Immunosuppressant, preparation method and application thereof

Abstract

An immunosuppressant with the structure of formula (I), its preparation method and application. The series of compounds of the present invention can be widely used in the preparation of drugs for preventing and / or treating cancer or tumors mediated by the PD-1 / PD-L1 signaling pathway, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases, and are expected to be developed into a new generation of PD-1 / PD-L1 inhibitors.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to an immunosuppressant, a preparation method and application thereof. Technical Background

[0002] The immune system plays a very important role in controlling and eliminating diseases such as cancer. However, tumor cells often develop strategies to escape or suppress the surveillance of the immune system to promote their own malignant growth. One of the important mechanisms is to change the expression of co-stimulatory and co-inhibitory immune checkpoint molecules on immune cells. Blocking the signaling pathway of immune checkpoint molecules such as PD1 has been proven to be a very promising and effective treatment.

[0003] Programmed cell death molecule 1 (PD-1), also known as CD279, is a receptor molecule expressed on the surface of activated T cells, natural killer T cells, B cells and macrophages. Its structure includes an extracellular domain similar to the variable region of immunoglobulin, a transmembrane region and an intracellular region. The intracellular region contains two phosphorylation sites, located in the inhibitory domain based on immunoreceptor tyrosine kinase and the conversion domain based on immunoreceptor tyrosine kinase, suggesting that PD1 can negatively regulate T cell receptor-mediated signaling pathways.

[0004] PD1 has two ligands, PD-L1 and PDL2, which differ in their expression profiles. PDL1 protein is upregulated in macrophages and dendritic cells after treatment with lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and in T cells and B cells after stimulation of the T cell receptor and B cell receptor signaling pathways. It is also highly expressed in almost all tumor cells and is upregulated after interferon (IFN) gamma stimulation. In fact, the expression status of tumor PDL1 is considered to be prognostic in many tumor types. PD-L2 expression, in contrast, is more concentrated and is mainly expressed on dendritic cells.

[0005] When PD-1-expressing T cells come into contact with cells expressing their ligands, the functional activities after antigen stimulation, such as cell proliferation, cytokine release, and cell lysis activity, are inhibited. Therefore, the interaction between PD1 and its ligands functions as an intrinsic negative feedback regulatory mechanism that prevents overactivation of T cells during infection, immune tolerance, or tumorigenesis, thereby reducing autoimmune diseases and promoting autoimmune tolerance. Long-term antigen stimulation, such as that occurring in tumors or long-term infections, causes T cells to express high levels of PD-1 and lack activity and function in response to these long-term antigens, which is what people call T cell exhaustion. B cells also have the inhibitory effects of PD1 and its ligands and the corresponding functional failure.

[0006] Several preclinical animal studies have shown that PD-1 and its ligands can negatively regulate immune responses. PD-1-deficient mice develop lupus-like acute proliferative glomerulonephritis and dilated cardiomyopathy. Blocking the PD-1 / PDL1 interaction using antibodies to PDL1 has been shown to restore and enhance T cell activation in many systems. Monoclonal antibodies to PDL1 have also been shown to benefit patients with advanced cancer. Several preclinical animal tumor models have also shown that blocking the PD-1 / PD-L1 signaling pathway with monoclonal antibodies can enhance immune responses and lead to immune responses against a range of histologically distinct tumors. Using a chronic LCMV infection model, the PD-1 / PD-L1 interaction has been found to inhibit virus-specific CD8 T cell activation, expansion, and acquisition of effector cell function. In addition to enhancing immune responses to chronic antigens, blocking the PD-1 / PDL1 pathway has also been found to enhance responses to vaccines, including therapeutic vaccines in the setting of chronic infection.

[0007] In summary, in addition to the existing monoclonal antibodies, if compounds that block the interaction between PD1-PDL1 proteins can be developed, it will be an effective treatment to block the inhibitory signaling pathway mediated by PD-1 / PDL1 to enhance or restore the function of T cells. Therefore, compounds that target and block the interaction between PD-1 / PD-L1 will have a good therapeutic effect in the immunotherapy of various cancers and other immune-related diseases. Summary of the invention

[0008] The purpose of the present invention is to provide an immunosuppressant that blocks the PD-1 / PD-L1 interaction, thereby hopefully developing a new generation of PD-1 / PD-L1 inhibitors.

[0009] The first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein, m is 0, 1, 2, 3 or 4;

[0012] L1 and L2 are each independently selected from -CR7=CR8-, -NH-C(O)-, -NR9-C(R 10 R 11 )-、-NR 12 - or key,

[0013] The connection direction of the group defined by "L1 or L2" includes two directions. For example, the "nitrogen atom" in "-NH-C(O)-" can be connected to ring A or the pyridine ring, or to the benzene ring.

[0014] Ring A is selected from the following groups:

[0015]

[0016] R1 and R2 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-10 Alkyl, C 3-10 Cycloalkyl or C 1-10 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0017] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 1-10 Alkoxy or C 3-10 Cycloalkoxy, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0018] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-10 Alkyl, C 3-10 Cycloalkyl or C 1-10 Alkoxy, or, when m ≥ 2, two R5 and the carbon atom to which they are directly attached together form a carbonyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0019] R6 is selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl or 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0020] R7 and R8 are each independently selected from hydrogen, deuterium, fluorine, cyano, hydroxyl, C 1-10 Alkyl or C 3-10 Cycloalkyl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0021] R9, R 12 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl or C 3-10 Cycloalkyl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0022] R 10 , R 11 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8-OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 , or, R 10 With R 11 Together with the carbon atoms directly connected thereto, they form a 3-12 membered cycloalkyl or a 3-12 membered heterocyclic group, wherein the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0023] Each R 13 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl or 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0024] p is 0 or 1;

[0025] q is 1 or 2;

[0026] Each n is independently 0, 1, 2, 3 or 4;

[0027] Each R 14 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-10 Alkyl, C 3-10 Cycloalkyl or C 1-10 Alkoxy, or, when n ≥ 2, two R 14 Together with the carbon atom to which it is directly attached, it forms a carbonyl group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0028] R 15 Selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl or 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0029] Each R 16 , R 17 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-10 Alkyl, C 3-10 Cycloalkyl or C 1-10 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0030] R 18 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 1-10 Alkoxy or C 3-10 Cycloalkoxy, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0031] R 19a , R 20a are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-8 Alkyl, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group C 1-8 Alkyl, C 5-10 Aryl, C 5-10 Aryl C 1-8 alkyl or 5-10 membered heteroaryl, or, R 19a With R 20a Together with the nitrogen atom to which it is directly connected, it forms a 3-10 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0032] R 19b , R 20b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl C 1-8 Alkyl, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group C 1-8 Alkyl, C 5-10 Aryl, C 5-10 Aryl C 1-8 alkyl or 5-10 membered heteroaryl, or, R 19b With R 20b Together with the nitrogen atom to which it is directly connected, it forms a 3-10 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0033] Each R 21 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl or -NR 24 R 25 The above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent;

[0034] Each R 22 are each independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl or 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent;

[0035] Each R 23 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 24 R 25 The above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent;

[0036] Each R 24 , R 25 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino or C 1-10 Alkanoyl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-8 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 substituted with an alkanoyl substituent;

[0037] Or, R 24 , R 25 Together with the nitrogen atom to which it is directly connected, it forms a 4-10 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 Aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 substituted with an alkanoyl substituent;

[0038] Each r is independently 0, 1 or 2;

[0039] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, L1 and L2 are each independently selected from -CR7=CR8-, -NH- or -NH-C(O)-;

[0040] R1 and R2 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0041] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-4 Alkoxy or C 3-6 Cycloalkoxy, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0042] Wherein, R7 and R8 are as described in the compound of formula (I).

[0043] As a further preferred embodiment, each R5 in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, or, when m ≥ 2, two R5 and the carbon atom to which they are directly attached together form a carbonyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 The alkoxy group is substituted with an alkoxy substituent.

