WO2020011209A1 - Immunosuppressive agent, preparation method therefor and pharmaceutical use thereof - Google Patents

Abstract

An immunosuppressive agent having the structure of formula (I), a preparation method therefor, and pharmaceutical use thereof. A series of the compounds have strong inhibitory activity on PD-1/PD-L1 interaction, can be widely used for preparing medicaments for preventing and/or treating cancers or tumors, immune-related diseases and disorders, communicable diseases, infectious diseases or metabolic diseases mediated by PD-1/PD-L1 signaling pathway, and is expected to be developed into a new generation of PD-1/PD-L1 inhibitors.

Description

Immunosuppressant, its preparation method and its pharmacological application Technical field

The invention belongs to the field of pharmaceutical synthesis, and particularly relates to an immunosuppressive agent, a preparation method thereof and pharmaceutical application.

technical background

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

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 contains a Extracellular immunoglobulin variable domain similar domains, a transmembrane region and an intracellular region, where the intracellular region contains two phosphorylation sites, located in the immunoreceptor tyrosine kinase-based inhibitory domain and The switch domain based on immune receptor tyrosine kinases suggests that PD1 can negatively regulate T cell receptor-mediated signaling pathways.

PD1 has two ligands, PD-L1 and PDL2, which have different expression profiles. PDL1 protein is up-regulated in macrophages and dendritic cells after lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. B cell receptor signaling pathways are also upregulated after stimulation. It is also highly expressed in almost all tumor cells and is upregulated after stimulation with interferon (IFN) gamma. In fact, the expression status of tumor PDL1 is considered to have a prognostic correlation with PD-L2 expression in a variety of tumor types. On the contrary, it is more concentrated and mainly expressed on dendritic cells.

When PD-1 expressing T cells are in contact with cells expressing their ligands, functional activities such as cell proliferation, cytokine release, and cytolytic activity after stimulation of those antigens are inhibited. Therefore, the interaction of PD1 and its ligands functions as an intrinsic negative feedback regulation mechanism, which can enable people to prevent excessive activation 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, will cause T cells to express high levels of PD-1, and lack of activity in response to these long-term antigens, without function, which is what people call T-cell function Exhausted. B cells also have the inhibitory effect of PD1 and its ligands and corresponding functional failure.

Some evidence from preclinical animal studies suggests that PD-1 and its ligands can negatively regulate the immune response. PD-1 deficient mice develop lupus-like acute proliferative glomerulonephritis and dilated cardiomyopathy. The use of PDL1 antibodies to block PD-1 / PDL1 interactions has been shown to restore and enhance T cell activation in many systems. PDL1 monoclonal antibodies can also benefit patients with advanced cancer. Some preclinical animal tumor models have also shown that blocking PD-1 / PD-L1 signaling pathways with monoclonal antibodies can enhance the immune response and lead to immune responses to a range of histologically significantly different tumors, using long-term infection The LCMV model, PD-1 / PD-L1 interaction, has been found to inhibit virus-specific CD8T cell activation, expansion, and acquisition of effector cell functions. In addition to enhancing the immune response to long-term antigens, blocking the PD-1 / PDL1 pathway has also been found to enhance the response to vaccines, including the response to therapeutic vaccines in the context of long-term infection.

In summary, in addition to the existing monoclonal antibodies, if compounds that block PD1-PDL1 protein-protein interactions can be developed, they will be able to block PD-1 / PDL1-mediated inhibitory signaling pathways. Effective treatment to enhance or restore T cell function. Therefore, compounds targeted to block the PD-1 / PD-L1 interaction will have a very good effect in immunotherapy of various cancers and other immune-related diseases.

Summary of the invention

The object of the present invention is to provide a compound having a blocking effect on the PD-1 / PD-L1 interaction, so that it is expected to develop a new generation of PD-1 / PD-L1 inhibitors.

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

Wherein X and Y are each independently selected from N or C (R ₈ );

R ₁ and R ₂ 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 Heterocyclic group, C _5-10 aryl group or 5-10 membered heteroaryl group, or R ₁ and R ₂ together with the nitrogen atom to which it is directly attached form a 3-10 membered heterocyclic group. The above group is optionally further Is selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkane Group, 3-10 membered heterocyclic group, C _5-10 aryl group, 5-10 membered heteroaryl group, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from the group consisting of deuterium, halogen, cyano, nitro, Azide, 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 ring alkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered _{Aryl, = O, -C 0-8 -S (} O) r R 19, -C 0-8 -OR 20, -C 0-8 -C (O) OR 20, -C 0-8 -C ( O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8- Substitution of N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ Superseded by

R ₃ and R ₈ are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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 group, 5-10 membered heteroaryl group, -C _0-8 -S (O) _r R ₁₉ , -C _0-8- OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more selected from the group consisting of 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or- C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

R ₄ and R ₅ are each independently selected from hydrogen or fluorine, or R ₅ and R ₆ and the directly connected group together form a 4-10 membered carbocyclic group or a 4-10 membered heterocyclic group, with the proviso that R _4. R _{5 is} not selected from hydrogen at the same time;

R _{6 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _{0 - 8 -C (O) OR 20} , -C 0-8 -C (O) R 20, -C 0-8 -OC (O) R 21, -C 0-8 -NR 22 R 23, -C 0 _-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 heterocyclyl , C _5-10 aryl, 5-10 membered heteroaryl, = O, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C ( O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C ( = NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

Each R _{7 is} independently selected from the following groups:

Each R _{9 is} independently selected from -C _0-4 -NR ₁₇ R ₁₈ , and the above-mentioned groups are optionally further selected from one or more of 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 member Heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _{0- 8} -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

Each R ₁₀ , R _{11 is} independently selected from hydrogen, fluorine, cyano or methyl;

Each R _{12 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _{0 -8} -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _{0 -8} -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ substituted with a substituent;

Each of R ₁₃ , R ₁₄ , and R _{15 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S (O) _r R ₁₉ ,- C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _{0 -8} -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8- C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro , Azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8- OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

R _{16 is} selected from hydrogen, deuterium, halogen, cyano, C _1-10 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl , -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ or -C _0-8 -OC (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 heterocyclyl, C _{5- 10} aryl, 5-10 membered heteroaryl, = O, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further further substituted by one or more selected from the group consisting of 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = O, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ 、 -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ 、 -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) substituted by a substituent of -C (O) R ₂₁ ;

Each of R ₁₇ and R _{18 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 A -10 membered heterocyclic group, a C _5-10 aryl group or a 5-10 membered heteroaryl group, or R ₁₇ and R ₁₈ together with its directly attached nitrogen atom form a 3-10 membered heterocyclic group. Is further selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8- OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, cyano, nitrate Radical, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered _{heteroaryl, = O, -C 0-8 -S (} O) r R 19, -C 0-8 -OR 20, -C 0-8 -C (O) OR 20, -C 0 _-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ ,- C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O ) Substituted by a substituent of R ₂₁ ;

Each R _{19 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, 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 heterocyclic Aryloxy or -NR ₂₂ R ₂₃ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, 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 heterocyclic Substituted with aryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ substituents;

Each R _{20 is} independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl Or 5- to 10-membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of 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 Substituted by heteroaryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ substituents;

Each R _{21 is} 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 heterocyclic Aryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, cyano, C _1-10 alkyl, C _{1- 10} alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 Substituted with aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ ;

Each of R ₂₂ and R _{23 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkoxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C _1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium , Halogen, hydroxyl, 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 _1-10 Alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aromatic Substituted by oxo, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents;

Alternatively, R ₂₂ and R ₂₃ and the directly connected nitrogen atom together form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, and hydroxyl group. , Carboxyl, 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 _1-10 alkoxy Group, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents;

(Z) / (E) means cis, trans isomers or a mixture of cis and trans isomers thereof;

m is 0, 1 or 2;

Each p is independently 0, 1, 2 or 3;

Each n, q is independently 0, 1, 2, 3 or 4;

Each r is independently 0, 1, or 2.

As a preferred embodiment, R _{6 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, and C. _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered hetero Aryl, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is further selected from substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl group, a halogen substituted C ₁ to _-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _{0 -4} -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C ( _{= NR 23) R 21, -C} 0-4 -C (O) NR 22 R 23 _{-C 0-4 -N (R 22) -C} (O) R ₂₁ group substituted with _{substituents, R 19, 20, R 21} , R 22, R 23, R r as the compound of formula (I).

As a further preferred embodiment, R _{6 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, bromine, cyano, and nitrate. Radical, azide, methyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl, pyridyl, di Azozole, triazole, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl, or acetylamino, these groups are optional Further substituted with one or more members selected from the group consisting of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl, or amino Group.

As a further preferred embodiment, R _{6 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, bromine, cyano, Nitro, azide, methyl, cyclopropyl, phenyl, pyridyl, diazole, triazole, methoxy, or carboxyl, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine , Chloro, hydroxy, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl or amino.

As a preferred embodiment, R ₁ and R _{2 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, or 5-8 membered heteroaryl, or R ₁ forms a 3-8 membered heterocyclic group together with R ₂ and the nitrogen atom directly connected to it, and the above group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, and C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl Base, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O ) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ Instead, the above-mentioned group is optionally further further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl group, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-8 aryl, 5-8 membered _{heteroaryl, = O, -C 0-4 -S (} O) r R 19, -C 0-4 -OR 20, -C 0-4 -C ( O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C ( = NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent, and R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in the compound of formula (I).

As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R _{1 is} selected from hydrogen, deuterium or methyl; R _{2 is} selected from hydrogen, deuterium, or C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, or R ₁ and R ₂ together with the nitrogen atom to which they are directly attached form 3 -8-membered heterocyclic group, the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8-membered heterocyclic group, C _5-6 aryl, 5-6 membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC ( O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or Multiple selected from deuterium, halogen, cyano, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-6 aryl, 5-6 membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ is substituted with R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r as described in the compound of formula (I).

上述基团任选再进一步被一个或多个选自氘、氟、氯、羟基、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、甲氧基、甲酰氧基、乙酰氧基、丙酰氧基、异丁酰氧基、羧基或氨基的取代基所取代。 As a still further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R _{1 is} selected from hydrogen, deuterium or methyl; R _{2 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, or R ₁ and R ₂ together with the nitrogen atom to which it is directly attached form a 3-6 membered heterocyclic group, the above group Optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxy, cyano, methyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl , Pyridyl, diazole, triazole, = O, methanesulfonyl, aminosulfonyl, methoxy, methoxyl, ethoxyl, isopropoxyl, carboxyl, acetyl, acetoxy, amino , Dimethylamino, aminoacyl, acetamino, or

The aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methoxy , Formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents.

As a preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R _{3 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azido, and C. _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered hetero Aryl, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is further selected from substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl group, a halogen substituted C ₁ to _-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _{0 -4} -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C ( _{= NR 23) R 21, -C} 0-4 -C (O) NR 22 R 23 _{-C 0-4 -N (R 22) -C} (O) R ₂₁ group substituted with _{substituents, R 19, 20, R 21} , R 22, R 23, R r as the compound of formula (I).

As a further preferred embodiment, R _{3 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further One or more selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkane Group, deuterium substituted C _1-4 alkyl group, C _3-8 cycloalkyl group, 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -O- C (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described for the compound of formula (I).

As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a compound selected from the group consisting of a compound of formula (IIa) or a compound of formula (IIb) as follows structure:

among them,

X and Y in the compound of the formula (IIa) are each independently selected from N or C (R ₈ ), and R _{8 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0- 4} -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, halogen, cyano, nitro, azide, 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, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = 0, -C _0-4 -S (O ) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ generation;

In the compound of formula (IIb), X and Y are each independently selected from N or C (R ₈ ). R ₅ and R ₆ and the directly connected group together form a 5-6 membered carbocyclic group or a 5-6 membered heterocyclic group. Cyclic group, R _{8 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ Or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3-8 member Heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R _{7 are} as described for the compound of formula (I).

As a still further preferred embodiment, each R _{7 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from the following groups:

among them,

Each R _{9 is} independently selected from -CH ₂ -NR ₁₇ R ₁₈ , and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _1-4 alkane , C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4- N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

Each R ₁₀ , R _{11 is} independently selected from hydrogen, fluorine, cyano or methyl;

Each R _{12 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _{0- 4} -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3- 8-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, = 0, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _{0 -4} -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _{0 -4} -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ substituted with a substituent;

Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _{0- 4} -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4- NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O ) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide Alkyl, 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 , 3-8 membered heterocyclic group, C _5-8 aryl group, 5- 8 membered heteroaryl group, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ Or substituted by -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ substituents;

Each of R ₁₇ and R _{18 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 Heterocyclic group, C _5-8 aryl group or 5-8 membered heteroaryl group, or R ₁₇ and R ₁₈ together with the nitrogen atom to which it is directly attached form a 3-8 membered heterocyclic group. The above group is optionally further Is selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkane Group, 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, = 0, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from the group consisting of deuterium, halogen, cyano, nitro, Azide, 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 ring Alkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = 0, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4- OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

R _22a and R _23b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkoxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, P-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C _1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium, halogen , Hydroxyl, 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 _1-10 alkoxy Group, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents,

Alternatively, R _22a and R _23b together with the directly connected nitrogen atom form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more selected from the group consisting of deuterium, halogen, and hydroxyl group. , carboxy, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl group, a halo substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _1-10 alkoxy Group, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents;

R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described for the compound of formula (I).

As a still further preferred embodiment, each R _{12 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, Bromine, cyano, nitro, azido, methyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azatidine, benzene Methyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl, or acetylamino The above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methoxy With carboxyl or amino substituents;

Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ ,- C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C ( O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3-8 -Membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ substituents;

R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described for the compound of formula (I).

As a still further preferred embodiment, each R _{9 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from -CH ₂ -NR ₁₇ R ₁₈ . The group is optionally further one or more selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halide Substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O , -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₁ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

Each of R ₁₇ and R _{18 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, Alternatively, R ₁₇ and R ₁₈ and its directly attached nitrogen atom together form a 3-6 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, and C _1-4 alkyl , C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R _23, or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, and deuterium-substituted C _{1- 4-} alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, = 0, -S (O) _r R ₁₉ , -OR ₂₀ , -C ( O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R _23, or -N (R ₂₂ ) -C (O) R ₂₁ R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , r are as described for the compound of formula (I).

上述基团任选再进一步被一个或多个选自氘、氟、氯、羟基、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、甲磺酰基、甲氧基、甲酰氧基、乙酰氧基、丙酰氧基、异丁酰氧基、羧基或氨基的取代基所取代。 As a still further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R _{17 is} selected from hydrogen or deuterium; R _{18 is} selected from hydrogen, deuterium, C _{1- 4} alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, or R ₁₇ and R ₁₈ together with its directly attached nitrogen atom form 3-6 Heterocyclic group, the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, isopropyl, cyclopropyl, 3-oxetanyl, 3- Azetidine, phenyl, pyridyl, diazole, triazole, = 0, methanesulfonyl, aminosulfonyl, methoxy, methoxyl, ethoxyl, carboxyl, acetyl, acetyloxy Group, isopropoxyacyl, amino, dimethylamino, aminoacyl, acetylamino, or

The above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, = 0, methanesulfonyl, Substituted by methoxy, formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents.

