Chimeric compound for targeted degradation of BCL-2 protein, preparation method of chimeric compound and application of chimeric compound in medicine

Abstract

The invention relates to a chimera compound for targeted degradation of BCL-2 protein, a preparation method of the chimera compound and application of the chimera compound in medicine. Specifically, the invention relates to a heterocyclic compound as shown in a general formula (I), a preparation method of the heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound and application of the heterocyclic compound as a therapeutic agent, in particular to application of the heterocyclic compound as a BCL-2 degradation agent and application of the heterocyclic compound in preparation of drugs for treating and / or preventing BCL-2 mediated or dependent diseases or symptoms. # imgabs0 #

Description

A chimeric compound for targeted degradation of BCL-2 protein, its preparation method and its application in medicine

[0001] The present disclosure relates to a novel protein degradation targeting chimera (PROTAC) compound, a method for preparing the same, and its use in medicine. Specifically, the present disclosure relates to a heterocyclic compound represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and its use as a therapeutic agent, particularly as a BCL-2 degrader and in the preparation of a medicament for treating and / or preventing BCL-2-mediated or dependent diseases or conditions.

[0002] PROTAC (Proteolysis Targeting Chimera) is a hybrid bifunctional small molecule compound. Its structure contains two different ligands: one is the ubiquitin ligase E3 ligand, and the other is the target protein binding ligand, and the two ligands are connected by a linker arm. PROTAC works by bringing the target protein and the ubiquitin ligase E3 in the cell together to form a target protein-PROTAC-E3 ternary complex. The E3 ubiquitin ligase then tags the target protein with a ubiquitinated protein tag, subsequently activating the powerful ubiquitination-proteasome system in the cell to specifically degrade the target protein, thereby inhibiting the corresponding protein signaling pathway. Compared with traditional small molecule inhibitors, PROTAC exhibits unique advantages: 1. PROTAC does not require long-term and high-intensity binding to the target protein, and the target protein degradation process is similar to a catalytic reaction, which can cyclically bind and degrade the target protein. This reduces the systemic exposure of the drug and the occurrence of toxic side effects. 2. After being degraded, the target protein needs to be resynthesized to restore its function. Therefore, degrading the target protein shows a more efficient and lasting anti-tumor effect than inhibiting its activity, and is less likely to cause drug resistance due to target protein mutations. 3. PROTACs also have therapeutic potential for targets currently considered undruggable, such as transcription factors, scaffold proteins, and regulatory proteins.

[0003] Inhibiting apoptosis signaling pathways can promote tumorigenesis and render cancer cells resistant to various anticancer drugs. Anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2 and BCL-xL, are considered key survival factors in various cancers. Abnormal amplification of the BCL-2 gene can be detected in many hematologic malignancies (such as non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia). BCL-xL is overexpressed in many solid tumor cells (such as colorectal cancer and cervical cancer) and in subsets of hematologic malignancies.

[0004] Currently, the BCL-2 selective small molecule inhibitor venetoclax has been approved for the treatment of adult chronic lymphocytic leukemia or small lymphocytic lymphoma, and in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of adults (over 75 years old) with newly diagnosed acute myeloid leukemia or patients with comorbidities who cannot use intensive induction chemotherapy, with good clinical efficacy. However, some patients will develop drug resistance after a period of treatment, mainly due to BCL-2 mutations (such as G101V, D103Y mutations, etc.) and upregulation of BCL-xL. In addition, venetoclax has limited therapeutic effects on solid tumors because most solid tumor cells do not rely on BCL-2 for survival. Therefore, the development of drugs targeting BCL-xL may overcome the limitations of venetoclax in treating diseases, expand its indications, and overcome drug resistance.

[0005] BCL-xL is currently one of the most important cancer targets, but because BCL-xL is essential for platelet survival, no safe and effective BCL-xL-targeting drugs have been approved for marketing. ABT-263, an inhibitor of BCL-2, BCL-xL, and BCL-w, demonstrated excellent tumor suppression in preclinical studies. However, in clinical trials, it was not approved due to the severe toxicity of BCL-xL inhibition, which induced on-target and dose-limiting thrombocytopenia. Circumventing the platelet toxicity caused by BCL-xL targeting is a key issue in drug development. Due to the low expression of E3 ligases in platelets, PROTAC technology can be used to mitigate the thrombocytopenia caused by BCL-xL targeting. By converting BCL-xL inhibitors into BCL-xL PROTACs, anti-tumor activity is enhanced while platelet toxicity is reduced. BCL-xL PROTACs have the potential to become promising cancer treatments.

[0006] Published patent applications for BCL-2 protein targeted degradation PROTAC compounds include WO2019144117A1, WO2017184995A1, WO2021222114A1, and WO2020163823A2.

[0007]

[0008] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] Ring A is *The end is connected to the benzene ring;

[0011] R 1is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0012] R 1a 、R 1b 、R 1c and R 1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; said alkyl and cycloalkyl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents in;

[0013] or R 1a and R 1b Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0014] or R 1c and R 1d Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0015] Each R 1e are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0016] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, hydroxy, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0017] Z is CR 0 or N;

[0018] R 0 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0019] R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; or, R 3 and R 4 together with the carbon atoms to which they are attached to form a heterocyclic group; said heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0020] Each R 3a and each R 4a are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0021] X is O or NH;

[0022] R 5 Selected from -S(O)R 5a 、-S(O)2R 5a , halogen, nitro, cyano and haloalkyl;

[0023] R 5aselected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl;

[0024] R is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0025] Y is selected from a bond, O, NR 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -heterocyclyl-O-*, -heterocyclyl-NR 6 -*and * end is connected to L; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0026] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0027] Ring C is aryl or heteroaryl; said aryl or heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0028] Ring D is a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0029] R 2a and R 2b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0030] L is the connection unit;

[0031] A is selected from

[0032] R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, amino, cyano, hydroxy, cycloalkyl, heterocyclyl, cycloalkylalkyl and heterocyclylalkyl;

[0033] R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, an alkylthio group, a cycloalkyl group, a cycloalkylalkyl group, and a heteroaryl group;

[0034] Ring E is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; said aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl;

[0035] Ring F is a cycloalkyl group or a heterocyclyl group; the cycloalkyl group or the heterocyclyl group are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl;

[0036] Ring G is aryl or heteroaryl;

[0037] Each R 12 and each R 15 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, -SH, -OC(O)alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, cyano, cycloalkyl, and cycloalkylalkyl;

[0038] W 1 C or N;

[0039] W 2 C or N;

[0040] a is 0, 1, 2, or 3;

[0041] b is 0, 1, 2, or 3;

[0042] m is 0, 1, 2, 3 or 4;

[0043] x is 0, 1, 2, or 3;

[0044] y is 0, 1, 2, or 3;

[0045] s is 0, 1, 2, or 3;

[0046] n is 0, 1, 2, or 3;

[0047] w is 0, 1, 2, or 3; and

[0048] u is 0, 1, 2, or 3.

[0049] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0050] in:

[0051] Ring A is *The end is connected to the benzene ring;

[0052] R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0053] R 1a 、R 1b 、R 1c and R 1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; said alkyl and cycloalkyl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0054] or R 1a and R 1b Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0055] or R 1c and R 1dTogether with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0056] Each R 1e are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0057] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, hydroxy, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0058] Z is CR 0 or N;

[0059] R 0 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0060] R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; or, R 3 and R 4 together with the carbon atoms to which they are attached to form a heterocyclic group; said heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0061] Each R 3a and each R4a are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0062] X is O or NH;

[0063] R 5 Selected from -S(O)R 5a 、-S(O)2R 5a , halogen, nitro, cyano and haloalkyl;

[0064] R 5a selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl;

[0065] R is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0066] Y is selected from a bond, O, NR 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -heterocyclyl-O-*, -heterocyclyl-NR 6 -*and * end is connected to L; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0067] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0068] Ring C is aryl or heteroaryl; said aryl or heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0069] Ring D is a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0070] R 2a and R 2b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0071] L is the connection unit;

[0072] A is selected from

[0073] R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, amino, cyano, hydroxy, cycloalkyl, heterocyclyl, cycloalkylalkyl and heterocyclylalkyl;

[0074] R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, an alkylthio group, a cycloalkyl group, a cycloalkylalkyl group, and a heteroaryl group;

[0075] Ring E is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl; said aryl, heteroaryl, cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl;

[0076] Ring F is a cycloalkyl group or a heterocyclyl group; the cycloalkyl group or the heterocyclyl group are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl;

[0077] Ring G is aryl or heteroaryl;

[0078] Each R 12 and each R 15 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, -SH, -OC(O)alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, cyano, cycloalkyl, and cycloalkylalkyl;

[0079] W1 C or N;

[0080] W 2 C or N;

[0081] m is 0, 1, 2, 3 or 4;

[0082] x is 0, 1, 2, or 3;

[0083] y is 0, 1, 2, or 3;

[0084] s is 0, 1, 2, or 3;

[0085] n is 0, 1, 2, or 3;

[0086] w is 0, 1, 2, or 3; and

[0087] u is 0, 1, 2, or 3.

[0088] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0089] in:

[0090] Ring A is *The end is connected to the benzene ring;

[0091] R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0092] R 1a 、R 1b 、R 1c and R 1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; said alkyl and cycloalkyl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0093] or R 1a and R1b Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0094] or R 1c and R 1d Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0095] Each R 1e are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0096] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, hydroxy, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0097] Z is CR 0 or N;

[0098] R 0 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0099] R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; or, R3 and R 4 together with the carbon atoms to which they are attached to form a heterocyclic group; said heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0100] Each R 3a and each R 4a are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0101] X is O or NH;

[0102] R 5 Selected from -S(O)R 5a 、-S(O)2R 5a , halogen, nitro, cyano and haloalkyl;

[0103] R 5a selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl;

[0104] R is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0105] Y is selected from a bond, O, NR 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -heterocyclyl-O-*, -heterocyclyl-NR 6 -*and * end is connected to L; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl;

[0106] R 6is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0107] Ring C is aryl or heteroaryl; said aryl or heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0108] Ring D is a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0109] R 2a and R 2b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0110] L is the connection unit;

[0111] A is

[0112] R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, amino, cyano, hydroxy, cycloalkyl, heterocyclyl, cycloalkylalkyl and heterocyclylalkyl;

[0113] R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, an alkylthio group, a cycloalkyl group, a cycloalkylalkyl group, and a heteroaryl group;

[0114] Ring E is aryl or heteroaryl; the aryl or heteroaryl groups are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl;

[0115] Ring F is a cycloalkyl group or a heterocyclyl group; the cycloalkyl group or the heterocyclyl group are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl;

[0116] Ring G is aryl or heteroaryl;

[0117] Each R 12 and each R 15 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, -SH, -OC(O)alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, cyano, cycloalkyl, and cycloalkylalkyl;

[0118] W 1 C or N;

[0119] W 2 C or N;

[0120] m is 0, 1, 2, 3 or 4;

[0121] x is 0, 1, 2, or 3;

[0122] y is 0, 1, 2, or 3;

[0123] s is 0, 1, 2, or 3;

[0124] n is 0, 1, 2, or 3;

[0125] w is 0, 1, 2, or 3; and

[0126] u is 0, 1, 2, or 3.

[0127] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0128] in:

[0129] Ring A is *The end is connected to the benzene ring;

[0130] R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0131] R 1a 、R 1b 、R 1c and R 1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2band cycloalkyl; said alkyl and cycloalkyl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0132] or R 1a and R 1b Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0133] or R 1c and R 1d Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0134] Each R 1e are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0135] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, hydroxy, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0136] Z is CR 0 or N;

[0137] R 0 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, and a hydroxyl group;

[0138] R 3 and R4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; or, R 3 and R 4 together with the carbon atoms to which they are attached to form a heterocyclic group; said heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents;

[0139] Each R 3a and each R 4a are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0140] X is O or NH;

[0141] R 5 Selected from -S(O)R 5a 、-S(O)2R 5a , halogen, nitro, cyano and haloalkyl;

[0142] R 5a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;

[0143] R is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0144] Y is selected from a bond, O, NR 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -heterocyclyl-O-*, -heterocyclyl-NR 6 -*and * end is connected to L; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) sNR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0145] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkylalkyl group, and a cycloalkyl group;

[0146] Ring C is aryl or heteroaryl; said aryl or heteroaryl are each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0147] Ring D is a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is each independently optionally selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and substituted by one or more substituents in a cycloalkyl group;

[0148] R 2a and R 2b are the same or different and are each independently a hydrogen atom or an alkyl group;

[0149] L is the connection unit;

[0150] A is selected from

[0151] R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, amino, cyano, cycloalkyl, heterocyclyl, cycloalkylalkyl and heterocyclylalkyl;

[0152] R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, and a heteroaryl group;

[0153] R 11 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, a nitro group, a cycloalkyl group, and a heterocyclic group;

[0154] Ring E is an aryl or heteroaryl group; the aryl or heteroaryl group is each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino and cycloalkyl;

[0155] Ring F is a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino and cycloalkyl;

[0156] Ring G is aryl or heteroaryl;

[0157] Each R 12 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, and cycloalkyl;

[0158] R 13 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group;

[0159] R 14 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group and a cyano group;

[0160] W 1 C or N;

[0161] W 2 C or N;

[0162] m is 0, 1, 2, 3 or 4;

[0163] x is 0, 1, 2, or 3;

[0164] y is 0, 1, 2, or 3;

[0165] s is 0, 1, 2, or 3;

[0166] n is 0, 1, 2 or 3; and

[0167] u is 0, 1, 2, or 3.

[0168] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein when A is (A-19), (A-20) or (A-21), R 3 and R 4 Not hydrogen at the same time.

[0169] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein when A is (A-18), R 3 and R 4together with the carbon atoms to which they are attached to form a heterocyclic group; said heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents; R 2a 、R 2b and s are as defined in formula (I);

[0170] Or ring A is R 1e and m are as defined in formula (I);

[0171] Or ring A is And R 1c and R 1d Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano and -(CH2) s NR 2a R 2b is substituted by one or more substituents; R 1a 、R 1b 、R 2a 、R 2b and s are as defined in formula (I);

[0172] Or ring A is And R 1a and R 1b Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, and -(CH2) s NR 2a R 2b is substituted by one or more substituents; R 1c 、R 1d 、R 2a 、R 2b and s are as defined in formula (I);

[0173] Or Y is Ring C and ring D are as defined in the general formula (I).

[0174] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is L 1 Connected to Y, L5 Connected to A;

[0175] in:

[0176] L 1 、L 2 、L 3 and L 4 are each independently selected from a bond, -NR A -, -O-, -S-, -C(O)-, -C(S)-, -S(O)2-, -C(O)NR A -、-NR A C(O)-、-NR A C(O)NR B -, -C(O)O-, -OC(O)-, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylene-O-, -O-alkylene-, -alkylene-O-alkylene-, -alkylene-O-alkylene-O-alkylene-, -alkylene-cycloalkyl-alkylene-, -alkylene-heterocyclyl-alkylene-, -alkylene-aryl-alkylene-, -alkylene-heteroaryl-alkylene-, and * The end is connected to the right group; the alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, nitro, amino, -(CH2) s NR 2a R 2b , cycloalkyl, heterocyclyl and cycloalkylalkyl;

[0177] p is an integer from 0 to 5;

[0178] q is an integer from 0 to 5;

[0179] f is an integer from 0 to 10;

[0180] L 5 Selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -O-, -S-, -S(O)2-, -NR A -, -C(O)-, -C(S)-, -O-alkylene-, -alkylene-O-, -C(O)NR A -、-NR A C(O)-, -C(O)O-, -OC(O)-, -C(O)-alkylene-, -alkylene-C(O)-, -NR A -alkylene-, -alkylene-NR A -、-NR A (CH2) 0-3O(CH2) 0-3 O-, -O(CH2) 0-3 O(CH2) 0-3 NR A -、-NR A C(O)(CH2) 0-3 NR B -、-NR B (CH2) 0-3 C(O)NR A -and The alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from oxo, halogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyalkyl, -(CH2) s NR 2a R 2b , cycloalkyl, heterocyclyl and cycloalkylalkyl;

[0181] R A and R B are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxy, cycloalkyl, alkoxyalkyl, cycloalkylalkyl and -(CH2) s NR 2a R 2b ; R 2a 、R 2b and s are as defined in the general formula (I).

[0182] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is L 1 Connected to Y, L 5 Connected to A;

[0183] in:

[0184] L 1 、L 2 、L 3 and L 4 are each independently selected from a bond, -NR A -, -O-, -S-, -C(O)-, -C(S)-, -S(O)2-, -C(O)NR A -、-NR A C(O)-、-NR A C(O)NR B-, -C(O)O-, -OC(O)-, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylene-O-, -O-alkylene-, -alkylene-O-alkylene-, -alkylene-O-alkylene-O-alkylene-, -alkylene-cycloalkyl-alkylene-, -alkylene-heterocyclyl-alkylene-, -alkylene-aryl-alkylene-, -alkylene-heteroaryl-alkylene-, and * The end is connected to the right group; the alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, nitro, amino and cycloalkyl;

[0185] p is an integer from 0 to 5;

[0186] q is an integer from 0 to 5;

[0187] f is an integer from 0 to 10;

[0188] L 5 Selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -O-, -S-, -S(O)2-, -NR A -, -C(O)-, -C(S)-, -O-alkylene-, -alkylene-O-, -C(O)NR A -、-NR A C(O)-, -C(O)O-, -OC(O)-, -C(O)-alkylene-, -alkylene-C(O)-, -NR A -alkylene-, -alkylene-NR A -、-NR A (CH2) 0-3 O(CH2) 0-3 O-, -O(CH2) 0-3 O(CH2) 0-3 NR A -、-NR A C(O)(CH2) 0-3 NR B -、-NR B (CH2) 0-3 C(O)NR A -and The alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, haloalkyl and hydroxy;

[0189] R A and R Bare the same or different and are each independently a hydrogen atom or an alkyl group.

[0190] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R A A hydrogen atom or C 1-6 Alkyl; in some embodiments, R A A hydrogen atom.

[0191] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from C(O), -C(O)NR A -and-NR A C(O)-;R A As defined in formula (I); in some embodiments, L 1 is selected from C(O), -C(O)NH-, and -NHC(O)-; in some embodiments, L 1 is C(O); in some embodiments, L 1 is -C(O)NH-; in some embodiments, L 1 It is -NHC(O)-.

[0192] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 2 C 1-10 Alkylene; preferably C 3-6 Alkylene; more preferably C 4-6 Alkylene.

[0193] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6-; in some embodiments, L 2 is selected from -(CH2)4-, -(CH2)5-, and -(CH2)6-; in some embodiments, L 2 is -(CH2)3-; in some embodiments, L 2 is -(CH2)4-; in some embodiments, L 2 is -(CH2)5-; in some embodiments, L 2 It is -(CH2)6-.

[0194] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is L 3 、L 4 and L 5As defined in formula (X); t is an integer from 0 to 10 (i.e., t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); preferably, L is L 5 is a bond or O; t is an integer from 0 to 10; more preferably, L is selected from * is connected to A.

[0195] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is selected from In some embodiments, L is In some embodiments, L is In some embodiments, L is * is connected to A.

