Heterocyclic compound, preparation method therefor, and pharmaceutical use thereof

Abstract

The present disclosure relates to a heterocyclic compound, a preparation method therefor, and the pharmaceutical use thereof. Specifically, the present disclosure relates to a heterocyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the heterocyclic compound, and the use thereof as a therapeutic agent, particularly the use thereof as a VAV1 inhibitor or degrader, and in the preparation of a drug for treating and / or preventing VAV1-mediated or VAV1-dependent diseases or disorders. Each group in general formula (I) is as defined in the description.

Description

Heterocyclic compounds, their preparation methods and their applications in medicine Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a heterocyclic 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-mediated degradation of VAV1 protein, it regulates TCR and BCR-mediated activation, inhibiting 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 specifically for VAV1 degradation. 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] X is N or CR 6a ;

[0006] Y is either N or C;

[0007] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0008] R 1a and R 1b Together with the attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. X replace;

[0009] R X Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0010] Or, two Rs X Together with the 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;

[0011] Each R a 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0012] Or, two Rs a Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0013] R 2 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, and cycloalkyl groups;

[0014] R 3 R 4 R 5 R 6a R 6b and R 6c 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;

[0015] R 7 Selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups;

[0016] R 0 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, heteroaryloxy, oxo, =S, -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 and = CR 20 R 21The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy groups are each independently and independently labeled with one or more R groups. t replace;

[0017] 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. t Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. t Substituted heterocyclic groups;

[0018] R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0019] 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;

[0020] R t 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;

[0021] m is an integer from 0 to 15;

[0022] v can be 0, 1, or 2.

[0023] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Connected to the same ring atom, or R 1a and R1b Each is connected to two adjacent ring atoms; in some implementations, R 1a and R 1b Connected to the same ring atom; in some implementations, R 1a and R 1b Each is connected to two adjacent ring atoms; in some implementations, R 1a and R 1b Together with the attached ring atoms, it forms a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, wherein each of the 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, and 5- to 10-membered heteroaryl group is independently and optionally influenced by one or more R atoms. X Replace; R X As defined in general formula (I); in some implementations, R on the same carbon atom 1a and R 1b Together with the attached carbon atom, it forms a cyclopropyl, piperidinyl, and pyrrolidinyl group, wherein the piperidinyl or pyrrolidinyl group is optionally surrounded by one or more R groups. X Replace; R X As defined in general formula (I); in some implementations, R on the same carbon atom 1a and R 1b Together with the attached carbon atom, it forms a cyclopropyl or piperidinyl group, wherein the piperidinyl group is optionally reacted with one or more R atoms. X Replace; R X As defined in general formula (I); in some implementations, R on adjacent ring atoms 1a and R 1b Together with their respective attached ring atoms, they form pyridone or cyclobutyl groups.

[0024] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 7-membered heterocyclic group or a 5- or 6-membered heteroaryl group; in some embodiments, ring A is a 5- to 7-membered heterocyclic group.

[0025] 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.

[0026] in:

[0027] M 1 Selected from bonds, C(O), O, S, NR d NR d C(O) and C(O)NR d ;

[0028] p and q are each independently 0, 1, 2 or 3;

[0029] Cyclone B' is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. X replace;

[0030] R d The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups is independently and optionally selected by one or more R groups. 0 replace;

[0031] R 11a R 11b R 11c and R 11d The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0032] Or, R 11a and R 11b Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0Replace; or, R 11a and R 11b Together they form = O;

[0033] Or, R 11c and R 11d Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 11c and R 11d Together they form = O;

[0034] R 2 -R 5 X, R 6b R 6c R X R 0 R 16 -R 19 And v is as defined in general formula (I).

[0035] 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.

[0036] in:

[0037] M 1 Selected from bonds, C(O), O, S, NR d NR d C(O) and C(O)NR d ;

[0038] p and q are each independently 0, 1, 2 or 3;

[0039] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently optionally influenced by one or more R groups. X replace;

[0040] R d The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups is independently and optionally selected by one or more R groups. 0 replace;

[0041] R 11a R 11b R 11c and R 11dThe same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0042] Or, R 11a and R 11b Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 11a and R 11b Together they form = O;

[0043] Or, R 11c and R 11d Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 11c and R 11d Together they form = O;

[0044] R 2 -R 5 X, R 6b R 6c R X R 0 R 16 -R 19And v is as defined in general formula (I).

[0045] 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 (II-1) or general formula (II-2), or a pharmaceutically acceptable salt thereof.

[0046] in:

[0047] k1 can be 0, 1, 2, or 3;

[0048] k2 is 0, 1, 2, 3, 4, 5, 6 or 7;

[0049] d is 0, 1, or 2;

[0050] Q is selected from key, CR 8b R 8c O, S and NR 8d ;

[0051] R 8 R 8a R 8b and R 8c 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0052] Or, two adjacent R 8 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;

[0053] Or, R 8a and R 8b Together with the 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;

[0054] Or, R 8b and R 8c Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0055] Or, two Rs 8a Together with the 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;

[0056] R 8d The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups is independently and optionally selected by one or more R groups. 0 replace;

[0057] Or, R 8a and R 8d Together with the attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0058] R 2 -R 5 R 6a R 6b R 6c R 0 R 11a R 11b R 11c R 11d M 1 p, q, R 16 -R 19And v is as defined in general formula (II).

[0059] 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 (III) or general formula (M) or a pharmaceutically acceptable salt thereof.

[0060] in:

[0061] M 2 Selected from bonds, C(O), O, S, NR 9B NR 9B C(O) and C(O)NR 9B ;

[0062] r can be 0, 1, 2, 3, or 4;

[0063] The ring C is a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R groups. X replace;

[0064] R 9B Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0065] R 12a and R 12b The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0066] Or, R 12a and R 12b Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 12a and R 12b Together they form = O;

[0067] R 2 -R 5 X, R 6b R 6c R X R 0 R 16 -R 19 And v is as defined in general formula (I).

[0068] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III), or general formula (M), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III-1), general formula (III-2), general formula (M-1), or general formula (M-2), or a pharmaceutically acceptable salt thereof.

[0069] in:

[0070] k3 is 0, 1, 2, 3, 4, 5 or 6;

[0071] k4 is 0, 1, 2, 3, 4, 5, or 6;

[0072] G is selected from bonds, C(O), O, S, NR 9C NR 9C C(O) and C(O)NR 9C ;

[0073] x and y are each independently 0, 1, 2 or 3;

[0074] t1 and t2 are each independently 0, 1, 2 or 3;

[0075] R 9A R 9B and R 9C They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16、 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0076] R 9 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0077] Or, two Rs 9 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0078] R 2 -R 5 R 6a R 6b R 6c R 0 R 16 -R 19 And v as defined in general formula (I) or general formula (III).

[0079] 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 (IV) or a pharmaceutically acceptable salt thereof.

[0080] in:

[0081] The ring D is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. X replace;

[0082] Z 1 and Z 2 Each can be N or C independently;

[0083] Z is selected from O, S, N, NR 14 and CR 15 ;

[0084] R 14 Selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18Heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0085] R 15 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0086] R 2 -R 5 X, R 6b R 6c Y, R X R 0 R 16 -R 19 And v is as defined in general formula (I).

[0087] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (IV), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV-1), general formula (IV-2), or general formula (IV-3), or a pharmaceutically acceptable salt thereof.

[0088] in:

[0089] m1 and m2 are each independently 0, 1, 2, 3 or 4;

[0090] W is selected from bonds, C(O), O, S, NR 10A NR 10A C(O) and C(O)NR 10A ;

[0091] k5 can be 0, 1, 2, 3, 4, 5, or 6;

[0092] R 10A Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0093] R 10 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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) vR 16 and -S(O) v NR 17 R 18 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0094] Z is N or CR 15 ;

[0095] R 2 -R 5 R 6a R 6b R 6c R 0 R 15 R 16 -R 19 And v is as defined in general formula (IV).

[0096] 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 (V) or a pharmaceutically acceptable salt thereof.

[0097] in:

[0098] Cycloalkyl D' is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently and optionally converted by one or more R groups. X replace;

[0099] Z 1 and Z 2 Each can be N or C independently;

[0100] Z is selected from O, S, N, NR 14 and CR 15 ;

[0101] R 14 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0102] R 15 Selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0103] R 2 -R 5 X, R 6b R 6c Y, R X R 0 R 16 -R 19 And v is as defined in general formula (I).

[0104] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (V), or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (V-1), general formula (V-2), or a pharmaceutically acceptable salt thereof.

[0105] in:

[0106] m1 and m2 are each independently 0, 1, 2, 3 or 4;

[0107] W is selected from bonds, C(O), O, S, NR 10A NR 10A C(O) and C(O)NR 10A ;

[0108] k5 can be 0, 1, 2, 3, 4, 5, or 6;

[0109] R 10A Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0110] R 10 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0111] Z is N or CR 15 ;

[0112] R 2 -R 5 R 6a R 6b R 6c R 0 R 15 R 16 -R 19 And v is as defined in general formula (V).

[0113] 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 (VI) or a pharmaceutically acceptable salt thereof.

[0114] in:

[0115] A 1 and A 2 Each is independently N or CR 13 ;

[0116] B 1 and B 2 Each is independently selected from bonds, C(O), O, S, NR 13c NR 13c C(O) and C(O)NR 13c ;

[0117] u can be 0, 1, 2, 3, 4, 5, or 6;

[0118] R 13 R 13a and R 13b The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR17 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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0119] Or, R 13a and R 13b Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 13a and R 13b Together they form = O;

[0120] R 13c Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace;

[0121] R 2 -R 5 R 6a R 6b R 6c R 0 R 16 -R 19And v is as defined in general formula (I).

[0122] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is C; in some embodiments, Y is N.

[0123] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen atoms, halogens, and hydroxyl groups; in some embodiments, R 7 It is a hydrogen atom.

[0124] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; in some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; in some embodiments, m is 0, 1, 2, 3, 4, 5 or 6; in some embodiments, m is 0, 1, 2, 3 or 4; in some embodiments, m is 0, 1 or 2; in some embodiments, m is 0 or 1; in some embodiments, m is 1; in some embodiments, m is 0.

[0125] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, oxo, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl C 1-6 Alkyl; the 5- or 6-membered heteroaryl and the 5- or 6-membered heteroaryl C 1-6 Each alkyl group is independently selected from C1. 1-6 Alkyl, halogen, C 1-6 Alkoxy and C 1-6 One or more of the haloalkyl groups are substituted; or, two R groups are substituted. a Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R a It can be a hydrogen atom; or two R atoms on the same carbon atom. a Together with the attached atoms, it forms a cyclopropyl group; in some embodiments, R a It is a 5- or 6-membered heteroaryl C 1-6 Alkyl, of which 5 or 6-membered heteroaryl C 1-6 Alkyl groups are optionally enclosed by one or more C24 groups. 1-6 Alkyl substitution; in some embodiments, R a It is a -CH2-5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally bonded by one or more C2-membered carbon atoms. 1-6 Alkyl substitution.

[0126] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II'), (II), (III), (M), (IV), or (V), or their pharmaceutically acceptable salts, wherein R X Selected from halogens, C 1-6 Alkyl, C(O)R 16 C(O)OR 16 , oxo group, 5 or 6-membered heteroaryl and 5 or 6-membered heteroaryl C 1-6 Alkyl; the 5- or 6-membered heteroaryl and the 5- or 6-membered heteroaryl C 1-6 Each alkyl group is independently selected from C1. 1-6 Alkyl, halogen, C 1-6 Alkoxy and C 1-6 One or more of the haloalkyl groups are substituted; R 16 C 1-6 Alkyl; or, two Rs X Together with the attached atoms, they form 3 to 6-membered cycloalkyl groups.

[0127] In some implementations, two R atoms on the same carbon atom X Together with the attached atoms, they form a cyclopropyl group; in some embodiments, two adjacent R groups... X Together with the attached atoms, it forms a cyclobutyl group; in some embodiments, R X Selected from oxo groups, C 1-6 Alkyl, C(O)OR 16 and 5 or 6-membered heteroaryl C 1-6 Alkyl, the 5- or 6-membered heteroaryl C 1-6 Alkyl groups are optionally enclosed by one or more C24 groups. 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; in some embodiments, R X Selected from C 1-6 Alkyl, C(O)OR 16 and 5 or 6-membered heteroaryl C 1-6 Alkyl, the 5- or 6-membered heteroaryl C 1-6 Alkyl groups are optionally enclosed by one or more C24 groups. 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; in some embodiments, R X Selected from C 1-6 Alkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; in some embodiments, R X C 1-6Alkyl; in some embodiments, R X For methyl; in some embodiments, R X For Boc; in some implementations, R X It is a -CH2-5-membered heteroaryl group; the 5-membered heteroaryl group is optionally coated with one or more C2-C2 groups. 1-6 Alkyl substitution; in some embodiments, R X Selected from In some implementation schemes, R X for

[0128] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II'), (II), (III), (M), (IV), (V) or their pharmaceutically acceptable salts, wherein X is a CR 6a ;R 6a As defined in general formula (I); in some implementations, X is CH; in some implementations, X is N.

[0129] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (II), or pharmaceutically acceptable salts thereof, wherein ring B is a 5- to 10-membered heteroaryl or a 3- to 8-membered heterocyclic group; the 5- to 10-membered heteroaryl and the 3- to 8-membered heterocyclic group are each independently and optionally composed of one or more R X Replace; R X As defined in general formula (I); in some embodiments, ring B is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclic group; the 5- or 6-membered heteroaryl and the 5- or 6-membered heterocyclic group are each independently and optionally converted by one or more R X Replace; R X As defined in general formula (I); in some implementations, ring B is In some implementation schemes, ring B is In some implementation schemes, ring B is k1, k2, R 8 R 8a Q and d are as defined in general formula (II) or general formula (II-1); in some embodiments, ring B is selected from... In some implementation schemes, ring B is selected from... In some implementation schemes, ring B is The * end is connected to the ring containing X.

[0130] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (II') or their pharmaceutically acceptable salts, wherein ring B' is a 5- to 10-membered heteroaryl group or a 3- to 8-membered heterocyclic group; the 5- to 10-membered heteroaryl group and the 3- to 8-membered heterocyclic group are each independently and optionally composed of one or more R groups. X Replace; R X As defined in general formula (I); in some embodiments, ring B' is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclic group; the 5- or 6-membered heteroaryl and the 5- or 6-membered heterocyclic group are each independently and optionally composed of one or more R X Replace; R X As defined in general formula (I); ring B' is selected from The * end is connected to the ring containing X.

[0131] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II'), (II), (II-1), and (II-2), or their pharmaceutically acceptable salts, wherein M 1 Selected from bonds, O, C(O) and NR d C(O); R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, M 1 For key or O; in some implementations, M 1 It is O.

[0132] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II'), (II), (II-1), and (II-2) or their pharmaceutically acceptable salts, wherein p and q are each independently 0, 1, or 2; in some embodiments, p is 0 or 1; q is 1; in some embodiments, p is 0; q is 1; in some embodiments, p is 1; q is 1; in some embodiments, p is 0; q is 2; in some embodiments, p is 2; q is 0.

[0133] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II'), general formula (II), general formula (II-1) or general formula (II-2), or their pharmaceutically acceptable salts, wherein R 11a R 11b R 11c and R 11d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or, R 11a and R 11b Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups; or R 11c and R 11dTogether with the attached atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 11a R 11b R 11c and R 11d They may be the same or different, and each is independently selected from a hydrogen atom or a methyl group; or, R on the same carbon atom 11a and R 11b Together with the adjacent atoms, they form a cyclopropyl group; or R on the same carbon atom 11c and R 11d Together with the attached atoms, they form a cyclopropyl group; in some embodiments, R 11a R 11b R 11c and R 11d It is a hydrogen atom, or R 11a and R 11b Together with the attached atoms, they form a cyclopropyl group, or R 11c and R 11d Together with the attached atoms, they form a cyclopropyl group; in some embodiments, R 11a R 11b R 11c and R 11d For hydrogen atoms; in some implementations, R 11a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 11b R 11c and R 11d For hydrogen atoms; in some implementations, R 11a C 1-6 Alkyl; R 11b R 11c and R 11d For hydrogen atoms; in some implementations, R 11a Methyl; R 11b R 11c and R 11d It is a hydrogen atom.

[0134] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (II), or general formula (II-1), or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy groups; or, two adjacent R groups. 8 Together with their respective attached atoms, they form a 4- to 6-membered cycloalkyl group; in some embodiments, R 8 It is a hydrogen atom, or two adjacent R atoms. 8 Together with their respective connected atoms, they form a cyclobutyl group; in some embodiments, R 8 It is a hydrogen atom.

[0135] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-2), or pharmaceutically acceptable salts thereof, wherein R 8a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy group; or, two R groups 8a Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 8a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy group; or, two R groups on the same carbon atom. 8a Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 8a It can be a hydrogen atom, or two R atoms on the same carbon atom. 8a Together with the attached atoms, they form a cyclopropyl group; in some embodiments, R 8a It is a hydrogen atom.

[0136] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1) or their pharmaceutically acceptable salts are used, wherein k1 is 0, 1 or 2; in some embodiments, k1 is 0; in some embodiments, k1 is 1; and in some embodiments, k1 is 2.

