, 2, or 3; the condition is that when d1 is 0, a1 is selected from 2, 3, 4, or 5; when k is 0, b is selected from 2, 3, 4, or 5; R 1k Selected from hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, cycloalkylalkyl groups, and heterocyclic alkyl groups; R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterylalkoxy, alkoxyalkyl, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, R 1b and R 1c Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1e Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1d and R 1h Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1f and R 1g Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or, R 1e and R 1k Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 Replace; R 0 R 16 -R 19 and v as defined in claim 1; Preferably, R 1 selected from The compound of general formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 2 is halogen; preferably, R 2 is Cl. The compound of general formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, is selected from the following compounds: Compounds or salts thereof: A method of preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, comprising: The compound of general formula (IA) or a salt thereof is coupled with the compound of general formula (IB) or a salt thereof to obtain the compound of general formula (I) or a pharmaceutically acceptable salt thereof; wherein: R w selected from Bpin and -B(OH)2; R L is a leaving group; preferably, R L is halogen; more preferably, R L is Br; R 1 -R 5 、R 2 , X, Y, L, R 6b and R 6c as defined in claim 1 or 2. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable thereof or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for inhibiting or degrading VAV1. Use of a compound according to any one of claims 1 to 10 or a pharmaceu- tically acceptable thereof or a pharmaceutical composition according to claim 13 for the manufacture of a medicament to treat and / or prevent a disease or disorder mediated or dependent on VAV1. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable thereof or a pharmaceutical composition according to claim 13 for the manufacture a medicament to treat and / or prevent a tumor, an autoimmune disease and an inflammatory disease; wherein the autoimmune disease or inflammatory disease is preferably selected from the group consisting of autoimmune encephalomyelitis (EAE), multiple sclerosis, arthritis, rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes mellitus and related diseases, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, psoriatic, Graves ophthalmopathy, Graves' disease, alopecia areata, allergic disease, asthma, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, allergic contact dermatitis, colitis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, scleroderma, chronic inflammatory demyelinating polyneuropathy, Alzheimer's disease, autoimmune liver disease, hepatitis, amyloidosis, macular degeneration, lupus nephritis, pulmonary arterial hypertension, chronic graft-versus-host disease, acute graft-versus-host disease, biliary sclerosis, sclerosing cholangitis and axial spondyloarthritis.

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