As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a compound selected from the group consisting of a compound of formula (IIIa) or a compound of formula (IIIb) as follows structure:

among them,

X in the compound of formula (IIIa) is selected from N or CH;

X in the compound of formula (IIIb) is selected from N or CH;

上述基团任选再进一步被一个或多个选自氘、氟、氯、羟基、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、甲氧基、甲酰氧基、乙酰氧基、丙酰氧基、异丁酰氧基、羧基或氨基的取代基所取代； R _{1 is} selected from hydrogen, deuterium or methyl; R _{2 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, or R ₁ and R ₂ and The directly connected nitrogen atoms together form a 3-6 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, isopropyl, and cyclopropyl. , 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, = O, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, Ethoxyl, carboxyl, acetyl, acetoxy, isopropoxyl, amino, dimethylamino, aminoacyl, acetylamino or

The aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methoxy , Formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents;

Each R _{3 is} independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, benzene Group, 5-6 membered heteroaryl group, -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ or -NR ₂₂ R ₂₃ , the above-mentioned group is optionally further Is substituted by one or more selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 -Membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, = O, -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ or -NR ₂₂ Substituted by a substituent of R ₂₃ ;

R _{6 is} selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine With hydroxy, cyano, methyl, cyclopropyl, phenyl or methoxy substituents;

Each R _{7 is} independently selected from the following groups:

Each of R ₁₀ and R _{11 is} independently selected from hydrogen or fluorine;

Each R _{9 is} independently selected from -CH ₂ -NR ₁₇ R ₁₈ , and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _1-4 alkane , C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-8 aryl, 5-8 membered heteroaryl, = 0, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₁ ,- OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent;

上述基团任选再进一步被一个或多个选自氘、氟、氯、羟基、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、＝O、甲磺酰基、甲氧基、甲酰氧基、乙酰氧基、丙酰氧基、异丁酰氧基、羧基或氨基的取代基所取代； R _{17 is} selected from hydrogen or deuterium; R _{18 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, Alternatively, R ₁₇ and R ₁₈ and the directly connected nitrogen atom together form a 3-6 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, and methyl , Isopropyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl, pyridyl, diazole, triazole, = 0, methanesulfonyl, aminosulfonyl, Methoxy, methoxy, ethoxy, isopropoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl, acetylamino, or

The above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, = 0, methanesulfonyl, Substituted with methoxy, formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents;

Each R _{12 is} independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the above-mentioned groups are optionally further selected from one or more Substituted with deuterium, fluorine, chlorine, hydroxy, cyano, methyl, cyclopropyl, phenyl or methoxy;

Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 Heteroaryl, -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ or -NR ₂₂ R ₂₃ , the above-mentioned groups are optionally further substituted by one or more Substituted with a substituent selected from deuterium, fluorine, chlorine, hydroxy, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl or amino;

R _22a , R _23b and the directly connected nitrogen atom together form a 4- to 10-membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, 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 _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group, 5-10 membered heteroaryl group, 5 -10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents;

R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described for the compound of formula (I).

As a still further preferred embodiment, each R _{19 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, and hydroxyl groups. , C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3 -6 membered heterocyclic oxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkyl Amino, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxy, carbonyl, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heterocyclic Substituted by aryloxy, amino, monoalkylamino, dialkylamino substituents;

Each R _{20 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _{5- 8} aryl Or 5-8 membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _{3 -6} cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, diazole , Triazole, pyridine, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino substituents;

Each R _{21 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heterocyclic Aryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxy, cyano, C _1-4 Alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclooxy, C _5-8 aromatic With C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino substituents;

Each of R ₂₂ and R _{23 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C _1-4 alkanoyl, the above-mentioned groups are optionally further selected from one or more of deuterium , Halogen, hydroxy, 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 _1-4 Alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclooxy, C _5-8 aryl, C _5-8 aromatic Aryl, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, amino, monoalkylamino, dialkylamino, or a C _1-4 alkanoyl substituent; or R ₂₂ , R ₂₃ and its directly attached nitrogen atom together form a 4- to 6-membered heterocyclyl or 4- to 6-membered heteroaryl, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, 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 _1-4 alkoxy, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heterocyclic Substituted by aryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-4 alkanoyl substituents.

As a still further preferred embodiment, each R _{3 in the} compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, and halogen. , Cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, benzyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, cyano-substituted phenyl, C _1-4 alkoxy Phenyl, 5- to 6-membered heteroaryl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, carboxyl, methoxy, ethoxy, iso Propionyl, acetyl, acetoxy, amino, monomethylamino, dimethylamino or

Each R _{12 is} independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the methyl, cyclopropyl, methoxy is Optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, cyclopropyl, phenyl or methoxy;

Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 Alkoxy C _1-4 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, benzyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl , Phenyl, cyano-substituted phenyl, C _1-4 alkoxyphenyl, 5-6 membered heteroaryl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _{1 -4} alkoxy, carboxy, methoxy, ethoxy, isopropoxy, acetyl, acetoxy, amino, monomethylamino, dimethylamino or

R _22a , R _23b and its directly connected nitrogen atom together form a 4- to 6-membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, _C1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, phenyl, phenoxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, Substituted by amino, monoalkylamino, dialkylamino, or C _1-4 alkanoyl substituents.

As a most preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

According to a second aspect of the present invention, a method for preparing the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is provided, including the following steps:

或者，R ₇’选自如下基团： Where R ₇ 'is

Alternatively, R ₇ 'is selected from the group:

Where R ₉ 'is -C _0-3 -CHO; X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , m, n, p, q are as described for the compound of formula (I).

A third aspect of the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to a fourth aspect of the present invention, there is provided the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for the prevention and / or treatment of PD-1 / PD- Application of L1 Signaling Pathway to Related Drugs

As a preferred solution, the aforementioned 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.

As a further preferred embodiment, the infectious disease is selected from the group consisting of a bacterial infectious disease, a viral infectious disease, and a fungal infectious disease.

As a further preferred embodiment, the aforementioned 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, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma), melanoma, glioblastoma, synovial tumor, meningiomas, biliary tumor, thymic tumor, neurotumor, seminoma, nephroblastoma Tumors, pleomorphic adenomas, hepatocellular papillomas, tubular adenomas, cystadenomas, papillomas, adenomas, leiomyomas, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondroma, lipomas , Fibroma, central nervous system tumor, spinal axoma, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, prostate cancer , Prostate cancer, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureter cancer, uterine cancer, ovarian cancer, fallopian tube cancer, relapsed or resistant to existing drugs, Endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, Merkel cell cancer, embryo cancer, 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 cancer, cyst Adenocarcinoma, 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 cancer, abdominal wall cancer, renal cell cancer, transitional cell cancer or chorionic cancer, and metastatic tumors, especially PD-L1 of metastatic tumors.

As a further preferred embodiment, the immune-related diseases and disorders are selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies, fibrosis, anemia fibromyalgia, Alz Hemer disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis And multiple sclerosis.

As a further preferred embodiment, the aforementioned infectious disease or infectious disease is selected from the group consisting of sepsis, liver infection, HTV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, or influenza.

As a further preferred embodiment, the aforementioned metabolic disease is selected from the group consisting of diabetes, diabetic ketoacidosis, hyperglycemia and hypertonic syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, and vitamin D deficiency Or osteoporosis.

A fifth aspect of the present invention provides the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition for use in the prevention and / or treatment of PD-1 / PD-L1 signaling pathway-mediated drugs for cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases.

detailed description

After extensive and intensive research, the inventors of the present application have developed a series of compounds of the general formula (I). The series of compounds of the present invention have a strong inhibitory effect on the PD-1 / PD-L1 interaction and can be widely used. Applied to the preparation of drugs for the prevention and / or treatment of cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway, which is expected to develop into a new generation PD-1 / PD-L1 inhibitor. Based on this, the present invention has been completed.

Detailed description: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group. For example, "C _1-10 alkyl" refers to a linear alkyl group containing 1 to 10 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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 Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 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-bis Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched chains thereof Isomers, etc.

The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, and cyanide. Radical, nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _{0- 8} -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, " _C3-10 cycloalkyl" refers to a cycloalkyl group comprising 3 to 10 carbon atoms , Divided into monocyclic cycloalkyl, polycyclic cycloalkyl, of which:

Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.

Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl. "Spirocycloalkyl" refers to polycyclic groups that share one carbon atom (called a spiro atom) between 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. Spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings. Spirocycloalkyl includes but is not limited to:

"Fused cycloalkyl" refers to a full-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated π-electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings. The fused cycloalkyl includes but is not limited to:

"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 them The ring has a completely conjugated π-electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings. The bridged cycloalkyl includes but is not limited to:

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

A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ ,- C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _{0- 8} -OC (O) R ₂₁ , -C _{0 -8} -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8- C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent.

"Heterocyclyl" or "heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which 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, 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. For example, "4- to 10-membered heterocyclic group" refers to a cyclic group containing 4 to 10 ring atoms, and "3 to 6-membered heterocyclic group" refers to a cyclic group containing 3 to 6 ring atoms.

Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen and oxygen Or S (O) _r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings have a completely conjugated pi electron system. Spiro heterocyclyl is classified into monospiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings. Spiro heterocyclyl includes, but is not limited to:

"Fused heterocyclyl" refers to a polycyclic heterocyclic group where each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more (preferably 1, 2, 3, or 4) rings may Contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings have a completely conjugated π electron system, in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected A heteroatom from nitrogen, oxygen, or S (O) _r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl according to the number of constituent rings. The fused heterocyclyl includes but is not limited to:

"Bridged heterocyclyl" 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 them The ring has a completely conjugated π-electron system in which 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, 2) Heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:

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

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ ,- C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _{0- 8} -OC (O) R ₂₁ , -C _{0 -8} -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8- C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent.

"Aryl" or "aromatic ring" refers to a full-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated π-electron system (that For carbon atom ring) groups, for example, "C _5-10 aryl" refers to a full-carbon aryl group containing 5-10 carbons, and "5-10 member aryl" refers to a full-carbon group containing 5-10 carbons Aryl includes, but is 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:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _{0- 8} -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8- NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O ) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"Heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2) Heteroatom, for example, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, and 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, including but It is not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ ,- C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _{0- 8} -OC (O) R ₂₁ , -C _{0 -8} -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8- C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent.

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

Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _{0- 8} -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8- NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O ) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"Alkynyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, C _2-10 alkynyl refers to a straight or branched chain containing 2 to 10 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

The alkynyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _{0- 8} -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8- NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O ) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"Alkoxy" refers to -O- (alkyl), where alkyl is as defined above, for example, "C _1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy and the like.

The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium and halogen. , Cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkane , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _{0- 8} -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"Cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, "C _3-10 cycloalkoxy" refers to a cycloalkyloxy group containing 3-10 carbons Including, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

The cycloalkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen , Cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkane Group, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _{5- 10} aryl group, 5-10 membered heteroaryl group, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ ,-C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"Heterocyclyloxy" refers to -O-heterocyclyl, wherein the definition of heterocyclyl is as described above, for example, " _C3-10 heterocyclyl" refers to heterocyclyloxy containing 3-10 carbons Including, but not limited to, azetidinyloxy, oxetanyloxy, azetyloxy, nitrogen, oxethanyloxy, and the like.

The heterocyclooxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium and halogen. , Cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkane Group, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _{5- 10} aryl group, 5-10 membered heteroaryl group, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent.

"C _1-10 alkanoyl" refers to the monovalent atomic group remaining after the C _1-10 alkyl acid has been removed from the hydroxyl group, and is usually also expressed as "C _0-9 -C (O)-", for example, "C ₁ -C (O)-"means acetyl;" C ₂ -C (O)-"means propionyl;" C ₃ -C (O)-"means butyryl or isobutyryl.

"-C _0-8 -S (O) _r R ₁₉ " means that the sulfur atom in -S (O) _r R ₁₉ is attached to a C _0-8 alkyl group, where C ₀ alkyl refers to a bond, and C _1- The definition of _8- alkyl is as described above.

"-C _0-8 -OR ₂₀ " means that the oxygen atom in -OR ₂₀ is attached to a C _0-8 alkyl group, where C ₀ alkyl refers to a bond, and the definition of C _1-8 alkyl group is as described above.

"-C _0-8 -C (O) OR ₂₀ " means that the carbonyl group in -C (O) OR ₂₀ is attached to a C _0-8 alkyl group, where C ₀ alkyl refers to a bond and C _1-8 alkyl group The definition is as described above.

"-C _0-8 -C (O) R ₂₁ " means that the carbonyl group in -C (O) R ₂₁ is attached to a C _0-8 alkyl group, where C ₀ alkyl refers to a bond, and C _1-8 alkyl group The definition is as described above.

_{"-C 0-8 -OC (O) R} 21" refers to a -OC (O) R ₂₁ is an oxygen atom attached to C _0-8 alkyl, wherein C ₀ alkyl means a bond, C _{1- 8} alkyl The definition of base is as described above.

"-C _0-8 -NR ₂₂ R ₂₃ " means that the nitrogen atom in -NR ₂₂ R ₂₃ is attached to a C _0-8 alkyl group, where C ₀ alkyl refers to a bond, and the definition of C _1-8 alkyl is as above As described.

"-C _0-8 -C (= NR ₂₂ ) R ₂₁ " means that the nitrogen atom in -C (= NR ₂₂ ) R ₂₁ is attached to a C _0-8 alkyl group, where the C ₀ alkyl group refers to a bond and C The definition of _1-8 alkyl is as described above.

"-C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ " means that a nitrogen atom in -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ is attached to a C _0-8 alkyl group In the above, where C ₀ alkyl refers to a bond, C _1-8 alkyl is as defined above.

"-C _0-8 -C (O) NR ₂₂ R ₂₃ " means that the carbonyl group in -C (O) NR ₂₂ R ₂₃ is attached to a C _0-8 alkyl group, where C ₀ alkyl refers to a bond and C ₁ The definition of _-8 alkyl is as described above.

"-C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ " means that the nitrogen atom in -N (R ₂₂ ) -C (O) R ₂₁ is attached to a C _0-8 alkyl group, where C ₀ alkyl means a bond, and C _1-8 alkyl is as defined above.

"Halo-substituted C _1-10 alkyl" refers to a 1-10 carbon alkyl group optionally substituted with hydrogen on the alkyl by fluorine, chlorine, bromine, or iodine atoms, including, but not limited to, difluoromethyl, di Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

"Halo-substituted _C1-10 alkoxy" refers to a _1-10 carbon alkoxy group optionally substituted with hydrogen on the alkyl group by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"Deuterium-substituted _C1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl is optionally substituted with a deuterium atom. Including, but not limited to, monodeuteryl, dideuteryl, trideuteryl, and the like.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Optional" or "optionally" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted with alkyl group" means that the alkyl group may but need not exist, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group are substituted independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, 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 having free hydrogen may be unstable when combined with a carbon atom (such as an olefin) having an unsaturated bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

The following describes the present invention in further detail and completeness with reference to the examples, but it is by no means limited to the present invention, and the present invention is not limited to the content of the examples.

The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCE-500 nuclear magnetic analyzer. The measurement solvents were deuterated dimethylsulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD), and deuterated water (D ₂ O). And deuterated chloroform (CDCl ₃ ) with an internal standard of tetramethylsilane (TMS).

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications adopted by TLC are 0.15mm ～ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ～ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.

Unless otherwise specified, all the 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 unit is degrees Celsius (° C).

First, the preparation of intermediates

Intermediate A1: methyl (Z) -4- (1-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) vinyl ) -2,6-Dimethoxybenzoate

Step 1: Synthesis of methyl 4-bromo-2,6-dimethoxybenzoate

Methyl 4-bromo-2,6-difluorobenzoate (7.5 g, 30 mmol) was dissolved in methanol (50 mL), and a 30% sodium methoxide methanol solution (20.16 mL, 120 mmol) was added. The reaction was stirred at 80 ° C for 16 hours. After the reaction was completed, it was poured into ice water (300 mL), and then extracted with ethyl acetate (200 mL * 2). The organic phase was sequentially washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the compound Methyl 4-bromo-2,6-dimethoxybenzoate (7.7 g, yield 93%). ESI-MS 275.2 [M + H] ⁺ .

Step 2: Synthesis of methyl 2,6-dimethoxy-4-((trimethylsilyl) ethynyl) benzoate

Dissolve methyl 4-bromo-2,6-dimethoxybenzoate (7.7 g, 28 mmol) and ethynyltrimethylsilane (5.5 g, 56 mmol) in tetrahydrofuran (50 mL), and add subiodide Copper (1.06 g, 5.6 mmol), bistriphenylphosphonium palladium dichloride (1.96 g, 2.8 mmol) and triethylamine (20 mL) were stirred at 55 ° C for 2 hours. After filtration and concentration, column chromatography [eluent: petroleum ether to petroleum ether / ethyl acetate (5/1)] gave methyl 2,6-dimethoxy-4-((trimethylsilyl) ) Ethynyl) benzoate (7.7 g, 94% yield). ESI-MS 293.4 [M + H] ⁺ .

Step 3: Synthesis of methyl 4-ethynyl-2,6-dimethoxybenzoate

Methyl 2,6-dimethoxy-4-((trimethylsilyl) ethynyl) benzoate (7.7 g, 27.26 mmol) was dissolved in methanol (150 mL) and potassium carbonate (3.76 g , 27.26 mmol), and the reaction was stirred at room temperature for 10 minutes. After completion of the reaction, filtration and concentration were performed after column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (3/1)] to obtain methyl 4-ethynyl-2,6-dimethoxybenzoate (5.0 g, yield 83.4%). ESI-MS 221.2 [M + H] ⁺ .

Step 4: Synthesis of methyl 4- (bromoethynyl) -2,6-dimethoxybenzoate

Methyl 4-ethynyl-2,6-dimethoxybenzoate (5.0 g, 22.73 mmol) was dissolved in acetone (150 mL), and silver nitrate (386 mg, 2.273 mmol) and N-bromobutane were added. The imide (5.26 g, 29.54 mmol) was stirred at room temperature for 2 hours. After filtration, it was poured into water (300 mL), and then extracted with ethyl acetate (200 mL * 2). The organic phase was washed with water (100 mL) and saturated brine (100 mL) in this order, and dried over anhydrous sodium sulfate. -(Bromoethynyl) -2,6-dimethoxybenzoate (6.3 g, yield 92.7%). ESI-MS 301.0 [M + H] ⁺ .