[0137] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-2) or their pharmaceutically acceptable salts are used, wherein k2 is 0, 1 or 2; in some embodiments, k2 is 0; in some embodiments, k2 is 1; and in some embodiments, k2 is 2.

[0138] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-2), or their pharmaceutically acceptable salts, wherein Q is selected from CH2, O, and NR. 8d ;R 8d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, Q is selected from CH2, O and N(CH3); in some embodiments, Q is CH2.

[0139] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-2) or their pharmaceutically acceptable salts are used, wherein d is 0 or 1; in some embodiments, d is 0; in some embodiments, d is 1.

[0140] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1) or general formula (II-2), or their pharmaceutically acceptable salts, wherein:

[0141] M 1 Selected from bonds, O, C(O) and NR d C(O); R d It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0142] And / or p and q are each independently 0, 1 or 2;

[0143] and / or R 11a R 11b R 11c and R 11d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or, R 11a and R 11b Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups; or R 11c and R 11d Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups;

[0144] and / or R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy groups; or, two adjacent R groups. 8 Together with their respective attached atoms, they form 4- to 6-membered cycloalkyl groups;

[0145] and / or R 8a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy group; or, two R groups on the same carbon atom. 8a Together with the adjacent carbon atoms, they form 3- to 6-membered cycloalkyl groups;

[0146] And / or k1 is 0, 1, or 2;

[0147] And / or k2 is 0, 1, or 2;

[0148] And / or Q is selected from CH2, O and NR 8d ;R 8d It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0149] And / or d is 0 or 1.

[0150] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-2), or pharmaceutically acceptable salts thereof, wherein R 8d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 8d C 1-6 Alkyl; in some embodiments, R 8d It is a methyl group.

[0151] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-2), or pharmaceutically acceptable salts thereof, wherein R 8b and R 8c 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 8b and R 8c It is a hydrogen atom.

[0152] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II'), (II), (II-1), and (II-2), or their pharmaceutically acceptable salts, wherein R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R d C 1-6 Alkyl; in some embodiments, R d It is a methyl group.

[0153] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III) or general formula (M) or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b It is a hydrogen atom, or R 12a and R 12b Together they form = O; in some implementations, R 12a and R 12b For hydrogen atoms; in some implementations, R 12a and R 12b Together they form = O.

[0154] In some embodiments of this disclosure, the compounds of general formula (I), general formula (III), or general formula (M), or pharmaceutically acceptable salts thereof, have a ring C of 3 to 8-membered cycloalkyl or 3 to 8-membered heterocyclic group; the 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic groups are each independently and optionally converted by one or more R X Replace; R XAs defined in general formula (I); in some embodiments, the ring C is a 3- to 6-membered cycloalkyl group; in some embodiments, the ring C is a 3- to 5-membered cycloalkyl group; in some embodiments, the ring C is cyclopropyl or cyclopentyl; in some embodiments, the ring C is cyclopropyl; in some embodiments, the ring C is a 3- to 8-membered heterocyclic group; the 3- to 8-membered heterocyclic group is optionally surrounded by one or more R... X Replace; R X As defined in general formula (I); in some embodiments, ring C is a 6-membered heterocyclic group; the 6-membered heterocyclic group is optionally surrounded by one or more R X Replace; R X As defined in general formula (I); in some embodiments, ring C is a 5- or 6-membered heterocyclic group; the 5- or 6-membered heterocyclic group is optionally surrounded by one or more R X Replace; R X As defined in general formula (I); in some embodiments, ring C is a 5- or 6-membered heterocyclic group; the 5- or 6-membered heterocyclic group is optionally surrounded by one or more R X Replace; R X Selected from oxo groups, C 1-6 Alkyl, -C(O)OR 16 and 5 or 6-membered heteroaryl C 1-6 Alkyl, the 5- or 6-membered heteroaryl C 1-6 Alkyl groups are optionally enclosed by one or more C24 groups. 1-6 Alkyl substitution; R 16 C 1-6 alkyl.

[0155] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III) or general formula (M) or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; in some embodiments, r is 1.

[0156] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III) or general formula (M), or a pharmaceutically acceptable salt thereof, wherein M 2 For O or NR 9B ;R 9B As defined in general formula (III); in some implementations, M 2 For O; in some implementations, M 2 For NR 9B ;R 9B As defined in general formula (III); in some implementations, M 2 For NR 9B ;R 9B It is a -CH2-5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally bonded by one or more C2-membered carbon atoms. 1-6 Alkyl substitution.

[0157] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (III), general formula (M), general formula (III-1) or general formula (M-1), or their pharmaceutically acceptable salts, wherein R 9A Selected from C 1-6 Alkyl, 3- to 6-membered cycloalkyl, C(O)OR 16 and 5 or 6-membered heteroaryl C 1-6 Alkyl, the 5- or 6-membered heteroaryl C 1-6 Alkyl groups are optionally selected from C 1-6 Alkyl, halogen, C 1-6 Alkoxy and C 1-6 One or more of the haloalkyl groups are substituted; R 16 C 1-6 Alkyl; in some embodiments, R 9A Selected from C 1-6 Alkyl, C(O)OR 16 and 5 or 6-membered heteroaryl C 1-6 Alkyl, the 5- or 6-membered heteroaryl C 1-6 Alkyl groups are optionally selected from C 1-6 Alkyl, halogen, C 1-6 Alkoxy and C 1-6 One or more of the haloalkyl groups are substituted; R 16 C 1-6 Alkyl; in some embodiments, R 9A Selected from C 1-6 Alkyl, 3- to 6-membered cycloalkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; in some embodiments, R 9A Selected from C 1-6 Alkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; in some embodiments, R 9A It is a -CH2-5-membered heteroaryl group; the 5-membered heteroaryl group is optionally coated with one or more C2-C2 groups. 1-6 Alkyl substitution; in some embodiments, R 9A Selected from methyl, isopropyl, cyclopropyl, Boc, In some implementation schemes, R 9A Selected from methyl, isopropyl, cyclopropyl, Boc and In some implementation schemes, R 9ASelected from methyl, Boc, In some implementation schemes, R 9A Selected from In some implementation schemes, R 9A For Boc; in some implementations, R 9A for

[0158] In some embodiments of this disclosure, the compound or its pharmaceutically acceptable salt represented by general formula (I), general formula (III), general formula (M), general formula (III-1) or general formula (M-1) is used, wherein x is 0, 1 or 2; y is 0, 1 or 2; in some embodiments, x is 0 or 1; y is 1 or 2; in some embodiments, x is 1; y is 1; in some embodiments, x is 0; y is 1; in some embodiments, x is 1; y is 0; in some embodiments, x is 0; y is 2; in some embodiments, x is 2; y is 0; in some embodiments, x is 1 or 2; y is 0 or 1.

[0159] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (III), general formula (M), general formula (III-2) or general formula (M-2), or their pharmaceutically acceptable salts, wherein R 9B It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heteroaryl C 1-6 Alkyl; the 5- or 6-membered heteroaryl and the 5- or 6-membered heteroaryl C 1-6 Each alkyl group is independently selected from C1. 1-6 Alkyl, halogen, C 1-6 Alkoxy and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, R 9B It is a 5- or 6-membered heterocyclic group or a -CH2-5-membered heteroaryl group, wherein the 5- or 6-membered heterocyclic group or the 5-membered heteroaryl group is optionally selected from an oxo group and a C-membered heterocyclic group. 1-6 One or more substituents are substituted in the alkyl group; in some embodiments, R 9B It is a -CH2-5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally bonded by one or more C2-membered carbon atoms. 1-6 Alkyl substitution; in some embodiments, R 9B Selected from In some implementation schemes, R 9B Selected from In some implementation schemes, R 9B Selected from In some implementation schemes, R 9B for In some implementation schemes, R 9B for

[0160] In some embodiments of this disclosure, the compound or pharmaceutically acceptable salt of the general formula (I), general formula (III), general formula (M), general formula (III-2) or general formula (M-2) is used, wherein t1 is 1 or 2; t2 is 1 or 2; in some embodiments, t1 is 1; t2 is 1; in some embodiments, t1 is 2; t2 is 2; in some embodiments, t1 is 1; t2 is 2; in some embodiments, t1 is 0; t2 is 2; in some embodiments, t1 is 0, 1 or 2; t2 is 1 or 2.

[0161] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (III), (M), (III-1), (M-1), (III-2), or (M-2) are used, wherein R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy and oxo groups; in some embodiments, R 9 It is a hydrogen atom or an oxo group; in some embodiments, R 9 For hydrogen atoms; in some implementations, R 9 It is an oxo group.

[0162] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III), general formula (M), general formula (III-1) or general formula (M-1) or its pharmaceutically acceptable salt, wherein k3 is 0, 1 or 2; in some embodiments, k3 is 0 or 1; in some embodiments, k3 is 0; in some embodiments, k3 is 1.

[0163] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (III), general formula (M), general formula (III-2) or general formula (M-2) or its pharmaceutically acceptable salt, wherein k4 is 0, 1 or 2; in some embodiments, k4 is 0 or 1; in some embodiments, k4 is 0; in some embodiments, k4 is 1.

[0164] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (III), general formula (M), general formula (III-2) or general formula (M-2) or their pharmaceutically acceptable salts, wherein G is selected from bonds, NR 9C and C(O)NR 9C ;R 9C It is a hydrogen atom or a carbon atom. 1-6Alkyl; in some embodiments, G is a bond or NR 9C ;R 9C It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, G is a bond or C(O)NR 9C ;R 9C It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, G is a bond; in some embodiments, G is NR. 9C ;R 9C It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, G is C(O)NR 9C ;R 9C It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, G is N(CH3); in some embodiments, G is C(O)N(CH3).

[0165] In some embodiments of this disclosure, the compounds represented by general formula (I), general formula (III), general formula (M), general formula (III-2) or general formula (M-2), or their pharmaceutically acceptable salts, wherein R 9C It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 9C For hydrogen atoms; in some implementations, R 9C C 1-6 Alkyl; in some embodiments, R 9C It is a methyl group.

[0166] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of general formulas (I), (III), (M), (III-1), (M-1), (III-2), or (M-2) are wherein:

[0167] x is 0, 1, or 2; y is 0, 1, or 2; in some implementations, x is 0 or 1; y is 1 or 2;

[0168] And / or t1 is 0, 1, or 2; t2 is 1 or 2;

[0169] and / or R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl groups and oxo groups;

[0170] And / or k3 is 0, 1, or 2;

[0171] And / or k4 is 0, 1, or 2;

[0172] and / or G is a bond or NR 9C;R 9C It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0173] and / or R 9A Selected from C 1-6 Alkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 alkyl;

[0174] and / or R 9B It is a -CH2-5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally bonded by one or more C2-membered carbon atoms. 1-6 Alkyl substitution.

[0175] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 2 For halogen; in some implementations, R 2 For F or Cl; in some implementations, R 2 It is Cl.

[0176] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 3 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3 It is a hydrogen atom.

[0177] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 4 It is a hydrogen atom.

[0178] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5 It is a hydrogen atom.

[0179] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein 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.

[0180] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 6a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6a It is a hydrogen atom.

[0181] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 6b Selected from hydrogen atoms, halogens and C 1-6Alkyl; in some embodiments, R 6b It is a hydrogen atom.

[0182] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 6c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6c It is a hydrogen atom.

[0183] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c It is a hydrogen atom.

[0184] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring D is a 5- or 6-membered heterocyclic group; in some embodiments, ring D is a 6-membered heterocyclic group.

[0185] In some embodiments of this disclosure, the compound represented by general formula (I) or general formula (V) or a pharmaceutically acceptable salt thereof, wherein ring D' is a 5- or 6-membered heterocyclic group; in some embodiments, ring D' is a 6-membered heterocyclic group.

[0186] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or their pharmaceutically acceptable salts are used, wherein W is O.

[0187] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or their pharmaceutically acceptable salts, wherein R 10 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 10 It is a hydrogen atom.

[0188] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or their pharmaceutically acceptable salts are used, wherein k5 is 0, 1, or 2; in some embodiments, k5 is 0 or 1; in some embodiments, k5 is 0; and in some embodiments, k5 is 1.

[0189] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or their pharmaceutically acceptable salts, wherein m1 and m2 are each independently 0, 1, 2, or 3; in some embodiments, m1 is 1; m2 is 2; in some embodiments, m1 is 0; m2 is 3; in some embodiments, m1 is 3; m2 is 0; in some embodiments, m1 is 2; m2 is 1; in some embodiments, m1 is 2; m2 is 0.

[0190] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or their pharmaceutically acceptable salts, wherein Z is N or CH; in some embodiments, Z is N; in some embodiments, Z is CH.

[0191] In some embodiments of this disclosure, the compounds represented by general formulas (I), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or their pharmaceutically acceptable salts, wherein R 15 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 15 It is a hydrogen atom.

[0192] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI), or pharmaceutically acceptable salts thereof, wherein A 1 For N or CH; in some implementations, A 1 Let N be the number of elements in the array.

[0193] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI), or pharmaceutically acceptable salts thereof, wherein A 2 For N or CH; in some implementations, A 2 For CH.

[0194] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI), or pharmaceutically acceptable salts thereof, wherein A 1 For N; A2 For CH.

[0195] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI), or pharmaceutically acceptable salts thereof, wherein B 1 It is O.

[0196] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI), or pharmaceutically acceptable salts thereof, wherein B 2 It is O.

[0197] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI), or pharmaceutically acceptable salts thereof, wherein B 1 For O; B 2 It is O.

[0198] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI) or their pharmaceutically acceptable salts are used, wherein u is 1 or 2; in some embodiments, u is 1; in some embodiments, u is 2.

[0199] In some embodiments of this disclosure, the compounds represented by general formula (I) and general formula (VI) or their pharmaceutically acceptable salts, wherein R 13a and R 13b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or, R 13a and R 13b Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R 13a and R 13b It is a hydrogen atom; or, R on the same carbon atom. 13a and R 13b Together with the attached atoms, it forms a cyclopropyl group; in some embodiments, R 13a and R 13b It is a hydrogen atom.

[0200] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 0 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and C 1-6Haloalkoxy; in some embodiments, R 0 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl; in some embodiments, R 0 C 1-6 Alkyl; in some embodiments, R 0 It is a methyl group.

[0201] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI) are wherein... for In some implementation schemes, for In some implementation schemes, for

[0202] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 16 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 16 C 1-6 Alkyl; in some embodiments, R 16 It is tert-butyl.

[0203] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein 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.

[0204] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein R 19 It is a hydrogen atom.

[0205] In some embodiments of this disclosure, the compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI), wherein 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.

[0206] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), (VI) or their pharmaceutically acceptable salts, wherein v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0207] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0208] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 7 It is a hydrogen atom; Selected from

[0209] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0210] In some embodiments of this disclosure, the compound represented by general formula (II-1) or its pharmaceutically acceptable salt is used.

[0211] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; M 1 For O; p and q are each independently 0 or 1; R 11a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 11b R 11c and R 11d For hydrogen atoms; R 8 k is a hydrogen atom; k1 is 0, 1, or 2.

[0212] In some embodiments of this disclosure, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0213] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; M 1 For O; p and q are each independently 0 or 1; R 11a C 1-6 Alkyl; R 11b R 11c and R 11d For hydrogen atoms; R 8 k is a hydrogen atom; k1 is 0, 1, or 2.

[0214] In some embodiments of this disclosure, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0215] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6bFor hydrogen atoms; R 6c For hydrogen atoms; M 1 For O; p and q are each independently 0 or 1; R 11a R 11b R 11c and R 11d For hydrogen atoms; R 8 k is a hydrogen atom; k1 is 0, 1, or 2.

[0216] In some embodiments of this disclosure, the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0217] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; x is 1 or 2; y is 0 or 1; R 9A Selected from C 1-6 Alkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; R 9 It can be a hydrogen atom or an oxo group; k3 can be 0, 1 or 2.

[0218] In some embodiments of this disclosure, the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0219] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; x is 2; y is 0; R 9A Selected from C 1-6 Alkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; R 9 It can be a hydrogen atom or an oxo group; k3 can be 0, 1 or 2.

[0220] In some embodiments of this disclosure, the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0221] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; x is 1; y is 1; R 9A Selected from C 1-6 Alkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 Alkyl; R 9 k is a hydrogen atom; k3 is 0, 1, or 2.

[0222] In some embodiments of this disclosure, the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0223] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; x is 1; y is 1; R 9A It is a -CH2-5-membered heteroaryl group; the 5-membered heteroaryl group is optionally coated with one or more C2-C2 groups. 1-6 Alkyl substitution; R 9 k is a hydrogen atom; k3 is 0, 1, or 2.

[0224] In some embodiments of this disclosure, the compound represented by the general formula (M-2) or a pharmaceutically acceptable salt thereof,

[0225] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c G is a hydrogen atom; G is a bond; t1 is 1; t2 is 1; R 9 For hydrogen atoms; k4 is 0, 1, or 2; R9B It is a -CH2-5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally bonded by one or more C2-membered carbon atoms. 1-6 Alkyl substitution.

[0226] Table A lists typical compounds disclosed herein, including but not limited to:

[0227] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0228] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0229] 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;

[0230] in:

[0231] R w Selected from Bpin and -B(OH)2;

[0232] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0233] Rings A and R a m, R 1a R 1b R 2 -R 5 R 7 X, Y, R 6b and R 6cAs defined in general formula (I).