[0044] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts, R6 is selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl or 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23, -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0045] Among them, R 21 , R 22 , R 23 , R 24 , R 25 , r are as described for the compound of formula (I).

[0046] As a further preferred embodiment, in the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, ring A is selected from the following groups:

[0047]

[0048] Among them, each R 13 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl or 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23 , -C 0-4 -C(O)NR 24 R 25or -C 0-4 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0049] Each R 14 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, or, when n ≥ 2, two R 14 Together with the carbon atom to which it is directly attached, it forms a carbonyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0050] R 15 Selected from hydrogen, deuterium, hydroxyl, C1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl or 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0051] Each R 16 , R 17 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0052] R 18 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-4 Alkoxy or C 3-6 Cycloalkoxy, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0053] R 19a , R 20a are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group C 1-4 Alkyl, C 5-8 Aryl, C 5-8 Aryl C 1-4 alkyl or 5-8 membered heteroaryl, or, R 19a With R 20a Together with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 substituted by a substituent;

[0054] R 19b , R 20b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group C 1-4 Alkyl, C 5-8 Aryl, C 5-8 Aryl C 1-4 alkyl or 5-8 membered heteroaryl, or, R 19b With R 20b Together with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(=NR 24 )R 23 , -C 0-4 -N(R 24 )-C(=NR 25 )R 23 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R24 )-C(O)R 23 substituted by a substituent;

[0055] Among them, R 21 , R 22 , R 23 , R 24 , R 25 , r, n, p, q are as described for the compound of formula (I).

[0056] As a further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is selected from the group consisting of a compound of formula (IIa), a compound of formula (IIb), a compound of formula (II C ), a compound of formula (IId) or a compound of formula (IIe):

[0057]

[0058] Wherein, L1 and L2 are each independently selected from -CR7=CR8- or -NH-C(O)-;

[0059] Each R1 and R2 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy;

[0060] Each R3 and R4 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-4 Alkoxy or C 3-6 Cycloalkoxy;

[0061] Each R5 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0062] Each R6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent;

[0063] R7 and R8 are each independently selected from hydrogen, deuterium, fluorine, cyano, hydroxyl, C 1-14 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0064] Each R 13 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23、-OC(O)R 23 or -NR 24 R 25 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 or -NR 24 R 25 substituted by a substituent;

[0065] Each R 14 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0066] R 15 Selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, C 5-8 Aryl or 5-8 membered heteroaryl;

[0067] R 16 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0068] Each R 17 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy, the above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, cyclopropyl, hydroxyl or C 1-4 substituted by an alkoxy substituent;

[0069] R18 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, C 1-4 Alkoxy or C 3-6 Cycloalkoxy;

[0070] R 19a , R 20a are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group or 3-6 membered heterocyclic group C 1-4 Alkyl, or R 19a With R 20a Together with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(=NR 24 )R 23 、-N(R 24 )-C(=NR 25 )R 23 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent;

[0071] R 19b , R 20b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group C 1-4 Alkyl, C 5-8 Aryl, C 5-8 Aryl C 1-4alkyl or 5-8 membered heteroaryl, or, R 19b With R 20b Together with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -S(O) r R 21 、-OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(=NR 24 )R 23 、-N(R 24 )-C(=NR 25 )R 23 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -S(O) r R 21 、-OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(=NR 24 )R 23 、-N(R 24 )-C(=NR 25 )R 23 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent;

[0072] Among them, R 21 , R 22 , R 23 , R 24 , R 25 , m, n, r, p, q are as described for the compound of formula (I).

[0073] As a further preferred embodiment, the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (IIIa), the compound of formula (IIIb), the compound of formula (IIIc), the compound of formula (IIId) or the compound of formula (IIIe):

[0074]

[0075] wherein each L1 is independently selected from -CH=CF- or -NH-C(O)-;

[0076] Each R1 and R2 are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy;

[0077] R5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy;

[0078] Each R6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent;

[0079] Each R 13 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 or -NR 24 R 25 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 or -NR 24 R 25 substituted by a substituent;

[0080] R 15 Selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen substituted C1-4 Alkyl, deuterium substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, C 5-8 Aryl or 5-8 membered heteroaryl;

[0081] R 18 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, 3-6 membered heterocyclic group, C 1-4 Alkoxy or C 3-6 Cycloalkoxy;

[0082] R 19a , R 20a are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 3-6 membered heterocyclic group or 3-6 membered heterocyclic group C 1-4 Alkyl, or R 19a With R 20a Together with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent;

[0083] R 19b , R 20b are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 aryl or 5-8 membered heteroaryl, or, R 19b With R 20bTogether with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent;

[0084] Among them, R 22 , R 23 , R 24 , R 25 , p, q are as described for the compound of formula (I).

[0085] As a further preferred embodiment, each R in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof 22 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8Aryl or 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent;

[0086] Each R 23 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or -NR 24 R 25 The above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent;

[0087] Each R 24 , R 25 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino or C 1-4 Alkanoyl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-4 substituted with an alkanoyl substituent;

[0088] Or, R 24 , R 25 Together with the nitrogen atom to which it is directly connected, it forms a 4-8 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-4 The alkanoyl group is substituted with an alkanoyl substituent.

[0089] As the most preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:

[0090]

[0091]

[0092]

[0093]

[0094] The second aspect of the present invention provides a method for preparing a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0095]

[0096] Optionally, further reacting to obtain the corresponding compound of formula (I) according to the different substituents;

[0097] Wherein, ring A, L1, L2, R1, R2, R3, R4, R5, R6, and m are as described for the compound of formula (I).

[0098] The third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0099] In a fourth aspect, the present invention provides a use of the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing and / or treating diseases mediated by the PD-1 / PD-L1 signaling pathway.

[0100] As a preferred embodiment, the related diseases mediated by the PD-1 / PD-L1 signaling pathway are selected from cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases.

[0101] As a further preferred embodiment, the infectious disease is selected from bacterial infectious diseases, viral infectious diseases or fungal infectious diseases; the cancer or tumor is selected from lymphoma (including but not limited to lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma), sarcoma (including but not limited to Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma), Myoma, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma), melanoma, glioblastoma, synovioma, meningioma, biliary tract tumor, thymic tumor, neural tumor, seminoma, Wilms tumor, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, spinal axon tumor, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome mesothelioma, prostate cancer, recurrent or resistant prostate cancer, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureteral cancer, uterine cancer, ovarian cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia (including but not limited to acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bronchial cancer, Esophageal cancer, nasopharyngeal cancer, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, basal cell carcinoma, lung cancer, breast cancer, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, rectal cancer, colon cancer, colorectal cancer, gastric cancer, pancreatic cancer, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal tract, bone cancer, skin cancer, small intestine cancer, endocrine system cancer, renal pelvis cancer, epidermoid carcinoma, abdominal wall cancer, renal cell carcinoma, transitional cell carcinoma or choriocarcinoma, and metastatic tumors, especially metastatic tumors expressing PD-L1;

[0102] The immune-related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis;

[0103] The infectious disease or contagious disease is selected from sepsis, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus or influenza;

[0104] The metabolic disease is selected from diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency or osteoporosis.

[0105] In a fifth aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, which is used as a drug for preventing and / or treating cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway.

[0106] The sixth aspect of the present invention provides a method for preventing and / or treating cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway, comprising administering to a patient in need thereof a compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0107] The inventors of this application have developed an immunosuppressant with the structure of formula (I) for the first time after extensive and in-depth research. The series of compounds of the present invention have a strong inhibitory effect on the interaction of PD-1 / PD-L1, and can be widely used in the preparation of drugs for preventing and / or treating cancer or tumors mediated by the PD-1 / PD-L1 signaling pathway, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases, and are expected to be developed into a new generation of PD-1 / PD-L1 inhibitors. On this basis, the present invention was completed.

[0108] Detailed Description: Unless stated to the contrary or specifically indicated, the following terms used in the specification and claims have the following meanings.