[0196] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is Ring C is a 5- or 6-membered heteroaryl; and Ring D is a 5- or 6-membered heterocyclyl; preferably, Y is * is connected to L.

[0197] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is a 4- to 11-membered heterocyclic group, wherein the 4- to 11-membered heterocyclic group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, Y is a 6- to 8-membered heterocyclic group, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, Y is a 6- to 8-membered heterocyclic group, which is optionally substituted with one or more C 1-6 In some embodiments, Y is a 6-membered heterocyclic group, which is optionally substituted with one or more C 1-6 In some embodiments, Y is piperazinyl or piperidinyl, which is optionally substituted with one or more C 1-6 In some embodiments, Y is piperazinyl, which is optionally substituted with one or more C 1-6 In some embodiments, Y is selected from In some embodiments, Y is selected from * is connected to L.

[0198] The compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, in some embodiments, Y is a 4- to 11-membered heterocyclic group; in some embodiments, Y is a 4- to 7-membered heterocyclic group; in some embodiments, Y is a 6-membered heterocyclic group; in some embodiments, Y is selected from In some embodiments, Y is selected from In some embodiments, Y is * is connected to L.

[0199] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is a 4- to 11-membered heterocyclic group or The 4 to 11 membered heterocyclic group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 substituted by one or more substituents in hydroxyalkyl; Ring C is a 5- or 6-membered heteroaryl; Ring D is a 5- or 6-membered heterocyclyl; In some embodiments, Y is a 6- to 8-membered heterocyclyl or The 6 to 8 membered heterocyclic group is optionally substituted by one or more C 1-6 substituted with hydroxyalkyl; Ring C is a 5- or 6-membered heteroaryl; Ring D is a 5- or 6-membered heterocyclyl; In some embodiments, Y is selected from In some embodiments, Y is selected from In some embodiments, Y is selected from In some embodiments, Y is selected from

[0200] In some embodiments, Y is selected from * is connected to L.

[0201] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is a 4- to 11-membered heterocyclic group or Ring C is a 5- or 6-membered heteroaryl; Ring D is a 5- or 6-membered heterocyclic group; Preferably, Y is selected from More preferably, Y is selected from Even more preferably, Y is selected from More preferably, Y is * is connected to L.

[0202] In some embodiments of the present 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:

[0203] in:

[0204] Ring B is a 4- to 11-membered nitrogen-containing heterocyclic group or * end is connected to C(O); the 4 to 11-membered nitrogen-containing heterocyclic group is optionally replaced by one or more R b replace;

[0205] Ring C is a 5- or 6-membered heteroaryl group; the 5- or 6-membered heteroaryl group is optionally substituted by one or more R b replace;

[0206] Ring D' is a 5- or 6-membered nitrogen-containing heterocyclic group; the 5- or 6-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R b replace;

[0207] Each R b are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl;

[0208] t is an integer from 0 to 10;

[0209] Ring A, R, R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 2a 、R 2b , Z, X, s, n, x, y and A are as defined in the general formula (I); L 3 、L 4 and L5 As defined in formula (X).

[0210] In some embodiments of the present disclosure, in the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, X is NH.

[0211] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom.

[0212] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein X is NH; and / or R is a hydrogen atom.

[0213] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof:

[0214] in:

[0215] Ring A, Ring B, Ring E, Ring F, Ring G, R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、R 12 、W 1 、W 2 , Z, L 3 、L 4 、L 5 , A, u, x, y, t and n are as defined in the general formula (II).

[0216] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof is not or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein L 3 is the key.

[0218] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein L 4 is the key.

[0219] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein L 5 is selected from a bond, O and OCH2, CH2 is connected to structure A; preferably, L 5 is a bond or O; in some embodiments, L 5 is a bond; in some embodiments, L 5 is O; in some embodiments, L 5 is O or OCH2, CH2 is connected to structure A; in some embodiments, L 5 It is OCH2, and CH2 is connected to structure A.

[0220] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein L 3 and L 4 is a key; and / or L 5 is selected from a bond, -O- and OCH2, CH2 is attached to structure A; in some embodiments, L 3 and L 4 is a key; and / or L 5 is a key or O.

[0221] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, wherein L 5 is O or OCH2, CH2 is connected to structure A; preferably, L 5 is O; in some embodiments, L 5 It is OCH2, and CH2 is connected to structure A.

[0222] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein L 5 is the key.

[0223] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; in some embodiments, R9 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 9 is a hydrogen atom; in some embodiments, R 9 C 1-6 Alkyl; in some embodiments, R 9 is methyl; in some embodiments, R 9 C 1-6 Hydroxyalkyl; in some embodiments, R 9 is hydroxymethyl; in some embodiments, R 9 is selected from hydrogen atoms, methyl groups and hydroxymethyl groups; preferably, R 9 is a hydrogen atom or a methyl group.

[0224] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 10 C 1-6 Alkyl; preferably, R 10 is tert-butyl or isopropyl; in some embodiments, R 10 is tert-butyl; in some embodiments, R 10 It is isopropyl.

[0225] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, wherein R 10 It is isopropyl.

[0226] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein R 10 For tert-butyl.

[0227] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring E is a 5- or 6-membered heteroaryl group; preferably a 5-membered heteroaryl group; more preferably selected from Most preferably, ring E is * is connected to L.

[0228] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring E is selected from * is connected to L.

[0229] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R 12 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 12 C 1-6 Alkyl; in some embodiments, R 12 It is a methyl group.

[0230] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1; preferably 0; in some embodiments, u is 1.

[0231] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring F is a 6- or 7-membered heterocyclic group.

[0232] In the compounds represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof described in the present disclosure, in some embodiments, ring F is a 6- or 7-membered heterocyclic group containing one oxygen atom; in some embodiments, ring F is a 6-membered heterocyclic group; in some embodiments, ring F is a 6-membered heterocyclic group containing one oxygen atom; in some embodiments, ring F is a 7-membered heterocyclic group; in some embodiments, ring F is a 7-membered heterocyclic group containing one oxygen atom.

[0233] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring G is a 5- or 6-membered heteroaryl group; in some embodiments, ring G is a 5-membered heteroaryl group; in some embodiments, G is a 6-membered heteroaryl group; in some embodiments, ring G is selected from pyrimidinyl, thiazolyl, oxazolyl and isoxazolyl; preferably, ring G is thiazolyl.

[0234] In some embodiments, the compound represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof described in the present disclosure is for Q is selected from a bond, O, NR f , S, C(O) and CR f1 R f2 ; R fR is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group; f1 and R f2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl; or R f1 and R f2 Together form =O; or R f1 and R f2 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; R 12a is a hydrogen atom or R 12 ; k is 0, 1, 2 or 3; v is 0, 1, 2 or 3; R 12 As defined in formula (I); in some embodiments, Selected from

[0235] In some embodiments, the compounds represented by formula (I), (II), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof disclosed herein, Q is O.

[0236] In some embodiments, the compounds of the present disclosure represented by formula (I), (II), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof, wherein k is 0.

[0237] In the compounds represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof disclosed herein, in some embodiments, v is 1 or 2; in some embodiments, v is 1; in some embodiments, v is 2.

[0238] The compounds of the present disclosure represented by general formula (I), (II), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof, in some embodiments, R 12a A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 12a is a hydrogen atom; in some embodiments, R 12a C 1-6 Alkyl; in some embodiments, R 12a It is a methyl group.

[0239] In some embodiments, the compound represented by the general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof disclosed herein has R 15 is hydroxyl; in some embodiments, R15 is hydroxy or -OC(O)CH3; in some embodiments, R 15 is -OC(O)CH3; in some embodiments, R 15 It is -SH.

[0240] In some embodiments, the compound represented by formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof disclosed herein, w is 1.

[0241] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Selected from In some embodiments, for More preferably

[0242] In some embodiments, the compound represented by the general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof disclosed herein is selected from Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 9 、R 10 、R 12 and u are as defined in formula (I); in some embodiments, A is selected from

[0243] Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 9 、R 10 、R 12 and u are as defined in formula (I); in some embodiments, A is Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 9 、R 10 、R 12 and u are as defined in formula (I); in some embodiments, A is selected from In some embodiments, A is selected from

[0244] In some embodiments, A is selected from

[0245] In some embodiments, A is selected from In some embodiments, A is selected from In some embodiments, A is In some embodiments, A is In some embodiments, A is

[0246] In some embodiments, the compound of the present disclosure represented by general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof, A is Q is selected from a bond, O, NR f , S, C(O) and CR f1 R f2 ; R f R is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a cycloalkyl group, and a cycloalkylalkyl group; f1 and R f2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl; or R f1 and R f2 Together form =O; or R f1 and R f2 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; R 12a is a hydrogen atom or R 12 ; k is 0, 1, 2 or 3; v is 0, 1, 2 or 3; ring E, R 9 、R 10 、R 12 、R 15 and w are as defined in formula (I); in some embodiments, A is selected from

[0247] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof, wherein A is selected from:

[0248] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof, wherein A is selected from Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 9 、R 10 、R 12 、R 15 , w and u are as defined in formula (I); in some embodiments, A is Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 9 、R 10 、R 12 、R 15 , w and u are as defined in formula (I); in some embodiments, A is selected from:

[0249] In some embodiments, A is selected from:

[0250] In some embodiments, A is selected from In some embodiments, A is selected from In some embodiments, A is selected from

[0251] In some embodiments, A is selected from In some embodiments, A is selected from In some embodiments, A is

[0252] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (II-4) or a pharmaceutically acceptable salt thereof, wherein A is selected from

[0253] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from halogen, preferably F or Cl, more preferably Cl.

[0254] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein a is 1 or 2; in some embodiments, a is 1.

[0255] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein b is 1 or 2; in some embodiments, b is 1.

[0256] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein a is 1 or 2; b is 1; in some embodiments, a is 1; b is 1.

[0257] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each independently is C 1-6 an alkyl group or a hydrogen atom; in some embodiments, R 1a and R 1b C 1-6 Alkyl; in some embodiments, R 1a and R 1b is methyl; preferably, R 1a and R 1b A hydrogen atom.

[0258] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d are each independently a hydrogen atom or a C 1-6 Alkyl; the C 1-6Alkyl is optionally selected from halogen, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in the haloalkoxy group; or R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclic group are each independently optionally selected from halogen, C 1-6 Alkyl and C 1-6 In some embodiments, R 1c and R 1d Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; or R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclic group are each independently optionally substituted with one or more C 1-6 Alkyl substituted.

[0259] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, R 1c and R 1d is a hydrogen atom; in some embodiments, R 1c and R 1d C 1-6 Alkyl; in some embodiments, R 1c C 1-6 Alkyl, R 1d Selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, R 1c is methyl; R 1d is selected from methyl, hydroxymethyl and methoxymethyl; preferably, R 1c and R 1d It is a methyl group.

[0260] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 1c and R 1d Together with the attached carbon atom it forms a cyclopropyl group.

[0261] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 4-membered heterocyclic group, wherein the 4-membered heterocyclic group is optionally substituted with one or more methyl groups; preferably, for

[0262] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 1c and R 1d Selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; or R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclic group are each independently optionally substituted with one or more C 1-6 alkyl; in some embodiments, R 1a and R 1b is a hydrogen atom; R 1c and R 1d C 1-6 Alkyl; the C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in the haloalkoxy group; preferably, R 1a and R 1b is a hydrogen atom; R 1c and R 1d are each independently methyl or methoxymethyl; more preferably, R 1a and R 1b is a hydrogen atom; R1c and R 1d It is a methyl group.

[0263] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 1c and R 1d C 1-6 alkyl.

[0264] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 1c and R 1d Together with the attached carbon atom, it forms a 4-membered heterocyclic group, which is optionally substituted with one or more methyl groups.

[0265] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d is a hydrogen atom; R 1a and R 1b C 1-6 Alkyl; preferably, R 1c and R 1d is a hydrogen atom; R 1a and R 1b It is a methyl group.

[0266] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 1c and R 1d are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; or R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclic group are each independently optionally substituted with one or more C 1-6In some embodiments, R 1a and R 1b is a hydrogen atom; R 1c and R 1d Selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxyalkyl; or R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclic group are each independently optionally substituted with one or more C 1-6 In some embodiments, R 1a and R 1b is a hydrogen atom; R 1c and R 1d Selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxyalkyl; in some embodiments, R 1a and R 1b is a hydrogen atom; R 1c and R 1d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclic group are each independently optionally substituted with one or more C 1-6 In some embodiments, R 1a and R 1b is a hydrogen atom; R 1c C 1-6 Alkyl, R 1d Selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, R 1a and R 1b is a hydrogen atom; R 1c is methyl; R 1d is selected from methyl, hydroxymethyl and methoxymethyl; in some embodiments, R 1c and R 1d is a hydrogen atom; R 1a and R 1b C 1-6 Alkyl; in some embodiments, R 1a and R 1b is a hydrogen atom; R 1c and R 1d A hydrogen atom.

[0267] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R 1e The same or different, and each independently halogen or C 1-6 alkyl.

[0268] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0269] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from Preferably The * end is connected to the benzene ring.

[0270] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom or a hydroxyl group, preferably a hydrogen atom; in some embodiments, R 2 It is a hydroxyl group.

[0271] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 0 It is a hydrogen atom or a halogen, and is preferably a hydrogen atom.

[0272] The compounds of the present disclosure represented by general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof, in some embodiments, R 0 C 1-6 Hydroxyalkyl; in some embodiments, R 0 is hydroxymethyl; in some embodiments, R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; in some embodiments, R 0In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Z is N or CH, preferably N.

[0273] The compounds of the present disclosure represented by general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof, in some embodiments, Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; in some embodiments, Z is CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; in some embodiments, Z is CH; in some embodiments, Z is selected from N, CH, and C(CH2OH); in some embodiments, Z is C(CH2OH).

[0274] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom or a hydroxyl group, preferably a hydrogen atom; and / or Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 In some embodiments, R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; in some embodiments, R 3 C 1-6 Hydroxyalkyl, R 4 is a hydrogen atom; or R 3 and R 4Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; in some embodiments, R 3 and R 4 are all hydrogen atoms; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; in some embodiments, R 3 and R 4 are all hydrogen atoms; in some embodiments, R 3 C 1-6 Hydroxyalkyl, R 4 is a hydrogen atom; in some embodiments, R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 In some embodiments, R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group.

[0275] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; in some embodiments, R 3 and R 4 are each independently selected from a hydrogen atom, a hydroxymethyl group, and -CH2CH2OH; in some embodiments, R 3 A hydrogen atom or C 1-6 Hydroxyalkyl; R 4 is a hydrogen atom; in some embodiments, R 3 is selected from the group consisting of a hydrogen atom, a hydroxymethyl group and -CH2CH2OH; R 4 is a hydrogen atom; in some embodiments, R 3 and R 4 All are hydrogen atoms.

[0276] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 In some embodiments, R 3 and R 4Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; preferably, R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered oxygen-containing heterocyclic group; in some embodiments, R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; in some embodiments, R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6-membered oxygen-containing heterocyclic group.

[0277] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein Selected from R 3a 、R 4a , x, y and Z are as defined in Formula (I); in some embodiments, Selected from R 3a 、R 4a , x, y and Z are as defined in formula (I); preferably, Selected from More preferably, for The * end is connected to C(O).

[0278] In some embodiments, the compounds of the present disclosure represented by general formula (I), (II), (II-1), (II-2) or (II-3) or pharmaceutically acceptable salts thereof, Selected from In some embodiments, Selected from In some embodiments, for In some embodiments, for In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, for In some embodiments, for The * end is connected to C(O).

[0279] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof, wherein Selected from In some embodiments, Selected from In some embodiments, for In some embodiments, for In some embodiments, for The * end is connected to C(O).

[0280] In some embodiments, the compound represented by the general formula (II-4) or a pharmaceutically acceptable salt thereof disclosed herein is Selected from In some embodiments, for In some embodiments, for In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, for In some embodiments, for The * end is connected to C(O).

[0281] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R 3a The same or different, and each independently selected from C 1-6 Alkyl, halogen, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl.

[0282] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 3a C 1-6 Hydroxyalkyl; in some embodiments, R 3a is hydroxymethyl or -CH2CH2OH; in some embodiments, R 3a is -CH2CH2OH; preferably, R 3a It is hydroxymethyl.

[0283] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R 4a The same or different, and each independently selected from C 1-6 Alkyl, halogen, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl.

[0284] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1, preferably 0.

[0285] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein y is 0 or 1, preferably 0.

[0286] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein y is 1.

[0287] The compounds of the present disclosure represented by general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof, in some embodiments, R 3aC 1-6 hydroxyalkyl; and y is 0 or 1; in some embodiments, R 3a C 1-6 hydroxyalkyl; and y is 1; in some embodiments, R 3a is hydroxymethyl; and y is 1; in some embodiments, R 3a is -CH2CH2OH; and y is 1.

[0288] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 5a C 1-6 Alkyl or C 1-6 The haloalkyl group is preferably a trifluoromethyl group.

[0289] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R 5 is -S(O)2R 5a ; R 5a As defined in formula (I); in some embodiments, R 5 C 1-6 Haloalkylsulfonyl; more preferably -S(O)2CF3.

[0290] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0291] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein t is an integer from 1 to 10 (i.e., t is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); in some embodiments, t is 3, 4, 5 or 6; preferably, t is 4, 5 or 6; in some embodiments, t is 4 or 5; in some embodiments, t is 5; in some embodiments, t is 4; in some embodiments, t is 3; in some embodiments, t is 6.

[0292] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R b are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0293] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein each R b are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 haloalkyl; in some embodiments, R b C 1-6 Hydroxyalkyl; in some embodiments, R b It is hydroxymethyl.

[0294] The compounds of the present disclosure represented by general formula (II), (II-1), (II-2), (II-3) or (II-4) or pharmaceutically acceptable salts thereof, in some embodiments, ring B is Ring C and Ring D' are as defined in Formula (II); in some embodiments, Ring B is The * end is connected to C(O).

[0295] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 11-membered nitrogen-containing heterocyclic group, and the 4- to 11-membered nitrogen-containing heterocyclic group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, ring B is a 6- to 8-membered nitrogen-containing heterocyclic group, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, ring B is a 6- to 8-membered nitrogen-containing heterocyclic group, which is optionally substituted with one or more C 1-6 In some embodiments, ring B is a 6-membered nitrogen-containing heterocyclic group, which is optionally substituted with one or more C 1-6 In some embodiments, ring B is piperazinyl or piperidinyl, which is optionally substituted with one or more C 1-6 In some embodiments, ring B is piperazinyl, which is optionally substituted with one or more C 1-6 In some embodiments, ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from * is connected to L.

[0296] In some embodiments, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) of the present disclosure or a pharmaceutically acceptable salt thereof, Ring B is a 4- to 11-membered nitrogen-containing heterocyclic group; Ring B is a 4- to 7-membered nitrogen-containing heterocyclic group; Ring B is a 6-membered nitrogen-containing heterocyclic group; Ring B is selected from The * end is connected to C(O).

[0297] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

[0298] In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from Ring B is selected from Preferably, ring B is selected from More preferably, ring B is The * end is connected to C(O).