Step 5: Synthesis of methyl (Z) -4- (2-bromo-1-fluorovinyl) -2,6-dimethoxybenzoate

Methyl 4- (bromoethynyl) -2,6-dimethoxybenzoate (6.3 g, 21.07 mmol) was dissolved in acetonitrile / water (120 mL / 6 mL), and silver fluoride (8.02 g, 63.21) was added. mmol), and the reaction was stirred at 80 ° C for 16 hours. Filtration and concentration column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (3/1)] to obtain methyl (Z) -4- (2-bromo-1-fluorovinyl) -2 , 6-dimethoxybenzoate (4.2 g, 62.5% yield). ESI-MS 321.2 [M + H] ⁺ .

The sixth step: methyl (Z) -4- (1-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) vinyl ) -2,6-Dimethoxybenzoate

Dissolve methyl (Z) -4- (2-bromo-1-fluorovinyl) -2,6-dimethoxybenzoate (1.1 g, 3.4 mmol) in 1,4-dioxane ( 20mL), add pinacol diborate (960mg, 3.78mmol), potassium acetate (1.0g, 10.2mmol), tris (diphenylmethyleneacetone) dipalladium (0) (311mg, 0.34mmol) and three Cyclohexylphosphine (190 mg, 0.68 mmol). The reaction was stirred at 80 ° C for 3 hours under a nitrogen atmosphere. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (1/1)] gives methyl (Z) -4- (1-fluoro-2- (4,4,5,5 -Tetramethyl-1,3,2-dioxopentyl-2-yl) vinyl) -2,6-dimethoxybenzoate (851 mg, yield 68.4%). ESI-MS 367.4 [M + H] ⁺ .

Preparation of intermediates A2-A5 is prepared by referring to the synthesis method of intermediate A1:

Intermediate B: Preparation of 3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-amine

First step: Synthesis of 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline

Dissolve 3-bromo-2-methylaniline (20.0g, 107.5mmol) in 1,4-dioxane (200mL), add pinacol diborate (32.7g, 129mmol), and potassium acetate (31.6 g, 322.5 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (5.0 g, 6.83 mmol). The reaction was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was poured into water (500 mL), and then extracted with ethyl acetate (300 mL * 2). The organic phase was washed with water (200 mL) and saturated brine (200 mL) in that order, dried over anhydrous sodium sulfate, and concentrated after column chromatography. Separation [eluent: petroleum ether ~ petroleum ether / ethyl acetate (3/2)] to obtain 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxane Borapent-2-yl) aniline (28.3 g, 100% yield). ESI-MS 234.0 [M + H] ⁺ .

Step 2: Synthesis of 3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-amine

Dissolve 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline (5.6 g, 24 mmol) in 1,4- To dioxane / water (150 mL / 40 mL), 1,3-dibromo-2-methylbenzene (6.0 g, 24 mmol), potassium carbonate (9.9 g, 72 mmol), [1,1'-bis ( Diphenylphosphino) ferrocene] dichloropalladium (II) (1.75 g, 2.4 mmol). The reaction was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. Column chromatography after concentration [eluent: petroleum ether ~ petroleum ether / ethyl acetate (2/1)] to obtain 3'-bromo-2,2'-dimethyl- [1,1'-biphenyl ] -3-amine (4.0 g, yield 60.34%). ESI-MS 277.2 [M + H] ⁺ .

Intermediate C: (Z) -2- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4,4,5,5-tetramethyl-1,3,2 -Preparation of Dioxolane

Step 1: Synthesis of (3-chloro-2-methylphenyl) methanol

3-Chloro-2-methylbenzoic acid (21 g, 123.1 mmol) was dissolved in tetrahydrofuran (100 mL), a borane tetrahydrofuran solution (184.6 mL, 184.6 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Methanol was slowly added dropwise under an ice bath until no gas was generated. After concentration, column chromatography was performed [eluent: petroleum ether ~ petroleum ether / ethyl acetate (2/1)] to obtain (3-chloro-2-methylphenyl) ) Methanol (15 g, 77.8% yield). ESI-MS 139.0 [M-18 + H] ⁺ .

The second step: the synthesis of 3-chloro-2-methylbenzene (m) aldehyde

(3-Chloro-2-methylphenyl) methanol (5.5 g, 35.12 mmol) was dissolved in ethyl acetate (150 mL), and 2-iodoacylbenzoic acid (19.66 g, 70.24 mmol) was added and stirred at 90 ° C. Reaction for 2 hours. After cooling, it was filtered and concentrated to obtain 3-chloro-2-methylbenzaldehyde (6.0 g, yield 100%).

Step 3: Synthesis of 1-chloro-3- (2,2-difluorovinyl) -2-methylbenzene

Dissolve 3-chloro-2-methylbenzaldehyde (3.0 g, 19.4 mmol) in N, N-dimethylformamide (39 mL) (that is, a 0.5 M solution of aldehyde), and add triphenyl Phosphine (6.1 g, 23.28 mmol) was heated to 100 ° C, and a solution of sodium chlorodifluoroacetate (4.4 g, 29.1 mmol) in N, N-dimethylformamide (2M) was added dropwise. The reaction was stirred at 100 ° C for 1 hour. Pour into water (200mL), and then extract with ethyl acetate (100mL * 2). The organic phase is washed with water (100mL) and saturated brine (100mL) in that order, dried over anhydrous sodium sulfate, and concentrated after column chromatography. Deagent: petroleum ether] gave 1-chloro-3- (2,2-difluorovinyl) -2-methylbenzene (2.2 g, yield 60.13%). ¹ H NMR (500MHz, CDCl ₃ ) δ 7.31 (dd, J = 7.9, 2.5 Hz, 2H), 7.15 (t, J = 7.9 Hz, 1H), 5.42 (dd, J = 24.8, 3.4 Hz, 1H) , 2.38 (s, 3H).

Fourth step: (Z) -2- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4,4,5,5-tetramethyl-1,3,2 -Synthesis of Dioxolane

1-chloro-3- (2,2-difluorovinyl) -2-methylbenzene (2.0 g, 10.6 mmol) was dissolved in tetrahydrofuran (30 mL), and pinacol diborate (4.04 g, 15.9) was added. mmol), cuprous chloride (10.5 mg, 0.106 mmol), tricyclohexylphosphine (59.4 mg, 0.212 mmol) and potassium acetate (1.25 g, 12.72 mmol). The reaction was stirred at 40 ° C for 16 hours. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (9/1)] gives (Z) -2- (2- (3-chloro-2-methylphenyl) -1 -Fluorovinyl) -4,4,5,5-tetramethyl-1,3,2-dioxolane (3.0 g, yield 95%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.53 (dd, J = 7.8, 1.3 Hz, 1H), 7.22 (dd, J = 8.0, 1.4 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H) , 6.45 (d, J = 44.5 Hz, 1H), 2.33 (s, 3H), 1.20 (s, 12H).

Intermediate D: Preparation of methyl 6-chloro-4-methoxynicotinate

Step 1: Synthesis of methyl 6-chloro-4-methoxynicotinate

Dissolve methyl 4,6-dichloronicotinate (25.0g, 121.36mmol) in tetrahydrofuran (150mL), add 30% sodium methoxide in methanol (24g, 133.49mmol), and pour into water (200mL). It was then extracted with ethyl acetate (200 mL * 2). The organic phase was washed with water (100 mL) and saturated brine (100 mL) in that order, dried over anhydrous sodium sulfate, then filtered, and slurried with ethyl acetate / petroleum ether = 2/1 Methyl 6-chloro-4-methoxynicotinate was obtained (17.8 g, yield 73%). ESI-MS 202.2 [M + H] ⁺ .

Preparation of intermediate E: 5-formyl-4-methoxy-o-picolinic acid

Step 1: Synthesis of methyl 4-methoxymethylpyridate

4-chloro-o-picolinic acid (100 g, 0.64 mol) was placed in methanol (500 mL), concentrated sulfuric acid (4 mL) was added, and the reaction was stirred at 80 ° C. for 60 hours. After completion of the reaction, the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed sequentially with water, saturated brine, and dried over sodium sulfate. The organic phase was filtered and concentrated. The crude product was separated by silica gel column chromatography [eluent: petroleum ether: ethyl acetate] to obtain methyl 4-methoxymethylpicolinate (55.6 g, yield 52%). ESI-MS 168 [M + H] ⁺ .

Step 2: Synthesis of methyl 5-bromo-4-methoxymethylpyridate

Methyl 4-methoxymethylpicolinate (20 g, 0.12 mol) was placed in concentrated sulfuric acid (150 mL), NBS (38.3 g, 0.22 mol) was added, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, water, an aqueous sodium hydrogen carbonate solution were sequentially added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed sequentially with water, saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated. The crude product was separated by silica gel column chromatography to obtain methyl 5-bromo-4-methoxymethylpicolinate (22.5 g, yield 77%). ESI-MS 246/248 [M + H] ⁺ .

Step 3: Synthesis of 5-bromo-4-methoxy-o-picolinic acid

Methyl 5-bromo-4-methoxymethylpicolinate (22.5 g, 91.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (80 mL), methanol (80 mL) and water (32 mL), and then NaOH (9.1 g, 0.23 mol), and the reaction was stirred at room temperature for half an hour. After the reaction was completed, it was concentrated, neutralized by adding a 1M aqueous HCl solution, and then extracted by adding a dichloromethane: methanol (12: 1) solution. The combined organic phases were sequentially washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain 5-bromo-4-methoxy-o-picolinic acid (19.1 g, yield 90%). ESI-MS 232.2 / 234.2 [M + H] ⁺ .

Intermediate F: 5-formyl-4-methoxy-N- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxolane- Preparation of 2-yl) phenyl) picolinamide

First step: 5-formyl-4-methoxy-N- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxolane- Synthesis of 2-yl) phenyl) methylpyridinamide

N, N-di (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline (400 mg, 1.71 mmol) To a solution of methyl formamide (10 mL) was added 5-formyl-4-methoxy-o-picolinic acid (373 mg, 2.06 mmol) and 3-oxohexafluorophosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridine positive ion (650 mg, 1.71 mmol) and diisopropylethylamine (661 mg, 5.13 mmol). The reaction was stirred at room temperature for 2 hours. Then poured into water (200mL), extracted with ethyl acetate (200mL * 2), the organic phase was washed with water (100mL) and saturated brine (100mL) in that order, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography. Eluent: petroleum ether to petroleum ether / ethyl acetate (2/1)] to give 5-formyl-4-methoxy-N- (2-methyl-3- (4,4,5,5- Tetramethyl-1,3,2-dioxopentyl-2-yl) phenyl) methylpyridinamide (350 mg, yield 52%). ESI-MS 397.4 [M + H] ⁺ .

Intermediate G: Preparation of (6- (3-bromo-2-chlorophenyl) -2-methoxy-4-methylpyridin-3-yl) methanol

Step 1: Synthesis of 6-chloro-2-methoxy-4-methylnicotinic acid

To a solution of methanol (2.56 g, 80 mmol) in tetrahydrofuran (50 mL) was added 60% sodium hydride (2.8 g, 70 mmol). After the reaction was stirred at room temperature for 20 minutes, 2,6-dichloro-4-methylnicotinic acid (4.1 g, 20 mmol) was added. The reaction was stirred at reflux for 3 hours. The pH was adjusted to 3 with 6M hydrochloric acid, and then the layer was washed with ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, and concentrated by filtration to obtain 6-chloro-2-methoxy-4-methylnicotinic acid (4.0 g, yield 100%). ESI-MS 202.1 [M + H] ⁺ .

Second step: Synthesis of (6-chloro-2-methoxy-4-methylpyridin-3-yl) methanol

To a solution of 6-chloro-2-methoxy-4-methyl nicotinic acid (4.0 g, 20 mmol) in tetrahydrofuran (20 mL) was added 1 M borane-tetrahydrofuran complex (40 mL, 40 mmol). The reaction was stirred under reflux for 2 hours. Ethyl acetate and a water layer were used, and the organic phase was sequentially washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography to separate [petroleum ether / ethyl acetate = 2/1] to obtain (6 -Chloro-2-methoxy-4-methylpyridin-3-yl) methanol (3.45 g, yield 92%). ESI-MS 188.1 [M + H] ⁺ .

Third step: (2-methoxy-4-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyridine-3 -Based) Synthesis of Methanol

To a solution of (6-chloro-2-methoxy-4-methylpyridin-3-yl) methanol (1.88 g, 10 mmol) in N, N-dimethylformamide (20 mL) was added pinacol diborate Lipid (3.0 g, 12 mmol), potassium acetate (3.0 g, 30 mmol) and [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloride (731 mg, 1 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 120 ° C for 2 hours. The reaction solution was used in the next step without any treatment. ESI-MS 280.2 [M + H] ⁺ .

Step 4: Synthesis of (6- (3-bromo-2-chlorophenyl) -2-methoxy-4-methylpyridin-3-yl) methanol

At (2-methoxy-4-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyridin-3-yl) To a reaction solution (10 mmol) of methanol in N, N-dimethylformamide (20 mL), 1,4-dioxane (50 mL), water (18 mL), 1,3-dibromo-2-chlorobenzene ( 3.3 g, 12 mmol), potassium carbonate (4.14 g, 30 mmol) and [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloride (731 mg, 1 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 95 ° C for 2 hours. Ethyl acetate and water layer. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether acid / ethyl acetate = 1/2] to obtain (6- (3-bromo-2- Chlorophenyl) -2-methoxy-4-methylpyridin-3-yl) methanol (1.38 g, yield 40%). ESI-MS 342.1 [M + H] ⁺ .

Intermediate H: Preparation of 4- (hydroxymethyl) -3-methoxybenzaldehyde

Step 1: Synthesis of (4-bromo-2-methoxyphenyl) methanol

To a solution of 4-bromo-2-methoxybenzoic acid (4.6 g, 20 mmol) in tetrahydrofuran (20 mL) was added 1 M borane-tetrahydrofuran complex (40 mL, 40 mmol). The reaction was stirred at room temperature for 1 hour. Ethyl acetate and water layer. The organic phase was sequentially washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 2/1] to obtain (4-bromo-2-methoxyphenyl) ) Methanol (4.5 g, 100% yield). ESI-MS 217.1 [M + H] ⁺ .

Step 2: Synthesis of (2-methoxy-4-vinylphenyl) methanol

To a solution of (4-bromo-2-methoxyphenyl) methanol (4.5 g, 8 mmol) in 1,4-dioxane / water (50 mL / 20 mL) was added potassium trifluoro (vinyl) borate (15.96 g , 120 mmol), potassium carbonate (8.28 g, 60 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (1.46 g, 2 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 100 ° C for 3 hours. Then use ethyl acetate and a water layer. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 2/1] to obtain (2-methoxy-4-vinylphenyl). Methanol (3.5 g, 100% yield). ESI-MS 165.1 [M + H] ⁺ .

The third step: the synthesis of 4- (hydroxymethyl) -3-methoxybenzaldehyde

To a solution of (2-methoxy-4-vinylphenyl) methanol (3.5 g, 21 mmol) in 1,4-dioxane / water (100 mL / 20 mL) was added potassium osmate monohydrate (368 mg, 1.05 mmol) and sodium periodate (26.7 g, 126 mmol). The reaction was stirred at room temperature for 1 hour. Then use dichloromethane and a water layer. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 2/1] to obtain 4- (hydroxymethyl) -3-methoxybenzene. (Formaldehyde) aldehyde (1.61 mg, 46% yield). ESI-MS 167.1 [M + H] ⁺ .

Intermediate I: Preparation of 5- (hydroxymethyl) -6-methoxymethylpyridaldehyde

Step 1: Synthesis of (6-chloro-2-methoxypyridin-3-yl) methanol

To a solution of 6-chloro-2-methoxynicotinic acid (3.8 g, 20 mmol) in tetrahydrofuran (20 mL) was added 1 M borane-tetrahydrofuran complex (40 mL, 40 mmol). The reaction was stirred under reflux for 2 hours. Ethyl acetate and water layer. The organic phase was sequentially washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 2/1] to obtain (6-chloro-2-methoxypyridine). -3-yl) methanol (2.28 g, 66% yield). ESI-MS174.1 [M + H] ⁺ .