[0109] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched alkyl group having 1 to 10, 1 to 6, or 1 to 4 carbon atoms, including, but not limited to, 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 or various branched chain isomers thereof. For example, “C 1-10 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 1 to 10 carbon atoms. 1-4 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 1 to 4 carbon atoms. 1-2 "Alkyl" refers to a straight chain alkyl group containing 1 to 2 carbon atoms, "C 0-8 " refers to C 0-8 Alkyl, "C 0-4 " refers to C 0-4 Alkyl, C0 means carbon atom is 0, "C 1-4 " refers to C 1-4 Alkyl: Alkyl is as defined above.

[0110] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0111] "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, preferably a cycloalkyl group comprising 3 to 12, 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 12 carbon atoms. 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms. 3-6 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms. 5-8 "Cycloalkyl" refers to a cycloalkyl group containing 5 to 8 carbon atoms. 5-10 "Cycloalkyl" refers to a cycloalkyl group comprising 5 to 10 carbon atoms. Cycloalkyl groups are divided into monocyclic cycloalkyl groups and polycyclic cycloalkyl groups, wherein:

[0112] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0113] Polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings and bridged rings. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl groups according to the number of spiro atoms shared between the rings. Spiroalkyl groups include but are not limited to:

[0114]

[0115] "Fused cycloalkyl" refers to a full-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and fused cycloalkyl includes but is not limited to:

[0116]

[0117] "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. Bridged cycloalkyl includes but is not limited to:

[0118]

[0119] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0120] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0121] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π-electron system, and wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer 0, 1, 2) of heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably the heterocyclyl comprises 3 to 12, 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl" refers to a ring radical containing 3 to 6 ring atoms, "3-8 membered heterocyclyl" refers to a ring radical containing 3 to 8 ring atoms, "4-6 membered heterocyclyl" refers to a ring radical containing 4 to 6 ring atoms, "4-8 membered heterocyclyl" refers to a ring radical containing 4 to 8 ring atoms, "4-10 membered heterocyclyl" refers to a ring radical containing 4 to 10 ring atoms, "5-10 membered heterocyclyl" refers to a ring radical containing 5 to 10 ring atoms, "5-8 membered heterocyclyl" refers to a ring radical containing 5 to 8 ring atoms, "5-6 membered heterocyclyl" refers to a ring radical containing 5 to 6 ring atoms, and "3-12 membered heterocyclyl" refers to a ring radical containing 3 to 12 ring atoms.

[0122] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0123] Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which the single rings share one atom (called spiro atom), wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are classified into mono-, di-, or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings. Spiro heterocyclic groups include, but are not limited to:

[0124]

[0125] "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups, and fused heterocyclic groups include but are not limited to:

[0126]

[0127] "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, and bridged heterocyclic groups include but are not limited to:

[0128]

[0129] The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring, including but not limited to:

[0130]

[0131] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0132] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aromatic group containing 6-10 or 6-8 carbon atoms, for example, "C 6-10 "Aryl" refers to all-carbon aromatic groups containing 6-10 carbon atoms, including but not limited to phenyl and naphthyl. 6-8 "Aryl" refers to an all-carbon aromatic group containing 6-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:

[0133]

[0134] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0135] "Heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms, including nitrogen, oxygen and S(O)r (wherein r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, a 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and a 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0136]

[0137] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0138] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., C 2-10 Alkenyl refers to a straight or branched chain alkenyl containing 2 to 10 carbon atoms. 2-4 Alkenyl refers to a straight or branched alkenyl group containing 2 to 4 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

[0139] Alkenyl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0140] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbon atoms, for example, C 2-10 Alkynyl refers to a straight or branched chain alkynyl containing 2 to 10 carbon atoms. 2-4 Alkynyl refers to a straight or branched chain alkynyl containing 2 to 4 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

[0141] Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24)-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0142] "Alkoxy" refers to an -O-alkyl group in which alkyl is as defined above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms, C 1-4 The term "alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0143] Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0144] "Cycloalkoxy" or "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above, for example, "C 3-10 The term "cycloalkyloxy" refers to cycloalkyloxy groups containing 3 to 10 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0145] "Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0146] "Heterocyclyloxy" or "heterocyclyloxy" refers to an -O-heterocyclyl group, wherein heterocyclyl is as defined above, for example, "C 3-10 The term "heterocyclyloxy" refers to a heterocyclyloxy group containing 3 to 10 carbon atoms, including but not limited to azetidinyloxy, oxetanyloxy, azepentyloxy, nitrogen, oxhexyloxy, and the like.

[0147] "Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, =O, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(=NR 24 )R 23 , -C 0-8 -N(R 24 )-C(=NR 25 )R 23 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 substituted by a substituent.

[0148] “C 1-10 "Alkanoyl" refers to C 1-10 The monovalent atomic group remaining after removing the hydroxyl group from the alkyl acid is usually expressed as "C 0-9 -C(O)-", for example, "C1-C(O)-" refers to acetyl; "C2-C(O)-" refers to propionyl; "C3-C(O)-" refers to butyryl or isobutyryl.

[0149] "-C 0-8 -S(O) r R 21 ” refers to -S(O) r R 21 The sulfur atom in the 0-8The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0150] "-C 0-8 -OR 22 "refers to -OR 22 The oxygen atom in the 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0151] "-C 0-8 -C(O)OR 22 ” means -C(O)OR 22 The carbonyl group in 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0152] "-C 0-8 -C(O)R 23 ” refers to -C(O)R 23 The carbonyl group in 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0153] "-C 0-8 -OC(O)R 23 ” refers to -OC(O)R 23 The oxygen atom in the 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0154] "-C 0-8 -NR 24 R 25 ” refers to -NR 24 R 25 The nitrogen atom in the 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0155] "-C 0-8 -C(=NR 24 )R 23 " refers to -C(=NR 24 )R 23 The nitrogen atom in the 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0156] "-C 0-8 -N(R 24 )-C(=NR 25 )R 23 ” refers to -N(R 24 )-C(=NR 25 )R 23 The nitrogen atom in the 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0157] "-C 0-8 -C(O)NR 24 R 25 ” refers to -C(O)NR 24 R 25 The carbonyl group in 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0158] "-C 0-8 -N(R 24 )-C(O)R 23 ” refers to -N(R 24 )-C(O)R 23 The nitrogen atom in the 0-8 The C0 alkyl group has 0 carbon atoms. 1-8 Alkyl is as defined above.

[0159] "Halogen-substituted C 1-10 The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

[0160] "Halogen-substituted C 1-10 "Alkoxy" refers to an alkoxy group of 1-10 carbon atoms in which the hydrogen on the alkyl group is optionally replaced by a fluorine, chlorine, bromine or iodine atom. It includes but is not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

[0161] "Deuterium replaces C 1-10 "Alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

[0162] "Halogen" refers to fluorine, chlorine, bromine or iodine. "PE" refers to petroleum ether, "EtOAc" / "EA" refers to ethyl acetate, "MeOH" refers to methanol, "DMF" refers to N,N-dimethylformamide, "THF" refers to tetrahydrofuran, "LiHMDS" refers to lithium hexamethyldisilazide, "Dess-Martin reagent" refers to Dess-Martin reagent, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzimidoyl-3-(1H)-one, "Pd(dppf)Cl 2· "DCM" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex.

[0163] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes the occasions where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted situations are included. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the situation where the heterocyclic group is substituted with an alkyl group and the situation where the heterocyclic group is not substituted with an alkyl group.

[0164] "Substituted" means that one or more "hydrogen atoms" in a group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the valence bond theory in chemistry, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefin).

[0165] "Stereoisomers" are called stereoisomers in English. They refer to isomers produced by different spatial arrangements of atoms in molecules. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in molecules, rings, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers, which are divided into R and S configurations. In the present invention, the "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.