[0299] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 is substituted by one or more substituents in the hydroxyalkyl group; x is 0; y is 0; R 5 is -S(O)2CF3; X is NH; R is a hydrogen atom; n is 1; Y is selected from * end is connected to L; L is selected from * end is connected to A; A is selected from

[0300] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; x is 0; y is 0; R 5 -S(O)2CF3; X is NH; R is a hydrogen atom; n is 1; Y is * end is connected to L; L is * end is connected to A; A is selected from

[0301] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 is substituted by one or more substituents in the hydroxyalkyl group; x is 0; y is 0; R 5 -S(O)2CF3; X is NH; R is a hydrogen atom; n is 1; Ring B is selected from

[0302] *The bond is connected to C(O); t is 3, 4, 5 or 6; L 3 and L 4 is the key; L 5 Selected from a bond, O and OCH2, CH2 is connected to A; A is selected from

[0303] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; x is 0; y is 0; R 5 -S(O)2CF3; X is NH; R is a hydrogen atom; n is 1; Ring B is *The bond is connected to C(O); t is 4 or 5; L 3 and L 4 is the key; L 5 is a key or O;

[0304] A is selected from

[0305] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 is substituted by one or more substituents in the hydroxyalkyl group; x is 0; y is 0; R 5 is -S(O)2CF3; n is 1; Ring B is selected from

[0306] *The bond is connected to C(O); t is 3, 4, 5 or 6; L 3 and L 4 is the key; L 5 is O or OCH2, CH2 is connected to ring E; ring E is a 5-membered heteroaryl group; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; Selected from

[0307] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; x is 0; y is 0; R 5 -S(O)2CF3; n is 1; Ring B is *The bond is connected to C(O); t is 4; L 3 and L 4 is the key; L5 is O; Ring E is a 5-membered heteroaryl group; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; for

[0308] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 is substituted by one or more substituents in the hydroxyalkyl group; x is 0; y is 0; R 5 is -S(O)2CF3; n is 1; Ring B is selected from

[0309] *The bond is connected to C(O); t is 3, 4, 5 or 6; L 3 and L 4 is the key; L 5 is a key; R 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 10 C 1-6 alkyl; Selected from

[0310]

[0311] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; x is 0; y is 0; R 5 -S(O)2CF3; n is 1; Ring B is *Bond connected to C(O); t is 5; L 3 and L 4 is the key; L 5 is a key; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; for

[0312] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C 1-6 Haloalkylsulfonyl; X is NH; R is a hydrogen atom; n is 1; x is 0; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; Y is selected from * end is connected to L; L is selected * end is connected to A; A is selected from

[0313] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group;5 C 1-6 Haloalkylsulfonyl; X is NH; R is a hydrogen atom; n is 1; x is 0; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; Ring B is selected from *The bond is connected to C(O); t is 4, 5 or 6; L 3 and L 4 is the key; L 5 is a bond or -O-; A is selected from

[0314] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C 1-6 Haloalkylsulfonyl; n is 1; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; t is 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is O; Ring B is selected from *end is connected to C(O); Ring E is a 5-membered heteroaryl group; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl.

[0315] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CH; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C 1-6haloalkylsulfonyl; n is 1; x is 0; y is 0; t is 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is O or OCH2, CH2 is connected to structure A; Ring B is selected from *end is connected to C(O); Ring E is selected from 5-membered heteroaryl; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl.

[0316] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; t is 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is O; Ring B is selected from *end is connected to C(O); Ring E is selected from 5-membered heteroaryl; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; for

[0317] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CH; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C1-6 haloalkylsulfonyl; n is 1; x is 0; y is 0; t is 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is O or OCH2, CH2 is connected to structure A; Ring B is selected from *end is connected to C(O); Ring E is selected from 5-membered heteroaryl; R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; Selected from

[0318] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are all hydrogen atoms, or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; t is 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is a bond; Ring B is selected from * end connected to C(O); R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; for

[0319] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CH; R 3 and R 4 are all hydrogen atoms, or R 3 and R4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group; 5 C 1-6 haloalkylsulfonyl; n is 1; x is 0; y is 0; t is an integer from 1 to 10; L 3 is the key; L 4 is the key; L 5 is a bond; Ring B is selected from * end connected to C(O); R 9 A hydrogen atom or C 1-6 Alkyl; R 10 C 1-6 alkyl; Selected from

[0320] In some embodiments of the present disclosure, the compound represented by the general formula (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; t is 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is a bond or O; Ring B is selected from * end is connected to C(O); A is selected from

[0321] In some embodiments of the present disclosure, the compound represented by the general formula (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0 or 1; R 3a C 1-6 Hydroxyalkyl; t is 4, 5 or 6; L 3is the key; L 4 is the key; L 5 is a bond or O; Ring B is selected from * end is connected to C(O); A is selected from

[0322] In some embodiments of the present disclosure, the compound represented by the general formula (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CH; R 5 C 1-6 haloalkylsulfonyl; n is 1; x is 0; y is 0; t is an integer from 0 to 10; L 3 is the key; L 4 is the key; L 5 Selected from a bond, O and OCH2, CH2 is connected to structure A; Ring B is selected from * end is connected to C(O); A is selected from

[0323] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 The hydroxyalkyl group is substituted by one or more substituents; R 5 C 1-6 Haloalkylsulfonyl; X is NH; R is a hydrogen atom; n is 1; x is 0; y is 0; Y is selected from * end is connected to L; L is selected * end is connected to A; A is selected from

[0324] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 C 1-6 Hydroxyalkyl, R 4 is a hydrogen atom; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; 5 C 1-6 Haloalkylsulfonyl; X is NH; R is a hydrogen atom; n is 1; x is 0; y is 0; Y is * end is connected to L; L is * end is connected to A; A is selected from

[0325] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 The hydroxyalkyl group is substituted by one or more substituents; R 5 C 1-6 Haloalkylsulfonyl; X is NH; R is a hydrogen atom; n is 1; x is 0; y is 0; Ring B is selected from *end is connected to C(O); t is 3, 4, 5 or 6; L 3 is the key; L 4 is the key; L 5Selected from a bond, O and OCH2, CH2 is connected to A; A is selected from

[0326] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 C 1-6 Hydroxyalkyl, R 4 is a hydrogen atom; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; R 5 C 1-6 Haloalkylsulfonyl; X is NH; R is a hydrogen atom; n is 1; x is 0; y is 0; Ring B is *end is connected to C(O); t is 3, 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is a bond or O; A is selected from

[0327] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 The hydroxyalkyl group is substituted by one or more substituents; R 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0; Ring B is selected from t is 3, 4, 5, or 6; L 3 is the key; L 4 is the key; L 5is O or OCH2, CH2 is connected to ring E; ring E is selected from *End and L 5 Connected; R 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 10 C 1-6 alkyl; Selected from

[0328] In some embodiments of the present disclosure, the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 C 1-6 Hydroxyalkyl, R 4 is a hydrogen atom; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; R 5 C 1-6 Halogenated alkylsulfonyl; n is 1; x is 0; y is 0; Ring B is t is 3, 4, 5, or 6; L 3 is the key; L 4 is the key; L 5 is O; Ring E is *End and L 5 Connected; R 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 10 C 1-6 alkyl; for

[0329] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 The hydroxyalkyl group is substituted by one or more substituents; R 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0; Ring B is selected from t is 3, 4, 5, or 6; L 3 is the key; L 4 is the key; L 5 is a key; R 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 10 C 1-6 alkyl; Selected from

[0330] In some embodiments of the present disclosure, the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 3 C 1-6 Hydroxyalkyl, R 4 is a hydrogen atom; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; R 5 C 1-6 Halogenated alkylsulfonyl; n is 1; x is 0; y is 0; Ring B is t is 3, 4, 5, or 6; L 3 is the key; L 4 is the key; L 5 is a key; R 9 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Hydroxyalkyl; R 10 C 1-6 alkyl; for

[0331] In some embodiments of the present disclosure, the compound represented by the general formula (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from * end is connected to the benzene ring; R 1 is halogen; R2 is a hydrogen atom or a hydroxyl group; Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl; R 5 C 1-6 Haloalkylsulfonyl; n is 1; x is 0; y is 0; Ring B is selected from t is 3, 4, 5, or 6; L 3 is the key; L 4 is the key; L 5 Selected from a bond, -O- and OCH2, CH2 is connected to structure A; A is selected from

[0332] In some embodiments of the present disclosure, the compound represented by the general formula (II-4) or a pharmaceutically acceptable salt thereof, wherein ring A is * end is connected to the benzene ring; R 1 is halogen; R 2 is a hydrogen atom; Z is N; R 5 C 1-6 Halogenated alkylsulfonyl; n is 1; x is 0; y is 0; Ring B is t is 3, 4, 5 or 6; L 3 is the key; L 4 is the key; L 5 is a bond or -O-; A is selected from

[0333] Table A Typical compounds of the present disclosure include, but are not limited to:

[0334] The present disclosure provides a compound represented by general formula (II-1B) or a salt thereof:

[0335] in:

[0336] Ring E, L 3 、L 4 、L 5 、R 9 、R 10 and t are as defined in the general formula (II-1).

[0337] The present disclosure provides a compound represented by general formula (II-2b) or a salt thereof:

[0338] in:

[0339] Ring E, Ring F, Ring G, L 3 、L 4 、L 5 、W 1 、W 2 、R 9 、R 10 、R 12 、R 15 , w, u and t are as defined in the general formula (II).

[0340] The present disclosure provides a compound represented by general formula (II-2B) or a salt thereof:

[0341] in:

[0342] Ring E, Ring F, Ring G, L 3 、L 4 、L 5 、W 1 、W 2 、R 9 、R 10 、R 12 , u and t are as defined in the general formula (II-2).

[0343] The present disclosure provides a compound represented by general formula (II-3b) or a salt thereof:

[0344] in:

[0345] Ring F, Ring G, Ring L 3 、L 4 、L 5 、W 1 、W 2 、R 9 、R 10 、R 12 、R 15 , w, u and t are as defined in the general formula (II).

[0346] The present disclosure provides a compound represented by general formula (II-3B) or a salt thereof:

[0347] in:

[0348] Ring F, Ring G, Ring W 1 、W 2 、R 9 、R 10 、R 12 、L 3 、L 4 、L 5 , u and t are as defined in the general formula (II-3).

[0349] In some embodiments of the present disclosure, the compound represented by the general formula (II-1B), (II-2B) or (II-2b) or a salt thereof, wherein L 5 It is O.

[0350] In some embodiments of the present disclosure, the compound represented by the general formula (II-3B), (II-3b) or a salt thereof, wherein L 5 is the key.

[0351] In some embodiments of the present disclosure, the compound represented by the general formula (II-1B), (II-2B), (II-2b), (II-3B) or (II-3b) or a salt thereof, wherein L 3 and L 4 is the key.

[0352] The present disclosure provides a compound represented by general formula (II-4A) or a salt thereof:

[0353] in:

[0354] Ring A, Ring B, R 1、R 2 、R 3a 、R 4a 、R 5 , Z, n, x and y are as defined in the general formula (II-4).

[0355] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0356] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0357] The compound represented by general formula (IIA) or its salt and the compound represented by general formula (IIB) or its salt undergo condensation reaction to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0358] in:

[0359] Ring A, Ring B, R, R 1 、R 2 、R 3 、R 3a 、R 4 、R4a 、R 5 , X, Z, x, y, n, t, L 3 、L 4 、L 5 and A are as defined in general formula (II).

[0360] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising:

[0361] The compound represented by the general formula (II-1A) or its salt and the compound represented by the general formula (II-1B) or its salt undergo a condensation reaction to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt;

[0362] in:

[0363] Ring A, Ring B, Ring E, R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、L 3 、L 4 、L 5 , Z, n, x, y and t are as defined in the general formula (II-1).

[0364] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, comprising:

[0365] The compound represented by the general formula (II-1A) or its salt and the compound represented by the general formula (II-2B) or its salt undergo a condensation reaction to obtain the compound represented by the general formula (II-2) or its pharmaceutically acceptable salt;

[0366] in:

[0367] Ring A, Ring B, Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、R 12 、L3 、L 4 、L 5 , Z, n, u, x, y and t are as defined in the general formula (II-2).

[0368] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-3) or a pharmaceutically acceptable salt thereof, comprising:

[0369] The compound represented by the general formula (II-1A) or a salt thereof and the compound represented by the general formula (II-3B) or a salt thereof undergo a condensation reaction to obtain the compound represented by the general formula (II-3) or a pharmaceutically acceptable salt thereof;

[0370] in:

[0371] Ring A, Ring B, Ring F, Ring G, Ring W 1 、W 2 、R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、R 12 , Z, L 3 、L 4 、L 5 , n, u, x, y and t are as defined in the general formula (II-3).

[0372] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-4) or a pharmaceutically acceptable salt thereof, comprising:

[0373] The compound represented by general formula (II-4A) or its salt and the compound represented by general formula (IIB) or its salt undergo condensation reaction to obtain the compound represented by general formula (II-4) or its pharmaceutically acceptable salt;

[0374] in:

[0375] Ring A, Ring B, R 1 、R 2 、R 3a 、R 4a 、R 5 , Z, n, x, y, t, L 3 、L 4 、L 5 and A are as defined in general formula (II-4).

[0376] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the above-mentioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0377] The present disclosure further relates to the use of the compounds represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for regulating BCL-2 protein ubiquitination in a subject.

[0378] The present disclosure further relates to the use of the compounds represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for degrading BCL-2 proteins.

[0379] The present disclosure further relates to the use of the compounds represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by or dependent on BCL-2.

[0380] The present disclosure further relates to the use of the compounds of the above-mentioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing myelofibrosis or cancer; the cancer is a solid tumor or a hematological malignancy, preferably selected from leukemia, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, small lymphocytic lymphoma, etc.), multiple myeloma, brain cancer, synovial sarcoma, neuroblastoma, glioblastoma, skin cancer, squamous cell carcinoma, basal cell carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, gallbladder cancer, bile duct cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, colorectal cancer, pancreatic cancer, Preferably, the leukemia is selected from the group consisting of: pancreatic cancer, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, bladder cancer, melanoma, seminoma, rhabdomyosarcoma, osteoma, sarcoma, osteochondroma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, renal cancer, thyroid cancer, polycythemia vera, ureteral tumor, choriocarcinoma and pediatric tumors (Ewing family sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.); the leukemia is preferably selected from the group consisting of chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloid leukemia; the lymphoma is preferably selected from the group consisting of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma.

[0381] The present disclosure also relates to a method for regulating BCL-2 protein ubiquitination in a subject, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0382] The present disclosure also relates to a method for degrading BCL-2 protein in a subject, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0383] The present disclosure also relates to a method for treating and / or preventing a disease or condition mediated by or dependent on BCL-2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0384] The present disclosure also relates to a method for treating and / or preventing myelofibrosis or cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of the above-mentioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the cancer is a solid tumor or a hematological malignancy, preferably selected from leukemia, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma, etc.), multiple myeloma, brain cancer, synovial sarcoma, neuroblastoma, glioblastoma, skin cancer, squamous cell carcinoma, basal cell carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, gallbladder cancer, bile duct cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, colorectal cancer Preferably, the leukemia is selected from the group consisting of: pancreatic cancer, liver cancer, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, bladder cancer, melanoma, seminoma, rhabdomyosarcoma, osteoma, osteochondroma, sarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, renal cancer, thyroid cancer, polycythemia vera, ureteral tumor, choriocarcinoma and pediatric tumors (Ewing family sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.); the leukemia is preferably selected from the group consisting of chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloid leukemia; the lymphoma is preferably selected from the group consisting of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma.

[0385] The present disclosure further relates to a compound of the above-mentioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0386] The present disclosure further relates to a compound represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for regulating BCL-2 protein ubiquitination in a subject.

[0387] The present disclosure further relates to a compound represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for degrading BCL-2 protein in a subject.

[0388] The present disclosure further relates to a compound represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for treating and / or preventing diseases or conditions mediated by or dependent on BCL-2.

[0389] The present disclosure further relates to compounds represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4), or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in regulating BCL-2 protein ubiquitination in a subject.

[0390] The present disclosure further relates to compounds represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in degrading BCL-2 protein in a subject.

[0391] The present disclosure further relates to compounds represented by the aforementioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and / or preventing diseases or conditions mediated by or dependent on BCL-2.

[0392] The present disclosure further relates to a compound of the above-mentioned general formula (I), (II), (II-1), (II-2), (II-3), (II-4) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing myelofibrosis or cancer; the cancer is a solid tumor or a hematological malignancy, preferably leukemia, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma, etc.), multiple myeloma, brain cancer, synovial sarcoma, neuroblastoma, glioblastoma, skin cancer, squamous cell carcinoma, basal cell carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, gallbladder cancer, Biliary tract cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, colorectal cancer, pancreatic cancer, liver cancer, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, bladder cancer, melanoma, seminoma, rhabdomyosarcoma, osteoma, osteochondroma, sarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, renal cancer, thyroid cancer, polycythemia vera, ureteral tumor, choriocarcinoma and pediatric tumors; the leukemia is preferably selected from chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloid leukemia; the lymphoma is preferably selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma.

[0393] Preferably, the BCL-2-mediated or dependent disease or condition described in the present disclosure is myelofibrosis or cancer; the cancer is a solid tumor or a hematological malignancy, preferably selected from leukemia, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma, etc.), multiple myeloma, brain cancer, synovial sarcoma, neuroblastoma, glioblastoma, skin cancer, squamous cell carcinoma, basal cell carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, gallbladder cancer, bile duct cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, colorectal cancer, pancreatic cancer , liver cancer, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, bladder cancer, melanoma, seminoma, rhabdomyosarcoma, osteoma, osteochondroma, sarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, renal cancer, thyroid cancer, polycythemia vera, ureteral tumor, choriocarcinoma and pediatric tumors; the leukemia is preferably selected from chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloid leukemia; the lymphoma is preferably selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma.

[0394] Preferably, the BCL-2 described in the present disclosure is BCL-xL.

[0395] "Cancer" includes, but is not limited to, hematological malignancies (eg, lymphoma, leukemia, myeloma) and solid malignancies.

[0396] In some embodiments, “cancer” as used herein includes, but is not limited to, T-cell leukemia, T-cell lymphoma, acute lymphoblastic lymphoma (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AML), multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, and solid tumors, e.g., non-small cell lung cancer (NSCLC, e.g., EGF mutant NSCLC, KRAS mutant NSCLC), small cell lung cancer (SCLC), breast cancer, neuroblastoma, ovarian cancer, prostate cancer, melanoma (e.g., BRAF mutant melanoma, KRAS mutant melanoma), pancreatic cancer, cervical cancer, endometrial cancer, and colon cancer (e.g., KRAS mutant colon cancer, BRAF mutant colon cancer).