[0234] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II') or a pharmaceutically acceptable salt thereof, comprising:

[0235] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (II'B) or a salt thereof to give a compound of general formula (II') or a pharmaceutically usable salt thereof;

[0236] in:

[0237] R w Selected from Bpin and -B(OH)2;

[0238] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0239] Ring B', R 11a R 11b R 11c R 11d M 1 p, q, R 2 -R 5 X, R 6b and R 6c As defined in general formula (II').

[0240] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0241] 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;

[0242] in:

[0243] R w Selected from Bpin and -B(OH)2;

[0244] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0245] Ring B, R 11a R 11b R11c R 11d M 1 p, q, R 2 -R 5 X, R 6b and R 6c As defined in general formula (II).

[0246] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising:

[0247] The compound represented by general formula (IIA) or its salt undergoes a coupling reaction with the compound represented by general formula (II-1B) or its salt.

[0248] The reaction yields a compound of general formula (II-1) or a pharmaceutically usable salt thereof;

[0249] in:

[0250] R w Selected from Bpin and -B(OH)2;

[0251] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0252] R 11a R 11b R 11c R 11d M 1 p, q, R 2 -R 5 R 6a R 6b R 6c R 8 k1 is defined as in general formula (II-1).

[0253] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-2) or a pharmaceutically acceptable salt thereof, comprising:

[0254] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (II-2B) or its salt to give the compound of general formula (II-2) or its pharmaceutically usable salt.

[0255] in:

[0256] R w Selected from Bpin and -B(OH)2;

[0257] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0258] R 11a R 11b R 11c R 11d M 1 p, q, R 2 -R 5 R 6a R 6b R 6c Q, d, R 8a k2 is defined as in general formula (II-2).

[0259] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0260] 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;

[0261] in:

[0262] R w Selected from Bpin and -B(OH)2;

[0263] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0264] Ring C, R 12a R 12b ,r,M 2 R 2 -R 5 X, R 6b and R 6c As defined in general formula (III).

[0265] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising:

[0266] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (III-1B) or its salt to give the compound of general formula (III-1) or its pharmaceutically usable salt.

[0267] in:

[0268] R w Selected from Bpin and -B(OH)2;

[0269] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0270] R 2 -R 5 R 6a R 6b R 6c x, y, R 9A R 9 k3 is defined as in general formula (III-1).

[0271] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-2) or a pharmaceutically acceptable salt thereof, comprising:

[0272] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (III-2B) or its salt to give the compound of general formula (III-2) or its pharmaceutically usable salt.

[0273] in:

[0274] R w Selected from Bpin and -B(OH)2;

[0275] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0276] R 2 -R 5 R 6a R 6b R 6c R 9B t1, t2, G, R 9 k4 is as defined in general formula (III-2).

[0277] Another aspect of this disclosure relates to a method for preparing a compound of general formula (M) or a pharmaceutically acceptable salt thereof, comprising:

[0278] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (MB) or a salt thereof to give a compound of general formula (M) or a pharmaceutically usable salt thereof;

[0279] in:

[0280] R w Selected from Bpin and -B(OH)2;

[0281] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0282] Ring C, R 12a R 12b ,r,M 2 R 2 -R 5 X, R 6b and R 6c As defined in general formula (M).

[0283] Another aspect of this disclosure relates to a method for preparing a compound of general formula (M-1) or a pharmaceutically acceptable salt thereof, comprising:

[0284] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (M-1B) or its salt to give the compound of general formula (M-1) or its pharmaceutically usable salt.

[0285] in:

[0286] R w Selected from Bpin and -B(OH)2;

[0287] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0288] R 2 -R 5 R 6a R 6b R 6c x, y, R 9A R 9k3 is defined as in general formula (M-1).

[0289] Another aspect of this disclosure relates to a method for preparing a compound of general formula (M-2) or a pharmaceutically acceptable salt thereof, comprising:

[0290] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (M-2B) or its salt to give the compound of general formula (M-2) or its pharmaceutically usable salt.

[0291] in:

[0292] R w Selected from Bpin and -B(OH)2;

[0293] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0294] R 2 -R 5 R 6a R 6b R 6c R 9B t1, t2, G, R 9 k4 is defined as in general formula (M-2).

[0295] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0296] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IVB) or a salt thereof to give a compound of general formula (IV) or a pharmaceutically usable salt thereof;

[0297] in:

[0298] R w Selected from Bpin and -B(OH)2;

[0299] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0300] Ring D, R 2 -R 5 X, R 6b R 6cY, Z, Z 1 and Z 2 As defined in general formula (IV).

[0301] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-1) or a pharmaceutically acceptable salt thereof, comprising:

[0302] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (IV-1B) or its salt to give the compound of general formula (IV-1) or its pharmaceutically usable salt.

[0303] in:

[0304] R w Selected from Bpin and -B(OH)2;

[0305] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0306] R 2 -R 5 R 6a R 6b R 6c Z, W, m1, m2, R 10 k5 is as defined in general formula (IV-1).

[0307] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-2) or a pharmaceutically acceptable salt thereof, comprising:

[0308] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (IV-2B) or its salt to give the compound of general formula (IV-2) or its pharmaceutically usable salt.

[0309] in:

[0310] R w Selected from Bpin and -B(OH)2;

[0311] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0312] R 2 -R 5 R6a R 6b R 6c Z, W, m1, m2, R 10 And k5 is as defined in general formula (IV-2).

[0313] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV-3) or a pharmaceutically acceptable salt thereof, comprising:

[0314] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (IV-3B) or its salt to give the compound of general formula (IV-3) or its pharmaceutically usable salt.

[0315] in:

[0316] R w Selected from Bpin and -B(OH)2;

[0317] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0318] R 2 -R 5 R 6a R 6b R 6c Z, W, m1, m2, R 10 k5 is as defined in general formula (IV-3).

[0319] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V) or a pharmaceutically acceptable salt thereof, comprising:

[0320] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (VB) or a salt thereof to give a compound of general formula (V) or a pharmaceutically usable salt thereof;

[0321] in:

[0322] R w Selected from Bpin and -B(OH)2;

[0323] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0324] Ring D', R2 -R 5 X, R 6b R 6c Y, Z, Z 1 and Z 2 As defined in general formula (V).

[0325] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V-1) or a pharmaceutically acceptable salt thereof, comprising:

[0326] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (V-1B) or its salt to give the compound of general formula (V-1) or its pharmaceutically usable salt.

[0327] in:

[0328] R w Selected from Bpin and -B(OH)2;

[0329] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0330] R 2 -R 5 R 6a R 6b R 6c Z, W, m1, m2, R 10 k5 is defined as in general formula (V-1).

[0331] Another aspect of this disclosure relates to a method for preparing a compound of general formula (V-2) or a pharmaceutically acceptable salt thereof, comprising:

[0332] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (V-2B) or its salt to give the compound of general formula (V-2) or its pharmaceutically usable salt.

[0333] in:

[0334] R w Selected from Bpin and -B(OH)2;

[0335] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0336] R 2 -R 5 R 6a R 6b R 6c Z, W, m1, m2, R 10 And k5 is as defined in general formula (V-2).

[0337] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0338] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (VIB) or a salt thereof to obtain a compound of general formula (VI) or a pharmaceutically usable salt thereof;

[0339] in:

[0340] R w Selected from Bpin and -B(OH)2;

[0341] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L For Br;

[0342] R 2 -R 5 R 6a R 6b R 6c A 1 A 2 B 1 B 2 u, R 13a and R 13b As defined in general formula (VI).

[0343] In some embodiments of this disclosure, the preparation methods of compounds or pharmaceutically acceptable salts of the general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) are described, wherein R w for

[0344] In some embodiments of this disclosure, the preparation methods of compounds of general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or pharmaceutically acceptable salts thereof, wherein the coupling reaction is carried out under alkaline conditions and in the presence of a metal catalyst; the metal catalyst includes, but is not limited to, [1,1'-bis(diphenylphosphine)di... [Ferrocene] Palladium dichloride; the reagents providing alkaline conditions include 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 alkaline conditions is potassium phosphate.

[0345] In some embodiments of this disclosure, the preparation methods of compounds of general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or pharmaceutically acceptable salts 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.

[0346] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the above general formula (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0347] This disclosure further relates to the use of compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting or degrading VAV1.

[0348] This disclosure further relates to the use of compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) 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.

[0349] This disclosure further relates to the use of the compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) 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.

[0350] This disclosure further relates to the use of compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of tumors, autoimmune diseases, and inflammatory diseases.

[0351] 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'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0352] 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'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0353] 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'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0354] 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'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0355] This disclosure further relates to a compound of the above general formula (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament.

[0356] This disclosure further relates to a compound of the above general formula (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicament for regulating the ubiquitination and degradation of VAV1 protein in a subject.

[0357] This disclosure further relates to a compound of the above general formula (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) 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.

[0358] This disclosure further relates to compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the purpose of modulating the ubiquitination and degradation of VAV1 protein in a subject.

[0359] This disclosure further relates to compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading VAV1 in a subject.

[0360] This disclosure further relates to compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2) or (VI) 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.

[0361] This disclosure further relates to compounds of the above general formulas (I), (II'), (II), (II-1), (II-2), (III), (III-1), (III-2), (M), (M-1), (M-2), (IV), (IV-1), (IV-2), (IV-3), (V), (V-1), (V-2), or (VI) 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.

[0362] 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.

[0363] 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, Crohn's disease, etc. 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, axial spondyloarthritis.

[0364] 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.

[0365] 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.

[0366] In some implementations, the tumor described in this disclosure is cancer.

[0367] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0368] In some implementations, the lung cancer described in this disclosure is non-small cell lung cancer (NSCLC).

[0369] 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.

[0370] 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.

[0371] 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, expressed as unit doses 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 is 0.001 mg to 1000 mg. In some embodiments, the unit dose can be 0.1 to 1000 mg.

[0372] 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.

[0373] 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.

[0374] 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.

[0375] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0376] 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.

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] Terminology Explanation

[0387] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] The term "bridged alkylene" refers to an alkylene ring formed by the connection of two non-adjacent atoms, as defined above. Non-limiting examples include: bridged ethylene (-CH2CH2-) and bridged methylene (-CH2-).

[0393] 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.

[0394] 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).

[0395] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0396] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0397] 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:

[0398] Its connection point can be anywhere;

[0399] wait.

[0400] 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:

[0401] Its connection point can be anywhere;

[0402] wait.

[0403] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings. The ring 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) 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 or tricyclic bridged cycloalkyl.

[0404] Non-restrictive examples include: Its connection point can be anywhere.

[0405] 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.

[0406] 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) or a heterocyclic group having 4 to 11 ring atoms (i.e., a 4 to 11-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 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 6 ring atoms (i.e., a 4 to 6-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 to 7 ring atoms (i.e., a 5 to 7-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 6 ring atoms (i.e., a 6-membered heterocyclic group).

[0407] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0408] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0409] 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:

[0410] wait.

[0411] 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:

[0412] wait.

[0413] 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:

[0414] wait.

[0415] 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.

[0416] 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:

[0417] wait.

[0418] 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.

[0419] 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). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0420] 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.

[0421] 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 include:

[0422] wait.

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 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.

[0429] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0430] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0431] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0432] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0437] 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.

[0438] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0439] The term "hydroxyl group" refers to -OH.

[0440] The term "thiol" refers to -SH.

[0441] The term "amino" refers to -NH2.

[0442] The term "cyano" refers to -CN.

[0443] The term "nitro" refers to -NO2.

[0444] The term "oxo" or "oxo group" refers to "=O".

[0445] The term "carbonyl" refers to C=O.

[0446] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0447] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0448] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0449] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0450] “TBS” refers to tert-butyldimethylsilyl substituent.

[0451] “Boc” refers to the tert-butyloxycarbonyl substituent.

[0452] “SEM” refers to (trimethylsilyl)ethoxymethyl substituent.

[0453] The “oxazepin” mentioned in this disclosure is “oxazepin”.

[0454] 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 of the conjugate acid means that the corresponding leaving group does not need to combine with other atoms, and its tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include, but are not limited to, halogens, -OTs, or -OH.

[0455] 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.

[0456] In the chemical structure of the compounds described in this disclosure, the bonds... 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.

[0457] 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:

[0458] 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:

[0459] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] "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.

[0465] "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).

[0466] "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.

[0467] "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.

[0468] 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.

[0469] 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.

[0470] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0471] 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. Detailed Implementation

[0472] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0473] Example

[0474] 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 ohms. -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).

[0475] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0476] 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.

[0477] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0478] High-performance liquid chromatography (HPLC) preparative chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0479] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0480] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0481] 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.

[0482] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0483] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0484] 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.

[0485] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0486] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0487] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0488] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0489] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0490] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0491] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0492] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0493] 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.

[0494] Example 1

[0495] 3-(2-chloro-3-(10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione

[0496] first step

[0497] 6-(chloromethyl)pyridin-2(1H)-one 1b

[0498] 6-(hydroxymethyl)pyridin-2(1H)-one 1a (200 mg, 1.60 mmol, Bioderm) was dissolved in dichloromethane (5 mL), and 3 drops of N,N-dimethylformamide were added, followed by the addition of thionyl chloride (760 mg, 6.39 mmol, Sinopharm). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give target compound 1b (200 mg, yield: 87.1%).

[0499] Step 2

[0500] 6-((5-bromo-2-iodophenoxy)methyl)pyridin-2(1H)-one 1c

[0501] Compound 5-bromo-2-iodophenol (420 mg, 1.40 mmol, Bio-D) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (160 mg, 4.17 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at room temperature for 0.5 hours. Then, compound 1b (200 mg, 1.39 mmol) was added, and the mixture was reacted at 80 °C for 2 hours. The mixture was then allowed to return to room temperature, and 3 mL of methanol was added dropwise to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the target compound 1c (210 mg, yield: 37.1%).

[0502] MS m / z (ESI): 407.8 [M+2] + .

[0503] Step 3

[0504] 3-Bromobenzo[b]pyrido[1,2-d][1,4]oxazine-10(6H)-one 1d

[0505] Compound 1c (200 mg, 0.49 mmol), cuprous iodide (10 mg, 0.052 mmol, Shaoyuan), N,N'-dimethylethane-1,2-diamine (5 mg, 0.056 mmol, Shaoyuan), and potassium carbonate (135 mg, 0.98 mmol, Sinopharm) were dissolved in 1,4-dioxane (15 mL). The mixture was purged with nitrogen three times and microwaved at 110 °C with stirring for 2 hours. The solution was dissolved in 30 mL of dichloromethane, washed with 30 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 silica gel column chromatography using eluent system A to give the title compound 1d (85 mg, yield: 62.0%).

[0506] MS m / z(ESI): 280.1 [M+2] + .

[0507] Step 4

[0508] 3-(2-chloro-3-(10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione

[0509] Compound 1d (50 mg, 0.18 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl)piperidin-2,6-dione 1e (70 mg, 0.20 mmol, prepared by the method disclosed in Intermediate A on page 182 of patent application WO2024151547 A1), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol, Adamas), and potassium phosphate (115 mg, 0.54 mmol, Adamas) were dissolved in N,N-dimethylformamide (2 mL), purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction mixture was cooled 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 1 (20 mg, yield: 26.4%).

[0510] MS m / z(ESI): 421.2 [M+1] + .

[0511] 1H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.80–8.75(m,1H),7.51(dd,1H),7.45–7.35(m,3H),7.22–7.16(m,2H), 6.57(dd,1H),6.40(dd,1H),5.04(s,2H),4.37(dd,1H),2.81(ddd,1H),2.58–2.54(m,2H),2.41–2.30(m,1H).

[0512] Example 2

[0513] 3-(2-chloro-3-(1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazheptan-9-yl)phenyl)piperidin-2,6-dione

[0514] first step

[0515] 6-(((5-bromo-2-iodobenzyl)oxy)methyl)pyridin-2(1H)-one 2b

[0516] Compound 1a (200 mg, 1.60 mmol, BIDE) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (280 mg, 7.0 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, 4-bromo-2-(bromomethyl)-1-iodobenzene 2a (848 mg, 2.23 mmol, BIDE) was added, and the mixture was reacted at 0 °C for 2 h. After being brought to room temperature, the mixture was quenched dropwise on crushed ice. The mixture was extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the target compound 2b (389 mg, yield: 57.9%).

[0517] MS m / z(ESI): 420.2 [M-1] - .

[0518] Step 2

[0519] 9-Bromo-7H-benzo[e]pyrido[2,1-c][1,4]oxazepane-1(5H)-one 2c

[0520] Compound 2b (90 mg, 0.21 mmol), cuprous iodide (5 mg, 0.026 mmol, Shaoyuan), N,N'-dimethylethane-1,2-diamine (2 mg, 0.023 mmol, Shaoyuan), and potassium carbonate (60 mg, 0.43 mmol, Sinopharm) were dissolved in 1,4-dioxane (5 mL). The mixture was purged with nitrogen three times and microwaved at 110 °C with stirring for 2 hours. The solution was dissolved in 30 mL of dichloromethane, washed with 30 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 silica gel column chromatography using eluent system A to give the title compound 2c (20 mg, yield: 32.0%).