[0166] "Prodrug" is also called prodrug, drug precursor, prodrug, etc. It refers to a compound that is inactive or has low activity in vitro after chemical structure modification of the drug, and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its efficacy. For example, a compound containing an "ester group" can be released into a "carboxyl" compound or a "hydroxyl" compound under the action of an enzyme.

[0167] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0168] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0169] The present invention is further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited to the contents of the embodiments.

[0170] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 or AVANCE-500 nuclear magnetic spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated water (D2O) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0171] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0172] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0173] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0174] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

[0175] 1. Preparation of intermediates

[0176] Intermediate A1: Preparation of N-(3-bromo-2-chlorophenyl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide

[0177]

[0178] Step 1: Synthesis of 2-(tert-butyl)6-ethyl3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate

[0179]

[0180] Ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (3.15 g, 13.3 mmol, prepared according to the literature "Heterocycl. Commun., 2000, 6, 25"), palladium carbon (500 mg) and anhydrous sodium acetate (1.75 g, 19.5 mmol) were dissolved in anhydrous methanol (100 mL) and stirred at room temperature for 24 hours under a hydrogen atmosphere. After the reaction was completed, the palladium carbon was filtered off, the filtrate was concentrated and dissolved in dichloromethane (50 mL), and then Boc anhydride (3.27 g, 15 mmol) was added and stirred at room temperature for 2 hours. After concentration, column chromatography was performed to separate [eluent: petroleum ether to petroleum ether / ethyl acetate (1:1)] to obtain 2-(tert-butyl) 6-ethyl 3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate (2.8 g, yield 70.2%). ESI-MS: 307[M+H] + .

[0181] Step 2: Synthesis of tert-butyl 6-((3-bromo-2-chlorophenyl)carbamoyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

[0182]

[0183] Dissolve 2-(tert-butyl) 6-ethyl 3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate (2.8 g, 9.3 mmol) and 3-bromo-2-chloroaniline (2 g, 9.77 mmol) in anhydrous tetrahydrofuran (100 mL). Add 1 M potassium tert-butoxide tetrahydrofuran solution (14 mL, 14 mmol) dropwise under ice bath. Continue to react at room temperature for 1 hour. The reaction solution was poured into water (200 mL), extracted with dichloromethane (100 mL*2), the organic phase was washed twice with water and brine, the organic phase was dried, filtered, concentrated and separated by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (1:1)] to obtain tert-butyl 6-((3-bromo-2-chlorophenyl)carbamoyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (2.66 g, yield 61.5%). ESI-MS: 466 [M+H] + .

[0184] Step 3: Synthesis of N-(3-bromo-2-chlorophenyl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide

[0185]

[0186] Dissolve tert-butyl 6-((3-bromo-2-chlorophenyl)carbamoyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-carboxylate (116 mg, 0.25 mmol) in dichloromethane (10 mL), and add trifluoroacetic acid (1 mL). After stirring the reaction solution at room temperature for 1 hour, evaporate the solvent under reduced pressure, and the residue is dissolved in dichloromethane (10 mL) again, and triethylamine (1 mL) and sodium triacetoxyborohydride (213 mg, 1 mmol) are added in sequence. The reaction solution is stirred for 2 hours. Pour into water (20mL), extract with ethyl acetate (50mL*2), combine the organic phases, dry, filter, concentrate and separate by column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (1:1)] to obtain N-(3-bromo-2-chlorophenyl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide (87mg, yield 85%). ESI-MS: 408[M+H] + .

[0187] The preparation of intermediates A2 to A28 can be prepared by referring to the preparation method of intermediate A1:

[0188]

[0189]

[0190]

[0191] Intermediate B: Preparation of (Z)-2-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0192]

[0193] Step 1: Synthesis of 2-chloro-3-(methoxymethoxy)benzaldehyde

[0194]

[0195] Dissolve 2-chloro-3-hydroxybenzaldehyde (10.0 g, 64.10 mmol) in acetonitrile (80 mL), add N,N-diisopropylethylamine (16.5 g, 128.20 mmol) and bromo-methoxy-methane (17.9 g, 128.20 mmol), seal the tube and heat to 80°C to react overnight. After cooling, pour into water (150 mL), then extract with ethyl acetate (100 mL*2), dry with anhydrous sodium sulfate, concentrate and separate by column chromatography [eluent: petroleum ether = 100% ~ ethyl acetate = 10%] to obtain 2-chloro-3-(methoxymethoxy)benzaldehyde (12.7 g, yield 100%).

[0196] 1 H NMR (400MHz, CDCl3) δ10.45 (d, J=0.8Hz, 1H), 7.52 (dd, J=7.7, 1.6Hz, 1H), 7.35 (dd,J=8.2,1.6Hz,1H),7.25(td,J=7.9,0.8Hz,1H),5.22(s,2H),3.47(s,3H).

[0197] Step 2: Synthesis of 2-chloro-1-(2,2-difluorovinyl)-3-(methoxymethoxy)benzene

[0198]

[0199] Dissolve 2-chloro-3-(methoxymethoxy)benzaldehyde (18.2g, 91.0mmol) in N,N-dimethylformamide (182mL) (i.e., 0.5M solution of aldehyde), add triphenylphosphine (28.6g, 109.2mmol), heat to 100℃, and then dropwise add 2M solution of sodium chlorodifluoroacetate (20.8g, 136.5mmol) in N,N-dimethylformamide. Continue to stir the reaction solution at 100℃ for 1 hour. Pour into water (250mL), then extract with petroleum ether (300mL*2), wash the organic phase with water (100mL) and saturated brine (100mL) in turn, and dry with anhydrous sodium sulfate. After concentration, separate by column chromatography [eluent: petroleum ether] to obtain 2-chloro-1-(2,2-difluorovinyl)-3-(methoxymethoxy)benzene (13.3g, yield 62%).

[0200] 1 H NMR (400MHz, CDCl3) δ7.24–7.14(m,2H),7.08(dd,J=6.8,3.0Hz,1H),5.72(dd,J=25.4,3.9Hz,1H),5.25(s,2H),3.52(s,3H).

[0201] 19 F NMR (377MHz, CDCl3) δ -81.31 (d, J = 24.9Hz), -82.22 (d, J = 25.0Hz).

[0202] Step 3: Synthesis of (Z)-2-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0203]

[0204] 2-Chloro-1-(2,2-difluorovinyl)-3-(methoxymethoxy)benzene (4.6 g, 19.65 mmol) was dissolved in tetrahydrofuran (150 mL), and diboric acid pinacol ester (6.0 g, 23.59 mmol), cuprous chloride (20 mg, 0.196 mmol), tricyclohexylphosphine (110 mg, 0.393 mmol) and potassium acetate (5.8 g, 58.97 mmol) were added. The reaction solution was stirred at 40°C for 16 hours, poured into water (100 mL), extracted with ethyl acetate (100 mL*2), and dried over anhydrous sodium sulfate. After concentration, column chromatography [eluent: petroleum ether = 100% ~ ethyl acetate = 10%] was performed to obtain (Z)-2-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.7 g, yield 55%).

[0205] 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J=7.8, 1.5Hz, 1H), 7.22 (t, J=8.0Hz, 1H), 7.14 (dd, J=8.3,1.5Hz,1H),6.87(d,J=45.4Hz,1H),5.27(s,2H),3.54(s,3H),1.37(s,12H).

[0206] 19 F NMR (377MHz,CDCl3)δ-122.01.

[0207] Intermediate C1: Preparation of (Z)-2-chloro-3-(2-fluoro-2-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenyl trifluoromethanesulfonic acid

[0208]

[0209] Step 1: Synthesis of 5-bromo-2-methoxy-4-methylpyridine

[0210]

[0211] Add 5-bromo-2-fluoro-4-methylpyridine (40.0 g, 0.21 mol) and methanol (200 mL) to a 1000 mL single-mouth bottle, and dropwise add 30% sodium methoxide methanol solution (75.8 g, 0.42 mol). The reaction solution was heated to reflux overnight. Methanol was evaporated under reduced pressure, water (500 mL) was added, and ethyl acetate was extracted (1000 mL*2). The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-bromo-2-methoxy-4-methylpyridine (41.1 g, yield 97%). ESI-MS: 202.1 [M+H] + .