[0397] In some embodiments, the "cancer" described in the present disclosure includes, but is not limited to, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendiceal cancer, astrocytoma (cerebellum or cerebrum in children), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor (cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid tumor, Burkitt's lymphoma, carcinoid tumor (children, gastrointestinal), unknown primary cancer, central nervous system lymphoma (primary), cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, Glioma, cervical cancer, childhood cancer, choriocarcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma of the Ewing family of tumors, extracranial germ cell tumor (children), extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer (intraocular melanoma, retinoblastoma), gallbladder cancer, gastric (gastric) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor (extracranial, extragonadal, ovarian in children), gestational trophoblastic tumor, glioblastoma, glioma (adult, brainstem in children, astrocytoma in children, visual pathway and hypothalamus in children), gastric Carcinoma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma (children), intraocular melanoma, pancreatic islet cell carcinoma, Kaposi's sarcoma, kidney cancer (renal cell carcinoma), laryngeal cancer, leukemias (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cancer, liver cancer (primary), lung cancer (non-small cell, small cell), lymphoma (AIDS-related, Burkitt's, cutaneous T-cell, Hodgkin, non-Hodgkin, primary central nervous system), macroglobulinemia (Waldenstrom's), malignant fibrous histiocytoma / osteosarcoma of bone, medulloblastoma (children), melanoma, intraocular melanoma, Merkel cell carcinoma , mesothelioma (malignant in adults, acute in children), metastatic squamous neck cancer with occult primary, oral cancer, multiple endocrine neoplasia syndrome (children), multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplasia syndrome, myelodysplasia / myeloproliferative disorders, myeloid leukemia (chronic), myeloid leukemia (acute in adults, acute in children), multiple myeloma, myeloproliferative disorders (chronic), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell transitional cell carcinoma of the renal pelvis, urethral cancer, uterine cancer (endometrial), uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma (children), vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms tumor (children).

[0398] In some embodiments, the cancer is selected from synovial sarcoma, Burkitt's lymphoma, Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioblastoma, small cell lung cancer, pancreatic cancer, hepatocellular (liver) cancer, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, bladder cancer, melanoma, rhabdomyosarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, kidney cancer (renal cell carcinoma), thyroid cancer, and leukemias (acute lymphocytic, acute myeloid, chronic lymphocytic, and chronic myeloid).

[0399] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be in the form of a tablet, capsule, cachet, bottled solution, powder, granules, lozenge, suppository, reconstituted powder, or liquid formulation.

[0400] As a general guide, suitable unit doses may be in the range of 0.1 to 1000 mg.

[0401] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0402] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily 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 the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical formulation. Tablets contain the active ingredient and, in admixture, nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include 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, thereby providing a sustained-release effect over a longer period of time.

[0403] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0404] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such 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 sweetening agents.

[0405] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents as described above may be added to provide a palatable formulation. These compositions may be preserved by the addition of antioxidants.

[0406] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0407] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solutions and microemulsions may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0408] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspensions for intramuscular and subcutaneous administration. The suspension can be prepared using known techniques with suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspending media. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

[0409] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0410] 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 following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0411] The disclosed compounds have high exposure in C57 mice, SD rats and dogs, and have obvious pharmacokinetic advantages.

[0412] Terminology

[0413] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0414] 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., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0415] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 10 carbon atoms (i.e., C 1-10 Alkylene); further more preferably an alkylene group having 1 to 6 carbon atoms (ie, C 1-6 Alkylene); further preferably an alkylene group having 4 to 6 carbon atoms (ie, C 4-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0416] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined 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 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0417] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined 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 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0418] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0419] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., a monocyclic cycloalkyl) or a polycyclic ring system (i.e., a 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., a 3- to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group).

[0420] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0421] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0422] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, 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., a 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably 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 monospirocycloalkyl group. Non-limiting examples include:

[0423] Its connection point can be at any position;

[0424] wait.

[0425] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, 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., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 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 cycloalkyl groups. Non-limiting examples include: , whose connection points can be at any position;

[0426] wait.

[0427] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring 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., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 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.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0428] Its connection point can be at any position.

[0429] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0430] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, 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., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); preferably a heterocyclic group having 4 to 11 ring atoms (i.e., a 4- to 11-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 6 to 7 ring atoms (i.e., a 6- or 7-membered heterocyclic group) or a heterocyclic group having 6 to 8 ring atoms (i.e., a 6- to 8-membered heterocyclic group) or a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group); preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group); most preferably a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group).

[0431] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0432] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0433] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment 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., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably has a spiro heterocyclic radical (i.e., 7 to 11 yuan spiro heterocyclic radical) of 7 to 11 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0434] wait.

[0435] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, 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., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0436] wait.

[0437] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), 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., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0438] wait.

[0439] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0440] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, a phenyl group. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group 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 include:

[0441] wait.

[0442] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0443] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0444] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, wait.

[0445] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment 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 heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0446] wait.

[0447] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0448] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0449] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0450] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkoxy and alkyl are as defined above, and non-limiting examples include methoxymethyl.

[0451] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0452] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0453] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0454] The term "alkylthio" refers to an -S-alkyl group, wherein alkyl is as defined above.

[0455] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0456] The term "hydroxy" refers to -OH.

[0457] The term "amino" refers to -NH2.

[0458] The term "cyano" refers to -CN.

[0459] The term "nitro" refers to -NO2.

[0460] The term "oxo" or "oxo" refers to "=0".

[0461] The term "carbonyl" refers to C=O.

[0462] TBS refers to tert-butyldimethylsilyl.

[0463] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein amino and alkyl are as defined above.

[0464] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, cerebellin is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation via the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first, a third to a second, and so on. Polyubiquitination marks proteins for degradation via the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead alter their cellular location or function, for example, through binding to other proteins with domains capable of binding ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by the E3 for chain preparation. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0465] The term "target protein" refers to proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Such proteins include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi and parasites, among many others, including humans, microorganisms, viruses, fungi and parasites as targets for drug therapy, other animals including domestic animals), microorganisms used as targets for the determination of antibiotics and other antimicrobials, and plants and even viruses, among many others.

[0466] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0467] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0468] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0469] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present 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. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0470] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0471] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another. It includes all possible tautomers, i.e., existing in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:

[0472] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0473] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0474] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds 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 can be introduced into the compounds of the present 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 I, etc., preferably deuterium.

[0475] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0476] When a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (ie, at least 15% deuterium incorporation). Examples of compounds having a greater than natural abundance of deuterium may be at least 1000 times more abundant in deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times more abundant in deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times more abundant in deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times more abundant in deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant in deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 50 ...0% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in de deuterium is incorporated at least 5000 times more abundant in deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times more abundant in deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times more abundant in deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times more abundant in deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times more abundant in deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times more abundant in deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times more abundant in deuterium (i.e., at least 99.5% deuterium incorporation), or more.

[0477] "Optional" or "optionally" means that the event or circumstances described below may but need not occur, and includes both situations where the event or circumstances occur or do not occur. For example, "C 1-6 The term "alkyl" includes both the case where the alkyl group is substituted by halogen or cyano and the case where the alkyl group is not substituted by halogen or cyano.

[0478] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0479] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0480] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately 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 inorganic acids and organic acids.

[0481] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0482] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0483] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0484] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary within ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0485] Synthesis method of the disclosed compound

[0486] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0487] Option 1

[0488] The present invention discloses a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0489] The compound represented by general formula (IIA) or its salt and the compound represented by general formula (IIB) or its salt undergo condensation reaction in the presence of a condensing agent and an alkaline reagent to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0490] in:

[0491] Ring A, Ring B, R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 ,R,X,Z,x,y,n,t,L 3 、L 4 、L 5 and A are as defined in general formula (II).

[0492] Option 2

[0493] The present invention discloses a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0494] The compound represented by general formula (II-1A) or its salt and the compound represented by general formula (II-1B) or its salt undergo condensation reaction in the presence of a condensing agent and an alkaline reagent to obtain the compound represented by general formula (II-1) or its pharmaceutically acceptable salt;

[0495] in:

[0496] Ring A, Ring B, Ring E, R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、L 3 、L 4 、L 5 , Z, n, x, y and t are as defined in the general formula (II-1).

[0497] Option 3

[0498] The present invention discloses a method for preparing a compound of formula (II-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0499] The compound represented by general formula (II-1A) or its salt and the compound represented by general formula (II-2B) or its salt undergo condensation reaction in the presence of a condensing agent and an alkaline reagent to obtain the compound represented by general formula (II-2) or its pharmaceutically acceptable salt;

[0500] in:

[0501] Ring A, Ring B, Ring E, Ring F, Ring G, Ring W 1 、W 2 、R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、R 12 、L 3 、L 4 、L 5 , Z, n, u, x, y and t are as defined in the general formula (II-2).

[0502] Option 4

[0503] The present invention discloses a method for preparing a compound of formula (II-3) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0504] The compound represented by general formula (II-1A) or its salt and the compound represented by general formula (II-3B) or its salt undergo condensation reaction in the presence of a condensing agent and an alkaline reagent to obtain the compound represented by general formula (II-3) or its pharmaceutically acceptable salt;

[0505] in:

[0506] Ring A, Ring B, Ring F, Ring G, Ring W 1 、W 2 、R 1 、R 2 、R 3 、R 3a 、R 4 、R 4a 、R 5 、R 9 、R 10 、R 12 、L 3 、L 4 、L 5 , Z, n, u, x, y and t are as defined in the general formula (II-3).

[0507] Plan 5

[0508] The present invention discloses a method for preparing a compound of formula (II-4) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0509] The compound represented by general formula (II-4A) or its salt and the compound represented by general formula (IIB) or its salt undergo condensation reaction in the presence of a condensing agent and an alkaline reagent to obtain the compound represented by general formula (II-4) or its pharmaceutically acceptable salt;

[0510] in:

[0511] Ring A, Ring B, R 1 、R 2 、R 3a 、R 4a 、R 5 , Z, n, x, y, t, L 3 、L 4 、L 5 and A are as defined in general formula (II-4).

[0512] In the above synthesis scheme, the condensing agent includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, fluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; preferably, the condensing agent is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate).

[0513] In the above synthesis scheme, the alkaline reagent includes organic bases and inorganic bases; the organic bases include but are not limited to triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the alkaline reagent is N,N-diisopropylethylamine or triethylamine.

[0514] The above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is 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.

[0515] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0516] Example

[0517] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0518] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0519] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0520] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)

[0521] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0522] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0523] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0524] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0525] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0526] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0527] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0528] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0529] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0530] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0531] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0532] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0533] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0534] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0535] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0536] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0537] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0538] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvents used in the reactions, the eluent systems for column chromatography and the developing solvent systems for thin layer chromatography used to purify the compounds included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0539] Example 1

[0540] (2S,4R)-1-(2-(3-((5-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1

[0541] first step

[0542] (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1b

[0543] Tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidine-1-carboxylate 1a (2.1 g, 4.87 mmol, prepared by the method disclosed in Example 1, compound 56 on page 42 of the specification of patent application WO2020142227A1) was dissolved in 4M hydrogen chloride in 1,4-dioxane (20 mL) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in 40 mL of dichloromethane and methanol (V / V = 1:1). Excess potassium carbonate was added and stirred for 15 minutes. The mixture was filtered and the filtrate was collected. The organic phase was concentrated to remove the solvent. The resulting residue was dissolved in dichloromethane (40 mL), and imidazole (3.3 g, 48.47 mmol) was added. The mixture was stirred until the reaction mixture became clear. Tert-butyldimethylsilyl chloride (1.1 g, 7.30 mmol) was added dropwise at room temperature, and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography using Elution System A to obtain the title compound 1b (1.4 g, 65.1% yield).

[0544] MS m / z(ESI):446.3[M+1].

[0545] Step 2

[0546] (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1d

[0547] Compound 1b (157 mg, 0.35 mmol) and (±)-2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid 1c (65 mg, 0.35 mmol, prepared using the method disclosed in Example 2, Intermediate 2, page 225 of patent application WO2019084030A1) were dissolved in dichloromethane (10 ml). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (267 mg, 0.70 mmol) and triethylamine (143 mg, 1.41 mmol) were added, and 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 A to obtain the title compound 1d (diastereoisomer mixture, 75 mg, yield: 43.6%). MS m / z (ESI): 613.6 [M+1].

[0548] Step 3

[0549] Methyl 5-((5-(1-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoate 1e

[0550] Compound 1d (75 mg, 0.12 mmol), methyl 5-bromopentanoate (36 mg, 0.18 mmol, Bidler), and anhydrous potassium carbonate (34 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 1e (diastereoisomer mixture, 70 mg, yield: 78.7%).

[0551] MS m / z(ESI):727.3[M+1].

[0552] Step 4

[0553] 5-((5-(1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid 1f

[0554] Compound 1e (70 mg, 0.1 mmol) and lithium hydroxide monohydrate (41 mg, 1.0 mmol) were dissolved in a mixture of tetrahydrofuran (2.5 mL), water (2.5 mL), and methanol (2.5 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, collected, and concentrated under reduced pressure to obtain the crude title compound 1f (diastereoisomer mixture, 44 mg), which was used directly in the next reaction without purification.

[0555] MS m / z(ESI):599.1[M+1].

[0556] Step 5

[0557] (2S,4R)-1-(2-(3-((5-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1

[0558] Compound 1f (44 mg, 0.07 mmol) and (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 1 g (72 mg, A mixture of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (56 mg, 0.15 mmol) and triethylamine (75 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1 (diastereoisomer mixture, 114 mg).

[0559] MS m / z(ESI):1553.1[M+1].

[0560] Example 1-1 and Example 1-2

[0561] (2S,4R)-1-((S)-2-(3-((5-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1-1

[0562] and

[0563] (2S,4R)-1-((R)-2-(3-((5-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1-2

[0564] Compound 1 (114 mg, 0.07 mmol) was purified by preparative HPLC (instrument model: Waters Autopurification-SQD2 column: Welch Xtimate Phenyl-hexyl, Prep 30×250 mm; 5 um; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30 mL / min) to give the title compounds (8 mg, yield: 7.0%) and (6 mg, yield: 5.3%).

[0565] Single configuration compound (shorter retention time, retention time 3.17 minutes, 8 mg, yield: 7.0%):

[0566] MS m / z(ESI):1553.5[M+1].

[0567] 1H NMR (500MHz, CDCl3): δ8.66(s,1H),8.35(s,1H),8.10(d,1H),7.70(d,2H),7.57(d,1H),7.42-7.21(m,8H),7.10(d, 1H), 7.00(d,2H),6.77(d,2H),6.62(d,1H),5.84(s,1H),5.54-5.29(m,2H),5.08(t,1H),4.67(t,1H),4.59-4.51(m ,1H),4.29-4.11(m,2H),3.96-3.81(m,2H),3.80-3.21(m,10H),3.16-2.93(m,3H),2.93-2.82(m,2H),2.64-1.85(m ,21H),1.82-1.56(m,5H),1.54-1.40(m,4H),1.38-1.15(m,7H),1.06-1.00(m,2H),0.97(s,3H),0.92-0.85(m,3H).

[0568] Single configuration compound (longer retention time, retention time 3.20 minutes, 6 mg, yield: 5.3%):

[0569] MS m / z(ESI):1553.5[M+1].

[0570] 1 H NMR (500MHz, CDCl3): δ8.67(s,1H),8.34(s,1H),8.10(d,1H),7.73(d,2H),7.44 -7.21(m,10H),7.07(d,1H),7.00(d,2H),6.75(d,2H),6.61(d,1H),5.87(s,1H), 5.62-5.46(m,1H),5.41-5.32(m,1H),5.04-4.92(m,1H),4.81-4.71(m,1H),4.67 -4.55(m,1H),4.27-4.12(m,2H),3.98-3.81(m,2H),3.75-3.62(m,2H),3.61-3.5 2(m,2H),3.50-3.34(m,3H),3.34-3.21(m,4H),3.17-2.96(m,3H),2.95-2.96(m, 2H),2.59-2.22(m,17H),2.17-1.93(m,6H),1.52-1.37(m,9H),1.08-0.93(m,9H).

[0571] Example 2-1 and Example 2-2

[0572] (2S,4R)-1-((S)-2-(7-(2-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 2-1

[0573] and

[0574] (2S,4R)-1-((S)-2-(7-(1-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-7-oxoheptylamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0575] first step

[0576] (R)-butyl 4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)methanesulfonate 2b

[0577] (R)-4-((4-Hydroxy-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide 2a (1 g, 2.06 mmol, prepared by the method disclosed in Example 14f on page 119 of the specification of patent application WO2014028381A1) was dissolved in dichloromethane (20 mL), and pyridine (408 mg, 5.16 mmol), p-dimethylaminopyridine (25 mg, 0.20 mmol, Shanghai Shaoyuan), and methanesulfonic anhydride (539 mg, 3.09 mmol, Shanghai Bid) were added. The reaction was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 2b (1.12 g, yield: 96%).

[0578] MS m / z(ESI):561.0[M-1].

[0579] Step 2

[0580] (R)-tert-Butyl 2-(4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate 2c-1

[0581] and

[0582] (R)-tert-Butyl 1-(4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate 2c-2

[0583] Tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (320 mg, 1.53 mmol, Shanghai Bidex) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (55 mg, 1.38 mmol) was added and stirred for 10 minutes. Compound 2b (774 mg, 1.38 mmol) was then added and the mixture was stirred for 16 hours. Water was then added and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent A to give a mixture of the title compounds 2c-1 and 2c-2 (230 mg). MS m / z (ESI): 676.0 [M+1].

[0584] Step 3

[0585] (R)-tert-Butyl 2-(3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate 2e-1

[0586] and

[0587] (R)-tert-Butyl 1-(3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate 2e-2

[0588] A mixture of compounds 2c-1 and 2c-2 (107 mg, 0.158 mmol), 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid 2d (107 mg, 0.158 mmol, prepared by the method disclosed in Example 1.3 of compound 3.7 on page 56 of the specification of patent application WO2017101851A1), 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.67 mmol, Shanghai Shaoyuan) and p-dimethylaminopyridine (25 mg, 0.204 mmol, Shanghai Shaoyuan) were dissolved in dichloromethane (5 mL), and triethylamine (69 mg, 0.68 mmol) was added. The reaction was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain a mixture of the title compounds 2e-1 and 2e-2 (100 mg, yield: 40%).

[0589] MS m / z(ESI):1096.8[M+1].

[0590] Step 4

[0591] (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 2f-1

[0592] and

[0593] (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 2f-2

[0594] A mixture of compounds 2e-1 and 2e-2 (170 mg, 0.155 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (8 mL) and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-75%, flow rate: 30 mL / min) to give the title compounds (15 mg, yield: 9.6%; 28 mg, yield: 18%).

[0595] MS m / z(ESI):996.1[M+1].

[0596] Single configuration compound (shorter retention time) (15 mg, yield: 9.6%)

[0597] HPLC analysis: retention time 1.73 minutes, purity: 92% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 30%-95%). Single configuration compound (longer retention time) (28 mg, yield: 18%)

[0598] HPLC analysis: retention time 1.80 minutes, purity: 95% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 30%-95%).