[0521] MS m / z(ESI): 292.1 [M+1] + .

[0522] Step 3

[0523] 3-(2-chloro-3-(1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazheptan-9-yl)phenyl)piperidin-2,6-dione

[0524] Compound 2c (20 mg, 0.068 mmol), compound 1e (24 mg, 0.068 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5 mg, 0.007 mmol, Adamas), and potassium phosphate (29 mg, 0.14 mmol, Adamas) were dissolved in N,N-dimethylformamide (2 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 2 (15 mg, yield: 50.4%).

[0525] MS m / z(ESI): 435.3 [M+1] + .

[0526] 1 H NMR (500MHz, DMSO-d6): δ10.95(s,1H),7.76-7.74(m,1H),7.63-7.54(m,3H),7.47-7.39(m,3H),6.64-6.54(m,2H),4.70-4. 68(m,1H),4.51-4.48(m,1H),4.40-4.37(m,2H),3.89-3.87(m,1H),2.82-2.79(m,1H),2.59-2.54(m,2H),2.38-2.36(m,1H).

[0527] Example 3

[0528] 6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 3

[0529] first step

[0530] 1-Benzyl-4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid methyl ester 3b

[0531] 2-(4-bromo-2-fluorophenyl)acetic acid methyl ester 3a (3 g, 12.14 mmol, Bioderm) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (418 mg, 10.91 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at room temperature for 30 minutes. Sodium iodide (183 mg, 1.22 mmol, Adamas) and N-benzyl-N,N-bis(2-chloroethyl)amine (3.39 g, 14.60 mmol, Shaoyuan) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to 30 mL of saturated ammonium chloride and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with 30 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 A to give title compound 3b (1.3 g, yield: 26.4%).

[0532] MS m / z (ESI): 407.3 [M+1] + .

[0533] Step 2

[0534] 4-(4-bromo-2-fluorophenyl)piperidine-4-carboxylic acid methyl ester 3c

[0535] Compound 3b (1.2 g, 2.95 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 1-chloroethyl chloroformate (4.23 g, 29.59 mmol) was added. The mixture was reacted at 60 °C for 12 hours. The reaction solution was concentrated to dryness, methanol (20 mL) was added, and the mixture was refluxed for 1 hour. The mixture was then concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 3c (380 mg, yield: 40.7%).

[0536] MS m / z(ESI): 317.2 [M+1] + .

[0537] Step 3

[0538] 1-(tert-butyl)4-methyl-4-(4-bromo-2-fluorophenyl)piperidine-1,4-dicarboxylic acid ester 3d

[0539] Compound 3c (380 mg, 1.20 mmol) was dissolved in dichloromethane (5 mL, Sinopharm), and triethylamine (365 mg, 3.61 mmol, Sinopharm) and di-tert-butyl dicarbonate (315 mg, 1.44 mmol, Adamas) were added. The mixture was stirred at room temperature for 2 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with 10 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 A to give the title compound 3d (300 mg, yield: 60.0%).

[0540] MS m / z(ESI): 417.2 [M+1] + .

[0541] Step 4

[0542] 4-(4-bromo-2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 3e

[0543] Compound 3d (300 mg, 0.72 mmol) was dissolved in tetrahydrofuran (4 mL), and lithium aluminum hydride (1 M, 0.74 mL, 0.74 mmol, Adamas) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3e (279 mg, yield: 99.7%). The product was used directly for the next reaction without purification.

[0544] MS m / z(ESI): 389.3 [M+1] + .

[0545] Step 5

[0546] 6-Bromo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 3f

[0547] Compound 3e (279 mg, 0.72 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (186 mg, 1.65 mmol, Adamas) was added. The tube was sealed and reacted at 100 °C for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to give the title compound 3f (200 mg, yield: 75.6%).

[0548] MS m / z(ESI): 369.9 [M+1] + .

[0549] Step 6

[0550] 6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 3

[0551] Following the synthetic route of Example 1, compound 1d was replaced with compound 3f to obtain title compound 3 (48 mg, yield: 24.1%).

[0552] MS m / z (ESI): 509.4 [M⁻¹] - .

[0553] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.36-7.29(m,4H),6.89-6.80(m,2H),4.50(s,2H),4.36-4.32(m,1H),3.95-3. 92(m,2H),3.33-3.31(m,1H),2.93-2.76(m,3H),2.35-2.31(m,1H),2.07-2.03(m,1H),1.82-1.69(m,4H),1.46(s,9H).

[0554] Example 4

[0555] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 4

[0556] first step

[0557] 6-Bromo-2H-spiro[benzofuran-3,4'-piperidine]4a

[0558] Compound 3f (200 mg, 0.54 mmol) was dissolved in tetrahydrofuran (5 mL, Sinopharm), and dioxane hydrochloride solution (4 M, 2 mL, 8.00 mmol, Adamas) was added. The mixture was reacted at room temperature for 1 hour. The solution was concentrated under reduced pressure, and 3 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (3 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title compound 4a (145 mg, yield: 99.6%).

[0559] MS m / z(ESI): 268.2 [M+1] + .

[0560] Step 2

[0561] 6-Bromo-1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidine]4b

[0562] Compound 4a (50 mg, 0.19 mmol), 3-(chloromethyl)-1-methyl-1H-pyrazole (25 mg, 0.19 mmol, Shaoyuan), and potassium carbonate (26 mg, 19 mmol, Sinopharm) were dissolved in acetonitrile (5 mL) and stirred at 25 °C for 1 hour. 30 mL of dichloromethane was added for further dissolution, followed by washing with 30 mL of saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 4b (65 mg, yield: 96.2%).

[0563] MS m / z(ESI): 362.3 [M+1] + .

[0564] Step 3

[0565] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 4

[0566] Following the synthetic route of Example 1, compound 1d was replaced with compound 4b to obtain title compound 4 (20 mg, yield: 22.1%).

[0567] MS m / z (ESI): 505.4 [M+1] + .

[0568] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.61-7.60(m,1H),7.37-7.28(m,4H) ,6.88-6.86(m,1H),6.78-6.77(m,1H),6.16-6.15(m,1H),4.41(s,2H),4.36- 4.32(m,1H),3.79(s,3H),3.44(s,2H),2.86-2.77(m,3H),2.57-2.55(m,1H) ,2.34-2.32(m,1H),2.07-2.01(m,3H),1.92-1.86(m,2H),1.70-1.67(m,2H).

[0569] Example 5

[0570] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidin-2,6-dione

[0571] 5'-Bromo-1'-((1-methyl-1H-pyrazol-3-yldi)-methylbutyryl)spiro[cyclopropane-1,3'-indoline]-2'-one 5b

[0572] 5'-Bromospiro[cyclopropane-1,3'-indoline]-2'-one 5a (500 mg, 2.10 mmol) was dissolved in N,N-dimethylformamide (6 mL, Adamas), and sodium hydride (100.8 mg, 2.52 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at 0 °C for 30 minutes, and then 3-(chloromethyl)-1-methyl-1H-pyrazole (274.2 mg, 2.1 mmol, Bide) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was added dropwise to 20 mL of saturated ammonium chloride solution and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with 20 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 A to give the title compound 5b (480 mg, yield: 68.8%).

[0573] MS m / z(ESI): 332.0 [M+1] + .

[0574] Step 2

[0575] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidin-2,6-dione

[0576] Referring to the synthetic route of Example 1, compound 1d was replaced with starting compound 5b to obtain title compound 5 (17 mg, yield: 39.6%).

[0577] MS m / z(ESI): 475.0 [M+1] + .

[0578] 1H NMR (500MHz, DMSO-d6): δ10.91(s,1H),7.61(d,1H),7.39-7.36(m,1H),7.34-7.32( m,1H),7.30-7.28(m,1H),7.25-7.23(m,1H),7.13-7.12(m,1H),7.08(d,1H),6.14( d,1H),4.91(s,2H),4.35-4.31(m,1H),3.80(s,3H),2.83-2.76(m,1H),2.65-2.64( m,1H),2.38-2.31(m,1H),2.05-2.02(m,1H),1.70-1.68(m,2H),1.59-1.57(m,2H).

[0579] Example 6

[0580] 3-(2-chloro-3-(1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione

[0581] first step

[0582] 6-Bromo-2,3-dihydrobenzofuran-3-carboxylic acid methyl ester 6b

[0583] Ethyl 6-bromobenzofuran-3-carboxylate 6a (2 g, 7.43 mmol, Bioderm) was dissolved in methanol (40 mL), and magnesium powder (904 mg, 37.19 mmol, Sinopharm) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 2 M hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6b (1.18 g, yield: 61.8%).

[0584] Step 2

[0585] 6-Bromo-2,3-dihydrobenzofuran-3-carboxylic acid 6c

[0586] Compound 6b (300 mg, 1.17 mmol, Bio-Tech) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (3 mL). Lithium hydroxide (245 mg, 5.84 mmol, Sinopharm) was added, and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to acidic with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 6c (280 mg, yield: 98.7%).

[0587] MS m / z(ESI): 242.9 [M-1] + .

[0588] Step 3

[0589] 6-Bromo-2,3-dihydrobenzofuran-3-formyl chloride 6d

[0590] Compound 6c (200 mg, 0.82 mmol) was dissolved in dichloromethane (5 mL), N,N-dimethylformamide (6 mg, 0.08 mmol) was added, and oxalyl chloride (136 mg, 1.07 mmol) was added dropwise at 0 °C. The mixture was stirred for 3 hours after returning to room temperature. The solution was concentrated under reduced pressure to give crude title compound 6d (215 mg, yield: 99.9%).

[0591] Step 4

[0592] 6-Bromo-N-(3-Bromopropyl)-N-methyl-2,3-dihydrobenzofuran-3-carboxamide 6e

[0593] Compound 6d (215 mg, 0.82 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (416 mg, 4.11 mmol, Adamas) was added. A solution of 3-bromo-N-methylprop-1-amine hydrochloride (200 mg, 1.06 mmol, Leyan) in dichloromethane (3 mL) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 10 mL of water and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with 10 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 silica gel column chromatography using eluent system B to give the title compound 6e (260 mg, yield: 83.9%).

[0594] MS m / z(ESI): 378.1 [M+1] + .

[0595] Step 5

[0596] 6-Bromo-1'-methyl-2H-spiro[benzofuran-3,3'-piperidine]-2'-one 6f

[0597] Compound 6e (260 mg, 0.69 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium tert-butoxide (1 M, 1.05 mL, 1.05 mmol, Adamas) was added dropwise at 0 °C. The mixture was stirred at room temperature for 0.5 h. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 6f (200 mg, yield: 97.9%).

[0598] MS m / z(ESI): 297.9 [M+1] + .

[0599] Step 6

[0600] 3-(2-chloro-3-(1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione

[0601] Compound 6f (200 mg, 0.68 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 1e (237 mg, 0.68 mmol, prepared by the method disclosed in Intermediate A on page 182 of patent application WO2024151547A1), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (99 mg, 0.14 mmol, Adamas), and potassium phosphate (431 mg, 2.03 mmol, Adamas) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The mixture was purged with nitrogen three times, heated to 95 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 6 (26 mg, yield: 8.8%).

[0602] MS m / z(ESI): 439.1 [M+1] + .

[0603] 1H NMR(500MHz,DMSO-d6)δ10.92(s,1H),7.40-7.20(m,4H),6.88-6.66(m,2H),4.82-4.80(m,1H),4.45- 4.33(m,2H),3.51-3.41(m,3H),2.99(s,3H),2.79-2.77(m,1H),2.35-2.33(m,2H),2.08-1.98(m,4H).

[0604] Example 6-1 or 6-2

[0605] 3-(2-chloro-3-((S)-1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 6-1

[0606] or

[0607] 3-(2-chloro-3-((R)-1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 6-2

[0608] first step

[0609] (S)-6-bromo-1'-methyl-2H-spiro[benzofuran-3,3'-piperidin]-2'-one 6f-1

[0610] and

[0611] (R)-6-bromo-1'-methyl-2H-spiro[benzofuran-3,3'-piperidine]-2'-one 6f-2

[0612] Compound 6f (1.5 g, 5.06 mol) was prepared chirally (separation conditions: Shimadzu LC-20AP Prep system, chiral preparation column: Chiral Art Amylose-C Neo, 10 μm, 20 mm ID*250 mm L (YMC, in-house packed); mobile phase: n-hexane and ethanol, gradient ratio: 15% ethanol, flow rate: 60 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to give the title compound (700 mg, yield: 46.7%) and (700 mg, yield: 46.7%).

[0613] (700 mg, yield: 46.7%) Single configuration compound (shorter retention time):

[0614] MS m / z(ESI): 296.1 [M+1] + .

[0615] Chiral HPLC analysis: retention time 15.252 min, chiral purity: 100% (column: Chiral Art Amylose-C Neo, 10 μm, 20 mm ID*250 mm L (YMC, in-house packed); mobile phase: n-hexane and ethanol, gradient ratio: 15% ethanol, flow rate: 60 mL / min).

[0616] (700 mg, yield: 46.7%) Single configuration compound (longer retention time):

[0617] MS m / z(ESI): 296.1 [M+1] + .

[0618] Chiral HPLC analysis: retention time 21.668 min, chiral purity: 100% (column: Chiral Art Amylose-C Neo, 10 μm, 20 mm ID*250 mm L (YMC, in-house packed); mobile phase: n-hexane and ethanol, gradient ratio: 15% ethanol, flow rate: 60 mL / min).

[0619] Step 2

[0620] 3-(2-chloro-3-((S)-1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 6-1

[0621] or

[0622] 3-(2-chloro-3-((R)-1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 6-2

[0623] Compounds 6f-1 and 6f-2 with shorter retention times (200 mg, 0.68 mmol), compound 1e (283.3 mg, 0.81 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (49.4 mg, 0.068 mmol, Adamas), and potassium phosphate (287 mg, 1.35 mmol, Adamas) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 6-1 or 6-2 (145 mg, yield: 48.9%).

[0624] MS m / z(ESI): 439.5 [M+1] + .

[0625] 1 H NMR(500MHz,DMSO-d6)δ10.92(s,1H),7.40-7.28(m,4H),6.88-6.82(m,2H),4.82-4.80(m,1H),4.45-4.43(m,1H),4.37-4.33(m,1H),3.52- 3.49(m,1H),3.43-3.39(m,1H),2.91(s,3H),2.80-2.77(m,1H),2.57- 2.54(m,1H),2.38-2.32(m,1H),2.08-2.02(m,4H),1.82-1.81(m,1H).

[0626] Example 6-2 or 6-1

[0627] 3-(2-chloro-3-((R)-1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 6-2

[0628] or

[0629] 3-(2-chloro-3-((S)-1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 6-1

[0630] Compounds 6f-2 and 6f-1 (200 mg, 0.68 mmol), compound 1e (283.3 mg, 0.81 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (49.4 mg, 0.068 mmol, Adamas), and potassium phosphate (287 mg, 1.35 mmol, Adamas) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compounds 6-2 or 6-1 (135 mg, yield: 45.6%).

[0631] MS m / z(ESI): 439.5 [M+1] + .

[0632] 1 H NMR(500MHz,DMSO-d6)δ10.92(s,1H),7.40-7.28(m,4H),6.88-6.82(m,2H),4.82-4.80(m,1H),4.45-4.43(m,1H),4.37-4.33(m,1H),3.52- 3.49(m,1H),3.43-3.39(m,1H),2.91(s,3H),2.82-2.76(m,1H),2.57- 2.54(m,1H),2.37-2.32(m,1H),2.08-2.02(m,4H),1.83-1.80(m,1H).

[0633] Example 7

[0634] 3-(2-chloro-3-(6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7

[0635] first step

[0636] 1-(6-methoxypyridin-2-yl)ethanol-1-ol 7b

[0637] 1-(6-methoxypyridin-2-yl)ethane-1-one 7a (1 g, 1.60 mmol, BID) was dissolved in methanol (15 mL), and sodium borohydride (275 mg, 7.26 mmol, Shaoyuan) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding 10 mL of saturated ammonium chloride solution, dissolved in 30 mL of dichloromethane, washed with 30 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 silica gel column chromatography using eluent system A to give the title compound 7b (925 mg, yield: 91.3%).

[0638] MS m / z (ESI): 154.1 [M+1] + .

[0639] Step 2

[0640] 2-(1-Chloroethyl)-6-methoxypyridine 7c

[0641] Compound 7b (925 mg, 6.04 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of 3 drops of N,N-dimethylformamide, and then thionyl chloride (2.87 g, 24.12 mmol, Sinopharm). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 7c, which could be used directly in the next step without further purification.

[0642] Step 3

[0643] 2-(1-(5-bromo-2-iodophenoxy)ethyl)-6-methoxypyridine 7d

[0644] 5-Bromo-2-iodophenol (1.80 g, 6.02 mmol, BIDE) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (460 mg, 12 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at room temperature for 0.5 h. Then, compound 7c (1.10 g, 6.41 mmol) and potassium iodide (300 mg, 1.81 mmol, Adamas) were added, and the mixture was reacted at 80 °C for 2 h. The mixture was then allowed to return to room temperature, and quenched dropwise with 3 mL of methanol. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 7d (1.64 g, yield: 62.7%).

[0645] MS m / z(ESI): 436.0 [M+2]+ .