Step 2: Synthesis of (2-methoxy-6-vinylpyridin-3-yl) methanol

To a solution of (6-chloro-2-methoxypyridin-3-yl) methanol (2.28 g, 13.1 mmol) in 1,4-dioxane / water (50 mL / 20 mL) was added trifluoro (vinyl) Potassium borate (10.45g, 78.6mmol), potassium carbonate (5.45g, 39.5mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (957mg, 1.31mmol) . After evacuation and nitrogen replacement, the reaction was stirred at 100 ° C for 8 hours. Then use ethyl acetate and a water layer. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 1/1] to obtain (2-methoxy-6-vinylpyridine-3 -Yl) methanol (1.6 g, yield 73%). ESI-MS 166.1 [M + H] ⁺ .

Step 4: Synthesis of 5- (hydroxymethyl) -6-methoxymethylpyridine

Ozone was passed through a solution of (2-methoxy-6-vinylpyridin-3-yl) methanol (1.6 g, 9.6 mmol) in dichloromethane (50 mL) for 2 minutes. Then concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 1/1] to obtain 5- (hydroxymethyl) -6-methoxymethylpyridaldehyde (1.17 g, yield 70%). ESI-MS 168.1 [M + H] ⁺ .

Intermediate J: 5-((4-chloro-2-formyl-5-((2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxane Preparation of pentyl-2-yl) benzyl) oxo) phenoxy) methyl) nicotyronitrile

Step 1: Synthesis of (3-bromo-2-methylphenyl) methanol

To a solution of 3-bromo-2-methylbenzoic acid (10.0 g, 46.5 mol) in tetrahydrofuran (50 mL), 1 M borane-tetrahydrofuran complex (70 mL, 70 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was poured into ice water, 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, and then separated by column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain (3-bromo-2-methylphenyl) methanol ( 9.0 g, yield 97%). ESI-MS 201.2 [M + H] ⁺ .

Step 2: Synthesis of 3-bromo-2-methylbromobenzyl

(3-Bromo-2-methylphenyl) methanol (9.0 g, 45 mmol) was dissolved in dichloromethane (200 mL), and triphenylphosphine (17.6 g, 67.1 mmol) was added, and added in portions in an ice bath. Carbon tetrabromide (22.3 g, 67.1 mmol). The reaction was stirred at room temperature for 1 hour. After the solvent was concentrated halfway, the column was separated by chromatography [pure petroleum ether] to obtain 3-bromo-2-methylbromobenzyl as a colorless oil (11.4 g, yield 95%).

Step 3: Synthesis of 4-((3-bromo-2-methylbenzyl) oxo) -5-chloro-2-hydroxybenzene (m) aldehyde

3-Bromo-2-methylbromobenzyl (11.1 g, 42 mmol) was dissolved in acetonitrile (100 mL), and 5-chloro-2,4-dihydroxybenzaldehyde (7.3 g, 42 mmol) was added, sodium bicarbonate (4.3 g, 50 mmol), and sodium iodide (3.1 g, 21 mmol). The reaction was stirred at 70 ° C overnight. After the solvent was concentrated, water (200 mL) was added, and the mixture was stirred for 1 hour and then filtered. The filter cake was washed twice with water and dried. Substitute) -5-chloro-2-hydroxybenzaldehyde (11.3 g, yield 75%). ESI-MS 354.9 [M + H] ⁺ .

Step 4: Synthesis of 5-((5-((3-bromo-2-methylbenzyl) oxo) -4-chloro-2-formylphenoxy) methyl) nicotinenitrile

Add N, N- to a single-necked bottle containing 4-((3-bromo-2-methylbenzyl) oxo) -5-chloro-2-hydroxybenzene (m) aldehyde (2.0 g, 5.6 mmol) Dimethylformamide (12 mL) was added with 5- (chloromethyl) nicotyronitrile (0.95 g, 6.1 mmol) and cesium carbonate (2.8 g, 8.4 mmol) in that order. The reaction was stirred at 70 ° C for 3 hours. After cooling, the reaction solution was poured into water (150 mL), stirred at room temperature for 1 hour, and then filtered. The filter cake was washed twice with water and dried, and 5-((5-((3-bromo-2-methyl) Benzyl) oxo) -4-chloro-2-formylphenoxy) methyl) nicotinenitrile (2.4 g, yield 90%). ESI-MS 471.7 [M + H] +.

The fifth step: 5-((4-chloro-2-formyl-5-((2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxane Synthesis of pentyl-2-yl) benzyl) oxo) phenoxy) methyl) nicotyronitrile

Contains 5-((5-((3-bromo-2-methylbenzyl) oxo) -4-chloro-2-formylphenoxy) methyl) nicotinenitrile (1.7g, 3.6mmol) Into a single-necked flask, 1,4-dioxane (60 mL) was added, followed by pinacol diborate (1.2 g, 4.7 mmol), potassium acetate (0.7 g, 7.2 mmol), and tricyclohexyl phosphine (0.2 g) , 0.7 mmol) and tris (dibenzylideneindeneacetone) dipalladium (0.33 g, 0.3 mmol). The reaction was stirred at 100 ° C overnight after evacuation and nitrogen replacement. Ethyl acetate and a water layer were used, and the organic phase was sequentially washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain 5- ((4-chloro-2-formyl-5-((2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl ) Benzyl) oxo) phenoxy) methyl) nicotinenitrile (1.3 g, yield 69%). ESI-MS 519.2 [M + H] ⁺ .

Intermediate K:

Preparation of (Z) -5-((5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-formylphenoxy) methyl) nicotinenitrile

Step 1: Synthesis of 5-bromo-2-hydroxymethylphenol

In a solution of 2-hydroxy-4-bromobenzoic acid (15.0 g, 69 mmol) in tetrahydrofuran (200 mL), 1M borane-tetrahydrofuran complex (138 mL, 138 mmol) was added in batches. The reaction was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and then extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 1: 1] to obtain 5-bromo-2-hydroxymethylphenol (12.5 g, Yield: 89%). ESI-MS 202.9 [M + H] ⁺ .

Step 2: Synthesis of 7-bromo-2,2-dimethyl-4H-benzo [d] [1,3] dioxin

5-Bromo-2-hydroxymethylphenol (12.5 g, 61 mmol) was dissolved in acetone (160 mL), and p-toluenesulfonic acid monohydrate (1.2 g, 6.1 mmol) and 2,2-dimethoxypropane (32 g) were added. , 305 mmol). The reaction was stirred at 45 ° C for 1 hour. After the solvent was concentrated halfway, it was extracted with ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [pure petroleum ether] to obtain 7-bromo-2,2- Dimethyl-4H-benzo [d] [1,3] dioxin (12.5 g, yield 86%). ¹ H NMR (500MHz, CDCl ₃ ) δ 7.03–6.98 (m, 2H), 6.83 (dt, J = 8.0, 0.9 Hz, 1H), 4.78 (d, J = 1.0 Hz, 2H), 1.53 (s, 6H).

Step 3: Synthesis of 2,2-dimethyl-4H-benzo [d] [1,3] dioxin-7-formaldehyde

7-Bromo-2,2-dimethyl-4H-benzo [d] [1,3] dioxin (12.5 g, 51 mmol) was dissolved in dry tetrahydrofuran (200 mL) under a nitrogen atmosphere at -70 ° C. 2.5M n-butyllithium (26.7mL, 67mmol) was added dropwise, and the reaction was stirred at this temperature for 1 hour after the completion of the dropwise addition, and N, N-dimethylformamide (19.8mL, 257mmol) was added dropwise at -70 ° C. After the dropwise addition was completed, the temperature was gradually raised to room temperature and the reaction was stirred for 1 hour. After quenching with saturated ammonium chloride, it was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 10: 1] to obtain 2,2-dimethyl-4H-benzo [d ] [1,3] Dioxin-7-formaldehyde (8.0 g, 80% yield). ESI-MS 193.2 [M + H] ⁺ .

Step 4: Synthesis of 7- (2,2-dibromovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin

Dissolve 2,2-dimethyl-4H-benzo [d] [1,3] dioxin-7-formaldehyde (8.0 g, 41 mmol) in dichloromethane (160 mL) and add carbon tetrabromide (20.6 g, 62 mmol), and a solution of triphenylphosphine (32.5 g, 124 mmol) in dichloromethane (100 mL) was added dropwise under an ice bath. The reaction was stirred at room temperature for 30 minutes. Then filtered, the filtrate was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography. [Petroleum ether / ethyl acetate = 10 : 1] 7- (2,2-dibromovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin (10 g, yield 70%) was obtained.

Step 5: Synthesis of 7- (bromoethynyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin

7- (2,2-Dibromovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin (10 g, 30 mmol) was dissolved in dimethyl sulfoxide (100 mL ), 1,8-diazabicyclo [5.4.0] undec-7-ene (18 mL, 120 mmol) was added dropwise at 15 ° C. After the dropwise addition was completed, the reaction was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water (300 mL), extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography. [Petroleum ether / ethyl acetate = 10: 1] 7- (bromoethynyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin (7.2 g, yield 93%) was obtained. ¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.08 (d, J = 7.9 Hz, 1H), 7.01 (dd, J = 7.8, 1.6 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H) , 4.82 (s, 2H), 1.46 (s, 6H).

Step 6: Synthesis of (Z) -7- (2-bromo-1-fluorovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin

7- (Bromoethynyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin (7.2 g, 27 mmol) was dissolved in acetonitrile / water (20: 1,56 mL) After adding silver fluoride (10.3 g, 81 mmol), the reaction was sealed at 85 ° C overnight. After cooling, the Celite was filtered, and the filtrate was concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 8: 1] to obtain (Z) -7- (2-bromo-1-fluorovinyl) -2,2-di Methyl-4H-benzo [d] [1,3] dioxin (4.5 g, yield 58%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.16 (d, J = 1.1 Hz, 2H), 7.05 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 30.6 Hz, 1H), 4.83 (s, 2H), 1.48 (s, 6H).

Seventh step: (Z) -2- (2- (2,2-dimethyl-4H-benzo [d] [1,3] dioxin-7-yl) -2-fluorovinyl)- Synthesis of 4,4,5,5-tetramethyl-1,3,2-dioxolane

(Z) -7- (2-bromo-1-fluorovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin (4.5 g, 16 mmol) Add a 1,4-dioxane (70 mL) to a single-necked flask, and then add pinacol diborate (4.8 g, 19 mmol), potassium acetate (4.6 g, 47 mmol), and tricyclohexyl phosphine (0.9 g, 3 mmol) And tris (dibenzylideneindeneacetone) dipalladium (1.4 g, 1.6 mmol). The reaction was stirred at 80 ° C for 3 hours after evacuation and nitrogen replacement. Filtered through diatomaceous earth, concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 6: 1] to obtain crude product (Z) -2- (2- (2,2-dimethyl-4H-benzo [d] [1,3] Dioxin-7-yl) -2-fluorovinyl) -4,4,5,5-tetramethyl-1,3,2-dioxolane (5.8 g, yield 100%).

Step 8: (Z) -7- (2- (3-Bromo-2-methylphenyl) -1-fluorovinyl) -2,2-dimethyl-4H-benzo [d] [1 3) Dioxin Synthesis

Containing (Z) -2- (2- (2,2-dimethyl-4H-benzo [d] [1,3] dioxin-7-yl) -2-fluorovinyl) -4, 4,5,5-tetramethyl-1,3,2-dioxolane (5.8g crude, 16mmol) in a single-necked flask was charged with 1,4-dioxane / water (4: 1,70mL) , 2,6-Dibromotoluene (4.7 g, 19 mmol), potassium carbonate (4.3 g, 31 mmol), and [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (1.2 g, 1.6 mmol). After evacuation, the reaction was stirred at 90 ° C. for 4 hours. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 9: 1] to obtain (Z) -7- ( 2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] dioxin (2.4g, produced Rate 40%).

Step 9: Synthesis of (Z) -5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2- (hydroxymethyl) phenol

(Z) -7- (2- (3-Bromo-2-methylphenyl) -1-fluorovinyl) -2,2-dimethyl-4H-benzo [d] [1,3] Dioxin (2.4 g, 6.4 mmol) was dissolved in acetonitrile (50 mL), 6M hydrochloric acid (7 mL) was added at room temperature, and the reaction was stirred at room temperature for 1 hour. After alkalization with saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain (Z) -5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2- (hydroxymethyl) phenol (2.1 g, yield 97%). ESI-MS 359.0 [M + Na] ⁺ .

Step 10: Synthesis of (Z) -4- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-hydroxybenzene (methyl) aldehyde

(Z) -5- (2- (3-Bromo-2-methylphenyl) -1-fluorovinyl) -2- (hydroxymethyl) phenol (2.1 g, 6.2 mmol) was dissolved in ethanol (50 mL ), Manganese dioxide (10.8 g, 125 mmol) was added at room temperature, and the reaction was stirred under reflux for 5 hours. After cooling, diatomaceous earth was filtered, and concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 5: 1] to obtain (Z) -4- (2- (3-bromo-2-methylphenyl) -1- Fluorovinyl) -2-hydroxybenzaldehyde (1.0 g, 50% yield).

Step 11: (Z) -5-((5- (2- (3-Bromo-2-methylphenyl) -1-fluorovinyl) -2-formylphenoxy) methyl) nicotine Synthesis of nitrile

Add to a single-necked bottle containing (Z) -4- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-hydroxybenzaldehyde (1 g, 2.8 mmol) N, N-dimethylformamide (20 mL), 5- (chloromethyl) nicotyronitrile (0.5 g, 3.4 mmol) and cesium carbonate (1.4 g, 4.2 mmol) were added in that order. The reaction was stirred at 50 ° C for 30 minutes. After cooling, it was poured into water (150 mL). After stirring at room temperature for 1 hour, it was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography. Ester = 3: 1] gives (Z) -5-((5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-formylphenoxy) methyl ) Nicotinonitrile (1.2 g, yield 95%). ESI-MS 451.0 [M + H] ⁺ .

Intermediate L: (R) -1- (3- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) Preparation of phenoxy) propyl) pyrrolidin-3-ol

Step 1: Synthesis of (R) -1- (3- (3-bromo-2-methylphenoxy) propyl) pyrrolidin-3-ol

In a single-necked flask containing 1-bromo-3- (3-chloropropoxy) -2-methylbenzene (1.3 g, 4.9 mmol), N, N-dimethylformamide (15 mL) was added, followed by ( R) -Pyrrolidin-3-ol (0.64 g, 7.4 mmol), potassium carbonate (1.4 g, 9.8 mmol) and sodium iodide (0.74 g, 4.9 mmol). The reaction was stirred at 75 ° C for 3 hours. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [dichloromethane / methanol = 10: 1] to obtain (R) -1- (3 -(3-bromo-2-methylphenoxy) propyl) pyrrolidin-3-ol (1.2 g, yield 73%). ESI-MS 314.0 [M + H] ⁺ .

Second step: (R) -1- (3- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) Synthesis of phenoxy) propyl) pyrrolidin-3-ol

In a single-necked bottle containing (R) -1- (3- (3-bromo-2-methylphenoxy) propyl) pyrrolidin-3-ol (1.2 g, 3.7 mmol), add 1,4-bis Hexane (20 mL), followed by pinacol diborate (1.4 g, 5.6 mmol), potassium acetate (1.1 g, 11.2 mmol), and [1,1'-bis (diphenylphosphino) diocene Iron] Palladium dichloride (0.27 g, 0.37 mmol). The reaction was stirred at 85 ° C for 6 hours after evacuation and nitrogen exchange. Filtered through diatomaceous earth, concentrated and separated by column chromatography [dichloromethane / methanol = 10: 1] to obtain (R) -1- (3- (2-methyl-3- (4,4,5,5-tetram Methyl-1,3,2-dioxoborolan-2-yl) phenoxy) propyl) pyrrolidine-3-ol (1.2 g, 91% yield). ESI-MS 362.1 [M + H] ⁺ .

Intermediate M: Preparation of 4-chloro-5- (dimethoxymethyl) o-picolinic acid

Step 1: Synthesis of methyl 4-chloro-5-methylmethylpyridate

In an ice bath, add sulfoxide (90 mL) to a single-necked bottle containing 5-methyl-o-picolinic acid (8.2 g, 60 mmol), and add sodium bromide (12.3 g, 120 mmol) in batches under stirring, at 85 ° C The reaction was stirred for 1 hour. N, N-dimethylformamide (1.2 mL) was added, and the reaction was stirred at 85 ° C overnight. After cooling, it was concentrated to remove sulfoxide, and toluene (60 mL) was added. N, N-diisopropylethylamine (20 mL) and methanol (12 mL) were added under stirring in an ice bath, and the reaction was stirred at room temperature for 1 hour. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 3: 1] to give methyl 4-chloro-5 -Methyl methyl picolinate (5.3 g, 47% yield). ESI-MS 186.0 [M + H] ⁺ .