[0212] Step 2: Synthesis of 6-methoxy-4-methylnicotinonitrile

[0213]

[0214] Add 5-bromo-2-methoxy-4-methylpyridine (41.1 g, 0.2 mol), zinc cyanide (47.6 g, 0.4 mol), tetrakistriphenylphosphine palladium (10 g, 8.65 mmol) and N,N-dimethylformamide (300 mL) to a 500 mL single-mouth bottle and react at 100 ° C overnight. After the reaction solution is cooled to room temperature, diatomaceous earth is used for filtration, and the filter cake is rinsed with ethyl acetate (300 mL*2). The filtrate is separated, and the aqueous phase is extracted with ethyl acetate (300 mL). The organic phases are combined and washed with water. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) is used to obtain 6-methoxy-4-methylnicotinonitrile (25 g, yield 84%). ESI-MS: 149.1 [M+H] + .

[0215] Step 3: Synthesis of 2-methyl-(5-cyano-2-methoxypyridin-4-yl)acetate

[0216]

[0217] Add 6-methoxy-4-methylnicotinonitrile (25g, 0.17mol) and tetrahydrofuran (300mL) to a 1000mL three-necked flask, and add 1M LiHMDS (340mL, 0.34mol) dropwise under an ice bath. The reaction solution is stirred at room temperature for 1 hour, and then diethyl carbonate (39.9g, 0.34mol) is added. The reaction solution is stirred at room temperature for 3 hours, the pH is adjusted to 8-9 with dilute hydrochloric acid, and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 2-methyl-(5-cyano-2-methoxypyridin-4-yl) acetate (26.2g, yield 70%). ESI-MS: 221.2 [M+H] + .

[0218] Step 4: Synthesis of 6-methoxy-1,4-dihydro-2,7-naphthyridin-3(2H)-one

[0219]

[0220] Dissolve 2-methyl-(5-cyano-2-methoxypyridin-4-yl)acetate (12.5 g, 56.8 mmol) in ethanol (300 mL), add Raney nickel (17.5 g) and ammonia water (30 mL). Stir the reaction solution at 50 ° C under a hydrogen atmosphere for 48 hours. Cool to room temperature, filter the reaction solution, and concentrate the filtrate to obtain crude 6-methoxy-1,4-dihydro-2,7-naphthyridin-3(2H)-one (10.5 g, yield 100%). ESI-MS: 179.0 [M+H] + .

[0221] Step 5: Synthesis of 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine

[0222]

[0223] Dissolve 6-methoxy-1,4-dihydro-2,7-naphthyridin-3(2H)-one (10.5 g, 60 mmol) in tetrahydrofuran (80 mL), and then add 1M borane tetrahydrofuran solution (300 mL, 300 mmol). The reaction solution was refluxed and stirred overnight. LC-MS showed that the reaction was complete. The reaction solution was quenched with methanol and dilute hydrochloric acid, and concentrated to obtain 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridin (crude product), which was directly used in the next step. ESI-MS: 165.3 [M+H] + .

[0224] Step 6: Synthesis of tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

[0225]

[0226] Dissolve 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine (crude product) in aqueous hydrobromic acid solution (50 mL) and stir at 100°C overnight. After the reaction solution is concentrated, it is dissolved in methanol (150 mL), and triethylamine (58.6 g, 58 mmol) and di-tert-butyl dicarbonate (15.4 g, 0.07 mol) are added. The reaction solution is stirred at room temperature for 1 hour. Methanol is evaporated under reduced pressure, water (100 mL) is added, and ethyl acetate is extracted (100 mL*2). The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (16.5 g, crude product). ESI-MS: 251.0 [M+H] + .

[0227] Step 7: Synthesis of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

[0228]

[0229] Dissolve tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (16.5g, 0.066mol) in dichloromethane (250mL), add triethylamine (20.0g, 0.2mmol) and trifluoromethanesulfonic anhydride (24.2g, 0.086mol). Stir the reaction solution at room temperature for 1 hour. Add water (100mL) and extract with dichloromethane (100mL*2). Wash the organic phase with saturated brine (100mL), separate the layers, dry over anhydrous sodium sulfate, filter, concentrate the crude product and separate it by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (11.5g, four-step yield 53%).

[0230] 1 H NMR (400MHz, DMSO-d6): δ8.33(s,1H),7.45(s,1H),4.61(s,2H),3.58(t,J=5.9Hz,2H),2.91(t,J=5.9Hz,2H),1.44(s,9H).ESI-MS:383.1[M+H] + .

[0231] Step 8: Synthesis of tert-butyl (Z)-6-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

[0232]

[0233] Tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (1.5 g, 3.93 mmol) was dissolved in tetrahydrofuran (40 mL) and water (20 mL), and (Z)-2-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g, 5.89 mmol), [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II)] (150 mg) and potassium phosphate (2.0 g, 9.82 mmol) were added, and the reaction solution was stirred at 40°C overnight under nitrogen protection. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated and then separated by column chromatography [eluent: petroleum ether (100%) ~ ethyl acetate (16%)] to obtain tert-butyl (Z)-6-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (1.22 g, yield 69%). ESI-MS: 479 [M+H] + .

[0234] Step 9: Synthesis of (Z)-2-chloro-3-(2-fluoro-2-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenol hydrochloride

[0235]

[0236] Tert-butyl (Z)-6-(2-(2-chloro-3-(methoxymethoxy)phenyl)-1-fluorovinyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-carboxylate (1.22 g, 2.72 mmol) was dissolved in THF (5 mL) and MeOH (5 mL), and a 4M hydrochloric acid solution of dioxane (10 mL) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated to obtain (Z)-2-chloro-3-(2-fluoro-2-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenol hydrochloride (crude product). ESI-MS: 305 [M+H] + .

[0237] Step 10: Synthesis of (Z)-2-chloro-3-(2-fluoro-2-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenol

[0238]

[0239] (Z)-2-chloro-3-(2-fluoro-2-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenol hydrochloride (720 mg crude product, 2.11 mmol) was dissolved in methanol (50 mL), and triethylamine (1 mL) and acetone (2 mL) were added. The reaction solution was stirred at 40°C for 1 hour, and sodium cyanoborohydride (400 mg, 6.35 mmol) was added. The reaction solution was stirred for another 2 hours and then concentrated, diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated and separated by column chromatography [eluent: petroleum ether (100%) to ethyl acetate (50%)] to obtain (Z)-2-chloro-3-(2-fluoro-2-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenol (386 mg, yield 53%). ESI-MS: 347 [M+H] + .

[0240] Step 11: Synthesis of (Z)-2-chloro-3-(2-fluoro-2-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenyl trifluoromethanesulfonic acid

[0241]

[0242] Dissolve (Z)-2-chloro-3-(2-fluoro-2-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenol (100 mg, 0.29 mmol) in anhydrous dichloromethane (12 mL) and add triethylamine (86 mg, 0.87 mmol). Add trifluoromethanesulfonic anhydride (106 mg, 0.376 mmol) at 0°C. The reaction solution was stirred for 1 hour and then diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain (Z)-2-chloro-3-(2-fluoro-2-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)vinyl)phenyltrifluoromethanesulfonic acid (crude product). ESI-MS: 479 [M+H] + .