[0646] Step 4

[0647] 6-(1-(5-bromo-2-iodophenoxy)ethyl)pyridin-2(1H)-one 7e

[0648] Compound 7d (500 mg, 1.15 mmol) and sodium iodide (535 mg, 3.57 mmol, Shaoyuan) were dissolved in acetonitrile (15 mL), and trimethylchlorosilane (389 mg, 3.58 mmol, Shaoyuan) was added. The mixture was reacted at 85 °C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 7e (300 mg, yield: 62.0%).

[0649] MS m / z(ESI): 422.1 [M+2] + .

[0650] Step 5

[0651] 3-Bromo-6-methylbenzo[b]pyrido[1,2-d][1,4]oxazine-10(6H)-one 7f

[0652] Compound 7e (300 mg, 0.71 mmol), cuprous iodide (15 mg, 0.078 mmol, Shaoyuan), N,N'-dimethylethane-1,2-diamine (10 mg, 0.11 mmol, Shaoyuan), and potassium carbonate (200 mg, 1.45 mmol, Sinopharm) were dissolved in 1,4-dioxane (15 mL). The mixture was purged with nitrogen three times and microwaved at 110 °C with stirring for 2 hours. After cooling to room temperature, 30 mL of dichloromethane was added for dissolution. The mixture was washed with 30 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 silica gel column chromatography using eluent system A to give the title compound 7f (100 mg, yield: 47.9%).

[0653] MS m / z(ESI): 293.8 [M+2] + .

[0654] Step 6

[0655] 3-(2-chloro-3-(6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidine

[0656] -2,6-dione7

[0657] Compound 7f (80 mg, 0.27 mmol), compound 1e (115 mg, 0.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, 0.03 mmol, Adamas), and potassium phosphate (175 mg, 0.82 mmol, Adamas) were dissolved in 1,4-dioxane (2 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 7 (13 mg, yield: 10.9%).

[0658] MS m / z(ESI): 435.2 [M+1] + .

[0659] 1 H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.73(d,1H),7.53(dd,1H),7.45–7.36(m,3H),7.20–7.15(m,2H),6.58(dd,1H),6. 39(dt,1H),5.09(q,1H),4.37(dd,1H),2.81(ddd,1H),2.56(dt,1H),2.39–2.30(m,1H),2.10–2.00(m,1H),1.59(d,3H).

[0660] Example 7-1 or 7-2

[0661] 3-(2-chloro-3-((R)-6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7-1

[0662] or

[0663] 3-(2-chloro-3-((S)-6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7-2

[0664] first step

[0665] (R)-3-bromo-6-methylbenzo[b]pyrido[1,2-d][1,4]oxazine-10(6H)-one 7f-1

[0666] and

[0667] (S)-3-bromo-6-methylbenzo[b]pyrido[1,2-d][1,4]oxazine-10(6H)-one 7f-2

[0668] Compound 7f (250 mg, 0.85 mmol) was prepared chirally (separation conditions: chiral preparation column ChiralPak IG-10, 10 μm, 20 mm * 250 mm (Daicel, in-house packed); mobile phase 1: ACN (20%); mobile phase 2: EtOH (80%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to give the title compound (100 mg, yield: 22.1%) and (95 mg, yield: 21.0%).

[0669] (100 mg, yield: 22.1%) Single configuration compound (shorter retention time):

[0670] MS m / z(ESI): 292.5 [M+1] + .

[0671] Chiral HPLC analysis: retention time 3.611 min, chiral purity: 100% (column: CHIRALCEL IG, 150*4, 6 mm (Phenomenex, 5 μm); mobile phase: EtOH / ACN / DEA = 80 / 20 / 0.1 (V / V / V), flow rate: 1 mL / min).

[0672] (95 mg, yield: 21.0%) Single configuration compound (longer retention time):

[0673] MS m / z(ESI): 292.5 [M+1] + .

[0674] Chiral HPLC analysis: retention time 5.556 min, chiral purity: 100% (column: CHIRALCEL IG, 150*4, 6 mm (Phenomenex, 5 μm); mobile phase: EtOH / ACN / DEA = 80 / 20 / 0.1 (V / V / V), flow rate: 1 mL / min).

[0675] Step 2

[0676] 3-(2-chloro-3-((R)-6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7-1

[0677] or

[0678] 3-(2-chloro-3-((S)-6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7-2

[0679] Compounds 7f-1 and 7f-2 with shorter retention times (100 mg, 0.34 mmol), compound 1e (143 mg, 0.41 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (25 mg, 0.03 mmol, Adamas), and potassium phosphate (217 mg, 1.02 mmol, Adamas) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compounds 7-1 or 7-2 (36 mg, yield: 24.1%).

[0680] MS m / z(ESI): 434.9 [M+1] + .

[0681] 1 H NMR(500MHz,DMSO)δ10.94(s,1H),8.74-8.73(m,1H),7.54-7.51(m,1H),7.44-7.37(m,3H),7.19-7.16(m,2H),6.66-6.57(m,1H),6.39-6.33 (m,1H),5.11-5.07(m,1H),4.38-4.35(m,1H),2.84-2.77(m,1H),2.58 -2.53(m,1H),2.37-2.31(m,1H),2.09-2.05(m,1H),1.60-1.57(m,3H).

[0682] Example 7-2 or 7-1

[0683] 3-(2-chloro-3-((S)-6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7-2

[0684] or

[0685] 3-(2-chloro-3-((R)-6-methyl-10-oxo-6,10-dihydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)phenyl)piperidin-2,6-dione 7-1

[0686] Compounds with longer retention times from 7f-2 and 7f-1 (95 mg, 0.32 mmol), compound 1e (137 mg, 0.39 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (23 mg, 0.03 mmol, Adamas), and potassium phosphate (207 mg, 0.97 mmol, Adamas) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compounds 7-2 or 7-1 (28 mg, yield: 19.8%).

[0687] MS m / z(ESI): 434.9 [M+1] + .

[0688] 1 H NMR(500MHz,DMSO)δ10.94(s,1H),8.74-8.72(m,1H),7.53-7.50(m,1H),7.44-7.36(m,3H),7.19-7.16(m,2H),6.67-6.57(m,1H),6.39-6.38 (m,1H),5.10-5.06(m,1H),4.38-4.35(m,1H),2.84-2.77(m,1H),2.58 -2.54(m,1H),2.39-2.31(m,1H),2.08-2.05(m,1H),1.59-1.55(m,3H).

[0689] Example 8

[0690] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione

[0691] first step

[0692] 5-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 8b

[0693] 1-(tert-Butoxycarbonyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid 8a (1.0 g, 4.40 mmol, Biotin) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum hydride (251 mg, 6.61 mmol, Sinopharm) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. Then, 0.25 mL of water, 0.25 mL of 15% sodium hydroxide solution, and 0.75 mL of water were added sequentially, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 8b (410 mg, yield: 43.7%).

[0694] Step 2

[0695] 5-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 8c

[0696] Compound 8b (410 mg, 1.92 mmol) was dissolved in dichloromethane (10 mL), and carbon tetrabromide (766 mg, 2.31 mmol, Sinopharm) and triphenylphosphine (606 mg, 2.31 mmol, Sinopharm) were added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 8c (356 mg, yield: 67.1%).

[0697] Step 3

[0698] 5-((5-bromo-2-iodophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 8d

[0699] 5-Bromo-2-iodophenol (424 mg, 1.42 mmol, BIDE) was dissolved in tetrahydrofuran (5 mL), and compound 8c (356 mg, 1.29 mmol, Sinopharm) and potassium carbonate (268 mg, 1.94 mmol, BIDE) were added at room temperature. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 8d (580 mg, yield: 91.1%).

[0700] MS m / z(ESI): 394.0 [M-100] - .

[0701] Step 4

[0702] 6-Bromo-2H-spiro[benzofuran-3,3'-piperidine]-1'-carboxylic acid tert-butyl ester 8e

[0703] Compound 8d (50 mg, 0.10 mmol) was dissolved in toluene (1 mL), and tri-n-butyltin hydride (45 mg, 0.15 mmol, BIDE) and azobisisobutyronitrile (25 mg, 0.15 mmol, BIDE) were added. The mixture was reacted at 120 °C for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 8e (35 mg, yield: 93.9%).

[0704] MS m / z(ESI): 312.0 [M-55] - .

[0705] Step 5

[0706] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione

[0707] The synthetic route of Example 4 was used, but the first step compound 3f was replaced with compound 8e to obtain title compound 8 (10 mg, yield: 23.9%).

[0708] MS m / z (ESI): 505.2 [M+1] + .

[0709] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.59-7.58(m,1H),7.37-7.27(m,4H),6. 86-6.84(m,1H),6.76-6.75(m,1H),6.14-6.13(m,1H),4.54-4.52(m,1H),4.35- 4.32(m,2H),3.79(s,3H),3.55-3.53(m,2H),2.83-2.77(m,2H),2.58-2.51(m,2 H),2.34-2.32(m,1H),2.06-2.01(m,3H),1.72-1.70(m,3H),1.68-1.66(m,1H).

[0710] Example 9

[0711] 3-(2-chloro-3-(5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazetane-9-yl)phenyl)piperidin-2,6-dione 9

[0712] first step

[0713] 2-(1-((5-bromo-2-iodobenzyl)oxy)ethyl)-6-methoxypyridine 9a

[0714] (5-Bromo-2-iodophenyl)methanol (3 g, 9.58 mmol, Adamas) was dissolved in N,N-dimethylformamide (40 mL), and sodium hydride (550 mg, 14.3 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at room temperature for 0.5 h. Then, compound 7c (2 g, 11.6 mmol) and potassium iodide (300 mg, 1.81 mmol, Adamas) were added, and the mixture was reacted at 80 °C for 16 h. The mixture was then brought to room temperature, and quenched dropwise with 3 mL of methanol. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 9a (1.8 g, yield: 41.9%).

[0715] MS m / z(ESI): 450.0 [M+2] + .

[0716] Step 2

[0717] 6-(1-((5-bromo-2-iodobenzyl)oxy)ethyl)pyridin-2(1H)-one 9b

[0718] Compound 9a (1.8 g, 4.02 mmol) and sodium iodide (1.8 g, 12 mmol, Shaoyuan) were dissolved in acetonitrile (40 mL), and trimethylchlorosilane (1.3 g, 12 mmol, Shaoyuan) was added. The mixture was reacted at 85 °C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 9b (1.2 g, yield: 68.8%).

[0719] MS m / z (ESI): 435.7 [M+2] + .

[0720] Step 3

[0721] 9-Bromo-5-methyl-7H-benzo[e]pyrido[1,2-c][1,4]oxazepane-1(5H)-one 9c

[0722] Compound 9b (300 mg, 0.69 mmol), cuprous iodide (14 mg, 0.073 mmol, Shaoyuan), N,N'-dimethylethane-1,2-diamine (10 mg, 0.11 mmol, Shaoyuan), and potassium carbonate (190 mg, 1.37 mmol, Sinopharm) were dissolved in N,N-dimethylformamide (12 mL). The mixture was purged with nitrogen three times and microwaved at 110 °C with stirring for 2 hours. After cooling to room temperature, 30 mL of dichloromethane was added for dissolution. The mixture was washed with 30 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 silica gel column chromatography using eluent system A to give the title compound 9c (140 mg, yield: 66.1%).

[0723] MS m / z(ESI): 307.9 [M+2] + .

[0724] Step 4

[0725] 3-(2-chloro-3-(5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazetane-9-yl)phenyl)piperidin-2,6-dione 9

[0726] Compound 9c (140 mg, 0.46 mmol), compound 1e (222 mg, 0.63 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.08 mmol, Adamas), and potassium phosphate (188 mg, 1.36 mmol, Adamas) were dissolved in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 9 (52.5 mg, yield: 25.5%).

[0727] MS m / z(ESI): 448.9 [M+1] + .

[0728] 1H NMR (500MHz, DMSO-d6): δ10.95(s,1H),7.73-7.71(m,1H),7.60-7.57(m,3H),7.47-7.39(m,3H),6.63-6.61(m,1H),6.50-6.48(m,1H),4.68-4. 65(m,1H),4.40-4.32(m,2H),4.09-4.05(m,1H),2.84-2.81(m,1H),2.5 8-2.54(m,1H),2.41-2.33(m,1H),2.10-2.07(m,1H),1.42-1.39(m,3H).

[0729] Example 9-1 or 9-2

[0730] 3-(2-chloro-3-((R)-5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazheptan-9-yl)phenyl)piperidin-2,6-dione 9-1

[0731] or

[0732] 3-(2-chloro-3-((S)-5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazepane-9-yl)phenyl)piperidin-2,6-dione 9-2

[0733] first step

[0734] (R)-9-bromo-5-methyl-7H-benzo[e]pyrido[1,2-c][1,4]oxazepane-1(5H)-one 9c-1

[0735] and

[0736] (S)-9-bromo-5-methyl-7H-benzo[e]pyrido[1,2-c][1,4]oxazepane-1(5H)-one 9c-2

[0737] Compound 9c (500 mg, 92.64 μmol) was prepared chirally (Gilson-281, column: (S,S)-Whelk-O1, 20 mm * 250 mm, 10 μm; mobile phase: n-hexane and ethanol, gradient ratio: n-hexane 50%, flow rate: 20 mL / min), and its corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds 9c-1 and 9c-2.

[0738] Single configuration compound (shorter retention time): 240 mg, yield: 48.0%.

[0739] MS m / z(ESI): 307.4 [M+1] + .

[0740] Chiral HPLC analysis: retention time 8.417 min, chiral purity: 100% (column: (S,S)-Whelk-O1, 20mm*250mm, 10μm; mobile phase: n-hexane and ethanol, gradient ratio: n-hexane 50%, flow rate: 20mL / min).

[0741] Single configuration compound (longer retention time): 240 mg, yield: 48.0%.

[0742] MS m / z(ESI): 307.4 [M+1] + .

[0743] Chiral HPLC analysis: retention time 20.863 min, chiral purity: 100% (column: (S,S)-Whelk-O1, 20mm*250mm, 10μm; mobile phase: n-hexane and ethanol, gradient ratio: n-hexane 50%, flow rate: 20mL / min).

[0744] Step 2: 3-(2-chloro-3-((S)-5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyridino[2,1-c][1,4]oxazeptane-9-yl)phenyl)piperidin-2,6-dione 9-1

[0745] or

[0746] 3-(2-chloro-3-((R)-5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazheptan-9-yl)phenyl)piperidin-2,6-dione 9-2

[0747] Compounds 9c-1 and 9c-2 with shorter retention times (240 mg, 0.78 mmol), compound 1e (329 mg, 0.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58 mg, 0.08 mmol, Adamas), and potassium phosphate (333 mg, 1.56 mmol, Adamas) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compounds 9-1 or 9-2 (133 mg, yield: 37.8%).

[0748] MS m / z(ESI): 448.9 [M+1] + .

[0749] 1 H NMR (500MHz, DMSO-d6): δ10.95(s,1H),7.72-7.71(m,1H),7.60-7.57(m,3H),7.46-7.40(m,3H),6.63-6.61(m,1H),6.50-6.48(m,1H),4.68-4. 65(m,1H),4.34-4.32(m,2H),4.07-4.06(m,1H),2.58-2.54(m,1H),2.5 0-2.48(m,1H),2.41-2.33(m,1H),2.10-2.08(m,1H),1.42-1.41(m,3H).

[0750] Example 9-2 or 9-1

[0751] 3-(2-chloro-3-((S)-5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazepane-9-yl)phenyl)piperidin-2,6-dione 9-2

[0752] or

[0753] 3-(2-chloro-3-((R)-5-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazheptan-9-yl)phenyl)piperidin-2,6-dione 9-1

[0754] Compounds with longer retention times in 9c-2 and 9c-1 (240 mg, 0.78 mmol), compound 1e (329 mg, 0.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58 mg, 0.08 mmol, Adamas), and potassium phosphate (333 mg, 1.56 mmol, Adamas) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compounds 9-2 or 9-1 (199 mg, yield: 56.6%).

[0755] MS m / z(ESI): 448.9 [M+1] + .

[0756] 1H NMR (500MHz, DMSO-d6): δ10.95(s,1H),7.73-7.71(m,1H),7.60-7.57(m,3H),7.46-7.40(m,3H),6.63-6.61(m,1H),6.50-6.48(m,1H),4.68-4. 65(m,1H),4.34-4.32(m,2H),4.07-4.06(m,1H),2.58-2.54(m,1H),2.5 0-2.48(m,1H),2.41-2.33(m,1H),2.10-2.08(m,1H),1.42-1.41(m,3H).

[0757] Example 10

[0758] 3-(2-chloro-3-(1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-5-yl)phenyl)piperidine-2,6-dione 10

[0759] first step

[0760] 2-Bromocyclobut-1-one 10b

[0761] Cyclobutanone 10a (50g, 713mmol, Adamas) was dissolved in dichloromethane (500mL), and liquid bromine (102g, 642mmol, Sinopharm) was added. The mixture was stirred at room temperature for about 2 hours, during which a large amount of gas was released and the solution gradually became colorless. The mixture was stirred for another 2 hours, and the reaction solution was concentrated and used directly in the next step of the reaction.