[0599] Step 5

[0600] (2S,4R)-1-((S)-2-(7-(2-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 2-1

[0601] and

[0602] (2S,4R)-1-((S)-2-(7-(1-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-7-oxoheptylamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0603] 2 g (16 mg, 27 μmol, prepared by the method disclosed in Intermediate 15 on page 61 of the specification of patent application WO2020163823A2) of 7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid was dissolved in dichloromethane (3 mL). The compound corresponding to the product with the longer retention time in the previous step (i.e., the longer retention time in 2f-1 and 2f-2) (28 mg, 28 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 42 μmol), and triethylamine (14 mg, 138 μmol) were added and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min) to obtain the title compound (20 mg, yield: 45%). MS m / z (ESI): 1564.4 [M+1].

[0604] 1H NMR (500MHz, CDCl3): δ8.69(s,1H),8.30(d,1H),8.05(d,1H),7.81(d,1H),7.76(d,1H),7.46-7.24(m ,9H),7.00(d,2H),6.91(d,1H),6.84(d,1H),6.77(d,2H),6.49(dd,1H),6.26(dd,1H),5.08(q,1H),4. 76(t,1H),4.67(d,1H),4.55-4.07(m,9H),3.70-3.56(m,2H),3.33-3.20(m,4H),3.12-2.92(m,2H),2 .89-2.80(m,2H),2.64-1.94(m,20H),1.79-1.55(m,5H),1.52-1.36(m,6H),1.04(s,9H),0.98(s,6H).

[0605] Compound 2g (9 mg, 15 μmol) was dissolved in dichloromethane (3 mL), and the compound corresponding to the shorter retention time of the product in the previous step (i.e., the shorter retention time in 2f-1 and 2f-2) (15 mg, 15 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9 mg, 24 μmol) and triethylamine (8 mg, 79 μmol) were added. The reaction was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound (15 mg, yield: 64%).

[0606] MS m / z(ESI):1564.3[M+1].

[0607] 1H NMR (500MHz, CDCl3): δ8.68(s,1H),8.42-8.35(m,1H),8.02(d,1H),7.84-7.70(m,2H),7.49-7. 20(m,10H),7.00(d,2H),6.93-6.86(m,1H),6.78(d,2H),6.53-6.42(m,1H),6.23(d,1H),5.08(q ,1H),4.81-4.71(m,1H),4.56-4.48(m,1H),4.48-3.92(m,7H),3.78-3.45(m,3H),3.27(s,3H),3 .13-2.94(m,2H),2.88-2.78(m,2H),2.53(s,3H),2.43-1.41(m,34H),1.04(s,9H),0.98(s,6H).

[0608] Example 3

[0609] (2S,4R)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methyl)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0610] first step

[0611] (5-Bromothiazol-4-yl)methanol 3b

[0612] Methyl 5-bromothiazole-4-carboxylate 3a (5.90 g, 26.57 mmol, Adamas) and anhydrous calcium chloride (14.7 g, 133.64 mmol) were dissolved in tetrahydrofuran (15 mL) and water (30 mL). Sodium borohydride (1.89 g, 49.74 mmol, Sinopharm) was added under ice-water bath and stirred for 16 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, and the layers were separated. The organic phase was washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to afford the title compound 3b (4.90 g, 95% yield).

[0613] MS m / z(ESI):194.0[M+1].

[0614] Step 2

[0615] 4-Bromo-3-hydroxybenzaldehyde 3d

[0616] 4-Bromo-3-methoxybenzaldehyde 3c (5.80 g, 26.97 mmol, Bid) was dissolved in dichloromethane (60 mL). Boron tribromide (60.0 mL, 1.0 M, 60.0 mmol) was added under ice-cooling and stirred at room temperature for 1 hour. The reaction solution was quenched with methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to afford the title compound 3d (8.50 g, 157% yield).

[0617] MS m / z(ESI):199.0[M-1].

[0618] Step 3

[0619] 4-Bromo-3-((5-bromothiazol-4-yl)methoxy)benzaldehyde 3e

[0620] Compound 3b (3 g, 15.36 mmol) and triethylamine (3.28 g, 32.44 mmol) were dissolved in dichloromethane (40 mL). Methanesulfonyl chloride (2.22 g, 19.47 mmol) was added at 0°C and allowed to react at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product and compound 3d (3 g, 14.92 mmol) were dissolved in N,N-dimethylformamide (60 mL), potassium carbonate (4.20 g, 30.43 mmol) was added, and the reaction was continued at 60°C for 1 hour. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to give the title compound 3e (850 mg, yield: 15%). MS m / z (ESI): 376.0 [M+1].

[0621] Step 4

[0622] 4H-chromeno[3,4-d]thiazole-7-carbaldehyde 3f

[0623] Compound 3e (830 mg, 2.20 mmol) was dissolved in 1,4-dioxane (15 mL), and potassium acetate (650 mg, 6.62 mmol), pinacol diboron (700 mg, 2.76 mmol, Shanghai Shaoyuan), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (200 mg, 0.27 mmol, Adamas) were added. The reaction was carried out at 90°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 3f (110 mg, yield: 23%).

[0624] MS m / z(ESI):218.1[M+1].

[0625] Step 5

[0626] (E)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methylidene)-2-methylpropane-2-sulfenamide 3g

[0627] Compound 3f (70 mg, 0.32 mmol) and tert-butylsulfinamide (50 mg, 0.41 mmol, Adamas) were dissolved in dichloromethane (3 mL). Cesium carbonate (160 mg, 0.49 mmol) was added and the reaction was stirred at room temperature for 16 hours. The filtrate was collected by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 3g (94 mg, yield: 91%).

[0628] MS m / z(ESI):321.2[M+1].

[0629] Step 6

[0630] N-((4H-chromeno[3,4-d]thiazol-7-yl)methyl)-2-methylpropane-2-sulfenamide 3h

[0631] Compound 3g (94 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride (20 mg, 0.53 mmol) was added at 0°C. The mixture was reacted at room temperature for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was collected, dried, filtered, and the filtrate was concentrated to obtain a crude product of the title compound 3h (94 mg).

[0632] MS m / z(ESI):323.4[M+1].

[0633] Step 7

[0634] tert-Butyl (2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine-1-carboxylate 3i

[0635] Compound 3h (94 mg, 0.29 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 h, and concentrated to obtain a crude product. The crude product and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (70 mg, 0.30 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (110 mg, 0.85 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (135 mg, 0.36 mmol) were added and reacted at room temperature for 1 h. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (10 mL x 2), and dried over anhydrous sodium sulfate. The filtrate was collected by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 3i (110 mg, yield: 87%).

[0636] MS m / z(ESI):432.3[M+1].

[0637] Step 8

[0638] tert-Butyl ((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 3j

[0639] Compound 3i (110 mg, 0.25 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 h, and concentrated to obtain a crude product. The crude product was then mixed with (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (65 mg, 0.29 mmol, Shanghai Shaoyuan) in N,N-dimethylformamide (3.0 mL), triethylamine (130 mg, 1.28 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) and allowed to react at room temperature for 1 h. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (10 mL x 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 3j (130 mg, yield: 93%).

[0640] MS m / z(ESI):545.3[M+1].

[0641] Step 9

[0642] Methyl 7-(((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate 3k

[0643] Compound 3j (130 mg, 0.24 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 hour, and concentrated to obtain the crude product. The crude product and 7-methoxy-7-oxoheptanoic acid (60 mg, 0.34 mmol, Leyan) were dissolved in N,N-dimethylformamide (3.0 mL), and N,N-diisopropylethylamine (200 mg, 1.55 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 0.34 mmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent A to obtain the title compound 3k (130 mg, 90% yield).

[0644] MS m / z(ESI):601.4[M+1].

[0645] Step 10

[0646] 7-(((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid 3l

[0647] Compound 3k (100 mg, 0.17 mmol) was added to a mixed solvent of water (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (30 mg, 0.71 mmol) was added. The reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 4-5 with dilute hydrochloric acid. The mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3l (80 mg). The product was used directly in the next reaction without purification.

[0648] MS m / z(ESI):587.4[M+1].

[0649] Step 11

[0650] (2S,4R)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methyl)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0651] Compound 31 (60 mg, 0.10 mmol) and compound 1g (90 mg, 0.93 mmol) were dissolved in N,N-dimethylformamide (3.0 mL). N,N-diisopropylethylamine (60 mg, 0.46 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Gilson 281 column: X-Bridge, Prep 30×150 mm, 5 μm, C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35% to 60%, flow rate: 30 mL / min) to obtain the title compound 3 (90 mg, yield: 62%). MS m / z(ESI):1541.5[M+1].

[0652] 1H NMR (500MHz, CDCl3): δ8.69(s,1H),8.39(d,1H),8.10(dd,1H),7.68(d,2H),7.39(d,2H),7.34-7.24(m,6H),7.16(d,1H),7.11(d, 1H),7.00(d,2H),6.92-6.88(m,2H),6.78(d,2H),6.66(d,1H),6.34(d,1H),5.44(s,2H),4.72(t,1H),4.59(d,1H),4.53-4.51(m,1 H),4.45(dd,1H),4.28(dd,1H),4.11(d,1H),3.98-3.88(m,1H),3.72-3.64(m,1H),3.61(dd,1H),3.47-3.24(m,6H),3.12(dd,1H), 3.03(dd,1H),2.95-2.82(m,2H),2.53-1.99(m,22H),1.74-1.53(m,4H),1.48(t,2H),1.32-1.28(m,4H),1.00(s,6H),0.97(s,6H).

[0653] Example 4

[0654] (R)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide

[0655] first step

[0656] (R)-tert-Butyl 4-(4-bromo-2-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate 4b

[0657] (R)-tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate 4a (10 g, 46.24 mmol, Shanghai Bidex) and 3,4-difluorobromobenzene (8.93 g, 46.27 mmol, Shanghai Shaoyuan) were dissolved in dimethyl sulfoxide (60 mL). Potassium hydroxide (10 g, 46.24 mmol, Sinopharm) was added at 0°C, and the mixture was stirred at 30°C for 16 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4b (18.0 g). The product was used directly in the next step without purification.

[0658] MS m / z(ESI):389.1[M+1].

[0659] Step 2

[0660] (R)-tert-Butyl 8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate 4c

[0661] Compound 4b (18 g, 46.24 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL). Lithium bis(trimethylsilyl)amide (60.0 mL, 1.0 M, 60.0 mmol) was added dropwise at 0°C. After complete addition, the temperature was raised to 60°C and the reaction was stirred for 1 hour. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent C to give the crude title compound 4c (2.7 g). The product was used directly in the next step without further purification.

[0662] MS m / z(ESI):313.1[M-55].

[0663] Step 3

[0664] 3-(tert-Butyl)8-methyl(R)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3,8(4H)-dicarboxylate 4d

[0665] Crude compound 4c (2.5 g) and triethylamine (3.26 g, 71.75 mmol) were dissolved in methanol (10 mL) and N,N-dimethylformamide (30 mL). Palladium acetate (300 mg, 1.34 mmol) and 1,3-bis(diphenylphosphino)propane (600 mg, 1.45 mmol) were added and reacted at 100°C under 5 atmospheres of carbon monoxide for 16 hours. Water (30 mL) was added and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was collected by filtration and concentrated. The residue was purified by silica gel column chromatography using eluent C to afford the title compound 4d (550 mg, 46% yield).

[0666] MS m / z(ESI):293.1[M-55].

[0667] Step 4

[0668] (R)-1,2,3,4,4a,5-Hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid methyl ester hydrochloride 4e

[0669] Compound 4d (230 mg, 0.66 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M) and stirred for 1 hour. The mixture was concentrated to give the crude title compound 4e (190 mg), which was used directly in the next step without purification.

[0670] MS m / z(ESI):249.3[M+1].

[0671] Step 5

[0672] (R)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid methyl ester 4g

[0673] (4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol 4f (170 mg, 0.68 mmol, prepared by the method disclosed in Example 8, compound f on page 43 of the specification of patent application WO2008061208A2) and triethylamine (200 mg, 1.98 mmol) were dissolved in dichloromethane (3 mL), and methanesulfonyl chloride (100 mg, 0.87 mmol) was added dropwise under ice bath. The mixture was stirred for 2 hours, quenched with water, extracted with dichloromethane, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL), and compound 4e (190 mg, 0.67 mmol) and potassium carbonate (280 mg, 2.0 mmol) were added. The temperature was raised to 75° C. and the reaction was allowed to react for 24 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and separated. The organic phase was 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 C to give 4 g of the title compound (200 mg, yield: 62%).

[0674] MS m / z(ESI):481.4[M+1].

[0675] Step 6

[0676] (R)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid 4h

[0677] Compound 4g (200 mg, 0.42 mmol) was added to a mixed solvent of water (1 mL), tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (100 mg, 2.3 mmol) was added. The mixture was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 3-4 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound 4h (200 mg). The product was used directly in the next reaction without purification.

[0678] MS m / z(ESI):467.5[M+1].

[0679] Step 7

[0680] tert-Butyl 4-((R)-3-((4-(N-((R)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)sulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 4j

[0681] Compound 4h (190 mg, 0.67 mmol) and (R)-tert-butyl 4-(4-(phenylthio)-3-((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)piperazine-1-carboxylate 4i (270 mg, 0.41 mmol, prepared by the method disclosed in Intermediate 9 on page 65 of the specification of patent application CN114144411A) were dissolved in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol), triethylamine (210 mg, 2.1 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol) were added respectively. The reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to give the title compound 4j (200 mg, yield: 44%).

[0682] MS m / z(ESI):1101.5[M+1].

[0683] Step 8

[0684] (R)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide

[0685] Compound 4j (100 mg, 0.092 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 hour, and concentrated to obtain a crude product. The crude product and compound 2g (60 mg, 0.10 mmol) were dissolved in dichloromethane (3.0 mL), and triethylamine (100 mg, 0.99 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281 column: X-Bridge, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give the title compound 4 (30 mg, yield: 20%).

[0686] MS m / z(ESI):1570.1[M+1].

[0687] 1 H NMR (500MHz, CD3OD-d4): δ8.88(s,1H),8.52(d,1H),8.29(d,1H),8.02(dd,1H),7.83(d,1H),7.46-7.39(m,9H),7.2 5-7.22(m,3H),7.10(d,2H),6.87(d,1H),6.81(d,1H),5.04-4.99(m,1H),4.65-4.57(m,6H),4.45-4.43(m,1H),4.21 -4.18(m,1H),4.11-4.08(m,1H),3.91-3.83(m,2H),3.77-374(m,2H),3.62-3.57(m,1H),3.51-3.48(m,3H),3.30-3 .27(m,2H),3.22-3.18(m,2H),2.98-2.78(m,5H),2.49-2.01(m,15H),1.66-1.35(m,13H),1.05(s,9H),1.03(s,6H).

[0688] Example 5

[0689] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 5

[0690] first step

[0691] (S)-tert-Butyl 4-(4-bromo-2-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate 5c

[0692] 4-Bromo-1,2-difluorobenzene 5a (8.9 g, 46.27 mmol, Shaoyuan) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate 5b (10 g, 46.23 mmol, Bid) were dissolved in dimethyl sulfoxide (100 mL). Potassium hydroxide (3.9 g, 69.51 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude title compound 5c (17.9 g). The product was used directly in the next reaction without purification.

[0693] MS m / z(ESI):389.2[M+1].

[0694] Step 2

[0695] (S)-tert-Butyl 8-bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate 5d

[0696] Crude compound 5c (19 g) was dissolved in tetrahydrofuran (200 mL) under nitrogen. The reaction mixture was cooled to 0°C and a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran (66.9 mL, 66.93 mmol) was added dropwise. The mixture was then heated to 60°C and allowed to react for 1 hour. The reaction mixture was cooled to room temperature, quenched by pouring into water (200 mL), and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 5d (1.2 g, 6.7% yield).

[0697] MS m / z(ESI):369.2[M+1].

[0698] Step 3

[0699] (S)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid 5e

[0700] Compound 5d (1.2 g, 3.25 mmol) was dissolved in tetrahydrofuran (25 mL) under nitrogen protection. A 2.5 M solution of n-butyllithium in hexane (2.6 mL, 6.51 mmol) was added dropwise at -78°C. The reaction was stirred at -78°C for 0.5 h and then purged with carbon dioxide gas for 2 h. Water (30 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (10 mL). The aqueous phase was collected and the pH was adjusted to 4-5 with dilute hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 5e (230 mg). The product was used directly in the next reaction without further purification.

[0701] MS m / z(ESI):279.2[M-55].

[0702] Step 4

[0703] (S)-1,2,3,4,4a,5-Hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid methyl ester 5f

[0704] Dissolve crude compound 5e (230 mg) in methanol (10 mL), add thionyl chloride (1 g, 8.41 mmol), and stir at 50°C for 16 hours. The reaction mixture is concentrated under reduced pressure to obtain the crude title compound 5f (164 mg), which is used directly in the next step without further purification.

[0705] MS m / z(ESI):249.1[M+1].

[0706] Step 5

[0707] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid methyl ester 5g

[0708] Compound 4f (177 mg, 0.71 mmol) and triethylamine (143 mg, 1.41 mmol) were dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (121 mg, 1.06 mmol) was added dropwise under ice-cooling and stirred at room temperature for 2 hours. The mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), compound 5f (100 mg, 0.35 mmol) and potassium carbonate (243 mg, 1.76 mmol) were added, and the mixture was heated to 75°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 5g (139 mg, 82.3% yield).

[0709] MS m / z(ESI):481.5[M+1].

[0710] Step 6

[0711] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid 5h

[0712] Compound 5g (139 mg, 0.29 mmol) was dissolved in a mixed solvent of water (2 mL), tetrahydrofuran (2 mL), and methanol (2 mL). Lithium hydroxide monohydrate (61 mg, 1.45 mmol) was added and the mixture was heated to 70°C with stirring for 16 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous phase was adjusted to a pH of 5-6 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5h (120 mg). The product was used directly in the next reaction without purification.

[0713] MS m / z(ESI):467.3[M+1].

[0714] Step 7

[0715] tert-Butyl 4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)sulfonylamino)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 5i

[0716] Crude compound 5h (120 mg) and compound 4i (118 mg, 0.19 mmol) were dissolved in dichloromethane (10 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol), triethylamine (133 mg, 1.29 mmol), and 4-dimethylaminopyridine (32 mg, 0.26 mmol) were added, respectively, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 5i (136 mg, 48.0% yield).

[0717] MS m / z(ESI):1101.3[M+1].

[0718] Step 8

[0719] (S)-3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 5j

[0720] Compound 5i (50 mg, 0.05 mmol) was added to a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 5j (46 mg), which was used directly in the next reaction without purification.

[0721] MS m / z(ESI):1001.7[M+1].

[0722] Step 9

[0723] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 5

[0724] The crude compound 5j (73 mg) and compound 2g (52 mg, 0.09 mmol) were dissolved in dichloromethane (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) and triethylamine (74 mg, 0.73 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281, column: Welch Xltimate, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30 mL / min) to give the title compound 5 (26 mg, yield: 22.7%).

[0725] MS m / z(ESI):1569.6[M+1].