[0243] The preparation of intermediates C2 to C9 can be prepared by referring to the preparation method of intermediate C1:

[0244]

[0245] Intermediate D: Preparation of methyl 4-(2-oxoethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0246]

[0247] Step 1: Synthesis of 4-(carbomethoxy)bicyclo[2.2.1]heptane-1-carboxylic acid

[0248]

[0249] Tetrahydrofuran (180 mL) was added to a single-mouth bottle containing dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (5.6 g, 26.4 mmol), and a methanol solution (11 mL) of sodium hydroxide (1.06 g, 26.4 mmol) was added dropwise using a constant pressure dropping funnel. The reaction solution was stirred overnight at room temperature. The reaction solution was concentrated until the solvent was dried, the solid was washed with petroleum ether and filtered, and the filter cake was dissolved in water (50 mL). The aqueous solution was acidified to pH = 4 with 2M hydrochloric acid and then extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(methyl ester) bicyclo[2.2.1]heptane-1-carboxylic acid (4.17 g, yield 80%).

[0250] Step 2: Synthesis of methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0251]

[0252] Under ice bath, add dry tetrahydrofuran (100mL) to a single-mouth bottle containing 4-(methyl ester) bicyclo[2.2.1]heptane-1-carboxylic acid (4.17g, 21.03mmol), and slowly add borane dimethyl sulfide complex (2.7mL, 27.35mmol, 10.0M) using a syringe. After the addition is completed, stir at room temperature overnight. Methanol (10mL) is added dropwise to the reaction solution, and refluxed for 4 hours to quench. Extract with ethyl acetate / water, wash the organic phase with water and saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain methyl 4-(hydroxymethyl) bicyclo[2.2.1]heptane-1-carboxylate (3.53g, yield 90%).

[0253] 1 H NMR (400MHz, CDCl3) δ3.70(s,2H),3.67(s,3H),2.06–1.93(m,2H),1.73–1.62(m,4H),1.58–1.54(m,2H),1.43–1.34(m,2H).

[0254] Step 3: Synthesis of methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate

[0255]

[0256] In a single-mouth bottle containing methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate (4.75 g, 25.7 mmol), dichloromethane (180 mL) was added to dissolve it, and Dess-Martin reagent (13.1 g, 30.9 mmol) was added to the solution. The reaction solution was stirred at room temperature, and the reaction was detected by TLC until the raw material disappeared. Filtered with diatomaceous earth, the filtrate was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate (3.38 g, yield 72%).

[0257] 1 H NMR (400MHz, CDCl3) δ9.81(s,1H),3.70(s,3H),2.13–2.00(m,4H),1.86–1.82(m,2H),1.79–1.68(m,2H),1.60–1.52(m,2H).

[0258] Step 4: Synthesis of methyl (E / Z)-4-(2-methoxyvinyl)bicyclo[2.2.1]heptane-1-carboxylate

[0259]

[0260] Under nitrogen atmosphere, potassium tert-butoxide (10 mL, 1.0 M) was added dropwise to a suspension of (methoxymethyl)triphenylphosphonium chloride (3.4 g, 9.87 mmol) in dry tetrahydrofuran (45 mL). After the addition was completed, the mixture was stirred at room temperature for half an hour. A tetrahydrofuran solution (12 mL) of methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate (1.2 g, 6.58 mmol) was added dropwise to the reaction solution. After the addition was completed, the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution was added to quench the reaction, ethyl acetate, and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain methyl (E / Z)-4-(2-methoxyvinyl)bicyclo[2.2.1]heptane-1-carboxylate (0.74 g, containing a small amount of triphenylphosphine).

[0261] Step 5: Synthesis of methyl 4-(2-oxoethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0262]

[0263] 1M HCl (47 mL) was added to a tetrahydrofuran solution (30 mL) of methyl (E / Z)-4-(2-methoxyvinyl)bicyclo[2.2.1]heptane-1-carboxylate (1.0 g, 4.7 mmol). The reaction solution was stirred at room temperature for 2 hours. After alkalization with saturated sodium bicarbonate, it was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain methyl 4-(2-oxoethyl)bicyclo[2.2.1]heptane-1-carboxylate (0.85 g).

[0264] 1 H NMR (400MHz, CDCl3) δ9.80(t,J=2.7Hz,1H),3.68(s,3H),2.60(d,J=2.6Hz,2H),2.06–1.95(m,2H),1.69–1.55(m,8H).

[0265] The preparation of intermediates D2 to D5 can be prepared by referring to the preparation method of intermediate D1:

[0266]

[0267] Intermediate E: Preparation of 5-(tert-butyl) 2-methyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate

[0268]

[0269] Step 1: Synthesis of N-methyl-3-nitropyridine-4-amine

[0270]

[0271] Dissolve 4-chloro-3-nitropyridine (25.0 g, 158.22 mmol) in dichloromethane (200 mL), and add methylamine aqueous solution (40%, 78 mL) dropwise under ice bath. Stir the reaction solution at room temperature for 3 hours, and separate the organic phase. Extract the aqueous phase with dichloromethane (200 mL*3), and dry the combined organic phases with anhydrous sodium sulfate. After concentration, N-methyl-3-nitropyridine-4-amine (24 g, yield 96%) was obtained. ESI-MS: 154 [M+H] + .

[0272] Step 2: N 4 -Synthesis of methylpyridine-3,4-diamine

[0273]

[0274] Dissolve N-methyl-3-nitropyridine-4-amine (23.7 g) in methanol (600 mL) and add wet powdered palladium carbon (10% Pd, 4.0 g). Stir the reaction mixture at room temperature overnight under hydrogen, filter the palladium carbon, and concentrate the filtrate to obtain N 4 -Methylpyridine-3,4-diamine (crude product). ESI-MS: 124 [M+H] + .

[0275] Step 3: Synthesis of 1-methyl-1H-imidazo[4,5-c]pyridine

[0276]

[0277] N 4 -Methylpyridine-3,4-diamine (crude product) was dissolved in 98% formic acid (150 mL), heated to 100°C and reacted for 48 hours. After the reaction solution was concentrated, dichloromethane (200 mL) was added and the pH was adjusted to 8-10 with 10% sodium hydroxide solution. The aqueous phase was extracted with dichloromethane: methanol = 10:1, and the combined organic phases were dried over anhydrous sodium sulfate. After concentration, column chromatography separation [eluent: dichloromethane (100%) ~ methanol (10%)] was obtained to obtain 1-methyl-1H-imidazo[4,5-c]pyridine (16 g). ESI-MS: 134 [M+H] + .

[0278] Step 4: Synthesis of 5-(2-(4-methoxyphenyl)-2-oxoethyl)-1-methyl-1H-imidazo[4,5-c]pyridinium-5-ol bromide

[0279]

[0280] Dissolve 1-methyl-1H-imidazo[4,5-c]pyridine (29.7 g, 223.30 mmol) in acetone (400 mL), and add dropwise a solution of 2-bromo-1-(4-methoxyphenyl)ethane-1-one (56 g, 245.63 mmol) in acetone (300 mL). Stir the reaction mixture at room temperature for 3 hours and filter. After drying the filter cake, 5-(2-(4-methoxyphenyl)-2-oxoethyl)-1-methyl-1H-imidazo[4,5-c]pyridine-5-cation bromide (78.5 g, yield 97%) was obtained. ESI-MS: 282 [M+H] + .

[0281] Step 5: Synthesis of 1-(4-methoxyphenyl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethane-1-ol

[0282]

[0283] Dissolve 5-(2-(4-methoxyphenyl)-2-oxoethyl)-1-methyl-1H-imidazo[4,5-c]pyridin-5-cation bromide (73.5 g, 203.60 mmol) in methanol (600 mL), slowly add sodium borohydride (23.2 g, 610.80 mmol) in batches under ice bath, and stir the reaction solution at room temperature overnight. After concentration, add water and ethyl acetate, separate the organic phase and dry it with anhydrous sodium sulfate, and after concentration, obtain 1-(4-methoxyphenyl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethane-1-ol (66 g crude product). ESI-MS: 288[M+H] + .