Step 2: Synthesis of methyl 4-chloro-5- (dibromomethyl) methylpyridine

Carbon tetrachloride (120 mL) was added to a single-necked bottle containing methyl 4-chloro-5-methylmethylpyridine (5.3 g, 28.5 mmol), followed by N-bromosuccinimide (11.1 g, 62.8 mmol), and azobisisobutyronitrile (0.94 g, 5.7 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 90 ° C for 24 hours. Dichloromethane / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 9: 1] to give methyl 4-chloro-5 -(Dibromomethyl) picolinate (7.4 g, yield 75%). ESI-MS 343.8 [M + H] ⁺ .

Step 3: Synthesis of methyl 4-chloro-5-formylmethylpyridate

In a single-necked flask containing methyl 4-chloro-5- (dibromomethyl) picolinate (7.4 g, 21.6 mmol) was added ethanol (120 mL), and an aqueous solution of silver nitrate (11 g, 64.8 mmol) ( 17mL). The reaction was stirred at 50 ° C for 4 hours. Diatomite was filtered, and the filtrate was concentrated and dissolved in dichloromethane (60 mL) and filtered. After the filtrate was concentrated, tetrahydrofuran (50 mL) was added, and 6M hydrochloric acid (25 mL) was added with stirring. The reaction was stirred at room temperature overnight. After alkalization with saturated aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain Methyl 4-chloro-5-formylmethylpicolinate (2.6 g, 60% yield). ESI-MS 200.0 [M + H] ⁺ .

Step 4: Synthesis of methyl 4-chloro-5- (dimethoxymethyl) methylpicolinate

In a single-necked flask containing methyl 4-chloro-5-formylmethylpicolinate (2.6 g, 13 mmol) was added methanol (50 mL), trimethyl orthoformate (4.3 mL, 39 mmol) and p-toluene monohydrate were added. Sulfonic acid (0.25 g, 1.3 mmol). The reaction was stirred at room temperature overnight. After alkalization with saturated aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain Methyl 4-chloro-5- (dimethoxymethyl) methylpicolinate (3.2 g, 99% yield). ESI-MS 246.0 [M + H] ⁺ .

Step 5: Synthesis of 4-chloro-5- (dimethoxymethyl) o-picolinic acid

Methanol / tetrahydrofuran / water (1: 1: 1, 54 mL) was added to a single-necked bottle containing methyl 4-chloro-5- (dimethoxymethyl) methylpicolinate (3.2 g, 13 mmol), and Lithium hydroxide monohydrate (1.1 g, 26 mmol). The reaction was stirred at room temperature for 1 hour, and methanol and tetrahydrofuran were concentrated to remove, acidified with a 732 type cation exchange resin, and acetonitrile (40 mL) was added. Filtration, the filtrate was concentrated to remove acetonitrile, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give 4-chloro-5- (dimethoxymethyl) o-picolinic acid (2.6 g, yield 86%). ESI-MS 232.0 [M + H] ⁺ .

Preparation of intermediate N: 4-cyclopropyl-5-formyl o-picolinic acid

Step 1: Synthesis of methyl 4-chloro-5-methylmethylpyridate

In an ice bath, add thionyl chloride (90mL) to a single-necked bottle containing 5-methyl-o-picolinic acid (8.2g, 60mmol), and add sodium bromide (12.3g, 120mmol) in batches under stirring, at 85 ° C Stir for 1 hour. N, N-dimethylformamide (1.2 mL) was added, and the reaction solution was stirred at 85 ° C overnight. After cooling, it was concentrated to remove sulfoxide, and toluene (60 mL) was added to the concentrate. N, N-diisopropylethylamine (20 mL) and methanol (12 mL) were added under stirring in an ice bath, and the reaction solution was stirred at room temperature for 1 hour. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated after column chromatography [petroleum ether / ethyl acetate = 3: 1] to give methyl 4-chloro- 5-methylmethylpicolinate (5.3 g, 47% yield). ESI-MS 186.0 [M + H] ⁺ .

Step 2: Synthesis of methyl 4-chloro-5- (dibromomethyl) methylpyridine

Carbon tetrachloride (120 mL) was added to a single-necked bottle containing methyl 4-chloro-5-methylmethylpyridine (5.3 g, 28.5 mmol), followed by N-bromosuccinimide (11.1 g, 62.8 mmol), and azobisisobutyronitrile (0.94 g, 5.7 mmol). After evacuation, the reaction solution was stirred at 90 ° C for 24 hours. Dichloromethane / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated after column chromatography [petroleum ether / ethyl acetate = 9: 1] to give methyl 4-chloro- 5- (Dibromomethyl) picolinate (7.4 g, yield 75%). ESI-MS 343.8 [M + H] ⁺ .

Step 3: Synthesis of methyl 4-chloro-5-formylmethylpyridate

In a single-necked flask containing methyl 4-chloro-5- (dibromomethyl) picolinate (7.4 g, 21.6 mmol) was added ethanol (120 mL), and an aqueous solution of silver nitrate (11 g, 64.8 mmol) ( 17mL). The reaction solution was stirred at 50 ° C for 4 hours. The celite was filtered, and the filtrate was concentrated and dissolved in dichloromethane (60 mL) and filtered. After the filtrate was concentrated, tetrahydrofuran (50 mL) was added, and 6M hydrochloric acid (25 mL) was added under stirring. The mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain Methyl 4-chloro-5-formylmethylpicolinate (2.6 g, 60% yield). ESI-MS 200.0 [M + H] ⁺ .

Step 4: Synthesis of methyl 4-cyclopropyl-5-formylmethylpyridate

4-Chloro-5-formylmethylpicolinate (1.0 g, 5.0 mmol) was dissolved in 1,4-dioxane (20 mL). To the solution were added cyclopropylboronic acid (516 mg, 6.0 mmol), cesium carbonate (3.2 g, 10.0 mmol), and Pd (dppf) Cl ₂ (366 mg, 0.5 mmol). The reaction solution was ventilated twice under a nitrogen atmosphere and stirred at 90 ° C for 3 hours. The reaction solution was filtered and concentrated through celite, and then subjected to column chromatography [eluent: dichloromethane to dichloromethane / ethyl acetate (9: 1)] to obtain methyl 4-cyclopropyl-5-formylmethylpyridine. Acid ester (400 mg, yield 40%). ESI-MS 206.2 [M + H] ⁺ .

Step 5: Synthesis of 4-cyclopropyl-5-formyl-o-picolinic acid

In a single-necked bottle containing methyl 4-cyclopropyl-5-formylmethylpyridate (0.94 g, 4.9 mmol), methanol / water (6: 1,21 mL) was added, and lithium hydroxide monohydrate (189 mg , 5.9 mmol). The reaction solution was stirred at room temperature for 2 hours. The methanol was removed by concentration and diluted with water (17 mL). Acidify with a 732-type cation exchange resin to a pH of about 6, and add 10 mL of acetonitrile. Filtration and lyophilization of the filtrate gave 4-cyclopropyl-5-formyl-o-picolinic acid (0.9 g, yield 100%). ESI-MS192.1 [M + H] ⁺ .

Preparation of specific example compounds

Example 1 (Z) -N- (3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3,5-dimethoxyphenyl) vinyl ) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxymethyl Of Pyridylamide

First step: methyl (Z) -4- (2- (3'-amino-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -1-fluoroethylene (Synyl) -2,6-dimethoxybenzoate

3'-Bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-amine (1.13 g, 4.1 mmol) was dissolved in 1,4-dioxane / water (20 mL / 5mL), methyl (Z) -4- (1-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) was added (Vinyl) -2,6-dimethoxybenzoate (1.5 g, 4.1 mmol), potassium carbonate (1.7 g, 12.3 mmol), [1,1'-bis (diphenylphosphino) ferrocene ] Dichloropalladium (II) (300 mg, 0.41 mmol). The reaction was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (4/1)] gives methyl (Z) -4- (2- (3'-amino-2,2'-di Methyl- [1,1'-biphenyl] -3-yl) -1-fluorovinyl) -2,6-dimethoxybenzoate (1.4 g, yield 78.4%). ESI-MS 436.4 [M + H] ⁺ .

Second step: (Z)-(4- (2- (3'-amino-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -1-fluorovinyl ) -2,6-Dimethoxyphenyl) methanol

Methyl (Z) -4- (2- (3'-amino-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -1-fluorovinyl)- 2,6-Dimethoxybenzoate (1.4 g, 3.2 mmol) was dissolved in dichloromethane (10 mL), diisobutylaluminum hydride (32 mL, 32 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (1/9)] gives (Z)-(4- (2- (3'-amino-2,2'-dimethylformaldehyde) -[1,1'-biphenyl] -3-yl) -1-fluorovinyl) -2,6-dimethoxyphenyl) methanol (0.5 g, yield 38%), ESI-MS 408.5 [M + H] ⁺ .

Step 3: (Z) -5- (Dimethoxymethyl) -N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) ) Vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -4-methoxymethylpyridinamide

To a solution of 5- (dimethoxymethyl) -4-methoxy-o-picolinic acid (375 mg, 1.65 mmol) in N, N-dimethylformamide (10 mL) was added (Z)-(4- (2- (3'-amino-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -1-fluorovinyl) -2,6-dimethoxyphenyl ) Methanol (450 mg, 1.1 mmol), 3-oxyhexafluorophosphate 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridine positive ion (418 mg, 1.1 mmol) and diisopropylethylamine (426 mg, 3.3 mmol). The reaction was stirred at room temperature for 2 hours. Then poured into water (50mL), extracted with ethyl acetate (50mL * 2), the organic phase was washed with water (50mL) and saturated brine (30mL) in that order, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography. Eluent: petroleum ether to petroleum ether / ethyl acetate (4/1)] to obtain (Z) -5- (dimethoxymethyl) -N- (3 '-(2-fluoro-2- (4 -(Hydroxymethyl) -3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -4-methoxy Methylpyridinamide (600 mg, 88% yield). ESI-MS 617.4 [M + H] ⁺ .

Step 4: (Z) -N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) vinyl) -2,2'-di Synthesis of methyl- [1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide

(Z) -5- (Dimethoxymethyl) -N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) vinyl ) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -4-methoxymethylpyridinamide (600 mg, 0.973 mmol) dissolved in tetrahydrofuran / water (10 mL / 5 mL), pyridine p-toluenesulfonate (2.4 g, 9.73 mmol) was added, and the reaction was stirred at room temperature for 3 hours. It was then poured into water (100 mL) and extracted with ethyl acetate (100 mL * 2). The organic phase was washed with water (100 mL) and saturated brine (50 mL) in this order, dried over anhydrous sodium sulfate, filtered and concentrated to obtain (Z)- N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- [1,1' -Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (400 mg, yield 72%). ESI-MS 571.4 [M + H] ⁺ .

Step 5: (Z) -N- (3 '-(2-fluoro-2- (4-formyl-3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- Synthesis of [1,1'-Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide

(Z) -N- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (400 mg, 0.7 mmol) was added with 2-iodoacylbenzoic acid (392 mg, 1.4 mmol) ) And stirred at 90 ° C for 5 hours. After cooling, it was filtered and concentrated to give (Z) -N- (3 '-(2-fluoro-2- (4-formyl-3,5-dimethoxyphenyl) vinyl) -2,2'-di Methyl- [1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (380 mg, yield 95.4%). ESI-MS 569.4 [M + H] ⁺ .

Step 6: (Z) -N- (3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3,5-dimethoxyphenyl) ethylene Phenyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxy Synthesis of Pyridylamide

Put (Z) -N- (3 '-(2-fluoro-2- (4-formyl-3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- [1, 1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (200mg, 0.35mmol) dissolved in N, N-dimethylformamide / acetic acid (2.0mL / (0.4 mL) was added ethanolamine (86 mg, 1.4 mmol). After stirring the reaction at room temperature for 0.5 hours, sodium cyanoborohydride (110 mg, 1.75 mmol) was added, and the reaction was stirred for 1 hour. Then reversed-phase column chromatography [eluent: 0.5% ammonium bicarbonate aqueous solution to 0.5% ammonium bicarbonate aqueous solution / acetonitrile (40:60)] to obtain (Z) -N- (3 '-(2-fluoro -2- (4-(((2-hydroxyethyl) amino) methyl) -3,5-dimethoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'- Biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxymethylpyridinamide (8 mg, yield 3.47%). ESI-MS 659.6 [M + H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.46 (s, 1H), 7.94–7.90 (m, 1H), 7.86 (s, 1H), 7.69 (d, J = 7.8Hz, 1H), 7.30 (dt , J = 18.0, 7.7Hz, 2H), 7.10–6.97 (m, 4H), 6.76 (d, J = 38.1Hz, 1H), 4.05 (s, 3H), 4.01–3.82 (m, 10H), 3.71– 3.62 (m, 4H), 2.74 (q, J = 5.8Hz, 4H), 2.12 (s, 3H), 2.08 (s, 3H).

Examples 2 to 16 were prepared by the synthetic method of Reference Example 1:

The NMR data of the compounds prepared in the above examples are as follows:

Example 17 Methyl ((6-((2-chloro-3 '-((Z) -2-fluoro-2- (4-((((R) -3-hydroxy-1-methoxy-1 -Carbonylpropane-2-yl) amino) methyl) -3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) carbamoyl) Preparation of 4-methoxypyridin-3-yl) methyl) -D-serine

The first step: Synthesis of 2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline

Dissolve 3-bromo-2-chloroaniline (1.54 g, 7.5 mmol) in 1,4-dioxane (20 mL), add diborate (2.85 g, 11.25 mmol) and potassium acetate (1.47 g) , 15.0 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (274 mg, 0.375 mmol). The nitrogen was evacuated 3 times, and the reaction was stirred at 90 ° C for 2 hours. After the reaction was completed, the celite was filtered. Water was added to the filtrate, and extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. After removing the solvent, the column was separated by silica gel column chromatography [petroleum ether: ethyl acetate = 3: 1] to obtain 2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxane Pentyl-2-yl) aniline (1.0 g, 52% yield). ESI-MS 254.2 [M + H] ⁺ .

Second step: N- (2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenyl) -5- (di Synthesis of methoxymethyl) -4-methoxymethylpyridamide

Dissolve 2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) aniline (690 mg, 2.71 mmol) in anhydrous tetrahydrofuran (20 mL ), Methyl 5- (dimethoxymethyl) -4-methoxymethylpicolinate (787 mg, 3.25 mmol) was added to the solution. Under the protection of nitrogen, a 1M tetrahydrofuran solution (4.0 mL) of potassium tert-butoxide was slowly added dropwise, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, it was filtered through celite. Water was added to the filtrate, and extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography was used to separate [petroleum ether: ethyl acetate = 3: 1] to obtain N- (2-chloro-3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl) -5- (dimethoxymethyl) -4-methoxymethylpyridinamide (147 mg, yield 12%). ESI-MS 463.4 [M + H] ⁺ .

Third step: (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2'-methyl Synthesis of-[1,1'-biphenyl] -3-yl) -5- (dimethoxymethyl) -4-methoxymethylpyridinamide

N- (2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenyl) -5- (dimethoxy Methyl) -4-methoxymethylpyridamide (147 mg, 0.32 mmol) was dissolved in a mixed solvent of tetrahydrofuran / water (2: 1, 12 mL), and (Z)-(4- (2- (3- (3- Bromo-2-methylphenyl) -1-fluorovinyl) -2-methoxyphenyl) methanol (102 mg, 0.29 mmol), potassium phosphate (123 mg, 0.58 mmol), Pd-Xphos-G3 (23 mg, 0.029 mmol). The nitrogen was evacuated and the reaction was stirred at 45 ° C for 2 hours. After completion of the reaction, it was filtered through celite. Water was added to the filtrate, and extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. After removing the solvent, silica gel column chromatography was used to separate [petroleum ether: ethyl acetate = 1: 1] to obtain (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4- (hydroxymethyl) ) -3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -5- (dimethoxymethyl) -4-methoxy Methylpyridinamide (63 mg, yield 32%). ESI-MS 607.4 [M + H] ⁺ .

Step 4: (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1 , 1'-Biphenyl] -3-yl) -5- (dimethoxymethyl) -4-methoxymethylpyridinamide

Put (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2'-methyl- [1 , 1'-biphenyl] -3-yl) -5- (dimethoxymethyl) -4-methoxymethylpyridinamide (63 mg, 0.10 mmol) was dissolved in dichloromethane (10 mL). To the solution was added Dess-Martin oxidant (64 mg, 0.15 mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was dried after washing with water, filtered and concentrated, and then separated by silica gel column chromatography [ethyl acetate: n-hexane = 1: 1] to obtain (Z) -N- (2-chloro-3'- (2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -5- (di (Methoxymethyl) -4-methoxymethylpyridamide (40 mg, yield 66%). ESI-MS 605.4 [M + H] ⁺ .