[0762] Step 2

[0763] 2-(4-bromo-2-fluorophenoxy)cyclobut-1-one 10c

[0764] 4-Bromo-2-fluorophenol (20 g, 104.71 mmol, BIDE) and compound 10b (39 g, 261.78 mmol) were dissolved in N,N-dimethylformamide (200 mL), and sodium carbonate (33.29 g, 314.14 mmol, Sinopharm) was added. The mixture was stirred at 80 °C for 4 hours. The reaction solution was poured into ice water (200 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 10c (8.8 g, yield: 34.57%).

[0765] Step 3

[0766] 2-(4-bromo-2-fluorophenoxy)cyclobut-1-ol 10d

[0767] Compound 10c (5 g, 19.30 mmol) was dissolved in tetrahydrofuran (50 mL), and tri-sec-butylborohydride (21.2 mL, 21.20 mmol, 1 M, Adamas) was slowly added dropwise at -78 °C. The reaction mixture was reacted at -78 °C for 1 hour. The reaction solution was quenched with water (50 mL), the pH was adjusted to 5–6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10d, which could be used directly in the next reaction without further purification.

[0768] Step 4

[0769] 5-Bromo-1,2,2a,8a-Tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-10e

[0770] Compound 10d (6 g, 2.98 mmol) was dissolved in dimethyl sulfoxide (60 mL), and cesium carbonate (22.40 g, 68.94 mmol, Adamas) was added. The reaction mixture was reacted at 120 °C for 2 h. The reaction solution was cooled to room temperature, and 50 mL of water was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 10e (2.8 g, yield: 50.54%).

[0771] Step 5

[0772] 3-(2-chloro-3-(1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-

[0773] Diketone 10

[0774] Compound 10e (50 mg, 0.21 mmol), compound 1e (108 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol, Adamas), and potassium phosphate (132 mg, 0.62 mmol, Adamas) were dissolved in 1,4-dioxane (5 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 10 (31 mg, yield: 38.9%).

[0775] MS m / z(ESI): 384.1 [M+1]+ .

[0776] 1 H NMR (500MHz, DMSO): δ10.92(s,1H),7.39–7.28(m,3H),6.98(d,1H),6.93(d,1H),6.89(dd,1H),4.80–4.74(m, 2H),4.34(dd,1H),2.79(ddd,1H),2.58–2.53(m,1H),2.37–2.29(m,1H),2.19–2.16(m,2H),2.09–2.03(m,3H).

[0777] Example 10-1 or 10-2

[0778] 3-(2-chloro-3-((2aR,8aS)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-dione 10-1

[0779] or

[0780] 3-(2-chloro-3-((2aS,8aR)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-dione 10-2

[0781] first step

[0782] (2aS,8aR)-5-bromo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo10e-1

[0783] and

[0784] (2aR,8aS)-5-bromo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo10e-2

[0785] Compound 10e (1.23 g, 5.10 mmol) was prepared chirally (separation conditions: CHIRALPAK IG chiral column, 20 mm × 250 mm; mobile phase: n-hexane / ethanol = 95 / 5 (V / V), flow rate: 20 mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compound (455 mg, yield: 37.0%) and (420 mg, yield: 34.1%).

[0786] (455 mg, yield: 37.0%) Single configuration compound (shorter retention time):

[0787] Chiral HPLC analysis: retention time 3.269 min, purity: 100% (instrument: Agilent 1260DAD, column: CHIRALPAK IG 150*4.6mm, 5μm, column temperature: 35℃, flow rate: 1.0mL / min, mobile phase: ethanol: n-hexane = 5:95).

[0788] (420 mg, yield: 34.1%) Single configuration compound (longer retention time):

[0789] Chiral HPLC analysis: retention time 3.711 min, purity: 97% (instrument: Agilent 1260DAD, column: CHIRALPAK IG 150*4.6mm, 5μm, column temperature: 35℃, flow rate: 1.0mL / min, mobile phase: ethanol: n-hexane = 5:95).

[0790] Step 2

[0791] 3-(2-chloro-3-((2aR,8aS)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-dione 10-1

[0792] or

[0793] 3-(2-chloro-3-((2aS,8aR)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-dione 10-2

[0794] Compounds with shorter retention times from 10e-1 and 10e-2 (50 mg, 0.21 mmol), compound 1e (110 mg, 0.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol, Adamas), and potassium phosphate (135 mg, 0.63 mmol, Adamas) were dissolved in 1,4-dioxane (5 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled 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 10-1 or 10-2 (10 mg, yield: 12.5%).

[0795] MS m / z(ESI): 384.1 [M+1] + .

[0796] 1H NMR (500MHz, DMSO): δ10.92(s,1H),7.40–7.28(m,3H),6.98(d,1H),6.93(d,1H),6.89(dd,1H),4.76(q,2H) ,4.34(dd,1H),2.79(ddd,1H),2.57–2.53(m,1H),2.35–2.29(m,1H),2.19–2.15(m,2H),2.09–1.99(m,3H).

[0797] Example 10-2 or 10-1

[0798] 3-(2-chloro-3-((2aS,8aR)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-dione 10-2

[0799] or

[0800] 3-(2-chloro-3-((2aR,8aS)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo-5-yl)phenyl)piperidine-2,6-dione 10-1

[0801] Compounds with longer retention times in 10e-2 and 10e-1 (50 mg, 0.21 mmol), compound 1e (109 mg, 0.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (16 mg, 0.02 mmol, Adamas), and potassium phosphate (133 mg, 0.63 mmol, Adamas) were dissolved in 1,4-dioxane (5 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled 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 10-2 or 10-1 (20 mg, yield: 25.1%).

[0802] MS m / z(ESI): 384.1 [M+1] + .

[0803] 1 H NMR (500MHz, DMSO): δ10.92(s,1H),7.39–7.29(m,3H),6.99–6.88(m,3H),4.77–4.75(m,2H),4.36–4.32 (m,1H),2.80–2.76(m,1H),2.57–2.56(m,1H),2.35–2.31(m,1H),2.19–2.15(m,2H),2.09–2.03(m,3H).

[0804] Example 11

[0805] 3-(2-chloro-3-(7-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazepane-9-yl)phenyl)piperidin-2,6-dione 11

[0806] first step

[0807] 6-((1-(5-bromo-2-iodophenyl)ethoxy)methyl)pyridin-2(1H)-one 11b

[0808] 1-(5-bromo-2-iodophenyl)ethanol-1-ol 11a (750 mg, 2.29 mmol, Biotin) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (176 mg, 4.59 mmol, 60% purity, Sinopharm) was added at 0 °C. The mixture was stirred at room temperature for 0.5 h. Then, compound 1b (330 mg, 2.30 mmol) was added, and the mixture was reacted at room temperature for 2 h. Subsequently, 3 mL of methanol was added dropwise to quench the reaction mixture. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 11b (630 mg, yield: 63.3%).

[0809] MS m / z(ESI): 434.0 [M+1] + .

[0810] Step 2

[0811] 3-(2-chloro-3-(7-methyl-1-oxo-1,5-dihydro-7H-benzo[e]pyrido[2,1-c][1,4]oxazepane-9-yl)phenyl)piperidin-2,6-dione 11

[0812] Using the synthetic route from step 3 to step 4 in Example 1, the starting compound 1c in step 3 was replaced with starting compound 11b to obtain title compound 11 (5 mg, yield: 22.7%).

[0813] MS m / z(ESI): 449.3 [M+1] + .

[0814] 1H NMR(500MHz,DMSO-d6)δ10.95-10.92(m,1H),7.73-7.71(m,1H),7.59-7.54(m,3H),7.46 -7.41(m,3H),6.64-6.52(m,2H),4.58-4.57(m,1H),4.48-4.37(m,3H),3.83-3.78( m,1H),2.82-2.78(m,1H),2.59-2.56(m,1H),2.52-2.50(m,1H),1.56-1.55(m,3H).

[0815] Example 12

[0816] 3-(2-chloro-3-(1-oxo-1,5-dihydrospiro[benzo[e]pyrido[2,1-c][1,4]oxazaheptan-7,1'-cyclopropyl]-9-yl)piperidin-2,6-dione

[0817] first step

[0818] 2-(chloromethyl)-6-methoxypyridine hydrochloride 12b

[0819] (6-Methoxypyridin-2-yl)methanol 12a (2 g, 14.37 mmol, Bioderm) was dissolved in dichloromethane (30 mL), followed by the addition of 3 drops of N,N-dimethylformamide, and then thionyl chloride (6.84 g, 57.49 mmol, Sinopharm). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 12b, which could be used directly in the next step without further purification.

[0820] Step 2

[0821] ((1-(5-bromo-2-iodophenyl)vinyl)oxy)(tert-butyl)dimethylsilane 12d

[0822] 1-(5-bromo-2-iodophenyl)ethyl-1-one 12c (2 g, 6.15 mmol, BIDE) and triethylamine (3.74 g, 36.96 mmol, Sinopharm) were dissolved in dichloromethane (15 mL). Tert-butyldimethoxysilyltrifluoromethanesulfonate (2.11 g, 7.98 mmol, Shaoyuan) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with 10 mL of saturated ammonium chloride solution, dissolved in 20 mL of dichloromethane, washed with 30 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 silica gel column chromatography using eluent system B to give the title compound 12d (1.89 g, yield: 69.9%).

[0823] Step 3

[0824] (1-(5-bromo-2-iodophenyl)cyclopropoxy)(tert-butyl)dimethylsilane 12e

[0825] Diethylzinc (843 mg, 6.82 mmol, Adamas) was dissolved in dichloromethane (15 mL). Chloroiodomethane (1.2 g, 6.80 mmol, Adamas) was added at 0 °C, and the mixture was stirred for 20 minutes. Then, compound 12d (1 g, 2.27 mmol) was added, and the mixture was stirred at 0 °C for 2 hours. The mixture was brought to room temperature, and the reaction was quenched with 10 mL of saturated ammonium chloride solution. The solution was then dissolved in 20 mL of dichloromethane, washed with 30 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 silica gel column chromatography using eluent system B to give the title compound 12e (910 mg, yield: 88.2%).

[0826] Step 4

[0827] 1-(5-bromo-2-iodophenyl)cycloprop-1-ol 12f

[0828] Compound 12e (910 mg, 2.0 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (675 mg, 3.0 mmol, Adamas) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 12f (400 mg, yield: 58.8%).

[0829] Step 5

[0830] 2-((1-(5-bromo-2-iodophenyl)cyclopropoxy)methyl)-6-methoxypyridine 12g

[0831] Compound 12f (370 mg, 1.09 mmol), compound 12b (425 mg, 2.19 mmol), and potassium iodide (181 mg, 1.09 mmol, Adamas) were dissolved in tetrahydrofuran (10 mL), and sodium hydride (125 mg, 3.26 mmol, 60%, Sinopharm) was added. The mixture was stirred at 55 °C for 1 hour. The reaction solution was cooled to room temperature, and the reaction was quenched by adding 10 mL of saturated ammonium chloride solution. The solution was dissolved by adding 20 mL of dichloromethane, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 12 g (100 mg, yield: 19.9%).

[0832] MS m / z(ESI): 462.0 [M+2] + .

[0833] Step 6

[0834] 6-((1-(5-bromo-2-iodophenyl)cyclopropoxy)methyl)pyridine-2-phenol 12h

[0835] 12 g (100 mg, 0.22 mmol) of compound and sodium iodide (98 mg, 0.65 mmol, Shaoyuan) were dissolved in acetonitrile (10 mL), and trimethylchlorosilane (71 mg, 0.65 mmol, Shaoyuan) was added. The mixture was reacted at 85 °C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 12h (50 mg, yield: 51.5%).

[0836] MS m / z(ESI): 448.1 [M+2] + .

[0837] Step 7

[0838] 9-Bromospiro[benzo[e]pyrido[2,1-c][1,4]oxazepane-7,1'-cyclopropane]-1(5H)-one 12i

[0839] Compound 12h (100 mg, 0.22 mmol), cuprous iodide (9 mg, 0.047 mmol, Shaoyuan), N,N'-dimethylethane-1,2-diamine (4 mg, 0.045 mmol, Shaoyuan), and potassium carbonate (62 mg, 0.45 mmol, Sinopharm) were dissolved in N,N-dimethylformamide (5 mL). The mixture was purged with nitrogen three times and stirred at 110 °C for 2 hours. After cooling to room temperature, 30 mL of dichloromethane was added for dissolution. The mixture was washed with 30 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 silica gel column chromatography using eluent system A to give the title compound 12i (25 mg, yield: 35.0%).

[0840] MS m / z(ESI): 320.2 [M+2] + .

[0841] Step 8

[0842] 3-(2-chloro-3-(1-oxo-1,5-dihydrospiro[benzo[e]pyrido[2,1-c][1,4]oxazaheptan-7,1'-cyclopropyl]-9-yl)phenyl)piperidin-2,6-dione 12

[0843] Compound 12i (25 mg, 0.078 mmol), compound 1e (33 mg, 0.094 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6 mg, 0.008 mmol, Adamas), and potassium phosphate (50 mg, 0.23 mmol, Adamas) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 12 (15 mg, yield: 41.4%).

[0844] MS m / z(ESI): 461.3 [M+1] + .

[0845] 1 H NMR (500MHz, DMSO): δ10.95(s,1H),7.76(d,1H),7.63–7.54(m,3H),7.48–7.40(m,3H),6.63(d,1H),6.54(d,1H),4.53(d,1H),4.39(dd,1H),4.00 (d,1H),2.82(t,1H),2.60–2.53(m,1H),2.09–2.06(m,1H),2.05–1.98(m ,1H),1.32–1.27(m,1H),1.01(dt,1H),0.73–0.64(m,1H),0.27(ddd,1H).

[0846] Example 13

[0847] 3-(2-chloro-3-(11-oxo-7,11-dihydro-6H-benzo[b]pyrido[1,2-d][1,4]oxazepane-3-yl)phenyl)piperidin-2,6-dione 13

[0848] first step

[0849] 2-(2-(5-bromo-2-iodophenoxy)ethyl)-6-methoxypyridine 13b

[0850] 5-Bromo-2-iodophenol (50 mg, 0.17 mmol, BIDE) and 2-(6-methoxypyridin-2-yl)ethanol-1-ol 13a (26 mg, 0.17 mmol, BIDE) were dissolved in tetrahydrofuran (2 mL), and diethyl azodicarbonate (44 mg, 0.25 mmol, Sinopharm) and triphenylphosphine (66 mg, 0.25 mmol, Sinopharm) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 13b (70 mg, yield: 96.4%).

[0851] MS m / z(ESI): 434.0 [M+1] + .

[0852] Step 2

[0853] 3-(2-chloro-3-(11-oxo-7,11-dihydro-6H-benzo[b]pyrido[1,2-d][1,4]oxazepane-3-yl)phenyl)piperidin-2,6-dione 13

[0854] Using the synthetic route from step four to step six in Example 7, the starting compound 7d in step four was replaced with starting compound 13b to obtain title compound 13 (5 mg, yield: 22.4%).

[0855] MS m / z(ESI): 435.2 [M+1] + .

[0856] 1 H NMR(500MHz,DMSO-d6)δ10.92(s,1H),7.66-7.65(m,1H),7.49-7.28(m,6H),6.50-6.3 7(m,2H),4.47-4.28(m,3H),2.90-2.78(m,2H),2.70-2.67(m,3H),2.37-2.35(m,1H).

[0857] Example 14

[0858] 3-(2-chloro-3-(6-methyl-11-oxo-7,11-dihydro-6H-benzo[b]pyrido[1,2-d][1,4]oxazepane-3-yl)phenyl)piperidin-2,6-dione 14

[0859] first step

[0860] 2-(2-(5-bromo-2-iodophenoxy)propyl)-6-methoxypyridine 14b

[0861] 5-Bromo-2-iodophenol (2.2 g, 7.36 mmol, BIDE) and 1-(6-methoxypyridin-2-yl)prop-2-ol 14a (1.1 g, 6.58 mmol, BIDE) were dissolved in tetrahydrofuran (30 mL), and diethyl azodicarbonate (2.0 g, 2.90 mmol, Sinopharm) and triphenylphosphine (2.6 g, 9.87 mmol, Sinopharm) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the target compound 14b (1.2 g, yield: 40.7%).

[0862] MS m / z(ESI): 448.1 [M+1] + .

[0863] Step 2

[0864] 3-(2-chloro-3-(6-methyl-11-oxo-7,11-dihydro-6H-benzo[b]pyrido[1,2-d][1,4]oxazepane-3-yl)phenyl)piperidin-2,6-dione 14

[0865] Using the synthetic route from step four to step six in Example 7, the starting compound 7d in step four was replaced with starting compound 14b to obtain title compound 14 (4 mg, yield: 27.3%).

[0866] MS m / z(ESI): 449.3 [M+1] + .

[0867] 1 H NMR(500MHz,DMSO-d6)δ10.94(s,1H),7.67-7.65(m,1H),7.47-7.20(m,6H),6.49-6.34(m,2H), 4.75-4.36(m,2H),2.82-2.78(m,2H),2.37-2.33(m,2H),2.08-1.98(m,2H),1.26-2.25(m,3H).