[0726] 1H NMR (500MHz, CDCl3): δ8.69(s,1H),8.36(s,1H),8.09(d,1H),7.50-7.21(m,11H), 7.09(d,1H),7.00(d,2H),6.66(dd,2H),6.36(d,1H),5.10(q,1H),4.76(t,1H),4. 61(d,1H),4.50(s,1H),4.18-4.07(m,2H),3.97-3.88(m,1H),3.85(t,1H),3.75-3 .65(m,2H),3.61(t,2H),3.47-3.18(m,5H),3.16-2.98(m,2H),2.90-2.76(m,4H), 2.73-2.65(m,2H),2.50(s,3H),2.42-1.97(m,20H),1.75-1.41(m,12H),1.03(s,9H),0.97(s,6H).

[0727] Example 6

[0728] 3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidine-1- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carboxamide 6-(((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane)-9-carboxamide 6- ...

[0729] first step

[0730] 4-Benzyl 1-tert-butyl 2-(((2-bromo-5-(methoxycarbonyl)benzyl)oxy)methyl)piperazine-1,4-dicarboxylate 6b

[0731] Methyl 4-bromo-3-(bromomethyl)benzoate 6a (2.64 g, 8.56 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.), (±)-4-benzyl 1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (2.5 g, 7.13 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.), silver trifluoromethanesulfonate (5.51 g, 21.40 mmol), and 2,6-di-tert-butylpyridine (4.10 g, 21.40 mmol) were added to dichloromethane (50 mL), stirred at room temperature for 12 hours, quenched with water, extracted with dichloromethane, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to give the title compound 6b (racemic, 1.5 g, yield: 36%).

[0732] MS m / z(ESI):477.5[M-100].

[0733] Step 2

[0734] (±)-Benzyl 3-(((2-bromo-5-(methoxycarbonyl)benzyl)oxy)methyl)piperazine-1-carboxylate 6c

[0735] Compound 6b (1.5 g, 2.597 mmol) was dissolved in ethyl acetate (5 mL), and a 4 M hydrogen chloride 1,4-dioxane solution (5 mL) was added. The mixture was stirred and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was dissolved in water and neutralized with sodium bicarbonate. The mixture was extracted with ethyl acetate and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the title compound 6c (racemate, 1 g). The product was used directly in the next reaction without purification.

[0736] MS m / z(ESI):477.1[M+1].

[0737] Step 3

[0738] (±)-3-Benzyl 9-methyl 1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazine-3,9(4H)-dicarboxylate 6d

[0739] The crude compound 6c (1.0 g), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (350 mg, 0.481 mmol), and cesium carbonate (2.1 g, 6.445 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was stirred at 110°C in a sealed tube under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 6d (racemic compound, 650 mg, yield: 78%).

[0740] MS m / z(ESI):397.5[M+1]

[0741] Step 4

[0742] (±)-1,2,3,4,4a,5-Hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carboxylic acid methyl ester 6e

[0743] Compound 6d (650 mg, 1.639 mmol) and palladium carbon (173 mg, 0.163 mmol, content 10%) were dissolved in methanol (10 mL) and stirred at room temperature under a hydrogen atmosphere for 5 hours. The filtrate was collected after filtration and concentrated under reduced pressure to give the title compound 6e (racemic form, 400 mg, yield: 93%).

[0744] MS m / z(ESI):263.3[M+1]

[0745] Step 5

[0746] (±)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carboxylic acid methyl ester 6f

[0747] Compound 4f (248 mg, 0.989 mmol) and triethylamine (231 mg, 2.287 mmol) were added to dichloromethane (5 mL), and methanesulfonyl chloride (113 mg, 0.914 mmol) was added dropwise under ice-cooling. The mixture was stirred for 2 hours, quenched with water, extracted with dichloromethane, separated, and the organic phase was added with anhydrous sodium sulfate to dryness. The filtrate was collected after filtration and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), and compound 6e (200 mg, 0.762 mmol) and potassium carbonate (317 mg, 2.281 mmol) were added. The mixture was heated to 75°C for 12 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with dichloromethane, separated, and the organic phase was added with anhydrous sodium sulfate to dryness. The filtrate was collected after filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 6f (racemic compound, 220 mg, yield: 58%).

[0748] MS m / z(ESI):495.2[M+1].

[0749] Step 6

[0750] (±)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carboxylic acid 6g

[0751] Compound 6f (220 mg, 0.444 mmol) was added to a mixed solvent of water (2 mL), tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (186 mg, 4.443 mmol) was added. The mixture was heated to 50°C and stirred for 10 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 3 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound 6 g (racemate, 200 mg). The product was used directly in the next reaction without purification.

[0752] MS m / z(ESI):481.2[M+1].

[0753] Step 7

[0754] tert-Butyl 4-((3R)-3-((4-(N-(3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carbonyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 6h

[0755] Compound 6g (200 mg, 0.419 mmol) and compound 4i (190 mg, 0.291 mmol) were dissolved in dichloromethane (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (239 mg, 1.246 mmol), triethylamine (210 mg, 2.075 mmol) and 4-dimethylaminopyridine (52 mg, 0.419 mmol) were added respectively. The reaction 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 with elution system A to give the title compound 6h (diastereomeric mixture, 330 mg, yield: 71%).

[0756] MS m / z(ESI):1115.6[M+1].

[0757] Step 8

[0758] 3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carboxamide 6i

[0759] Compound 6h (330 mg, 0.295 mmol) was added to a 4 M hydrogen chloride 1,4-dioxane solution (3 mL) and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 6i (diastereomeric mixture, 300 mg), which was used directly in the next reaction without purification.

[0760] MS m / z(ESI):1015.6[M+1].

[0761] Step 9

[0762] 3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-

[0763] Hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepane-9-carboxamide 6

[0764] Compound 6i (300 mg, 0.295 mmol) and compound 2g (173 mg, 0.295 mmol) were dissolved in dichloromethane (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (186 mg, 0.489 mmol) and triethylamine (165 mg, 1.631 mmol) were added. The reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281, column: X-Bridge, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 45%-55%, flow rate: 30 mL / min) to give the title compound 6 (a mixture of two diastereomers, 110 mg, yield: 23%).

[0765] MS m / z(ESI):1583.4[M+1].

[0766] 1 H NMR (500MHz, CDCl3): δ8.67(s,1H),8.34(d,1H),8.08(d,1H),7.69(d,1H),7.46-7.27(m,10H),7.12( d,1H),7.02(d,2H),6.82(d,1H),6.64(d,1H),6.30(d,1H),5.10(q,1H),4.75(t,2H),4.63(dd,1H),4 .51(s,1H),3.96-3.86(m,1H),3.78-3.56(m,4H),3.48-3.21(m,6H),3.13(dd,1H),3.02(dd,1H),2.9 8-2.72(m,3H),2.67-2.59(m,1H),2.55-2.00(m,24H),1.77-1.40(m,12H),1.03(s,9H),0.97(s,6H).

[0767] Example 7

[0768] 3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl) (ethyl)formylamino)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepan-9-carboxamide 7

[0769] first step

[0770] (±)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate 7b

[0771] Tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate 7a (3.0 g, 13.026 mmol, Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.) and sodium carbonate (2.761 g, 26.049 mmol) were added to a mixed solvent of 1,4-dioxane (45 mL) and water (15 mL), and 9-fluorenylmethyl chloroformate (4.043 g, 15.628 mmol) was added. The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was quenched with water and extracted with ethyl acetate. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 7b (racemic compound, 4.0 g, yield: 67%).

[0772] MS m / z(ESI):453.5[M+1].

[0773] Step 2

[0774] (±)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(2-(2-bromo-5-(methoxycarbonyl)phenoxy)ethyl)piperazine-1,4-dicarboxylate 7c

[0775] Compound 7b (4.0 g, 8.839 mmol) and methyl 4-bromo-3-hydroxybenzoate (2.1 g, 9.089 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were added to dichloromethane (50 mL), and triphenylphosphine (2.780 g, 10.599 mmol) and bis(4-chlorobenzyl)azodicarboxylate (3.891 g, 10.599 mmol) were added. The mixture was stirred at room temperature for 12 hours, filtered and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give the title compound 7c (racemic, 5.0 g, yield: 85%).

[0776] MS m / z(ESI):609.1[M-55].

[0777] Step 3

[0778] tert-Butyl (±)-3-(2-(2-bromo-5-(methoxycarbonyl)phenoxy)ethyl)piperazine-1-carboxylate 7d

[0779] Compound 7c (5.0 g, 7.532 mmol) was added to acetonitrile (50 mL), and diethylamine (5.459 g, 75.133 mmol) was added dropwise. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to obtain the title compound 7d (racemate, 2.8 g, 84% yield).

[0780] MS m / z(ESI):445.1[M+1+2].

[0781] Step 4

[0782] (±)-3-tert-Butyl 9-methyl 1,2,4,4a,5,6-tetrahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepane-3,9-dicarboxylate 7e

[0783] Compound 7d (1.0 g, 2.225 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (189 mg, 0.225 mmol), and cesium carbonate (2.205 g, 6.767 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was stirred in a sealed tube at 118°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 7e (racemic compound, 700 mg, yield: 85%).

[0784] MS m / z(ESI):363.4[M+1]

[0785] Step 5

[0786] (±)-2,3,4,4a,5,6-Hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepane-9-carboxylic acid methyl ester 7f

[0787] Compound 7e (700 mg, 1.931 mmol) was dissolved in ethyl acetate (5 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added. The mixture was stirred and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in water and neutralized with sodium bicarbonate. The mixture was extracted with ethyl acetate and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 7f (racemate, 400 mg). The product was used directly in the next reaction without further purification. MS m / z (ESI): 263.3 [M+1]

[0788] Step 6

[0789] (±)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepane-9-carboxylic acid methyl ester 7g

[0790] Compound 4f (248 mg, 0.989 mmol) and triethylamine (231 mg, 2.287 mmol) were added to dichloromethane (5 mL), and methanesulfonyl chloride (113 mg, 0.914 mmol) was added dropwise under ice-cooling. The mixture was stirred for 2 hours, quenched with water, extracted with dichloromethane, separated, and the organic phase was added with anhydrous sodium sulfate to dryness. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), and compound 7f (200 mg, 0.762 mmol) and potassium carbonate (317 mg, 2.281 mmol) were added. The mixture was heated to 75°C for 12 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with dichloromethane, separated, and the organic phase was added with anhydrous sodium sulfate to dryness. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 7g (racemate, 270 mg, yield: 71%).

[0791] MS m / z(ESI):495.2[M+1].

[0792] Step 7

[0793] (±)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepane-9-carboxylic acid 7h

[0794] Compound 7g (270 mg, 0.545 mmol) was added to a mixed solvent of water (2 mL), tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (228 mg, 5.433 mmol) was added. The mixture was heated to 50°C and stirred for 10 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 3 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane. The organic phase was separated, and anhydrous sodium sulfate was added to dry the organic phase. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound 7h (racemate, 160 mg). The product was used directly in the next reaction without purification.

[0795] MS m / z(ESI):481.2[M+1].

[0796] Step 8

[0797] tert-Butyl 4-((3R)-3-((4-(N-(3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepane-9-carbonyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 7i

[0798] Compound 7h (160 mg, 0.333 mmol) and compound 4i (152 mg, 0.233 mmol) were dissolved in dichloromethane (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 0.995 mmol), triethylamine (169 mg, 1.670 mmol), and 4-dimethylaminopyridine (41 mg, 0.332 mmol) were added respectively. The reaction 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 with elution system A to give the title compound 7i (diastereomeric mixture, 230 mg, yield: 62%).

[0799] MS m / z(ESI):1115.6[M+1].

[0800] Step 9

[0801] 3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepane-9-carboxamide 7j

[0802] Compound 7i (230 mg, 0.206 mmol) was added to a 4 M hydrogen chloride 1,4-dioxane solution (3 mL) and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 7j (diastereomeric mixture, 200 mg), which was used directly in the next reaction without purification.

[0803] MS m / z(ESI):1015.6[M+1].

[0804] Step 10

[0805] 3-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidine-1- (amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepan-9-carboxamide 7

[0806] Compound 7j (200 mg, 0.197 mmol) and compound 2g (116 mg, 0.197 mmol) were dissolved in dichloromethane (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (113 mg, 0.297 mmol) and triethylamine (100 mg, 0.988 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 28, chromatographic column: X-Bridge, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 45%-55%, flow rate: 30 mL / min) to give the title compound 7 (a mixture of two diastereomers, 100 mg, yield: 32%).

[0807] MS m / z(ESI):1583.3[M+1].

[0808] 1H NMR (500MHz, CDCl3): δ8.69(s,1H),8.37(s,1H),8.08(d,1H),7.49(s,1H),7.46-7.27(m,10H),7. 10(d,1H),7.00(d,2H),6.85(s,1H),6.64(s,1H),6.28(dd,1H),5.10(q,1H),4.77(t,1H),4.60(d ,1H),4.49(s,1H),4.27-4.10(m,2H),3.96-3.83(m,2H),3.75-3.66(m,2H),3.59(dd,1H),3.53-2 .95(m,12H),2.85-2.75(m,2H),2.55-1.89(m,25H),1.77-1.30(m,12H),1.03(s,9H),0.97(s,6H).

[0809] Example 8

[0810] (2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((7-(4-chlorophenyl)-2-methyl-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 8

[0811] first step

[0812] 2-(tert-Butyl)6-methyl7-hydroxy-2-azaspiro[3.5]non-6-ene-2,6-dicarboxylate 8b

[0813] Tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate 8a (3.9 g, 16.42 mmol, WuXi AppTec) was dissolved in tetrahydrofuran (100 mL). Sodium hydride (2.1 g, 49.35 mmol, 60%) was added portionwise at 0°C. The reaction was stirred at 0°C for 0.5 hours, followed by the dropwise addition of dimethyl carbonate (4.4 g, 49.29 mmol). After the addition was complete, the temperature was raised to 65°C and stirred for 3 hours. The reaction solution was cooled to room temperature and quenched by pouring into an excess of glacial saturated aqueous ammonium chloride. The solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 8b (3.6 g, 73.11% yield).

[0814] MS m / z(ESI):242.2[M-55].

[0815] Step 2

[0816] 2-(tert-Butyl)6-methyl7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.5]non-6-ene-2,6-dicarboxylate 8c

[0817] Compound 8b (3.6 g, 12.01 mmol) was dissolved in dichloromethane (100 mL), and N,N-diisopropylethylamine (4.7 g, 36.06 mmol) was added. Trifluoromethanesulfonic anhydride (5.1 g, 18.0 mmol) was added dropwise at -78°C. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 4 hours. The reaction mixture was quenched with water (50 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to obtain the title compound 8c (4.5 g, yield: 87.1%).

[0818] MS m / z(ESI):374.2[M-55].

[0819] Step 3

[0820] 2-(tert-Butyl)6-methyl7-(4-chlorophenyl)-2-azaspiro[3.5]non-6-ene-2,6-dicarboxylate 8d

[0821] Compound 8c (4.5 g, 10.46 mmol), 4-chlorophenylboronic acid (2.1 g, 13.62 mmol), tetrakistriphenylphosphine palladium (1.2 g, 1.05 mmol), and sodium carbonate (3.3 g, 31.42 mmol) were dissolved in a mixed solvent of toluene (75 mL), ethanol (25 mL), and water (25 mL). The reaction was stirred at 90°C under a nitrogen atmosphere overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to give the title compound 8d (3.8 g, 92.7% yield).

[0822] MS m / z(ESI):336.2[M-55].

[0823] Step 4

[0824] tert-Butyl 7-(4-chlorophenyl)-6-(hydroxymethyl)-2-azaspiro[3.5]non-6-ene-2-carboxylate 8e

[0825] Compound 8d (1.0 g, 2.55 mmol) was dissolved in tetrahydrofuran (20 mL), and a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (1.53 mL, 3.83 mmol) was added dropwise at 0°C. The reaction solution was stirred at 0°C for 15 minutes. The reaction solution was quenched by addition of sodium sulfate decahydrate and filtered. The filter cake was washed with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 8e (750 mg, 80.8% yield).

[0826] MS m / z(ESI):264.2[M-100].

[0827] Step 5

[0828] tert-Butyl 7-(4-chlorophenyl)-6-((4-(4-(ethoxycarbonyl)phenyl)piperazin-1-yl)methyl)-2-azaspiro[3.5]non-6-ene-2-carboxylate 8g

[0829] Compound 8e (520 mg, 1.43 mmol) and triethylamine (435 mg, 4.30 mmol) were dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (246 mg, 2.15 mmol) was added dropwise at room temperature. The mixture was stirred for 0.5 hours, quenched with water (15 mL), and extracted with dichloromethane (30 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL), and ethyl 4-(piperazin-1-yl)benzoate 8f (436 mg, 1.86 mmol) and potassium carbonate (593 mg, 4.29 mmol) were added. The mixture was heated to 75°C and reacted for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using Elution System B to afford the title compound 8g (569 mg, 68.6% yield).

[0830] MS m / z(ESI):580.4[M+1].

[0831] Step 6

[0832] Ethyl 4-(4-((7-(4-chlorophenyl)-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)benzoate 8h

[0833] Compound 8g (569 mg, 0.98 mmol) was dissolved in dichloromethane (15 mL), trifluoromethane (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (40 mL) and washed with an excess of saturated sodium bicarbonate solution. The layers were separated, and the resulting aqueous phase was extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 8h (470 mg). The product was used directly in the next reaction without further purification.

[0834] MS m / z(ESI):480.3[M+1].

[0835] Step 7

[0836] Ethyl 4-(4-((7-(4-chlorophenyl)-2-methyl-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)benzoate 8i

[0837] Compound 8h (470 mg, 0.98 mmol) was dissolved in methanol (5 mL), and 37-40% formaldehyde solution (159 mg, 1.96 mmol) was added, followed by portionwise addition of sodium triacetoxyborohydride (312 mg, 1.47 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to afford the title compound 8i (479 mg, 99.2% yield).

[0838] MS m / z(ESI):494.3[M+1].

[0839] Step 8

[0840] 4-(4-((7-(4-chlorophenyl)-2-methyl-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)benzoic acid 8j

[0841] Compound 8i (493 mg, 1.00 mmol) was dissolved in a mixture of water (5 mL), tetrahydrofuran (5 mL), and methanol (5 mL). Lithium hydroxide monohydrate (210 mg, 5.00 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid (1 M). A white solid precipitated and was filtered. The filter cake was washed twice with water and dried to afford the title compound 8j (300 mg, 64.5% yield).

[0842] MS m / z(ESI):466.3[M+1].

[0843] Step 9

[0844] (R)-tert-Butyl 4-(3-((4-(N-(4-(4-((7-(4-chlorophenyl)-2-methyl-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 8k

[0845] Compound 8j (200 mg, 0.43 mmol) and compound 4i (225 mg, 0.34 mmol) were dissolved in dichloromethane (10 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg, 1.29 mmol), triethylamine (131 mg, 1.29 mmol), and 4-dimethylaminopyridine (53 mg, 0.43 mmol) were added, respectively, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 8k (472 mg, 99.9% yield).

[0846] MS m / z(ESI):1100.7[M+1].

[0847] Step 10

[0848] (R)-4-(4-((7-(4-chlorophenyl)-2-methyl-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-N-((4-((1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 81

[0849] Compound 8k (185 mg, 0.17 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 8l (168 mg), which was used directly in the next reaction without purification.