Step 5: (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1 , 1'-Biphenyl] -3-yl) -5-Formyl-4-methoxymethylpyridinamide

Add (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1,1' -Biphenyl] -3-yl) -5- (dimethoxymethyl) -4-methoxymethylpyridinamide (40 mg, 0.066 mmol) was dissolved in dichloromethane (6 mL), and trifluoro was added Acetic acid (3 mL). The reaction was stirred at room temperature for 0.5 hours. After the reaction, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain (Z) -N- (2-chloro-3 '-(2 -Fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -5-formyl-4 -Crude methoxymethylpyridinamide (35 mg, yield 95%). ESI-MS 559.4 [M + H] ⁺ .

Sixth step: methyl ((6-((2-chloro-3 '-((Z) -2-fluoro-2- (4-((((R) -3-hydroxy-1-methoxy- 1-carbonylpropane-2-yl) amino) methyl) -3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) carbamoyl Synthesis of) -4-methoxypyridin-3-yl) methyl) -D-serine

Add (Z) -N- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1,1' -Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (35 mg, 0.062 mmol) was dissolved in N, N-dimethylformamide (5 mL). To the solution were added D-serine methyl ester (48 mg, 0.31 mmol), triethylamine (0.2 mL), and acetic acid (1 mL). The reaction was stirred at room temperature for 1 hour, and sodium cyanoborohydride (20 mg, 0.32 mmol) was added. After the reaction, methyl ((6-((2-chloro-3 '-((Z) -2-fluoro-2- (4-((((R) -3-hydroxyl -1-methoxy-1-carbonylpropane-2-yl) amino) methyl) -3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl]- 3-yl) carbamoyl) -4-methoxypyridin-3-yl) methyl) -D-serine (10 mg, yield 21%). ESI-MS 765.4 [M + H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 8.54 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H) , 7.28 (s, 1H), 7.15–7.10 (m, 2H), 6.88 (d, J = 39.6Hz, 1H), 4.87 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 3.84–3.63 (m, 5H), 3.60 (s, 3H), 3.59–3.56 (m, 7H), 3.28 (t, J = 5.2Hz, 2H), 2.12 (s, 3H).

Examples 18 to 20 are prepared by the synthetic method of reference example 17:

The NMR data of the compounds prepared in the above examples are as follows:

Example 21 (Z) -2-((((6- (2-chloro-3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3-methyl Oxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -2-methoxy-4-methylpyridin-3-yl) methyl) amino ) Preparation of ethane-1-ol

First step: (Z)-(6- (2-chloro-3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2'-form Of phenyl- [1,1'-biphenyl] -3-yl) -2-methoxy-4-methylpyridin-3-yl) methanol

Add (Z)-(4- (1-fluoro-2- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2- Phenyl) phenyl) vinyl) -2-methoxyphenyl) methanol (400 mg, 1.0 mmol) and (6- (3-bromo-2-chlorophenyl) -2-methoxy-4-methylpyridine -3-yl) methanol (245 mg, 0.715 mmol) was dissolved in tetrahydrofuran / water (3 mL / 6 mL), and methanesulfonic acid (2-di-tert-butylphosphino-2 ', 4', 6'-triisopropyl) was added. -1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (57 mg, 0.0715 mmol) and potassium phosphate (455 mg, 2.14 mmol). After nitrogen, the reaction was stirred at 40 ° C for 2 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (100 mL * 2). The organic phase was washed with water (100 mL) and saturated brine (50 mL) in this order, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography. Separation [eluent: petroleum ether ~ petroleum ether / ethyl acetate (3/2)] to obtain (Z)-(6- (2-chloro-3 '-(2-fluoro-2- (4- (hydroxymethyl) Yl) -3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -2-methoxy-4-methylpyridine-3- Methyl) methanol (300 mg, 78.5%). ESI-MS 534.2 [M + H] ⁺ .

Second step: (Z) -6- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1 , 1'-Biphenyl] -3-yl) -2-methoxy-4-methylnicotaldehyde

Add (Z)-(6- (2-chloro-3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2'-methyl- [ 1,1'-biphenyl] -3-yl) -2-methoxy-4-methylpyridin-3-yl) methanol (250 mg, 0.468 mmol), and 2-iodoacylbenzoic acid (655 mg, 2.34 mmol), and the reaction was stirred at 90 ° C for 3 hours. After cooling, it was filtered and concentrated to give (Z) -6- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl -[1,1'-biphenyl] -3-yl) -2-methoxy-4-methylnicotyraldehyde (230 mg, yield 93%). ESI-MS 530.2 [M + H] ⁺ .

Step 3: (Z) -2-((((6- (2-chloro-3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3- Methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl] -3-yl) -2-methoxy-4-methylpyridin-3-yl) methyl) Synthesis of Amino) ethane-1-ol

Add (Z) -6- (2-chloro-3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2'-methyl- [1,1' -Biphenyl) -3-yl) -2-methoxy-4-methyl nicotinaldehyde (80 mg, 0.15 mmol) in N, N-dimethylformamide / acetic acid (2.0 mL / 0.4 mL) solution To this was added ethanolamine (90 mg, 1.5 mmol). The reaction was stirred at room temperature for 0.5 hours, sodium cyanoborohydride (95 mg, 1.5 mmol) was added, and the reaction was stirred for 1 hour. Then separated by reversed-phase column chromatography [eluent: 0.5% formic acid aqueous solution to 0.5% formic acid aqueous solution / acetonitrile 35/65)] to obtain (Z) -2-(((6- (2-chloro-3'- (2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) vinyl) -2'-methyl- [1,1'-biphenyl Group] -3-yl) -2-methoxy-4-methylpyridin-3-yl) methyl) amino) ethane-1-ol (15.9 mg, yield 17%). ESI-MS 621.2 [M + H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 2.0 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.60 (dt, J = 7.7, 1.5 Hz, 1 H) , 7.51 (t, J = 7.5Hz, 1H), 7.43 (d, J = 7.9Hz, 1H), 7.37–7.30 (m, 4H), 7.13 (d, J = 7.0Hz, 2H), 6.89 (d, J = 39.6Hz, 1H), 3.90 (d, J = 1.1Hz, 3H), 3.89 (s, 3H), 3.79 (d, J = 3.2Hz, 4H), 3.51 (t, J = 5.6Hz, 4H) , 2.66 (dd, J = 18.5, 5.7 Hz, 4H), 2.40 (s, 3H), 2.14 (s, 3H).

Examples 22 to 29 are prepared by the synthetic method of Reference Example 21:

The NMR data of the compounds prepared in the above examples are as follows:

Example 30 2,2 '-((((((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) di (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxy-4,1-phenylene)) bis (methylene)) bis (azetanediyl)) di Preparation of (ethane-1-ol)

First step: dimethyl 4,4 '-((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) Synthesis of bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxybenzoate)

Dissolve 3,3'-dibromo-2,2'-dimethyl-1,1'-biphenyl (136 mg, 0.4 mmol) in 1,4-dioxane / water (6 mL / 1.5 mL) In addition, methyl (Z) -4- (1-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) vinyl) -2,6-dimethoxybenzoate (300mg, 0.82mmol), potassium carbonate (414mg, 3.0mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium ( II) (73 mg, 0.1 mmol). The reaction was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (1/1)] to obtain dimethyl 4,4 '-((1Z, 1'Z)-(2,2'- Dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxybenzoic acid Ester) (180 mg, 66.6% yield). ESI-MS659.6 [M + H] ⁺ .

The second step: (((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene- Synthesis of 2,1-diyl)) bis (2,6-dimethoxy-4,1-phenylene)) dimethanol

Dimethyl 4,4 '-((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) di (1 -Fluoroethylene-2,1-diyl)) bis (2,6-dimethoxybenzoate) (180 mg, 0.27 mmol) was dissolved in dichloromethane (10 mL), and diisobutylaluminum hydride ( 1.37 mL, 1.37 mmol), and the reaction was stirred at room temperature for 1 hour. Then add sodium decahydrate, concentrate and separate by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (1/9)] to obtain ((((1Z, 1'Z)-(2,2'- Dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxy-4 , 1-phenylene)) dimethanol (110 mg, yield 67.6%), ESI-MS 585.5 [M-18 + H] ⁺ .

Third step: 4,4 '-((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1 -Fluoroethylene-2,1-diyl)) bis (2,6-dimethoxybenzene (m) aldehyde)

Add (((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene-2,1 -Diyl)) bis (2,6-dimethoxy-4,1-phenylene)) dimethanol (110mg, 0.18mmol), 2-iodoacylbenzoic acid (101mg, 0.36mmol) was added, and The reaction was stirred at 90 ° C for 3 hours. After cooling, it was filtered and concentrated to give 4,4 '-((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) Bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxybenzene (m) aldehyde) (80 mg, yield 74%). ESI-MS 599.5 [M + H] ⁺ .

Step 4: 2,2 '-((((((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) Bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxy-4,1-phenylene)) bis (methylene)) bis (azetanediyl)) Synthesis of bis (ethane-1-ol)

Add 4,4 '-((1Z, 1'Z)-(2,2'-dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene -2,1-diyl)) bis (2,6-dimethoxybenzaldehyde) (80mg, 0.13mmol) dissolved in N, N-dimethylformamide / acetic acid (2.0mL / 0.4mL ) To the solution was added ethanolamine (32 mg, 0.52 mmol). After stirring the reaction at room temperature for 0.5 hours, sodium cyanoborohydride (41 mg, 0.65 mmol) was added, and stirring was continued for 1 hour. Then amino column column chromatography [eluent: dichloromethane to dichloromethane / methanol 1/1)] to obtain 2,2 '-((((((1Z, 1'Z)-(2,2'- Dimethyl- [1,1'-biphenyl] -3,3'-diyl) bis (1-fluoroethylene-2,1-diyl)) bis (2,6-dimethoxy-4 , 1-phenylene)) bis (methylene)) bis (azetanediyl)) bis (ethane-1-ol) (5.4 mg, yield 6.0%). ESI-MS 689.8 [M + H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.21 (s, 1H), 7.63 (d, J = 7.7Hz, 2H), 7.33 (t, J = 7.6Hz, 2H), 7.09-6.91 (m, 8H), 3.88 (s, 16H), 3.51 (t, J = 5.6Hz, 4H), 2.66 (t, J = 5.4Hz, 4H), 2.08 (s, 6H).

Examples 31 to 37 are prepared by the synthetic method of reference example 30:

The NMR data of the compounds prepared in the above examples are as follows:

Example 38 (Z) -N- (3 '-(2-fluoro-2- (5-(((2-hydroxyethyl) amino) methyl) -4-methoxypyridin-2-yl) ethylene Phenyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxy Preparation of methylpicolinamide

The first step: Synthesis of methyl (Z) -6- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4-methoxynicotanoate

Add (Z) -2- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4,4,5,5-tetramethyl-1,3,2-dioxane Borapentane (4.0 g, 13.4 mmol) and methyl 6-chloro-4-methoxy nicotinate (2.0 g, 10.0 mmol) were dissolved in tetrahydrofuran / water (7.5 mL / 15 mL), and methanesulfonic acid (2 -Di-tert-butylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (500 mg, 0.63 mmol) and potassium phosphate (6.36 g, 30 mmol), and the reaction was stirred at 40 ° C. for 3 hours after evacuation of nitrogen. The reaction solution was then poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with water (100 mL) and saturated brine (50 mL) in this order, dried over anhydrous sodium sulfate, and concentrated by filtration. Analytical separation [eluent: petroleum ether ~ petroleum ether / ethyl acetate (2/1)] to obtain methyl (Z) -6- (2- (3-chloro-2-methylphenyl) -1-fluoro Vinyl) -4-methoxynicotinate (2.5 g, 74.4%). ESI-MS 336.2 [M + H] ⁺ .

Step 2: Synthesis of (Z)-(6- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4-methoxypyridin-3-yl) methanol

Dissolve methyl (Z) -6- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4-methoxynicotinate (630 mg, 1.876 mmol) in dichloro To methane (10 mL), diisobutylaluminum hydride (9.4 mL, 9.4 mmol) was added, and the reaction was stirred at room temperature for 0.5 hours. Then add sodium decahydrate, filter and concentrate, and separate by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (2/3)] to obtain (Z)-(6- (2- (3-chloro- 2-methylphenyl) -1-fluorovinyl) -4-methoxypyridin-3-yl) methanol (300 mg, yield 52%), ESI-MS 308.2 [M-18 + H] ⁺ .

Third step: (Z) -N- (3 '-(2-fluoro-2- (5- (hydroxymethyl) -4-methoxypyridin-2-yl) vinyl) -2,2'- Synthesis of dimethyl- [1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide

5-formyl-4-methoxy-N- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl ) Phenyl) methylpyridinamide (350mg, 0.88mmol) and (Z)-(6- (2- (3-chloro-2-methylphenyl) -1-fluorovinyl) -4-methoxy Pyridine-3-yl) methanol (160 mg, 0.52 mmol) was dissolved in 1,4-dioxane / water (8 mL / 2 mL), and palladium acetate (12 mg, 0.052 mmol) and 2-dicyclohexyl phosphorus-2 were added. , 4,6-triisopropylbiphenyl (25 mg, 0.052 mmol) and potassium phosphate (331 mg, 1.56 mmol). After evacuation and nitrogen exchange, the reaction was stirred at 100 ° C for 4 hours. After concentration, column chromatography was performed [eluent: petroleum ether ~ petroleum ether / ethyl acetate (1/9)] to obtain (Z) -N- (3'- (2-fluoro-2- (5- (hydroxymethyl) -4-methoxypyridin-2-yl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (80 mg, yield 28.4%). ESI-MS 542.2 [M + H] ⁺ .

Step 4: (Z) -N- (3 '-(2-fluoro-2- (5-formyl-4-methoxypyridin-2-yl) vinyl) -2,2'-dimethyl -[1,1'-Biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide

(Z) -N- (3 '-(2-fluoro-2- (5- (hydroxymethyl) -4-methoxypyridin-2-yl) vinyl) -2,2'-dimethyl -[1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (80 mg, 0.148 mmol), and 2-iodoacrylic acid (83 mg, 0.296) was added mmol), and the reaction was stirred at 90 ° C for 2 hours. After cooling, it was filtered and concentrated to give (Z) -N- (3 '-(2-fluoro-2- (5-formyl-4-methoxypyridin-2-yl) vinyl) -2,2'- Dimethyl- [1,1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (80 mg, yield 100%). ESI-MS 540.2 [M + H] ⁺ .

Step 5: (Z) -N- (3 '-(2-fluoro-2- (5-(((2-hydroxyethyl) amino) methyl) -4-methoxypyridin-2-yl) Vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxy Of methylpyridylamide

(Z) -N- (3 '-(2-fluoro-2- (5-formyl-4-methoxypyridin-2-yl) vinyl) -2,2'-dimethyl- [1 , 1'-biphenyl] -3-yl) -5-formyl-4-methoxymethylpyridinamide (80mg, 0.148mmol) dissolved in N, N-dimethylformamide / acetic acid (2.0mL /0.4mL) solution was added ethanolamine (45mg, 0.74mmol). The reaction was stirred at room temperature for 0.5 hours, sodium cyanoborohydride (47 mg, 0.74 mmol) was added, and the reaction was stirred for 1 hour. Then reversed-phase column chromatography [eluent: 0.5% ammonium bicarbonate aqueous solution to 0.5% ammonium bicarbonate aqueous solution / acetonitrile (30:70)] to obtain (Z) -N- (3 '-(2-fluoro 2- (5-(((2-hydroxyethyl) amino) methyl) -4-methoxypyridin-2-yl) vinyl) -2,2'-dimethyl- [1,1 ' -Biphenyl] -3-yl) -5-(((2-hydroxyethyl) amino) methyl) -4-methoxymethylpyridamide (21.7 mg, yield 23.2%). ESI-MS 630.4 [M + H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.5Hz, 2H), 7.38–7.26 (m, 4H), 7.10 (d, J = 7.4Hz, 1H), 7.00 (d, J = 7.5Hz, 1H), 3.99 (s, 3H), 3.96 ( s, 3H), 3.79 (s, 2H), 3.74 (s, 2H), 3.47 (td, J = 5.8, 1.6 Hz, 4H), 2.59 (td, J = 5.7, 3.7 Hz, 4H), 2.09 (s 3H), 2.01 (s, 3H).