[0868] Example 15

[0869] 3-(2-chloro-3-(1-oxo-6,7-dihydro-1H-benzo[d]pyrido[2,1-b][1,3]oxazepane-9-yl)phenyl)piperidin-2,6-dione 15

[0870] first step

[0871] 2-(5-bromo-2-iodophenyl)acetonitrile 15b

[0872] 4-Bromo-2-bromomethyl-1-iodobenzene 15a (5 g, 13.30 mmol, Leyan) was dissolved in dichloromethane (50 mL), and trimethylcyanosilane (1.98 g, 19.96 mmol, Sinopharm) was added. Tetrabutylammonium fluoride (1 M, 19.96 mL, 19.96 mmol, Adamas) was added dropwise at 0 °C, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with 50 mL of water, extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 15b (4.15 g, yield: 96.9%).

[0873] Step 2

[0874] 15c of methyl 2-(5-bromo-2-iodophenyl)acetate

[0875] Compound 15b (4.15 g, 12.89 mmol) was dissolved in methanol (20 mL), and dioxane hydrochloride (4 M, 80 mL, 320 mmol, Adamas) was added. The tube was sealed and stirred at 65 °C for 12 hours. After returning to room temperature, the solution was concentrated to dryness, dissolved in 50 mL of dichloromethane, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 15c (4.23 g, yield: 92.4%). The product was directly used in the next reaction without purification.

[0876] MS m / z (ESI): 352.9 [M-1] - .

[0877] Step 3

[0878] 2-(5-bromo-2-iodophenyl)ethyl-1-ol 15d

[0879] Compound 15c (2 g, 5.63 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium borohydride (186 mg, 8.54 mmol) was added at 0 °C. The mixture was stirred for 12 hours after returning to room temperature. After returning to room temperature, the mixture was quenched with 50 mL of water, extracted with ethyl acetate (50 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 15d (1.11 g, yield: 60.3%).

[0880] Step 4

[0881] 6-(5-bromo-2-iodophenylethoxy)pyridine-2(1H)-one 15e

[0882] Compound 15d (1.11 g, 3.36 mmol) was dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere, 2,6-dihydroxypyridine (451 mg, 4.06 mmol) and triphenylphosphine (1.33 g, 5.07 mmol) were added, followed by diisopropyl azodicarbonate (1.03 mg, 5.09 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 15e (220 mg, yield: 15.6%).

[0883] MS m / z(ESI): 421.9 [M+1] + .

[0884] Step 5

[0885] 9-Bromo-6,7-dihydro-1H-benzo[d]pyrido[2,1-b][1,3]oxazepane-1-one 15f

[0886] Compound 15e (200 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cuprous iodide (18.4 mg, 0.10 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (15 mg, 0.11 mmol), and potassium carbonate (136 mg, 0.99 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 0 °C for 7 hours, then brought to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 15f (30 mg, yield: 21.6%).

[0887] MS m / z(ESI): 293.0 [M+1] + .

[0888] Step 6

[0889] 3-(2-chloro-3-(1-oxo-6,7-dihydro-1H-benzo[d]pyrido[2,1-b][1,3]oxazepane-9-yl)phenyl)piperidin-2,6-dione 15

[0890] Compound 15f (30 mg, 0.10 mmol), compound 1e (36 mg, 0.10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.6 mg, 0.01 mmol, Adamas), and potassium phosphate (44 mg, 0.20 mmol, Adamas) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure at room temperature. The residue was purified by silica gel column chromatography using eluent system A to give title compound 15 (5 mg, yield: 11.5%).

[0891] MS m / z(ESI): 435.3 [M+1] + .

[0892] 1 H NMR (500MHz, DMSO-d6): δ10.94(s,1H),7.60-7.40(m,6H),6.43-6.42(m,1H),6.10-6.09(m,1H) ,5.53-5.52(m,1H),4.43-4.37(m,3H),2.82-2.79(m,1H),2.97-2.95(m,2H),2.03-2.00(m,3H).

[0893] Example 16

[0894] 3-(2-chloro-3-(1'-isopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 16

[0895] first step

[0896] 6-Bromo-N-(3-hydroxypropyl)-N-isopropyl-2,3-dihydrobenzofuran-3-carboxamide 16a

[0897] Compound 6c (1.3 g, 5.34 mmol) and 3-(isopropylamino)-1-propanol (752 mg, 6.41 mmol, Bio-Tech) were dissolved in N,N-dimethylformamide (20 mL), and triethylamine (1.62 g, 16.00 mmol, Sinopharm) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.05 g, 8.02 mmol, Shaoyuan) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 16a (230 mg, yield: 12.5%).

[0898] MS m / z(ESI): 342.9 [M+1] + .

[0899] Step 2

[0900] 6-Bromo-1'-isopropyl-2H-spiro[benzofuran-3,3'-piperidine]-2'-one 16b

[0901] Compound 16a (230 mg, 0.67 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (204 mg, 2.01 mmol, Sinopharm) and methanesulfonic anhydride (175 mg, 1.00 mmol, Bioderm) were added at 0 °C, and the reaction was stirred at 0 °C for 1 hour. N,N-dimethylformamide (2 mL) was added to the reaction solution, and potassium tert-butoxide (226 mg, 2.01 mmol, Adamas) was added while maintaining 0 °C. The reaction solution was allowed to rise naturally to room temperature and stirred for half an hour. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 16b (15 mg, yield: 6.9%).

[0902] MS m / z(ESI): 323.9 [M+1] + .

[0903] Step 3

[0904] 3-(2-chloro-3-(1'-isopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 16

[0905] Compound 16b (15 mg, 0.05 mmol), compound 1e (20 mg, 0.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4 mg, 5.47 μmol, Adamas), and potassium phosphate (30 mg, 0.14 mmol, Adamas) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 16 (1.2 mg, yield: 5.5%).

[0906] MS m / z (ESI): 467.4 [M+1] + .

[0907] 1H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.39-7.23(m,4H),6.88-6.86(m,1H ),6.83(s,1H),4.83-4.81(m,1H),4.73-4.71(m,1H),4.45-4.43(m,1H),4. 38-4.34(m,1H),3.38-3.30(m,2H),2.84-2.81(m,1H),2.52-2.50(m,1H),2 .38-2.27(m,1H),2.05-2.01(m,4H),1.83-1.78(m,1H),1.15-1.10(m,6H).

[0908] Example 17

[0909] 3-(2-chloro-3-(1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17

[0910] first step

[0911] N-(3-Bromopropyl)cyclopropylamine 17b

[0912] (3-Bromopropyl)(cyclopropyl)carbamate tert-butyl ester 17a (2.86 g, 10.28 mmol, BID) was dissolved in dichloromethane (40 mL), and dioxane hydrochloride solution (4 M, 20 mL, 80.00 mmol, Adamas) was added. The reaction was carried out at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 30 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title compound 17b (1.84 g, yield: 99.7%).

[0913] MS m / z (ESI): 180.1 [M⁻¹] - .

[0914] Step 2

[0915] 3-(2-chloro-3-(1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione

[0916] 17

[0917] Using the synthetic route from step one to step six in Example 6, the starting compound 3-bromo-N-methylprop-1-amine hydrochloride in step four was replaced with compound 17b (550 mg, 3.09 mmol) to obtain title compound 17 (52 mg, yield: 48.0%).

[0918] MS m / z(ESI): 465.4 [M+1] + .

[0919] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.39-7.35(m,2H),7.31-7.29(m,1H),7.24-7.23(m,1H),6.87-6.82(m,2H),4.84-4.83(m,1H),4.43-4. 42(m,2H),3.35-3.34(m,1H),2.64-2.62(m,2H),2.51-2.50(m,2H),2.3 8-2.35(m,1H),2.04-2.00(m,4H),1.72-1.71(m,1H),0.70-0.68(m,4H).

[0920] Examples 17-1 and 17-2

[0921] 3-(2-chloro-3-((S)-1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17-1

[0922] or

[0923] 3-(2-chloro-3-((R)-1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17-2

[0924] first step

[0925] 6-Bromo-1'-Cyclopropyl-2H-spiro[benzofuran-3,3'-piperidine]-2'-one 17c

[0926] Using the synthetic route from step one to step five in Example 6, the starting compound 3-bromo-N-methylprop-1-amine hydrochloride in step four was replaced with 17b (550 mg, 3.09 mmol) to obtain the title compound 17c (250 mg, yield: 53.0%).

[0927] Step 2

[0928] (S)-6-bromo-1'-cyclopropyl-2H-spiro[benzofuran-3,3'-piperidin]-2'-one 17c-1

[0929] or

[0930] (R)-6-bromo-1'-cyclopropyl-2H-spiro[benzofuran-3,3'-piperidin]-2'-one 17c-2

[0931] Compound 17c (250 mg, 0.78 mmol) was prepared chirally (Gilson-281, column: ChiralPak IC, 20 mm * 250 mm, 5 μm; mobile phase: n-hexane and ethanol, gradient ratio: 40% ethanol, flow rate: 20 mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds 17c-1 and 17c-2.

[0932] Single configuration compound (longer retention time): 90 mg, yield: 36.0%.

[0933] MS m / z(ESI): 322.2 [M+1] + .

[0934] Chiral HPLC analysis: retention time 17.367 min, chiral purity: 100% (column: ChiralPak IC, 20 mm * 250 mm, 5 μm; mobile phase: n-hexane and ethanol, gradient ratio: 40% ethanol, flow rate: 20 mL / min).

[0935] Single configuration compound (shorter retention time): 90 mg, yield: 36.0%.

[0936] MS m / z(ESI): 322.1 [M+1] + .

[0937] Chiral HPLC analysis: retention time 10.147 min, chiral purity: 100% (column: ChiralPak IC, 20 mm * 250 mm, 5 μm; mobile phase: n-hexane and ethanol, gradient ratio: 40% ethanol, flow rate: 20 mL / min).

[0938] Step 2

[0939] 3-(2-chloro-3-((S)-1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17-1

[0940] or

[0941] 3-(2-chloro-3-((R)-1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17-2

[0942] Compounds 17c-1 and 17c-2 with longer retention times (90 mg, 0.28 mmol), compound 1e (118 mg, 0.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.03 mmol, Adamas), and potassium phosphate (119 mg, 0.56 mmol, Adamas) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 17-1 or 17-2 (52 mg, yield: 40.0%).

[0943] MS m / z (ESI): 465.6 [M+1] + .

[0944] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.39-7.36(m,3H),7.31-7.30(m,1H),6.87-6.82(m,2H),4.84-4.83(m,1H),4.43-4. 42(m,2H),3.35-3.34(m,1H),2.72-2.57(m,3H),2.43-2.42(m,1H),2.04–2.00(m,5H),1.72-1.71(m,1H)0.70-0.68(m,4H).

[0945] Examples 17-2 and 17-1

[0946] 3-(2-chloro-3-((R)-1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17-2

[0947] or

[0948] 3-(2-chloro-3-((S)-1'-cyclopropyl-2'-oxo-2H-spiro[benzofuran-3,3'-piperidin]-6-yl)phenyl)piperidin-2,6-dione 17-1

[0949] Compounds 17c-2, the shorter-retention compound from 17c-1 (90 mg, 0.28 mmol), compound 1e (118 mg, 0.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.03 mmol, Adamas), and potassium phosphate (119 mg, 0.56 mmol, Adamas) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 17-2 or 17-1 (51 mg, yield: 39.3%).

[0950] MS m / z (ESI): 465.6 [M+1] + .

[0951] 1 H NMR (500MHz, DMSO-d6): δ10.92(s,1H),7.39-7.36(m,3H),7.31-7.30(m,1H),6.87-6.82(m,2H),4.84-4.83(m,1H),4.43-4. 42(m,2H),3.35-3.34(m,1H),2.72-2.57(m,3H),2.43-2.42(m,1H),2.04–2.00(m,5H),1.72-1.71(m,1H)0.70-0.68(m,4H).

[0952] Example 18

[0953] 3-(2-chloro-3-(1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-pyrrolidine]-6-yl)phenyl)piperidin-2,6-dione 18

[0954] first step

[0955] 18a methyl 6-bromo-3-(cyanomethyl)-2,3-dihydrobenzofuran-3-carboxylate

[0956] Compound 6b (1.5 g, 5.83 mmol) was dissolved in tetrahydrofuran (20 mL), and diisopropylaminolithium (3.79 mL, 7.58 mmol, 2 M, Adamas) was slowly added dropwise at -78 °C. The reaction was continued at -78 °C for 0.5 h, followed by the addition of bromoacetonitrile (1.39 g, 11.58 mmol, Adamas), and the reaction was continued for 2 h. The reaction solution was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 18a (1.3 g, yield: 75.2%).

[0957] Step 2

[0958] 6-Bromo-2H-spiro[benzofuran-3,3'-pyrrolidine]-2'-one 18b

[0959] Compound 18a (600 mg, 2.02 mmol) was dissolved in methanol (45 mL), and cobalt chloride hexahydrate (1.1 g, 4.01 mmol, Adamas) and sodium borohydride (766 mg, 20.2 mmol, Sinopharm) were added under ice bath conditions. The reaction mixture was allowed to rise naturally to room temperature and stirred overnight. The reaction mixture was quenched with 2N hydrochloric acid (15 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 18b (275 mg, yield: 50.6%).

[0960] MS m / z(ESI): 269.9 [M+1] + .

[0961] Step 3

[0962] 6-Bromo-1'-methyl-2H-spiro[benzofuran-3,3'-pyrrolidine]-2'-one 18c

[0963] Compound 18b (225 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (4 mL), and sodium hydride (30 mg, 1.25 mmol, Sinopharm) was added under ice bath conditions. The mixture was stirred for half an hour, and then iodomethane (238 mg, 1.67 mmol, Sinopharm) was added. The reaction mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 18c (170 mg, yield: 71.8%).

[0964] MS m / z(ESI): 281.9 [M+1] + .

[0965] Step 4

[0966] 3-(2-chloro-3-(1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-pyrrolidine]-6-yl)phenyl)piperidin-2,6-dione 18

[0967] Compound 18c (170 mg, 0.60 mmol), compound 1e (232 mg, 0.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol, Adamas), and potassium phosphate (383 mg, 1.80 mmol, Adamas) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 18 (85 mg, yield: 33.2%).

[0968] MS m / z(ESI): 425.4 [M+1] + .

[0969] 1 H NMR (500MHz, DMSO): δ10.93(s,1H),7.40-7.34(m,2H),7.30-7.28(m,1H),7.2 5-7.23(m,1H),6.89-6.87(m,1H),6.83(s,1H),4.72-4.69(m,1H),4.51-4.49 (m,1H),4.36-4.33(m,1H),3.67-3.62(m,1H),3.44-3.39(m,1H),2.87(s,3H) ,2.83-2.76(m,1H),2.57-2.52(m,1H),2.36-2.29(m,3H),2.08-2.02(m,1H).

[0970] Example 19

[0971] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,3'-pyrrolidine]-6-yl)phenyl)piperidin-2,6-dione 19

[0972] 3-((5-bromo-2-iodophenoxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 19b

[0973] 5-Bromo-2-iodophenol (803 mg, 2.68 mmol, BIDE) and tert-butyl 3-(bromomethyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid ester 19a (640 mg, 2.44 mmol, BIDE) were dissolved in tetrahydrofuran (30 mL), and potassium carbonate (507 mg, 3.67 mmol, Sinopharm) was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 19b (1.1 g, yield: 93.8%).

[0974] MS m / z(ESI): 424.0 [M-55] - .

[0975] Step 2

[0976] 6-Bromo-2H-spiro[benzofuran-3,3'-pyrrolidine]-1'-carboxylic acid tert-butyl ester 19c

[0977] Compound 19b (100 mg, 0.21 mmol) was dissolved in toluene (3 mL), and tributyltin hydride (97 mg, 0.33 mmol, Sinopharm) and azobisisobutyronitrile (56 mg, 0.34 mmol, Sinopharm) were added. The mixture was stirred at 110 °C for 12 hours. After returning to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the target compound 19c (65 mg, yield: 88.1%).

[0978] Step 3

[0979] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2H-spiro[benzofuran-3,3'-pyrrolidine]-6-yl)phenyl)piperidin-2,6-dione 19

[0980] Using the synthetic route of Example 4, starting compound 3f was replaced with starting compound 19c to obtain title compound 19 (20 mg, yield: 23.6%).

[0981] MS m / z(ESI): 491.5 [M+1] + .

[0982] 1 H NMR(500MHz,DMSO-d6)δ10.92(s,1H),7.59(s,1H),7.39-7.28(m,4H),6.90-6.89(m,1H),6.77(s,1 H),6.17(s,1H),4.48-4.32(m,3H),3.78(s,3H),3.59(s,2H),2.83-2.57(m,6H),2.32-2.03(m,4H).

[0983] Example 20

[0984] 3-(2-chloro-3-(1'-(1-methyl-2-oxoperidin-3-yl)spiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidin-2,6-dione 20

[0985] first step

[0986] 3-(5'-bromospiro[cyclopropane-1,3'-indoline]-1'-yl)-1-methylpiperidin-2-one 20c

[0987] 3-Hydroxy-1-methylpiperidin-2-one 20a (12 mg, 0.092 mmol, BIDE) and 5'-bromospiro[cyclopropane-1,3'-indoline] 20b (20 mg, 0.089 mmol, BIDE) were dissolved in 1,2-dichloroethane (0.4 mL), and N,N-diisopropylethylamine (12 mg, 0.092 mmol, Sinopharm) was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 20c (10 mg, yield: 33.4%).