[0850] MS m / z(ESI):1000.8[M+1].

[0851] Step 11

[0852] (2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((7-(4-chlorophenyl)-2-methyl-2-azaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 8

[0853] Compound 81 (168 mg, 0.17 mmol) and compound 2g (80 mg, 0.13 mmol) were dissolved in dichloromethane (10 mL). Triethylamine (170 mg, 1.68 mmol) was added and the reaction was stirred at room temperature until all the starting materials were dissolved. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (96 mg, 0.25 mmol) was then added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Gilson 281 column: Sharpsil-T, Prep 30×150 mm, 5 μm, C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 50%-70%, flow rate: 30 mL / min) to obtain the title compound 8 (13 mg, yield: 4.9%).

[0854] MS m / z(ESI):1570.8[M+1+2].

[0855] 1 H NMR (500MHz, CDCl3): δ8.67(s,1H),8.30(s,1H),8.00-7.92(m,3H),7.51-7.45(m,1H),7.40-7.27(m,6H ),7.24-7.21(m,2H),6.97(d,2H),6.84(d,1H),6.60(d,2H),6.51(d,1H),6.37(d,1H),5.10(q,1H),4.75 (t,1H),4.62(d,1H),4.49(s,1H),4.43-4.30(m,1H),4.09(d,1H),3.92-3.54(m,6H),3.40-3.32(m,4H), 3.09-2.60(m,14H),2.51(s,3H),2.40-2.04(m,22H),1.65-1.55(m,6H),1.47-1.46(m,3H),1.03(s,9H).

[0856] Example 9

[0857] (2S,4R)-1-((2S)-2-(7-(4-((3R)-3-((4-(N-(4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 9

[0858] first step

[0859] tert-Butyl 4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperidine-1-carboxylate 9b

[0860] At -78 ° C, 2-bromo-4'-chloro-1,1'-biphenyl 9a (1.17 g, 4.37 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in tetrahydrofuran (10 mL), and 2.5 M n-butyl lithium (2.93 mL, 7.33 mmol) was slowly added dropwise. After stirring for 30 minutes, tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.00 g, 3.69 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) was added. The mixture was warmed to room temperature and stirred for 2 hours. Saturated ammonium chloride solution was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent C to give the title compound 9b (1.00 g, yield: 68%).

[0861] MS m / z(ESI):398.2[M-1].

[0862] Step 2

[0863] (4'-Chloro-[1,1'-biphenyl]-2-yl)(piperidin-4-yl)methanone 9c

[0864] Compound 9b (1.00 g, 2.50 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (10 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 9c (840 mg), which was used directly in the next step without purification.

[0865] MS m / z(ESI):302.1[M+2+1].

[0866] Step 3

[0867] Ethyl 4-(4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperidin-1-yl)benzoate 9d

[0868] Compound 9c (840 mg, 2.49 mmol), ethyl 4-fluorobenzoate (630 mg, 3.74 mmol, Shanghai Shaoyuan), and cesium carbonate (1.03 g, 7.45 mmol) were dissolved in dimethyl sulfoxide (10 mL) and heated to 120°C with stirring for 14 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System C to afford the title compound 9d (500 mg, 44% yield).

[0869] MS m / z(ESI):448.1[M+1]

[0870] Step 4

[0871] 4-(4-(4'-Chloro-[1,1'-biphenyl]-2-carbonyl)piperidin-1-yl)benzoic acid 9e

[0872] Compound 9d (500 mg, 1.11 mmol) and lithium hydroxide (140 mg, 3.33 mmol) were dissolved in a mixed solvent of ethanol (30 mL) and water (10 mL). The mixture was heated to 80°C and stirred for 3 hours. The reaction solution was concentrated to remove ethanol, and the pH of the residue was adjusted to 2 with 1M dilute hydrochloric acid. A large amount of solid precipitated, which was filtered, washed with water, and dried to obtain the title compound 9e (400 mg, 85% yield).

[0873] MS m / z(ESI):420.1[M+1]

[0874] Step 5

[0875] (R)-tert-Butyl 4-(3-((4-(N-(4-(4'-chloro-[1,1'-biphenyl]-2-carbonyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 9f

[0876] Compound 9e (200 mg, 0.419 mmol) and compound 4i (217 mg, 0.33 mmol) were dissolved in dichloromethane (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (273 mg, 1.42 mmol), triethylamine (144 mg, 1.42 mmol), and 4-dimethylaminopyridine (58 mg, 0.47 mmol) were added respectively. The reaction was stirred at room temperature for 12 hours, and the filtrate was collected by filtration. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with elution system A to give the title compound 9f (200 mg, yield: 39%).

[0877] MS m / z(ESI):1054.6[M+1].

[0878] Step 6

[0879] tert-Butyl 4-((3R)-3-((4-(N-(4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 9g

[0880] Compound 9f (200 mg, 0.19 mmol) was dissolved in methanol (10 mL) under ice-cooling, and sodium borohydride (21 mg, 0.55 mmol) 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 A to obtain the title compound 9g (diastereoisomer mixture, 150 mg, yield: 74%).

[0881] MS m / z(ESI):1056.6[M+1].

[0882] Step 7

[0883] 4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidin-1-yl)-N-((4-(((R)-1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 9h

[0884] Compound 9g (150 mg, 0.14 mmol) was added to a 4 M hydrogen chloride 1,4-dioxane solution (3 mL) and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 9h (a mixture of two diastereomers, 300 mg), which was used directly in the next reaction without purification.

[0885] MS m / z(ESI):956.6[M+1].

[0886] Step 8

[0887] (2S,4R)-1-((2S)-2-(7-(4-((3R)-3-((4-(N-(4-(4-((4'-chloro-[1,1'-biphenyl]-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 9

[0888] The crude product of compound 9h (130 mg) and compound 2g (79 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (77 mg, 0.20 mmol) and triethylamine (68 mg, 0.67 mmol) were added. The reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (instrument model: Gilson 28, chromatographic column: X-Bridge, Prep30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 45%-55%, flow rate: 30 mL / min) to give the title compound 9 (a mixture of two diastereomers, 30 mg, yield: 14%).

[0889] MS m / z(ESI):1524.3[M+1].

[0890] 1 H NMR (500MHz, CDCl3): δ8.69(s,1H),8.37(d,1H),8.11(d,1H),7.65(d,2H),7.60(d,1H),7.51-7.16(m,12H),7.11 (d,1H),6.75(d,2H),6.65-6.63(m,1H),6.30(d,1H),5.09(q,1H),4.74(t,1H),4.60(d,1H),4.51-4.49(m,2H),4 .13(d,1H),3.99-3.83(m,2H),3.75-3.64(m,2H),3.57(d,1H),3.45-3.26(m,3H),3.18-3.10(m,1H),3.06-3.01( m,1H),2.77(t,1H),2.66(t,1H),2.51(s,3H),2.47-1.99(m,14H),1.88-1.52(m,17H),1.48(d,3H),1.06(s,9H).

[0891] Example 10

[0892] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 10

[0893] Compound 5j (46 mg, 0.05 mmol) and 8-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoic acid 10a (31 mg, 0.05 mmol, prepared by the method disclosed in intermediate 16 on page 61 of the specification of patent application WO2020163823A2) were dissolved in dichloromethane (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) and triethylamine (47 mg, 0.46 mmol) were added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Waters Autopurification-SQD, chromatographic column: Welch Xtimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 65%-95%, flow rate: 30 mL / min) to obtain the title compound 10 (25 mg, yield: 34.3%).

[0894] MS m / z(ESI):1583.4[M+1].

[0895] 1H NMR (500MHz, CDCl3): δ8.67(s,1H),8.36(d,1H),8.10(dd,1H),7.46(d,1H),7.44-7.20(m,10H),7.11(d,1H),6.9 9(d,2H),6.66(dd,2H),6.36(d,1H),5.19(q,1H),4.75(t,1H),4.62(d,1H),4.49(s,1H),4.19-4.09(m,2H),3.97- 3.80(m,2H),3.75-3.55(m,4H),3.49-3.29(m,4H),3.24(t,1H),3.16-3.08(m,1H),3.07-2.98(m,1H),2.89-2.75 (m,4H),2.69(d,1H),2.50(s,3H),2.48-1.94(m,22H),1.89(t,1H),1.77-1.42(m,12H),1.03(s,9H),0.97(s,6H).

[0896] Example 11

[0897] (R)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl

[0898] 1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide

[0899] Compound 4j (100 mg, 0.092 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 hour, and concentrated to obtain a crude product. The crude product and compound 10a (60 mg, 0.10 mmol) were dissolved in dichloromethane (3.0 mL), and triethylamine (100 mg, 0.99 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281, chromatographic column: X-Bridge, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give the title compound 11 (30 mg, yield: 20%).

[0900] MS m / z(ESI):1584.4[M+1].

[0901] 1 H NMR (500MHz, CDCl3): δ8.69(s,1H),8.38(d,1H),8.10(dd,1H),7.51-7.18(m,11H),7.1 1(d,1H),6.99(d,2H),6.70(d,1H),6.68-6.62(m,1H),6.30-6.22(m,1H),5.11(q,1H),4 .77(t,1H),4.62(d,1H),4.55-4.53(m,1H),4.21-4.10(m,2H),4.01-2.62(m,21H),2.54 (s,1H),2.44-1.94(m,12H),1.82-1.52(m,18H),1.49(d,3H),1.06(s,9H),1.01(s,6H).

[0902] Example 12-1 or 12-2

[0903] (S)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 12-1

[0904] or

[0905] (S)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 12-2

[0906] first step

[0907] 2-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenol 12b

[0908] 2-Bromo-5-(hydroxymethyl)phenol 12a (6 g, 29.55 mmol) and imidazole (2.3 g, 33.34 mmol) were dissolved in a mixed solvent of dichloromethane (90 mL) and tetrahydrofuran (30 mL). A solution of tert-butyldimethylsilyl chloride (5.0 g, 33.31 mmol) in tetrahydrofuran (15 mL) was added dropwise at 0°C, followed by stirring at 0°C for 2 hours. The reaction solution was quenched by the addition of water (100 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to afford the title compound 12b (8.2 g, 84.5% yield).

[0909] MS m / z(ESI):339.0[M+23].

[0910] Step 2

[0911] 4-((2-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)methyl)thiazole 12d

[0912] Compound 12b (8.2 g, 25.84 mmol), thiazol-4-ylmethanol 12c (4.5 g, 38.73 mmol, Bid), and tri-n-butylphosphine (10.5 g, 51.70 mmol) were dissolved in toluene (100 mL). A solution of azodicarbonyldipiperidine (13.1 g, 51.72 mmol) in toluene (40 mL) was added dropwise under a nitrogen atmosphere. After the addition was complete, the mixture was heated to 60°C and stirred for 0.5 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to afford the title compound 12d (7.7 g, 71.9% yield).

[0913] MS m / z(ESI):414.2[M+1].

[0914] Step 3

[0915] 7-(((tert-Butyldimethylsilyl)oxy)methyl)-4H-chromeno[3,4-d]thiazole 12e

[0916] Compound 12d (500 mg, 1.21 mmol), anhydrous potassium carbonate (501 mg, 3.63 mmol), triphenylphosphine (317 mg, 1.21 mmol), and palladium acetate (135 mg, 601.31 μmol) were dissolved in N,N-dimethylformamide (10 mL). The temperature was raised to 100°C and stirred under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to provide the title compound 12e (225 mg, 55.9% yield).

[0917] MS m / z(ESI):334.0[M+1].

[0918] Step 4

[0919] (4H-chromeno[3,4-d]thiazol-7-yl)methanol 12f

[0920] Compound 12e (225 mg, 0.67 mmol) was dissolved in tetrahydrofuran (10 mL). A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.0 mL, 2.02 mmol) was added dropwise at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent B to afford the title compound 12f (62 mg, 41.9% yield).

[0921] MS m / z(ESI):220.1[M+1].

[0922] Step 5

[0923] 4H-chromeno[3,4-d]thiazole-7-carbaldehyde 12g

[0924] Compound 12f (760 mg, 3.46 mmol) was dissolved in dichloromethane (30 mL). Dess-Martin periodinane (2.2 g, 5.19 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane. The filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent B to obtain the title compound 12g (750 mg, 99.6% yield).

[0925] MS m / z(ESI):218.0[M+1].

[0926] Step 6

[0927] (E)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methylidene)-2-methylpropane-2-sulfenamide 12h

[0928] Compound 12g (750 mg, 3.45 mmol), tert-butylsulfenamide (1.3 g, 10.40 mmol), and cesium carbonate (5.6 g, 17.19 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane. The filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent B to obtain the title compound 12h (1.1 g, 99.4% yield).

[0929] MS m / z(ESI):321.2[M+1].

[0930] Step 7

[0931] N-(1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)-2-methylpropane-2-sulfenamide 12i

[0932] Compound 12h (1.1 g, 3.43 mmol) was dissolved in dichloromethane (25 mL). A 3M solution of methylmagnesium bromide in 2-methyltetrahydrofuran (5.7 mL, 17.19 mmol) was added dropwise at 0°C under a nitrogen atmosphere. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 3 hours. The reaction solution was quenched by the addition of glacial saturated aqueous ammonium chloride and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent A to obtain the title compound 12i (racemic compound, 789 mg, yield: 68.3%).

[0933] MS m / z(ESI):337.2[M+1].

[0934] Step 8

[0935] tert-Butyl (2S,4R)-2-((1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidine-1-carboxylate 12j

[0936] Compound 12i (789 mg, 2.34 mmol) was dissolved in 4 M hydrogen chloride 1,4-dioxane solution (3 mL) and stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure and the residue was dissolved in N,N-dimethylformamide (20 mL). (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (600 mg, 2.59 mmol, Shanghai Shaoyuan) and N,N-diisopropylethylamine (910 mg, 7.04 mmol) were added. After the solution was clarified, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.1 g, 2.89 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent A to give the title compound 12j (a mixture of two diastereomers, 1.0 g, yield: 95.7%).

[0937] MS m / z(ESI):446.3[M+1].

[0938] Step 9

[0939] tert-Butyl ((2S)-1-((2S,4R)-2-((1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 12k

[0940] Compound 12j (1.1 g, 2.40 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (10 mL) and stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in N,N-dimethylformamide (20 mL). (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (666 mg, 2.88 mmol) and triethylamine (1.2 g, 12.00 mmol) were added. After the solution clarified, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.4 g, 3.60 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent A to provide the title compound 12k (a mixture of two diastereomers, 1.3 g, yield: 97.0%).

[0941] MS m / z(ESI):559.1[M+1].

[0942] Step 10

[0943] tert-Butyl ((S)-1-((2S,4R)-2-(((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 12l-1

[0944] tert-Butyl ((S)-1-((2S,4R)-2-(((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 12l-2

[0945] Compound 12k (1.3 g, 2.33 mmol) was purified by preparative HPLC (Shimadzu LC-20AP, column: Sharpsil-T Prep C18, 50*250 mm, 8 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 80 mL / min) to give the title compound (300 mg, yield: 22.3%) and the title compound (400 mg, yield: 29.8%).

[0946] MS m / z(ESI):559.3[M+1].

[0947] Single configuration compound (shorter retention time, retention time: 1.83 min, 300 mg, yield: 22.3%);

[0948] MS m / z(ESI):559.4[M+1].

[0949] Single configuration compound (longer retention time, retention time: 1.88 min, 400 mg, yield: 29.8%).

[0950] Step 11

[0951] (2S,4R)-N-((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide 12m-1

[0952] or

[0953] (2S,4R)-N-((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide 12m-2

[0954] The compound with longer retention time (150 mg, 0.27 mmol) among compounds 12l-1 and 12l-2 was added to a 4M hydrogen chloride solution in 1,4-dioxane (5 mL), and the reaction was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 12m-1 or 12m-2 (123 mg). The product was used directly in the next reaction without purification.

[0955] MS m / z(ESI):459.3[M+1].

[0956] Step 12

[0957] 7-(((S)-1-((2S,4R)-2-(((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid methyl ester 12n-1

[0958] or

[0959] 7-(((S)-1-((2S,4R)-2-(((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid methyl ester 12n-2

[0960] Crude compound 12m-1 or 12m-2 (82 mg, 0.18 mmol) was dissolved in dichloromethane (5 mL) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) was added. Once the starting material was completely dissolved, 7-methoxy-7-oxoheptanoic acid (40 mg, 0.23 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (102 mg, 0.27 mmol) were added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent A to afford the title compound 12n-1 or 12n-2 (109 mg, 99.2% yield). MS m / z (ESI): 615.3 [M+1].

[0961] Step 13

[0962] 7-(((S)-1-((2S,4R)-2-(((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid 12o-1

[0963] or

[0964] 7-(((S)-1-((2S,4R)-2-(((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid 12o-2

[0965] Crude compound 12n-1 or 12n-2 (109 mg, 0.18 mmol) was dissolved in a mixed solvent of methanol (2.5 mL), water (2.5 mL), and tetrahydrofuran (2.5 mL). Lithium hydroxide monohydrate (75 mg, 1.78 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous phase was adjusted to pH 5-6 with 1M dilute hydrochloric acid and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 12o-1 or 12o-2 (100 mg).

[0966] MS m / z(ESI):601.3[M+1].

[0967] Step 14

[0968] (S)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 12-1

[0969] or

[0970] (S)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 12-2

[0971] Compound 12o-1 or 12o-2 (40 mg, 0.04 mmol) and compound 5j (55 mg, 0.06 mmol) were dissolved in dichloromethane (5 mL). Triethylamine (23 mg, 0.22 mmol) was added. Once all the starting materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545 column: YMC Triart-Exrs, Prep 30×150 mm, 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 55% to 75%, flow rate: 30 mL / min) to obtain the title compound 12-1 or 12-2 (16 mg, yield: 18.4%).

[0972] MS m / z(ESI):1583.5[M+1].

[0973] 1 H NMR (500 MHz, CDCl3)

[0974] δ8.70(s,1H),8.37(s,1H),8.15-7.99(m,1H),7.66-6.84(m,13H),6.76-6.58(m,2H),6.44-6.32(m,1H),5.63-6.29(m,2H), 5.06-4.93(m,1H),4.84-4.43(m,3H),4.23-4.03(m,2H),4.03-2.62(m,22H),2.60-1.15(m,30H),1.04(s,9H),1.00(s,6H).

[0975] Examples 13-1 and 13-2

[0976] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(5-((5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidone (1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide) (13-1)

[0977] or

[0978] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(5-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidone (1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 13-2

[0979] first step

[0980] 5-((5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid 13a-1

[0981] or

[0982] 5-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid 13a-2

[0983] Compound 1f (240 mg, 0.33 mmol) was purified by preparative HPLC (instrument model: Waters-2545 column: YMC Triart-Exrs, Prep 30×150 mm; 5 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compounds (30 mg, yield: 15.2%) and (40 mg, yield: 20.2%).

[0984] Single configuration compound (shorter retention time, retention time 1.48 minutes, 30 mg, yield: 15.2%):

[0985] MS m / z(ESI):599.3[M+1].

[0986] Single configuration compound (longer retention time, retention time 1.55 minutes, 40 mg, yield: 20.2%):

[0987] MS m / z(ESI):599.3[M+1].