[0284] Step 6: Synthesis of tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0285]

[0286] Dissolve 1-(4-methoxyphenyl)-2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethane-1-ol (55 g crude product) in ethanol (150 mL), add concentrated hydrochloric acid (100 mL), and stir the reaction solution at 110°C overnight. After concentration, add water and ethyl acetate, separate the organic phase, add acetone (150 mL) to the aqueous phase, adjust the pH to 8-9 with potassium carbonate, and add di-tert-butyl dicarbonate (41.8 g) dropwise. The reaction solution was stirred at room temperature overnight, acetone was dried by rotary evaporation, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography [eluent: dichloromethane (100% to methanol (6%))] to obtain tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (28 g). ESI-MS: 238 [M+H] + .

[0287] 1 H NMR (400MHz, CDCl3) δ7.27 (s, 1H), 4.38 (s, 2H), 3.67 (d, J = 6.1Hz, 2H), 3.46 (s, 3H), 2.53 (t, J = 5.8Hz, 2H), 1.40 (s, 9H).

[0288] Step 7: Synthesis of 5-(tert-butyl) 2-methyl-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate

[0289]

[0290] Dissolve tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3.5 g, 14.77 mmol) in anhydrous tetrahydrofuran (40 mL), and add n-butyl lithium (7 mL, 17.72 mmol) dropwise at -78°C. Stir at -78°C for 10 minutes. Then quickly add the reaction solution dropwise to methyl chloroformate (1.7 mL, 22.15 mmol) in anhydrous tetrahydrofuran (40 mL). Stir for another 30 minutes at -78°C, pour into water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate and separate by column chromatography [eluent: dichloromethane (100%) ~ methanol (6%)] to obtain 5-(tert-butyl) 2-methyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate (2.6 g, yield 60%). ESI-MS: 296 [M+H] + .

[0291] Intermediate F1: Preparation of tert-butyl 2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0292]

[0293] Dissolve 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 1.98 mmol) in anhydrous tetrahydrofuran (20 mL), add 5-(tert-butyl) 2-methyl 1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate (700 mg, 2.37 mmol). Stir the reaction solution at room temperature for ten minutes, and add 1M tetrahydrofuran solution of potassium tert-butoxide (4 mL, 3.95 mmol) dropwise. After stirring for half an hour, dilute with water, extract with ethyl acetate, and dry and concentrate the organic phase to obtain a crude product. The crude product was slurried with a solution of PE:EA=50:1, filtered and dried to give tert-butyl 2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (540 mg). ESI-MS: 517 [M+H] + .

[0294] The preparation of intermediates F2 to F10 can be prepared by referring to the preparation method of intermediate F1:

[0295]

[0296]

[0297] 2. Preparation of Specific Example Compounds

[0298] Example 1: Preparation of 4-(2-(2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbazylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid

[0299]

[0300] Step 1: Synthesis of tert-butyl 2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthylidene-3-carbamoyl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0301]

[0302] N-(3-bromo-2-chlorophenyl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide (160 mg, 0.39 mmol) was dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL), and tert-butyl 2-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (264 mg, 0.51 mmol), Pd(dppf)Cl 2· DCM (20 mg) and potassium carbonate (109 mg, 0.79 mmol), the reaction solution was stirred at 95 ° C overnight under nitrogen protection. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried and concentrated, and then separated by column chromatography [eluent: petroleum ether (100%) ~ ethyl acetate (100%), then dichloromethane (100%) ~ methanol (5%)] to obtain tert-butyl 2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbazylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (108 mg). ESI-MS: 718 [M+H] + .

[0303] Step 2: Synthesis of N-(2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carbazylamino)-[1,1'-biphenyl]-3-yl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide hydrochloric acid

[0304]

[0305] Tert-butyl 2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbazylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (108 mg, 0.15 mmol) was dissolved in THF (2 mL) and MeOH (2 mL), and 4 M hydrochloric acid solution in dioxane (2 mL) was added. The reaction solution was stirred at room temperature for 2 hours and then concentrated to obtain N-(2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carbazylamino)-[1,1'-biphenyl]-3-yl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide hydrochloride (crude product). ESI-MS: 309.7 [M / 2+H] + .

[0306] Step 3: Synthesis of methyl 4-(2-(2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthylidene-3-carbamoyl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0307]

[0308] N-(2,2'-dichloro-3'-(1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carbazylamino)-[1,1'-biphenyl]-3-yl)-7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide hydrochloric acid (crude product, 0.15mmol) was dissolved in dichloromethane (5mL), and triethylamine (0.3mL) and methyl 4-(2-oxoethyl)bicyclo[2.2.1]heptane-1-carboxylate (100mg crude product) were added. The reaction solution was stirred at room temperature for half an hour, and sodium triacetoxyborohydride (96mg, 0.45mmol) was added. The reaction solution was stirred at room temperature for another half an hour, diluted with water, extracted with ethyl acetate, and the organic phase was dried, concentrated, and then separated by column chromatography [eluent: dichloromethane (100%) to methanol (5%)] to obtain methyl 4-(2-(2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbazylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylate (135 mg). ESI-MS: 399.9 [M / 2+H] + .

[0309] Step 4: Synthesis of 4-(2-(2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbamoyl)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid

[0310]

[0311] Methyl 4-(2-(2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbazylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylate (135 mg, 0.17 mmol) was dissolved in THF:MeOH:H2O=1:1:1 (3 mL), and lithium hydroxide (100 mg) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered and separated by reverse phase column chromatography [eluent: water (0.5% formic acid) / acetonitrile, acetonitrile: 0-28%], and then freeze-dried to obtain 4-(2-(2-((2,2'-dichloro-3'-(7-isopropyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carbazylamino)-[1,1'-biphenyl]-3-yl)carbamoyl)-1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl)bicyclo[2.2.1]heptane-1-carboxylic acid (58 mg, yield 44%). ESI-MS: 392.8 [M / 2+H] + .

[0312] 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),10.71(s,1H),9.90(s,1H),8.55(dd,J=8.4,1.5Hz,1H) ,8.47(s,1H),8.38(dd,J=8.2,1.5Hz,1H),7.98(s,1H),7.51(dt,J=15.8,8.0Hz,2H),7.16(t d,J=7.8,1.6Hz,2H),3.90(s,3H),3.77(s,2H),3.42(s,2H),2.93(d,J=5.6Hz,3H),2.71(dd, J=32.6,5.6Hz,6H),2.53(s,2H),1.93–1.67(m,4H),1.57–1.30(m,8H),1.08(d,J=6.5Hz,6H).

[0313] Examples 2 to 78 can be prepared by referring to all or part of the synthesis method of Example 1 and selecting corresponding raw materials.

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328] The NMR data of the compound prepared in the above example are as follows:

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] Biological test evaluation

[0337] 1. PD1-PDL1 HTRF binding activity test

[0338] The effects of the compounds of the present invention on the PD-1 / PD-L1 protein interaction were determined using Cisbio's PD-1 / PD-L1 binding assay kit (#64ICP01PEG or 64ICP01PEH). The specific experimental method is as follows:

[0339] 1) Add the diluted compound, 4 μL of Tag1-PD-L1 protein and 4 μL of Tag2-PD1 protein to a 384-well plate;

[0340] 2) Incubate at room temperature for 15 minutes, then add 5 μL of anti-Tag1-Eu3+ antibody and 5 μL of anti-Tag2-XL665 antibody;

[0341] 3) After incubation at room temperature for 2 hours or at 4 degrees overnight, read the reading on the Pelkin Elmer Envision. Read the reading at 665nm and the reading at 620nm respectively, and take the ratio of the two as the reading of each well;

[0342] 4) Compare the readings of each well after compound treatment with the readings of the wells treated with DMSO to obtain the compound inhibition percentage;

[0343] 5) The IC of the compounds of the present invention was determined by nonlinear regression analysis of the inhibition percentage at different compound concentrations. 50 The specific experimental results are shown in Table 1.

[0344] 2. Jurkat reporter gene cell activity test

[0345] The effects of the compounds of the present invention on the interaction between PD-1 / PD-L1 proteins expressed on the cell surface and the resulting effects on T cell function were determined by Jurkat reporter gene cell activity assay.