[0988] MS m / z(ESI): 335.2 [M+1] + .

[0989] Step 2

[0990] 3-(2-chloro-3-(1'-(1-methyl-2-oxoperidin-3-yl)spiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidin-2,6-dione 20

[0991] Using the fourth step of the synthetic route in Example 1, starting compound 1d was replaced with starting compound 20c to obtain title compound 20 (10 mg, yield: 5.8%).

[0992] MS m / z(ESI): 478.4 [M+1] + .

[0993] 1 H NMR(500MHz,DMSO-d6)δ10.93(m,1H),7.54-7.14(m,6H),5.23-5.212(m,1H),4.30-4.25(m,2H),4.11-4. 09(m,1H),3.52-3.24(m,5H),3.01-2.74(m,5H),2.53-2.51(m,1H),2.27-2.24(m,1H),2.02-1.93(m,5H).

[0994] Example 21

[0995] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,2'-indoline]-5'-yl)phenyl)piperidin-2,6-dione 21

[0996] first step

[0997] 1-(5'-bromo-3'-hydroxyspiro[cyclopropane-1,2'-indoline]-1'-yl)ethyl-1-one 21b

[0998] 1'-Acetyl-5'-bromospiro[cyclopropane-1,2'-indoline]-3'-one 21a (2.8 g, 10.0 mmol, prepared according to the method disclosed in Chemical and Pharmaceutical Bulletin, 1981, vol. 29, #7, pp. 1912-1919) was dissolved in methanol (50 mL, Sinopharm), and sodium borohydride (378 mg, 10.0 mmol, Shaoyuan) was added at 0 °C. The mixture was stirred at room temperature for 1 hour, and the system was concentrated under reduced pressure. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 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 21b (1.48 g, yield: 52.5%).

[0999] MS m / z(ESI): 282.2 [M+1] + .

[1000] Step 2

[1001] 1-(5'-bromospiro[cyclopropane-1,2'-indoline]-1'-yl)ethyl-1-one 21c

[1002] Compound 21b (1.48 g, 5.25 mmol) was dissolved in dichloromethane (30 mL, Anegaly), and triethylsilane (2.51 mL, 15.7 mmol, Bioderm) and trifluoroacetic acid (2.41 mL, 31.5 mmol, Adamas) were added at 0 °C. The mixture was stirred overnight at room temperature. The pH of the mixture was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 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 21c (700 mg, yield: 50.1%).

[1003] MS m / z(ESI): 266.2 [M+1] + .

[1004] Step 3

[1005] 5'-Bromospiro[cyclopropane-1,2'-indoline]21d

[1006] Compound 21c (438 mg, 1.65 mmol) was dissolved in 1,4-dioxane (10 mL, Anaiji), and hydrochloric acid (4.1 mL, 2 M, 8.2 mmol, Sinopharm) was added. The mixture was microwaved at 100 °C for 1 hour, then allowed to return to room temperature. The system was neutralized with triethylamine, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 21d (250 mg, yield: 67.8%).

[1007] MS m / z(ESI): 224.0 [M+1] + .

[1008] Step 4

[1009] 5'-Bromo-1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,2'-indoline]21e

[1010] Compound 21d (210 mg, 0.94 mmol) and 3-bromomethyl-1-methylpyrazole (246 mg, 1.41 mmol, Leyan) were dissolved in triethylamine (5 mL, Sinopharm) and N,N-dimethylformamide (3 mL, Anaiji). The mixture was microwaved at 120 °C for 5 hours, then allowed to return to room temperature. The system was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 21e (92 mg, yield: 30.9%).

[1011] MS m / z(ESI): 318.1 [M+1] + .

[1012] Step 5

[1013] 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,2'-indoline]-5'-yl)phenyl)piperidin-2,6-dione 21

[1014] Compound 21e (92 mg, 0.29 mmol), compound 1e (121 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 57 μmol, Adamas), and potassium phosphate (122 mg, 0.57 mmol, Adamas) were dissolved in N,N-dimethylformamide (3 mL). The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 21 (5 mg, yield: 3.8%).

[1015] MS m / z(ESI): 461.3 [M+1] + .

[1016] 1 H NMR(500MHz,DMSO-d6)δ10.91(s,1H),7.60(s,1H),7.35-7.30(m,1H),7.29 -7.23(m,2H),7.08-7.04(m,1H),7.01(s,1H),6.63-6.57(m,1H),6.14(s,1 H),4.37-4.27(m,3H),4.22-4.14(m,1H),3.85(s,1H),3.80(s,2H),2.82-2 .74(m,1H),2.56(s,2H),2.34(s,1H),2.23-2.15(m,2H),2.04-1.89(m,3H).

[1017] Example 22

[1018] 3-(2-chloro-3-(spiro[cyclopropane-1,2'-indoline]-5'-yl)phenyl)piperidine-2,6-dione 22

[1019] first step

[1020] 3-(2-chloro-3-(spiro[cyclopropane-1,2'-indoline]-5'-yl)phenyl)piperidine-2,6-dione 22

[1021] Compound 21d (600 mg, 2.68 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 1e (1.4 g, 4.02 mmol, prepared by the method disclosed in Intermediate A on page 182 of patent application WO2024151547 A1), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (196 mg, 0.27 mmol, Adamas), and potassium phosphate (1.14 g, 5.36 mmol, Adamas) were dissolved in 1,4-dioxane (16 mL) and water (1.6 mL), purged with nitrogen three times, heated to 90 °C, and stirred for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 22 (500 mg, yield: 50.91%).

[1022] MS m / z(ESI): 367.4.1 [M+1] + .

[1023] 1 H NMR(500MHz,DMSO-d6)δ10.91(s,1H),7.37-7.34(m,1H),7.30-7.28(m,2H),7.14-7.09(m,2H),6.78-6.77(m,1H),4.45-4.41(m,1H),4.34-4.3 1(m,1H),2.82-2.75(m,2H),2.65-2.61(m,2H),2.43-2.40(m,2H),2.35 -2.32(m,1H),2.16-2.12(m,1H),2.06-2.03(m,1H),1.97-1.92(m,1H).

[1024] Biological evaluation

[1025] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[1026] Test Example 1: VAV1 Degradation Experiment in T Cells

[1027] 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.

[1028] Experimental steps:

[1029] 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 S600 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 is used to reflect the degradation activity of different compounds on VAV1.

[1030] Table 1. Degradation activity of the compounds disclosed herein against VAV1.

[1031] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1.

[1032] Test Example 2: Solubility of the Compounds Disclosed

[1033] 1. Experimental materials

[1034] 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).

[1035] Instrument: Agilent 1200DAD high-performance liquid chromatograph (Agilent Technologies, Inc.)

[1036] 2. Material preparation

[1037] 2.1 Preparation of FassIF solution

[1038] 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).

[1039] 2.2 Preparation of FessIF solution

[1040] 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).

[1041] 2.3 Preparation of PBS solution

[1042] 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).

[1043] 3. Experimental Procedure

[1044] 3.1 Solubility test in FassIF and FessIF solutions

[1045] 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.

[1046] 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.

[1047] 3.2 Solubility test in PBS solution

[1048] 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.

[1049] 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.

[1050] 4. Experimental Results

[1051] 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

[1052] The average of the two measurements was taken as the final solubility in FassIF, FessIF, and PBS solutions.

[1053] Table 2. Solubility of the compounds disclosed herein

[1054] Conclusion: The compounds of the present disclosure have good solubility in PBS, FassIF, and FessIF solutions.

[1055] Test Example 3: Pharmacokinetic Evaluation

[1056] I. Experiment on C57 Mice

[1057] 1. Abstract

[1058] Taking C57 mice as the test animals, the LC / MS / MS method was used to determine the drug concentrations in the plasma of C57 mice at different time points after intragastric administration (i.g.) of the compounds of the examples, study the pharmacokinetic behavior of the compounds of the present disclosure in C57 mice, and evaluate their pharmacokinetic characteristics.

[1059] 2. Test Protocol

[1060] 2.1. Test Drug

[1061] The compounds of the present disclosure.

[1062] 2.2. Test Animals

[1063] C57 mice, female, provided by Shanghai Shilin Biotechnology Co., Ltd. (Animal Production License: SCXK (Shanghai) 2022-0009; Animal Use License: SYXK (Jiangsu) 2020-0018).

[1064] 2.3. Drug Preparation

[1065] Weighed a certain amount of the test compound respectively, added 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a colorless and transparent solution of 0.1 mg / mL.

[1066] 2.4. Drug Administration

[1067] The administration dose was 2 mg / kg, and the administration volume was 10 mL / kg.

[1068] 3. Operation

[1069] After intragastric administration, 0.1 mL of blood was collected from the orbital venous plexus at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 11.0 h, and 24.0 h after administration, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 2 minutes at 4°C to separate plasma, completed within 1 hour, and stored at -80°C for future measurement.

[1070] The LC / MS / MS method was used to determine the content of the test compound in the plasma of C57 mice after administration of different compounds.

[1071] Conclusion: The compounds of the present disclosure have high blood drug concentration and high exposure in C57 mice, showing pharmacokinetic advantages.

[1072] II. SD Rat Experiment

[1073] 1. Abstract

[1074] Taking SD rats as the test animals, the LC / MS / MS method was used to determine the drug concentration in plasma at different time points after the test compounds were administered by gavage (i.g.) to SD rats, study the pharmacokinetic behavior of the compounds of the present disclosure in SD rats, and evaluate their pharmacokinetic characteristics.

[1075] 2. Test Protocol

[1076] 2.1. Test Drug

[1077] The compounds of the present disclosure.

[1078] 2.2. Test Animals

[1079] SD rats, half male and half female, provided by Vital River Laboratory Animal Technology Co., Ltd. (SCXK(Zhe)2024 - 0001).

[1080] 2.3. Drug Preparation

[1081] Weighed a certain amount of the test compound respectively, added 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a colorless and transparent solution of 0.2 mg / mL.

[1082] 2.4. Drug Administration

[1083] The drug administration dose was 2 mg / kg, and the administration volume was 10 mL / kg.

[1084] 3. Operations

[1085] After administration by gavage, 0.2 mL of blood was collected from the orbital venous plexus at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 11.0 h, and 24.0 h after administration, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 2 minutes at 4°C to separate plasma, completed within 1 hour, and stored at -20°C for further measurement.

[1086] The LC / MS / MS method was used to determine the content of the test compound in the plasma of SD rats after administration of different compounds.

[1087] Conclusion: The compounds of the present disclosure have high blood drug concentration and high exposure in SD rats, showing pharmacokinetic advantages.

[1088] Test Example 4. Degradation Experiment of VAV1 in Human PBMC Cells

[1089] 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.

[1090] Experimental steps:

[1091] 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 and 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). The VAV1-antibody complex was then tagged with a SULFO-TAG-labeled goat anti-rabbit antibody (MSD, #R32AB-1). VAV1 was measured using a MESO SECTOR S 600 instrument, where electrochemical excitation of the SULFO-TAG™ label elicited a strong light signal. The content of VAV1 was calculated using a standard curve of recombinant VAV1 protein. DMSO-treated wells served as positive controls, and blank cell lysates served as negative controls. 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 is used to reflect the degradation activity of different compounds on VAV1.

[1092] Table 4. Degradation activity of the compounds disclosed herein against VAV1 in human PBMC cells.

[1093] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1 in human PBMC cells.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: X is N or CR 6a ; Y is either N or C; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 1a and R 1b Together with the attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. X replace; R X Selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, two Rs X Together with the 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; Each R a 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, two Rs a Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 2 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, and cycloalkyl groups; R 3 R 4 R 5 R 6a R 6b and R 6c 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 hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups; R 0 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclic oxy, aryloxy, heteroaryloxy, oxo, =S, -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 and = CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy groups are each independently and independently labeled with one or more R groups. t replace; 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. t Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. t Substituted heterocyclic groups; R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups; 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; R t 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; m is an integer from 0 to 15; v can be 0, 1, or 2.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a pharmaceutically acceptable salt thereof. in: M 1 Selected from bonds, C(O), O, S, NR d NR d C(O) and C(O)NR d ; p and q are each independently 0, 1, 2 or 3; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, each of which is independently optionally influenced by one or more R groups. X replace; R d The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups is independently and optionally selected by one or more R groups. 0 replace; R 11a R 11b R 11c and R 11d The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, R 11a and R 11b Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 11a and R 11b Together they form = O; Or, R 11c and R 11d Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 11c and R 11d Together they form = O; R 2 -R 5 X, R 6b R 6c R X R 0 R 16 -R 19 and v as defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof. in: k1 can be 0, 1, 2, or 3; k2 is 0, 1, 2, 3, 4, 5, 6 or 7; d is 0, 1, or 2; Q is selected from key, CR 8b R 8c O, S and NR 8d ; R 8 R 8a R 8b and R 8c 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, two adjacent R 8 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; Or, R 8a and R 8b Together with the 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; Or, R 8b and R 8c Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs 8a Together with the 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 8d The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups is independently and optionally selected by one or more R groups. 0 replace; Or, R 8a and R 8d Together with the attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 2 -R 5 R 6a R 6b R 6c R 0 R 11a R 11b R 11c R 11d M 1 p, q, R 16 -R 19 As defined in claim 2.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (III) or formula (M) or a pharmaceutically acceptable salt thereof. in: M 2 Selected from bonds, C(O), O, S, NR 9B NR 9B C(O) and C(O)NR 9B ; r can be 0, 1, 2, 3, or 4; The ring C is a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R groups. X replace; R 9B Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace; R 12a and R 12b The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, R 12a and R 12b Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, R 12a and R 12b Together they form = O; R 2 -R 5 X, R 6b R 6c R X R 0 R 16 -R 19 and v as defined in claim 1.

5. The compound of general formula (I) according to claim 1 or 4, wherein the compound is of general formula (III-1), general formula (III-2), general formula (M-1) or general formula (M-2), or a pharmaceutically acceptable salt thereof. in: k3 is 0, 1, 2, 3, 4, 5 or 6; k4 is 0, 1, 2, 3, 4, 5, or 6; G is selected from bonds, C(O), O, S, NR 9C NR 9C C(O) and C(O)NR 9C ; x and y are each independently 0, 1, 2 or 3; t1 and t2 are each independently 0, 1, 2 or 3; R 9A R 9B and R 9C They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl is independently optionally composed of one or more R 0 replace; R 9 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, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, oxo, -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, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, two Rs 9 Together with the attached atoms, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 2 -R 5 R 6a R 6b R 6c R 0 R 16 -R 19 and v as defined in claim 1.

6. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: M 1 Selected from bonds, O, C(O) and NR d C(O); R d It is a hydrogen atom or a carbon atom. 1-6 alkyl; And / or p and q are each independently 0, 1 or 2; and / or R 11a R 11b R 11c and R 11d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; or, R 11a and R 11b Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups; or R 11c and R 11d Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups; and / or R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy groups; or, two adjacent R groups. 8 Together with their respective attached atoms, they form 4- to 6-membered cycloalkyl groups; and / or R 8a They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy group; or, two R groups on the same carbon atom. 8a Together with the adjacent carbon atoms, they form 3- to 6-membered cycloalkyl groups; And / or k1 is 0, 1, or 2; And / or k2 is 0, 1, or 2; And / or Q is selected from CH2, O and NR 8d ;R 8d It is a hydrogen atom or a carbon atom. 1-6 alkyl; And / or d is 0 or 1.

7. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein: x is 0, 1, or 2; y is 0, 1, or 2; preferably, x is 0 or 1; y is 1 or 2. And / or t1 is 0, 1, or 2; t2 is 1 or 2; and / or R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl groups and oxo groups; And / or k3 is 0, 1, or 2; And / or k4 is 0, 1, or 2; and / or G is a bond or NR 9C ;R 9C It is a hydrogen atom or a carbon atom. 1-6 alkyl; and / or R 9A Selected from C 1-6 Alkyl, 3- to 6-membered cycloalkyl, -C(O)OR 16 and -CH2-5-membered heteroaryl; the 5-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl substitution; R 16 C 1-6 alkyl; and / or R 9B It is a 5- or 6-membered heterocyclic group or a -CH2-5-membered heteroaryl group, wherein the 5- or 6-membered heterocyclic group or the 5-membered heteroaryl group is optionally selected from an oxo group and a C-membered heterocyclic group. 1-6 One or more substituents in the alkyl group are substituted.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; preferably, R 2 It is Cl.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein 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.

10. The compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c It is a hydrogen atom.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

12. A compound or a salt thereof, selected from the following compounds:

13. A method for preparing a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, comprising: 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; in: R w Selected from Bpin and -B(OH)2; R L It is a leaving group; preferably, R L Halogen; more preferably, R L For Br; Rings A and R a m, R 1a R 1b R 2 -R 5 R 7 X, Y, R 6b and R 6c As defined in claim 1.

14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 14 in the preparation of a medicament for inhibiting or degrading VAV1.

16. Use of the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 14 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on VAV1.

17. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating and / or preventing tumors, autoimmune diseases, and inflammatory diseases; wherein the autoimmune disease or inflammatory disease is preferably 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, 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, axial spondyloarthritis.

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