[0988] Step 2

[0989] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(5-((5-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidone (1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide) (13-1)

[0990] or

[0991] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(5-((5-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)formamido)pyrrolidone (1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 13-2

[0992] The compound with a shorter retention time among compounds 13a-1 and 13a-2 (30 mg, 0.05 mmol) and compound 5j (50 mg, 0.05 mmol) were dissolved in dichloromethane (5 mL), and triethylamine (31 mg, 0.30 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (38 mg, 0.10 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281, column: Welch Xltimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30 mL / min) to obtain the title compound 13-1 or 13-2 (25 mg, yield: 31.7%).

[0993] MS m / z(ESI):1581.2[M+1].

[0994] 1 H NMR (500MHz, CDCl3): δ8.69(s,1H),8.37(s,1H),8.10(d,1H),7.44-7.24(m,11H), 7.20(s,1H),7.12(d,1H),6.99(d,2H),6.69(d,1H),6.64(d,1H),5.87(s,1H),4.9 9(q,1H),4.82-4.74(m,1H),4.69-4.60(m,1H),4.28-4.12(m,3H),4.01-3.79(m,3 H),3.79-3.22(m,10H),3.17-2.69(m,9H),2.66-1.18(m,31H),1.09-0.88(m,12H).

[0995] The compound with longer retention time among compounds 13a-1 and 13a-2 (30 mg, 0.05 mmol) and compound 5j (33 mg, 0.03 mmol) were dissolved in dichloromethane (5 mL), and triethylamine (31 mg, 0.30 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (38 mg, 0.10 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281, column: Welch Xltimate, Prep 30×250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 60%-95%, flow rate: 30 mL / min) to obtain the title compound 13-1 or 13-2 (25 mg, yield: 31.7%).

[0996] MS m / z(ESI):1581.3[M+1].

[0997] 1H NMR (500MHz, CDCl3): δ8.87-8.61(m,1H),8.36(s,1H),8.10(d,1H),7.60(d,1 H),7.48-7.17(m,11H),7.10(d,1H),6.99(d,2H),6.74-6.59(m,2H),5.85(s, 1H),5.09(q,1H),4.72-4.55(m,2H),4.29-4.08(m,3H),4.01-2.63(m,24H),2 .61-1.87(m,18H),1.85-1.67(m,5H),1.60-1.42(m,6H),1.16-0.79(m,12H).

[0998] Example 14

[0999] (S)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 14

[1000] Compound 5i (50 mg, 0.045 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 h, and concentrated to obtain a crude product. The crude product and compound 3l (30 mg, 0.051 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (30 mg, 0.232 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.053 mmol) were added, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281 column: X-Bridge, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give the title compound 14 (25 mg, yield: 35.1%).

[1001] MS m / z(ESI):1571.7[M+1+2].

[1002] 1 H NMR (500MHz, CDCl3): δ8.70(s,1H),8.39(d,1H),8.08(dd,1H),7.68(d,2H),7.45-7.22(m,4H),7.21(d,1H),7.16(d,1H ),7.11(d,1H),6.99(d,2H),6.92-6.86(m,2H),6.69(d,1H),6.66(d,1H),6.37(d,1H),5.44(s,2H),4.75(t,1H),4.59(d ,1H),4.55-4.51(m,1H),4.47(dd,1H),4.26(dd,1H),4.14(t,2H),3.95-3.91(m,1H),3.86(t,1H),3.77-3.56(m,3H),3. 48-3.19(m,4H),3.17-2.99(m,2H),2.90-2.76(m,3H),2.75-2.66(m,1H),2.58-1.21(m,34H),1.00(s,6H),0.97(s,9H).

[1003] Example 15

[1004] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((4,5-dihydrobenzo[6,7]oxepinano[4,5-d]thiazol-8-yl)methyl)formamido)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)formamido)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)formamido)- 1-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 15

[1005] first step

[1006] 4-(2-(2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)ethyl)thiazole 15b

[1007] Compound 12b (750 mg, 2.36 mmol), 2-(thiazol-4-yl)ethan-1-ol 15a (350 mg, 2.71 mmol, prepared using the method disclosed for intermediate S25 on page 65 of patent application WO2021 / 102114A1), and tri-n-butylphosphine (1.46 g, 7.27 mmol) were dissolved in toluene (20 mL). A solution of azodicarbonyldipiperidine (1.82 g, 7.22 mmol) in toluene (10 mL) was added dropwise under a nitrogen atmosphere. After completion of the addition, the mixture was heated to 60°C and stirred for 0.5 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to afford the title compound 15b (430 mg, 42.4% yield).

[1008] MS m / z(ESI):428.1[M+1].

[1009] Step 2

[1010] 8-(((tert-Butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[4,5]oxepano[2,3-d]thiazole 15c

[1011] Compound 15b (410 mg, 0.958 mmol), anhydrous potassium carbonate (400 mg, 2.90 mmol), triphenylphosphine (260 mg, 0.992 mmol), and palladium acetate (110 mg, 0.491 mmol) were dissolved in N,N-dimethylformamide (10 mL). The temperature was raised to 100°C and stirred under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to provide the title compound 15c (150 mg, 45.0% yield).

[1012] MS m / z(ESI):348.1[M+1].

[1013] Step 3

[1014] (5,6-Dihydrobenzo[4,5]oxepinano[2,3-d]thiazol-8-yl)methanol 15d

[1015] Compound 15c (150 mg, 0.432 mmol) was dissolved in tetrahydrofuran (3.0 mL). A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.3 mL, 1.3 mmol) was added dropwise at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent A to afford the title compound 15d (70 mg, 69.5% yield).

[1016] MS m / z(ESI):234.1[M+1].

[1017] Step 4

[1018] 5,6-Dihydrobenzo[4,5]oxepin[2,3-d]thiazole-8-carbaldehyde 15e

[1019] Compound 15d (70 mg, 0.300 mmol) was dissolved in dichloromethane (5.0 mL). Dess-Martin periodinane (200 mg, 0.471 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane. The filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to afford the title compound 15e (60 mg, 86.4% yield).

[1020] MS m / z(ESI):232.1[M+1].

[1021] Step 5

[1022] (E)-N-((5,6-Dihydrobenzo[4,5]oxepinano[2,3-d]thiazol-8-yl)methylidene)-2-methylpropane-2-sulfenamide 15f

[1023] Compound 15e (60 mg, 0.259 mmol), tert-butylsulfenamide (35 mg, 0.289 mmol), and cesium carbonate (110 mg, 0.337 mmol) were dissolved in dichloromethane (3.0 mL) and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane. The filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent C to afford the title compound 15f (80 mg, 92.1% yield).

[1024] MS m / z(ESI):335.2[M+1].

[1025] Step 6

[1026] N-((5,6-dihydrobenzo[4,5]oxepinano[2,3-d]thiazol-8-yl)methyl)-2-methylpropane-2-sulfenamide 15g

[1027] Compound 15f (80 mg, 0.239 mmol) was dissolved in methanol (2.0 mL), and sodium borohydride (10 mg, 0.263 mmol) was added at 0°C. The mixture was reacted at room temperature for 10 minutes. Water was added and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and the filtrate was collected by filtration and concentrated to give the crude title compound 15g (80 mg). The product was used directly in the next reaction without purification.

[1028] MS m / z(ESI):337.2[M+1].

[1029] Step 7

[1030] tert-Butyl (2S,4R)-2-(((4,5-dihydrobenzo[6,7]oxepinano[4,5-d]thiazol-8-yl)methyl)formamido)-4-hydroxypyrrolidine-1-carboxylate 15h

[1031] Compound 15g (80 mg, 0.237 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 hour, and concentrated to obtain a crude product. The crude product and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (60 mg, 0.259 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (90 mg, 0.696 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg, 0.289 mmol) were added and reacted at room temperature for 1 hour. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was collected after filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 15h (100 mg, yield: 94.4%).

[1032] MS m / z(ESI):446.2[M+1].

[1033] Step 8

[1034] tert-Butyl ((S)-1-((2S,4R)-2-(((4,5-dihydrobenzo[6,7]oxepinano[4,5-d]thiazol-8-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 15i

[1035] Compound 15h (100 mg, 0.224 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 hour, and concentrated to obtain a crude product. The crude product and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (60 mg, 0.259 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and triethylamine (150 mg, 1.16 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.263 mmol) were added. The reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was collected by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 15i (120 mg, yield: 95.6%).

[1036] MS m / z(ESI):559.3[M+1].

[1037] Step 9

[1038] 7-(((S)-1-((2S,4R)-2-(((4,5-dihydrobenzo[6,7]oxepinano[4,5-d]thiazol-8-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid methyl ester 15j

[1039] Compound 15i (120 mg, 0.214 mmol) was dissolved in a hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 h, and concentrated to obtain a crude product. The crude product and 7-methoxy-7-oxoheptanoic acid (40 mg, 0.230 mmol, Leyan) were dissolved in dichloromethane (3.0 mL), and N,N-diisopropylethylamine (140 mg, 1.06 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.262 mmol) were added. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was collected after filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 15j (130 mg, yield: 90%).

[1040] MS m / z(ESI):615.4[M+1].

[1041] Step 10

[1042] 7-(((S)-1-((2S,4R)-2-(((4,5-dihydrobenzo[6,7]oxepinano[4,5-d]thiazol-8-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid 15k

[1043] Compound 15j (130 mg, 0.211 mmol) was added to a mixed solvent of water (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (45 mg, 1.07 mmol) was added. The reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 4-5 with dilute hydrochloric acid. The mixture was extracted with dichloromethane, separated, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude title compound 15k (120 mg). The product was used directly in the next reaction without purification.

[1044] MS m / z(ESI):601.4[M+1].

[1045] Step 11

[1046] (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((4,5-dihydrobenzo[6,7]oxepinano[4,5-d]thiazol-8-yl)methyl)formamido)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)formamido)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)formamido)- 1-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 15

[1047] Compound 5i (50 mg, 0.045 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (2 mL, 4.0 M), stirred for 0.5 hour, and concentrated to obtain a crude product. The crude product and compound 15k (30 mg, 0.050 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (30 mg, 0.232 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.053 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Gilson 281 column: X-Bridge, Prep 30×150 mm, 5 μm, C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient: 35% to 60% acetonitrile, flow rate: 30 mL / min) to afford the title compound 15 (25 mg, yield: 34.8%). MS m / z (ESI): 1585.9 [M+2+1].

[1048] 1 H NMR (500MHz, CDCl3-d): δ8.66(s,1H),8.38(s,1H),8.08(dd,1H),7.56-7.16(m,8H),7.11(d,1 H),7.02-6.93(m,4H),6.68(d,1H),6.66(d,1H),6.37(d,1H),4.75(t,1H),4.59(d,1H),4.53-4 .51(m,1H),4.48(dd,1H),4.37-4.24(m,2H),4.14(t,2H),4.06-3.80(m,5H),3.76-3.67(m,1H ),3.62(d,2H),3.54-2.74(m,17H),2.70(d,1H),2.58-1.17(m,26H),1.00(s,6H),0.97(s,9H).

[1049] Example 16-1 or 16-2

[1050] (S)-N-((4-(((R)-4-(4-(8-(((S)-1-((2S,4R)-2-(((R)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl)- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxamide 16-1

[1051] or

[1052] (S)-N-((4-(((R)-4-(4-(8-(((S)-1-((2S,4R)-2-(((S)-1-(4H-chromeno[3,4-d]thiazol-7-yl)ethyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctanoyl)piperazin-1-yl) -1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)met...

Claims

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is * end connected to the benzene ring; R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; R 1a , R 1b , R 1c and R 1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; the alkyl and cycloalkyl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents in; or R 1a and R 1b Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents in; or R 1c and R 1d Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents in; each R 1e are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, hydroxyl, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; Z is CR 0 or N; R 0 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkylalkyl and cycloalkyl; R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; or, R 3 and R 4 together with the carbon atoms to which they are attached form a heterocyclic group; the heterocyclic group is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cycloalkylalkyl, cycloalkyl, hydroxy, cyano, nitro and -(CH2) s NR 2a R 2b is substituted by one or more substituents in; each R 3a and each R 4a are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; X is O or NH; R 5 Selected from -S(O)R 5a 、-S(O)2R 5a , halogen, nitro, cyano and haloalkyl; R 5a is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl; R is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; Y is selected from a bond, O, NR 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -heterocyclyl-O-*, -heterocyclyl-NR 6 -*and * end connected to L; the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, nitro, -(CH2) s NR 2a R 2b , cycloalkyl and cycloalkylalkyl; R 6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and cycloalkyl; Ring C is aryl or heteroaryl; the aryl or heteroaryl are each independently selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxyl, cyano, -(CH2) s NR 2a R 2b and cycloalkyl; Ring D is cycloalkyl or heterocyclic; The cycloalkyl or heterocyclic groups are each independently selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, -(CH2) s NR 2a R 2b and one or more substituents in the cycloalkyl group; R 2a and R 2b are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a cycloalkylalkyl group; L is a linking unit; A is selected from R 9 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, amino, cyano, hydroxy, cycloalkyl, heterocyclyl, cycloalkylalkyl and heterocyclylalkyl; R 10 Ring E is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclic groups; the aryl, heteroaryl, cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl; Ring F is cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is each independently optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amino, cycloalkyl and cycloalkylalkyl; Ring G is aryl or heteroaryl; each R 12 and each R 15 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxy, -SH, -OC(O)alkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, alkylthio, haloalkoxy, cyano, cycloalkyl and cycloalkylalkyl; W 1 C or N; W 2 is C or N; a is 0, 1, 2 or 3; b is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; s is 0, 1, 2 or 3; n is 0, 1, 2 or 3; w is 0, 1, 2 or 3; and u is 0, 1, 2 or 3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is L 1 Connected to Y, L 5 Connected to A; where: L 1 , L 2 , L 3 and L 4 are each independently selected from a bond, -NR A -, -O-, -S-, -C(O)-, -C(S)-, -S(O)2-, -C(O)NR A -、-NR A C(O)-、-NR A C(O)NR B -, -C(O)O-, -OC(O)-, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylene-O-, -O-alkylene-, -alkylene-O-alkylene-, -alkylene-O-alkylene-O-alkylene-, -alkylene-cycloalkyl-alkylene-, -alkylene-heterocyclyl-alkylene-, -alkylene-aryl-alkylene-, -alkylene-heteroaryl-alkylene-, and * is connected to the right side group; the alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, nitro, amino and cycloalkyl; p is an integer from 0 to 5; q is an integer from 0 to 5; f is an integer from 0 to 10; L 5 is selected from the group consisting of a bond, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -O-, -S-, -S(O)2-, -NR A -, -C(O)-, -C(S)-, -O-alkylene-, -alkylene-O-, -C(O)NR A -、-NR A C(O)-, -C(O)O-, -OC(O)-, -C(O)-alkylene-, -alkylene-C(O)-, -NR A -Alkylene-, -Alkylene-NR A -、-NR A (CH2) 0-3 O(CH2) 0-3 O-, -O(CH2) 0-3 O(CH2) 0-3 NR A -、-NR A C(O)(CH2) 0-3 NR B -、-NR B (CH2) 0-3 C(O)NR A -and The alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from oxo, halogen, alkyl, haloalkyl and hydroxyl; R A and R B The same or different, and each independently is a hydrogen atom or an alkyl group; preferably, L is selected from * is connected to A. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Y is a 4- to 11-membered heterocyclic group or The 4 to 11 membered heterocyclic group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 is substituted by one or more substituents in hydroxyalkyl; Ring C is a 5- or 6-membered heteroaryl; Ring D is a 5- or 6-membered heterocyclic group; Preferably, Y is selected from More preferably, Y is * terminal is connected to L. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: in: Ring B is a 4- to 11-membered nitrogen-containing heterocyclic group or * is connected to C(O); the 4- to 11-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R b Ring C is a 5- or 6-membered heteroaryl group; the 5- or 6-membered heteroaryl group is optionally substituted by one or more R b Ring D' is a 5- or 6-membered nitrogen-containing heterocyclic group; the 5- or 6-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R b Replace; each R b are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, nitro, -(CH2) s NR 2a R 2b and cycloalkyl; t is an integer from 0 to 10; Ring A, R, R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , R 2a , R 2b , Z, X, s, n, x, y, L 3 , L 4 , L 5 and A as defined in claim 2. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X is NH; and / or R is a hydrogen atom. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 5, wherein L 3 and L 4 is a key; and / or L 5 is selected from a bond, -O- and OCH2, CH2 is connected to structure A; preferably, L 3 and L 4 is a key; and / or L 5 is a bond or -O-. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein A is selected from Preferably selected from The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 is a halogen, preferably F or Cl, more preferably Cl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein ring A is selected from Preferably The * end is connected to the benzene ring. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 is a hydrogen atom or a hydroxyl group, preferably a hydrogen atom; and / or Z is N or CR 0 ; R 0 A hydrogen atom or C 1-6 Hydroxyalkyl. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 3 and R 4 are independently a hydrogen atom or a C 1-6 Hydroxyalkyl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group, wherein the 6- or 7-membered heterocyclic group is optionally selected from oxo and C 1-6 Preferably, R 3 and R 4 are all hydrogen atoms; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 6- or 7-membered heterocyclic group. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 5 C 1-6 Preferably, R 5 It is -S(O)2CF3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claims 4 to 12, wherein ring B is selected from Preferably, ring B is The * bond is connected to C(O). A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof: A compound represented by the general formula (II-1B), (II-2B), (II-3B) or (III-4A) or a salt thereof: in: Ring A, Ring B, Ring E, Ring F, Ring G, W 1 , W 2 , R 1 , R 2 , R 3a , R 4a , R 5 , R 9 , R 10 , R 12 , Z, L 3 , L 4 , L 5 , u, t, n, x and y are as defined in claim 4. A compound or a salt thereof selected from: A method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, comprising the following steps: The compound represented by the general formula (IIA) or its salt and the compound represented by the general formula (IIB) or its salt undergo condensation reaction to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt; wherein: Ring A, Ring B, R, R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , X, Z, x, y, n, t, L 3 , L 4 , L 5 and A as defined in claim 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of a medicament for regulating the ubiquitination of BCL-2 protein or for degrading BCL-2 protein. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating a disease or condition mediated by or dependent on BCL-2. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing myelofibrosis or cancer; wherein the cancer is a solid tumor or a hematological malignancy, preferably selected from leukemia, lymphoma, multiple myeloma, brain cancer, synovial sarcoma, neuroblastoma, glioblastoma, skin cancer, squamous cell carcinoma, basal cell carcinoma, lung cancer, gastric cancer, gallbladder cancer, bile duct cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, colorectal cancer, pancreatic cancer, liver cancer, endometrial cancer, Ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, bladder cancer, melanoma, seminoma, rhabdomyosarcoma, osteoma, osteochondroma, sarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, choriocarcinoma, renal cancer, thyroid cancer, polycythemia vera, ureteral tumors, choriocarcinoma and pediatric tumors; the leukemia is preferably selected from chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myeloid leukemia; the lymphoma is preferably non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and small lymphocytic lymphoma.

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