Examples 39 to 58 are prepared by the synthetic method of reference example 38:

The NMR data of the compounds prepared in the above examples are as follows:

Example 59 (Z) -2-(((7-chloro-2- (3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3-methyl Oxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methyl) amino) ethyl Preparation of Alkan-1-ol

First step: methyl (Z) -4- (1-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) vinyl ) -2-Methoxybenzoate

In a solution of methyl (Z) -4- (2-bromo-1-fluorovinyl) -2-methoxybenzoate (1.26 g, 4.37 mmol) in 1,4-dioxane (35 mL) Add pinacol diborate (1.45g, 5.6mmol), potassium acetate (1.3g, 12.9mmol), tricyclohexylphosphine (245mg, 0.86mmol) and tris (dibenzylideneacetone) dipalladium (400mg, 0.43 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 80 ° C for 4 hours. Ethyl acetate and water layer. The organic phase was sequentially washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 2/1] to obtain methyl (Z) -4- (1- Fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) vinyl) -2-methoxybenzoate (1.2g, produced Rate 81%). ESI-MS337.2 [M + H] ⁺ .

Second step: methyl (Z) -4- (1-fluoro-2- (3 '-(hydroxymethyl) -2,2'-dimethyl- [1,1'-biphenyl] -3 -Yl) vinyl) -2-methoxybenzoate

In methyl (Z) -4- (1-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) vinyl) -2 -Methoxybenzoate (1.2g, 3.6mmol) in a solution of 1,4-dioxane / water (50mL / 18mL) was added (3'-bromo-2,2'-dimethyl- [1 , 1'-biphenyl] -3-yl) methanol (1.0 g, 3.6 mmol), potassium carbonate (1.49 g, 10.8 mmol) and [1,1'-bis (diphenylphosphine) ferrocene] di Palladium (II) chloride (260 mg, 0.36 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 100 ° C for 2 hours. Ethyl acetate and water layer. The organic phase was washed with water and saturated sodium chloride in this order, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether acid / ethyl acetate = 1/1] to obtain methyl (Z) -4- (1 -Fluoro-2- (3 '-(hydroxymethyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzoic acid Ester (900 mg, yield 59%). ESI-MS 421.2 [M + H] ⁺ .

Third step: methyl (Z) -4- (1-fluoro-2- (3'-formyl-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) Synthesis of vinyl) -2-methoxybenzoate

In methyl (Z) -4- (1-fluoro-2- (3 '-(hydroxymethyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) To a suspension of vinyl) -2-methoxybenzoate (900 mg, 2.14 mmol) in ethyl acetate (20 mL) was added 2-iodobenzoic acid (1.8 g, 6.41 mmol). The reaction was stirred at 90 ° C for 3 hours. After filtration and concentration, methyl (Z) -4- (1-fluoro-2- (3'-formyl-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) Vinyl) -2-methoxybenzoate (850 mg, yield 95%). ESI-MS 419.2 [M + H] ⁺ .

Fourth step: methyl (Z) -7-chloro-2- (3 '-(2-fluoro-2- (3-methoxy-4- (methylyl) phenyl) vinyl) -2, Synthesis of 2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazole-5-carboxylic acid ester

In methyl (Z) -4- (1-fluoro-2- (3'-formyl-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) To a solution of 2-methoxybenzoate (850 mg, 2 mmol) in ethanol (20 mL) was added methyl 3-amino-5-chloro-4-hydroxybenzoate (400 mg, 2 mmol). After the reaction was stirred at room temperature for 1 hour, it was concentrated. Dichloromethane (20 mL) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (400 mg, 2 mmol) were then added. The reaction was stirred at room temperature for 1 hour. Layer with dichloromethane and water. The organic phase was washed with water and saturated sodium chloride in that order, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether acid / ethyl acetate = 2/1] to obtain methyl (Z) -7-chloro- 2- (3 '-(2-fluoro-2- (3-methoxy-4- (methylyl) phenyl) vinyl) -2,2'-dimethyl- [1,1'-bi Phenyl] -3-yl) benzo [d] oxazole-5-carboxylic acid ester (350 mg, yield 29%). ESI-MS 600.2 [M + H] ⁺ .

Step 5: (Z)-(7-chloro-2- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2' Of dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methanol

-78 ° C, under nitrogen protection, in methyl (Z) -7-chloro-2- (3 '-(2-fluoro-2- (3-methoxy-4- (methylyl) phenyl) ethene) Yl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazole-5-carboxylic acid ester (350 mg, 0.58 mmol) in dichloromethane (10 mL) was added a 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (3.5 mL, 3.5 mmol). The reaction was stirred at -78 ° C for 30 minutes. After quenching by adding sodium decahydrate, the temperature was raised to room temperature, and after concentration, column chromatography was separated [dichloromethane / methanol = 20/1] to obtain (Z)-(7-chloro-2- (3 '-(2-fluoro) 2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [ d] Oxazol-5-yl) methanol (230 mg, yield 73%). ESI-MS 544.2 [M + H] ⁺ .

Step 6: (Z) -7-chloro-2- (3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl Synthesis of-[1,1'-biphenyl] -3-yl) benzo [d] oxazole-5-carboxaldehyde

(Z)-(7-chloro-2- (3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl (1,1'-biphenyl) -3-yl) benzo [d] oxazol-5-yl) methanol (230 mg, 0.42 mmol) in dichloromethane (20 mL) was added (1,1 , 1-triacetoxy) -1,1-dihydro-1,2-phenyliodo-3 (1H) -one (1.07 g, 2.54 mmol). The reaction was stirred at room temperature for 5 minutes. After concentration, it was separated by column chromatography [dichloromethane / methanol = 10/1] to obtain (Z) -7-chloro-2- (3 '-(2-fluoro-2- (4-formyl-3-methoxybenzene). Yl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazole-5-carboxaldehyde (120 mg, yield 53%). ESI-MS 540.2 [M + H] ⁺ .

Seventh step: (Z) -2-(((7-chloro-2- (3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3- Methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methyl) amino) Synthesis of ethane-1-ol

(Z) -7-Chloro-2- (3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1 , 1'-biphenyl] -3-yl) benzo [d] oxazole-5-carboxaldehyde (40 mg, 0.07 mmol) in a solution of N, N-dimethylformamide / acetic acid (2 mL / 1 mL), Ethanolamine (50 mg, 0.7 mmol) was added. The reaction was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (50 mg, 0.7 mmol) was added. The reaction was stirred at room temperature for 30 minutes. Column chromatography [0.05% formic acid / acetonitrile] gave (Z) -2-(((7-chloro-2- (3 '-(2-fluoro-2- (4-(((2-hydroxyethyl)) Amino) methyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) benzo [d] oxazole-5 -Yl) methyl) amino) ethane-1-ol (13 mg, yield 25%). ESI-MS 630.4 [M + H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.35 (s, 2H), 8.14 (dd, J = 8.1, 1.4 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.69 (d, J = 7.7Hz, 2H), 7.57 (d, J = 1.3Hz, 1H), 7.54 (t, J = 7.7Hz, 1H), 7.44–7.38 (m, 2H), 7.37–7.32 (m, 2H), 7.30 (d, J = 1.7Hz, 1H), 7.11 (d, J = 7.5Hz, 1H), 6.89 (d, J = 39.6Hz, 1H), 3.88 (s, 3H), 3.87 (s, 2H), 3.76 (s, 2H), 3.50-3.48 (m, 4H), 2.62-2.58 (m, 4H), 2.42 (s, 3H), 2.09 (s, 3H).

Examples 60 to 61 are prepared by the synthetic method of reference example 59:

The NMR data of the compounds prepared in the above examples are as follows:

Example 62 (Z) -2-((4- (1-fluoro-2- (3 '-((3-(((2-hydroxyethyl) amino) methyl) -1,7-diaza Naphthalene-8-yl) amino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) amino) ethane-1 -Alcohol preparation

Step 1: Synthesis of 3-bromo-8-chloro-1,7-diazanaphthalene

A solution of 3-bromo-1,7-diazanaphthalene-8-ol (2.0 g, 8.8 mmol) in phosphorus oxychloride (10 mL) was stirred and reacted at 95 ° C for 2 hours. After concentration, the layers were separated with dichloromethane and saturated sodium bicarbonate solution. The organic phase was sequentially washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [pure dichloromethane] to obtain 3-bromo-8-chloro-1,7-diazanaphthalene ( 1.96 g, yield 91%). ESI-MS 243.2 [M + H] ⁺ .

Step 2: Synthesis of 8-chloro-3-vinyl-1,7-diazanaphthalene

Trifluoro (vinyl) was added to a suspension of 3-bromo-8-chloro-1,7-diazanaphthalene (1.96 g, 8 mmol) in 1,4-dioxane / water (50 mL / 20 mL). Potassium borate (1.25 g, 9.6 mmol), sodium carbonate (2.5 g, 24 mmol), and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (584 mg, 0.8 mmol). The reaction was stirred at 95 ° C for 2 hours. Then use dichloromethane and a water layer. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [pure dichloromethane] to obtain 8-chloro-3-vinyl-1,7-diazanaphthalene (1.2g , Purity 80%). ESI-MS 191.1 [M + H] ⁺ .

Third step: N- (3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -3-vinyl-1,7-diazepine -8-amine synthesis

To a suspension of 8-chloro-3-vinyl-1,7-diazanaphthalene (1.2 g, 6.28 mmol) in tert-butanol (50 mL) was added 3'-bromo-2,2'-dimethyl -[1,1'-biphenyl] -3-amine (2.05 g, 7.53 mmol). The reaction was stirred at 130 ° C for 48 hours. After concentration, the layers were separated with dichloromethane and saturated sodium bicarbonate. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain N- (3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3- (Yl) -3-vinyl-1,7-diazanaphthalene-8-amine (2.2 g crude). ESI-MS 430.1 [M + H] ⁺ .

Step 4: 8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3 -Synthesis of formaldehyde

In crude N- (3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) -3-vinyl-1,7-diazanaphthalene-8 -A solution of amine (2.2 g, 5.1 mmol) in 1,4-dioxane / water (50 mL / 20 mL) was added potassium osmate monohydrate (187 mg, 0.51 mmol) and sodium periodate (6.5 g, 30.6 mmol ). The reaction was stirred at room temperature for 1 hour. Then use dichloromethane and a water layer. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [dichloromethane / ethyl acetate = 10/1] to obtain 8-((3'-bromo-2,2 ' -Dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3-carboxaldehyde (650 mg, purity 90%, yield 27%). ESI-MS 432.1 [M + H] ⁺ .

Step 5: (8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene- Synthesis of 3-yl) methanol

In 8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3-carboxaldehyde ( To a solution of 650 mg, 1.5 mmol) in methanol (20 mL) was added sodium borohydride (166 mg, 4.5 mmol). The reaction was stirred at room temperature for 2 hours. After concentration, dichloromethane and a water layer were used. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 2/1] to obtain (8-((3'-bromo-2,2 ' -Dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) methanol (350 mg, yield 54%). ESI-MS 434.2 [M + H] ⁺ .

The sixth step: methyl (Z) -4- (1-fluoro-2- (3 '-((3- (hydroxymethyl) -1,7-diazanaphthalene-8-yl) amino) -2 Synthesis of 2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzoate

At (8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl ) Methanol (350mg, 0.8mmol) in a solution of 1,4-dioxane / water (20mL / 8mL), methyl (Z) -4- (1-fluoro-2- (4,4,5, 5-tetramethyl-1,3,2-dioxopentyl-2-yl) vinyl) -2-methoxybenzoate (270 mg, 0.8 mmol), potassium carbonate (331 mg, 2.4 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (60 mg, 0.08 mmol). The reaction was stirred at 100 ° C for 1 hour, and then the layer was washed with ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether / ethyl acetate = 1/1] to obtain methyl (Z) -4- (1-fluoro-2 -(3 '-((3- (hydroxymethyl) -1,7-diazanaphthalene-8-yl) amino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzoate (160 mg, yield 35%). ESI-MS 564.2 [M + H] ⁺ .

Seventh step: (Z)-(4- (1-fluoro-2- (3 '-((3- (hydroxymethyl) -1,7-diazanaphthalene-8-yl) amino) -2, Synthesis of 2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxyphenyl) methanol

At methyl (Z) -4- (1-fluoro-2- (3 '-((3- (hydroxymethyl) -1,7-diazanaphthalene-8-yl) amino) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzoate (160 mg, 0.28 mmol) in dichloromethane (10 mL) was added with 1 M of Tetrahydrofuran solution of diisobutylaluminum hydride (1 mL, 1 mmol). The reaction was stirred at room temperature for 10 minutes. After adding sodium sulfate decahydrate to quench it, it was concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 1/1] to obtain (Z)-(4- (1-fluoro-2- (3 '-((3- (Hydroxymethyl) -1,7-diazanaphthalene-8-yl) amino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl)- 2-methoxyphenyl) methanol (160 mg, yield 100%). ESI-MS 536.2 [M + H] ⁺ .

Step 8: (Z) -8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1 , 1'-Biphenyl] -3-yl) amino) -1,7-Diazanaphthalene-3-carbaldehyde

(Z)-(4- (1-fluoro-2- (3 '-((3- (hydroxymethyl) -1,7-diazanaphthalene-8-yl) amino) -2,2'- To a suspension of dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxyphenyl) methanol (160 mg, 0.3 mmol) in ethyl acetate (20 mL) was added 2 -Iodoacylbenzoic acid (510 mg, 1.8 mmol). The reaction was stirred at 90 ° C for 3 hours. (Z) -8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1 , 1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3-carboxaldehyde (80 mg, yield 50%). ESI-MS 532.2 [M + H] ⁺ .

Ninth step: (Z) -2-((4- (1-fluoro-2- (3 '-((3-(((2-hydroxyethyl) amino) methyl) -1,7-diazo Heteronaphthalene-8-yl) amino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) amino) ethane- Synthesis of 1-alcohol

(Z) -8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1' -Biphenyl] -3-yl) amino) -1,7-diazanaphtho-3-carboxaldehyde (80mg, 0.15mmol) in N, N-dimethylformamide / acetic acid (4mL / 1.5mL) solution To this, ethanolamine (95 mg, 1.5 mmol) was added. The reaction was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (95 mg, 1.5 mmol) was added. The reaction was stirred at room temperature for 30 minutes. Column chromatography [0.05% formic acid / acetonitrile] gave (Z) -2-((4- (1-fluoro-2- (3 '-((3-(((2-hydroxyethyl) amino) amino) methyl ) -1,7-Diazanaphthalene-8-yl) amino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxy Benzyl) amino) ethane-1-ol (30 mg, yield 32%). ESI-MS 622.4 [M + H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 8.90 (d, J = 2.1Hz, 1H), 8.44 (d, J = 7.8Hz, 1H), 8.28 (s, 1H) , 8.20 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.36 --7.27 (m, 4H), 7.16 (d, J = 5.9Hz, 1H), 7.09 (d, J = 7.4Hz, 1H), 6.87 (dd, J = 23.5, 16.2Hz, 2H), 3.96 (s, 2H), 3.88 (s, 3H), 3.76 (s, 2H), 3.51-3.48 (m, 4H), 2.64-2.61 (m, 4H), 2.10 (d, J = 15.4 Hz, 6H).

Examples 63 to 71 are prepared by the synthesis method of reference example 62:

The NMR data of the compounds prepared in the above examples are as follows:

Example 72 (E) -5-(((2-hydroxyethyl) amino) methyl) -N- (3- (1- (4-(((2-hydroxyethyl) amino) methyl)- Preparation of 3,5-dimethoxybenzylidene) -2,3-dihydro-1H-inden-4-yl) -2-methylphenyl) -4-methoxymethylpyridinamide

Step 1: Synthesis of 4-bromo-2,3-dihydro-1H-inden-1-ol

To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (9.5 g, 45 mol) in methanol (100 mL) was added sodium borohydride (5.0 g, 1135 mmol). The reaction was stirred at room temperature for 1 hour. After concentration, dichloromethane and a water layer were used. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain 4-bromo-2,3-dihydro-1H-inden-1-ol (9.8 g, yield 100%). ESI-MS 213.2 [M + 1] ⁺ .

Step 2: Synthesis of 1,4-dibromo-2,3-dihydro-1H-indene

In a solution of 4-bromo-2,3-dihydro-1H-indene-1-ol (9.8 g, 45 mol) in dichloromethane (100 mL), 45% hydrobromic acid (50 mL) was added. The reaction was stirred at room temperature for 4 hours. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain 1,4-dibromo-2,3-dihydro-1H-indene (12.1 g, yield 97%). ESI-MS 277.0 [M + H] ⁺ .