[0346] In brief, the NF-κB-luc reporter gene plasmid and the human PD-1 plasmid were transfected into Jurkat cells to establish a stable cell line that stably expressed both PD-1 and NF-κB-Luc reporter genes. Flow cytometry was used to identify the surface expression level of PD-1, and the expression level of the reporter gene was identified by the response of the reporter gene after stimulation with OKT-3 and Raiji cells.

[0347] In addition, the expression plasmid of human PD-L1 was transfected into Raji cells to obtain a cell line that stably expressed PD-L1. Then, Jurkat / NF-κB-luc / PD1 cells and Raji-PD-L1 cells were co-cultured and stimulated with OKT-3. On this basis, the compound was added, and the reading of the reporter gene reaction was used to reflect the inhibitory effect of the compound on the PD-1 / PD-L1 interaction on the enhancement of the T cell activation signaling pathway. The specific experimental method is as follows:

[0348] 1) Add 30 μL of compounds or antibodies of different dilution concentrations to a white 96-well plate (corning, 3610), and then add 10 μL of OKT3 (Biolegend, 317326) (final concentration of OKT3 is 1 μg / mL);

[0349] 2) Add 20 μL Raji-PD-L1 cell suspension to each well, 5×10 4 cells, incubated in an incubator for 20 minutes;

[0350] 3) Add 20 μL of Jurkat / NF-κb-luc / PD-1 cell suspension to each well, 5×10 4 cells, mixed well, and detected with Bright-glo (Promega, E2620) after 6 h;

[0351] 4) Compare the readings of each well after compound treatment with the readings of the wells treated with DMSO to obtain the activation factor of the compound;

[0352] 5) The EC of the compounds of the present invention was determined by nonlinear regression analysis of the activation multiples at different compound concentrations. 50 The specific experimental results are shown in Table 1:

[0353] Table 1: Biological test results

[0354]

[0355]

[0356] From the biological activity data of the compounds in the specific examples, it can be seen that the series of compounds of the present invention have a strong inhibitory effect on the protein interaction of PD-1 / PD-L1, and this inhibitory effect can enhance or restore the activation of T cells at the cellular level.

[0357] 3. Pharmacokinetics in mice

[0358] 1. Research objectives

[0359] The purpose of this experiment is to study the pharmacokinetic behavior of some compounds of the present invention. The administration methods are: single oral administration (PO) to ICR mice, and the dosage is 10 mg / kg.

[0360] 2. Experimental plan

[0361] 2.1 Trial Drugs

[0362] The compounds used in this test are from the specific examples of the present invention.

[0363] 2.2 Experimental animals

[0364] ICR mice male N=3 Original source: Shanghai Xipul-Bike Experimental Animal Co., Ltd.

[0365] 2.3 Drug preparation and administration

[0366] Weigh the compound and dissolve it in 0.5% SDS+0.5% CMCNa solvent, shake well, and sonicate to make a colorless clear solution. 9 mice were fasted overnight and orally administered at a dose of 10 mg / kg.

[0367] 2.4 Sample collection:

[0368] 1) About 90 μL of blood was collected from the submandibular vein at each time point, anticoagulated with sodium heparin, placed on ice, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 degrees).

[0369] 2) Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The samples were stored in a refrigerator at -20 degrees.

[0370] 3) To 40 μL of plasma sample, add 160 μL of ice-cold acetonitrile containing internal standard, vortex for 3 minutes, and centrifuge at 11,000 rpm for 5 minutes.

[0371] 4) Take 100 μL of the supernatant and add it to 100 μL of water, and take 5 μL and inject it into LC / MS / MS for analysis.

[0372] Some representative compounds of the present invention were administered and tested according to the above method, and their original compounds were detected. The experimental results are shown in Table 2.

[0373] Table 2 PK results of single oral administration (PO) of 10 mg / kg compound in mice

[0374]

[0375]

[0376] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference separately. In addition, it should be understood that after reading the above content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the compounds of formula (IIIa) or (IIIb): wherein each L1 is independently selected from -CH=CF- or -NH-C(O)-; Each R1 and R2 are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, carboxyl, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl or C 1-4 Alkoxy; In the compound of formula (IIIa), R5 is selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl or deuterium substituted C 1-4 alkyl; Each R6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 The above groups are optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -OR 22 、-C(O)OR 22 、-C(O)R 23 、-OC(O)R 23 、-NR 24 R 25 、-C(O)NR 24 R 25 or -N(R 24 )-C(O)R 23 substituted by a substituent; In the compound of formula (IIIa), R 13 C 1-4 Alkyl, the above group is optionally further substituted with a C 3-8 The cycloalkyl group is optionally substituted by a -C(O)OR 22 substituted by a substituent; In the compound of formula (IIIa), R 15 C 1-4 alkyl; In the compound of formula (IIIb), R 18 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl or 3-6 membered heterocyclic group; In the compound of formula (IIIb), R 19a With R 20a Together with the nitrogen atom to which it is directly connected, it forms a 3-6 membered heterocyclic group, and the above group is optionally further substituted by a -C(O)OR 22 substituted by a substituent; Each R 22 are each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent; Each R 23 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or -NR 24 R 25 The above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy or -NR 24 R 25 substituted by a substituent; Each R 24 , R 25 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino or C 1-4 Alkanoyl, the above groups are optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino or C 1-4 substituted with an alkanoyl substituent; Or, R 24 , R 25 Together with the nitrogen atom to which it is directly connected, it forms a 4-8 membered heterocyclic group, wherein the above group is optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group, C 5-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino or C 1-4 The alkanoyl group is substituted with an alkanoyl substituent.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

3. A method for preparing the compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The steps include: wherein ring A, L1, L2, R1, R2, R3, R4, R5, R6, and m are as described in claim 1.

4. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 2, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. Use of a compound of formula (I) according to any one of claims 1 to 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating diseases mediated by the PD-1 / PD-L1 signaling pathway.

6. The use according to claim 5, characterized in that: The diseases mediated by the PD-1 / PD-L1 signaling pathway are selected from tumors, immune-related diseases and disorders, infectious diseases or infectious diseases. The tumor is selected from lymphoma, sarcoma, melanoma, glioblastoma, synovioma, meningioma, biliary tumor, thymic tumor, neural tumor, seminoma, Wilms tumor, hepatocellular papilloma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, spinal axon tumor, brain stem glioma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, anal cancer, testicular cancer, Cancer of the urethra, penis, bladder, ureter, uterus, fallopian tube, endometrium, cervix, vagina, vulva, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia, bronchial cancer, esophageal cancer, nasopharyngeal cancer, hepatocellular carcinoma, renal cell carcinoma, basal cell carcinoma, lung, papillary carcinoma, rectum, colon, colorectal cancer, stomach, head and neck cancer, bone cancer, skin cancer, small intestine cancer, endocrine system cancer, renal pelvis cancer, epidermoid carcinoma, abdominal wall cancer, transitional cell carcinoma, or choriocarcinoma; The immune-related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, allergic contact dermatitis and eczema, systemic sclerosis or multiple sclerosis; The infectious disease or infectious disease is selected from sepsis, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus or influenza.

7. The use according to claim 6, characterized in that: The adenoma is pleomorphic adenoma, renal tubular adenoma, cystadenoma, pituitary adenoma, prostate cancer, recurrent prostate cancer or prostate cancer resistant to existing drugs, thyroid cancer, parathyroid cancer, adrenal cancer, breast cancer, cystadenocarcinoma or pancreatic cancer; The lung cancer is small cell lung cancer, squamous non-small cell lung cancer or non-squamous non-small cell lung cancer; The head and neck cancer is head and neck squamous cell carcinoma.

8. The use according to claim 6, characterized in that: The lymphoma is selected from lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; The sarcoma is selected from Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma; The chronic or acute leukemia is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia.

9. The use according to claim 6, characterized in that: The tumor is a metastatic tumor, and the metastatic tumor is a metastatic tumor expressing PD-L1.

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