Step 3: Synthesis of dihydrogen bromide (4-bromo-2,3--1H-inden-1-yl) triphenylphosphonium

To a solution of 1,4-dibromo-2,3-dihydro-1H-indene (12.1 g, 44 mol) in toluene (50 mL), triphenylphosphine (12.7 g, 70 mmol) was added. The reaction was stirred under reflux for 16 hours. After filtration, the filter cake was dried to obtain dihydrobromo (4-bromo-2,3--1H-inden-1-yl) triphenylphosphonium (17.5 g, yield 73%).

Step 4: Synthesis of (E)-(4-((4-bromo-2,3-dihydro-1H-inden-1-ylidene) methyl) -2-methoxyphenyl) methanol

To a solution of dihydrobromide (4-bromo-2,3--1H-inden-1-yl) triphenylphosphonium (6.0 g, 11.1 mmol) in dichloromethane (50 mL) was added 4- (hydroxymethyl) ) -3-methoxybenzaldehyde (1.55 g, 9.6 mmol), potassium carbonate (13.2 g, 96 mmol), and 18-crown-6 (25 mg, 0.096 mmol). The reaction was stirred at 45 ° C for 4 hours. Then use dichloromethane and a water layer. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [pure dichloromethane] to obtain (E)-(4-((4-bromo-2,3-dihydro- 1H-Inden-1-ylidene) methyl) -2-methoxyphenyl) methanol (1.6 g, 48% yield). ESI-MS 345.1 [M + H] ⁺ .

Step 5: (E) -5-formyl-N- (3- (1- (4- (hydroxymethyl) -3-methoxybenzylidene) -2,3-dihydro-1H-indene Synthesis of 4--4-yl) -2-methylphenyl) -4-methoxymethylpyridinamide

1 in (E)-(4-((4-bromo-2,3-dihydro-1H-indene-1-ylidene) methyl) -2-methoxyphenyl) methanol (172 mg, 0.5 mmol) To a solution of 4,4-dioxane / water (10mL / 5mL) was added 5-formyl-4-methoxy-N- (2-methyl-3- (4,4,5,5-tetramethyl) -1,3,2-dioxopentyl-2-yl) phenyl) methylpyridinamide (198 mg, 0.5 mmol), potassium carbonate (207 mg, 1.5 mmol) and [1,1'-bis (di Phenylphosphine) ferrocene] palladium (II) dichloride (36 mg, 0.05 mmol). After evacuation, the reaction was stirred at 95 ° C for 2 hours. Ethyl acetate and water layer. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether acid / ethyl acetate = 1/2] to obtain (E) -5-formyl-N. -(3- (1- (4- (hydroxymethyl) -3-methoxybenzylidene) -2,3-dihydro-1H-inden-4-yl) -2-methylphenyl)- 4-methoxymethylpyridamide (90 mg, yield 34%). ESI-MS 535.2 [M + H] ⁺ .

Step 6: (E) -5-formyl-N- (3- (1- (4-formyl-3-methoxybenzylidene) -2,3-dihydro-1H-indene-4- Of methyl) -2-methylphenyl) -4-methoxymethylpyridamide

(E) -5-Formyl-N- (3- (1- (4- (hydroxymethyl) -3-methoxybenzylidene) -2,3-dihydro-1H-indene-4- (1,1,1-triacetoxy) -1 was added to a solution of (methyl) -2-methylphenyl) -4-methoxymethylpyridamide (90 mg, 0.17 mmol) in dichloromethane (20 mL) , 1-dihydro-1,2-benzoiodo-3 (1H) -one (285 mg, 0.67 mmol). The reaction was stirred at room temperature for 1 hour. After concentration, it was separated by column chromatography [dichloromethane / methanol = 10/1] to obtain (E) -5-formyl-N- (3- (1- (4-formyl-3-methoxybenzylidene)) -2,3-dihydro-1H-inden-4-yl) -2-methylphenyl) -4-methoxymethylpyridamide (52 mg, yield 58%). ESI-MS 533.2 [M + H] ⁺ .

Seventh step: methyl ((6-((3- (1-((E) -4-((((R) -3-hydroxy-1-methoxy-1-carbonylpropane-2-yl) Amino) methyl) -3-methoxybenzylidene) -2,3-dihydro-1H-inden-4-yl) -2-methylphenyl) carbamoyl) -4-methoxypyridine Synthesis of -3-yl) methyl) -D-serine

(E) -5-Formyl-N- (3- (1- (4-formyl-3-methoxybenzylidene) -2,3-dihydro-1H-inden-4-yl)- 2-Methylphenyl) -4-methoxymethylpyridamide (52mg, 0.097mmol) in N, N-dimethylformamide / acetic acid (2mL / 1mL) solution, D-serine methyl ester salt was added Acid salt (151 mg, 0.97 mmol) and triethylamine (98 mg, 0.97 mmol). The reaction was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (61 mg, 0.97 mmol) was added. The reaction was stirred at room temperature for 30 minutes. Column chromatography [0.05% formic acid / acetonitrile] gave methyl ((6-((3- (1-((E) -4-((((R) -3-hydroxy-1-methoxy-1 -Carbonylpropane-2-yl) amino) methyl) -3-methoxybenzylidene) -2,3-dihydro-1H-inden-4-yl) -2-methylphenyl) carbamoyl ) -4-methoxypyridin-3-yl) methyl) -D-serine (30 mg, yield 42%). ESI-MS 739.4 [M + H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.45 (s, 2H), 7.91 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.0 Hz, 2H) , 7.41-7.27 (m, 3H), 7.16-7.00 (m, 5H), 4.88 (s, 2H), 3.98 (s, 3H), 3.83 (d, J = 5.7Hz, 3H), 3.76-3.68 (m , 2H), 3.63-3.60 (m, 1H), 3.60 (d, J = 2.9Hz, 6H), 3.57 (d, J = 5.4Hz, 3H), 3.32-3.27 (m, 4H), 3.07 (s, 2H), 2.86–2.68 (m, 2H), 2.08 (s, 3H).

Examples 73 to 79 are prepared by the synthetic method of reference example 72:

The NMR data of the compounds prepared in the above examples are as follows:

Example 80 Dimethyl 2,2 '-((((((((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1'H- [4,4'-linked Indene] -1,1'-diylidene) bis (methylidene)) bis (2-methoxy-4,1-phenylene)) bis (methylene)) bis (azepinediyl )) (2R, 2'R) -bis (3-hydroxypropionate)

First step: (E)-(2-methoxy-4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) Synthesis of -2,3-dihydro-1H-inden-1-ylidene) methyl) phenyl) methanol

N in (E)-(4-((4-bromo-2,3-dihydro-1H-indene-1-ylidene) methyl) -2-methoxyphenyl) methanol (500 mg, 1.45 mmol) , N-dimethylformamide (20 mL) solution was added pinacol diborate (441 mg, 1.74 mmol), potassium acetate (426 mg, 4.35 mmol) and [1,1'-bis (diphenylphosphine) di Ferrocene] Palladium (II) dichloride (105 mg, 0.145 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 120 ° C for 2 hours. The reaction solution was used in the next step without any treatment. ESI-MS 393.2 [M + H] ⁺ .

Step 2: (((((1E, 1'E) -2,2 ', 3,3'-tetrahydro-1H, 1'H- [4,4'-biindene] -1,1'-di Synthesis of subunits) bis (methylidene)) bis (2-methoxy-4,1-phenylene)) dimethanol

In (E)-(2-methoxy-4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -2, 3-Dihydro-1H-inden-1-ylidene) methyl) phenyl) methanol in N, N-dimethylformamide (20 mL) reaction solution (1.45 mmol) was added with 1,4-dioxane (50 mL), water (18 mL), (E)-(4-((4-bromo-2,3-dihydro-1H-inden-1-ylidene) methyl) -2-methoxyphenyl) methanol (500 mg, 1.45 mmol), potassium carbonate (600 mg, 4.35 mmol) and [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloride (100 mg, 0.145 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 95 ° C for 2 hours. Ethyl acetate and water layer. The organic phase was washed with water and saturated sodium chloride in this order, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether acid / ethyl acetate = 1/1] to obtain ((((1E, 1'E) -2,2 ', 3,3'-tetrahydro-1H, 1'H- [4,4'-biindene] -1,1'-diylidene) bis (methylidene)) bis (2 -Methoxy-4,1-phenylene)) dimethanol (750 mg, yield 97%). ESI-MS 531.2 [M + H] ⁺ .

The third step: 4,4 '-(((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1'H- [4,4'-biindene] -1, Synthesis of 1'-diylidene) bis (methylidene)) bis (2-methoxybenzene (m) aldehyde)

In ((((1E, 1'E) -2,2 ', 3,3'-tetrahydro-1H, 1'H- [4,4'-biindene] -1,1'-diylidene) To a solution of bis (methylidene)) bis (2-methoxy-4,1-phenylene)) dimethanol (750 mg, 1.41 mmol) in dichloromethane (20 mL) was added (1,1,1- (Triacetoxy) -1,1-dihydro-1,2-phenyliodo-3 (1H) -one (3.6 g, 8.49 mmol). The reaction was stirred at room temperature for 1 hour. After concentration, it was separated by column chromatography [dichloromethane / methanol = 10/1] to obtain 4,4 '-((((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1 ' H- [4,4'-Bindene] -1,1'-diylidene) bis (methylidene)) bis (2-methoxybenzyl) aldehyde (450 mg, yield 60%) . ESI-MS 527.2 [M + H] ⁺ .

Fourth step: dimethyl 2,2 '-((((((((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1'H- [4,4'- Bindene] -1,1'-diylidene) bis (methylidene)) bis (2-methoxy-4,1-phenylene)) bis (methylene)) bis (azepinedi )) (2R, 2'R) -bis (3-hydroxypropionate)

At 4,4 '-(((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1'H- [4,4'-biindene] -1,1'- Dimethylene) bis (methyl subunit)) bis (2-methoxybenzaldehyde) (80 mg, 0.15 mmol) in a solution of N, N-dimethylformamide / acetic acid (2 mL / 1 mL) D-serine methyl ester hydrochloride (234 mg, 1.5 mmol) and triethylamine (155 mg, 1.5 mmol) were added. The reaction was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (95 mg, 1.5 mmol) was added. The reaction was stirred at room temperature for 30 minutes. Column chromatography [0.05% formic acid / acetonitrile] gave dimethyl 2,2 '-((((((((1E, 1'E) -2,2', 3,3'-tetrahydro-1H, 1 ' H- [4,4'-Bindene] -1,1'-diylidene) bis (methylidene)) bis (2-methoxy-4,1-phenylene)) bis (methylene )) Bis (azetanediyl)) (2R, 2'R) -bis (3-hydroxypropionate) (50 mg, yield 45%). ESI-MS 733.4 [M + H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.26 (s, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.7Hz, 2H), 7.20 (d, J = 7.4Hz, 2H), 7.11 (t, J = 2.7Hz, 2H), 7.08 (d, J = 7.7Hz, 4H), 3.82 (s, 6H), 3.71 (s, 2H), 3.64 (s, 2H), 3.60 (s, 6H), 3.58 (d, J = 5.4 Hz, 4H), 3.29 (t, J = 5.2 Hz, 2H), 3.11--3.03 (m, 4H), 2.89-2.87 (m, 4H).

Examples 81 to 87 were prepared by the synthetic method of Reference Example 80

The NMR data of the compounds prepared in the above examples are as follows:

Example 88 Methyl ((6- (2-chloro-3-((E) -1-((5-(((((R) -3-hydroxy-1-methoxy-1-carbonylpropane-2 -Yl) amino) methyl) -6-methoxypyridin-2-yl) methylene) -2,3-dihydro-1H-inden-4-yl) phenyl) -2-methoxy- Preparation of 4-methylpyridin-3-yl) methyl) -D-serine

First step: (E)-(6- (2-chloro-3- (1-((5- (hydroxymethyl) -6-methoxypyridin-2-yl) methylene) -2,3 -Dihydro-1H-inden-4-yl) phenyl) -2-methoxy-4-methylpyridin-3-yl) methanol

In (E)-(2-methoxy-6-((4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -2, 3-Dihydro-1H-inden-1-ylidene) methyl) pyridin-3-yl) methanol in N, N-dimethylformamide (10 mL) reaction solution (0.82 mmol) was added to 1,4-bis Hexane (50 mL), water (18 mL), (6- (3-bromo-2-chlorophenyl) -2-methoxy-4-methylpyridin-3-yl) methanol (350 mg, 1.0 mmol) , Potassium carbonate (340 mg, 2.46 mmol) and [1,1'-bis (diphenylphosphine) ferrocene] palladium (II) dichloride (60 mg, 0.082 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 95 ° C for 2 hours. Ethyl acetate and water layer. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by column chromatography [petroleum ether acid / ethyl acetate = 1/2] to obtain (E)-(6- (2- Chloro-3- (1-((5- (hydroxymethyl) -6-methoxypyridin-2-yl) methylene) -2,3-dihydro-1H-inden-4-yl) phenyl ) -2-methoxy-4-methylpyridin-3-yl) methanol (350 mg, yield 80%). ESI-MS 529.2 [M + H] ⁺ .

Second step: (E) -6- (2-chloro-3- (1-((5-formyl-6-methoxypyridin-2-yl) methylene) -2,3-dihydro- Synthesis of 1H-inden-4-yl) phenyl) -2-methoxy-4-methylnicotyraldehyde

(E)-(6- (2-chloro-3- (1-((5- (hydroxymethyl) -6-methoxypyridin-2-yl) methylene) -2,3-dihydro -1H-Inden-4-yl) phenyl) -2-methoxy-4-methylpyridin-3-yl) methanol (350 mg, 0.66 mmol) in dichloromethane (20 mL) was added (1,1 , 1-triacetoxy) -1,1-dihydro-1,2-phenyliodo-3 (1H) -one (1.68 g, 3.97 mmol). The reaction was stirred at room temperature for 1 hour. After concentration, it was separated by column chromatography [dichloromethane / methanol = 10/1] to obtain (E) -6- (2-chloro-3- (1-((5-formyl-6-methoxypyridine-2- (Methylene) methylene) -2,3-dihydro-1H-inden-4-yl) phenyl) -2-methoxy-4-methylnicotyraldehyde (340 mg, yield 98%). ESI-MS 525.2 [M + H] ⁺ .

Third step: methyl ((6- (2-chloro-3-((E) -1-((5-(((((R) -3-hydroxy-1-methoxy-1-carbonylpropane- 2-yl) amino) methyl) -6-methoxypyridin-2-yl) methylene) -2,3-dihydro-1H-inden-4-yl) phenyl) -2-methoxy Synthesis of 4-methylpyridin-3-yl) methyl) -D-serine

(E) -6- (2-chloro-3- (1-((5-formyl-6-methoxypyridin-2-yl) methylene) -2,3-dihydro-1H-indene 4-Alkyl) phenyl) -2-methoxy-4-methylnicotyraldehyde (60 mg, 0.12 mmol) in a solution of N, N-dimethylformamide / acetic acid (4 mL / 2 mL), and D- Serine methyl ester hydrochloride (186 mg, 1.2 mmol) and triethylamine (120 mg, 1.2 mmol). The reaction was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (76 mg, 1.2 mmol) was added. The reaction was stirred at room temperature for 30 minutes. Column chromatography [0.05% formic acid / acetonitrile] gave methyl ((6- (2-chloro-3-((E) -1-((5-(((((R) -3-hydroxy-1-methyl Oxy-1-carbonylpropane-2-yl) amino) methyl) -6-methoxypyridin-2-yl) methylene) -2,3-dihydro-1H-inden-4-yl) benzene Yl) -2-methoxy-4-methylpyridin-3-yl) methyl) -D-serine (45 mg, 51% yield). ESI-MS 731.4 [M + H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.81 (d, J = 7.7Hz, 1H), 7.67 (d, J = 7.5Hz, 1H), 7.58 (dd, J = 7.7, 1.8Hz, 1H) , 7.50 (t, J = 7.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.20 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 2.8 Hz, 2H), 7.04 (d, J = 7.5 Hz, 1H), 4.85 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.78 (d, J = 12.3 Hz, 1H), 3.72 (d, J = 6.4 Hz, 1H), 3.69 (d, J = 4.1Hz, 1H), 3.60 (d, J = 3.2Hz, 6H), 3.58 (d, J = 2.6Hz, 3H), 3.55 (t, J = 4.7Hz, 2H) , 3.40 (t, J = 7.1 Hz, 2H), 3.33-3.28 (m, 4H), 2.87 (t, J = 7.4 Hz, 2H), 2.39 (s, 3H).

Examples 89 to 94 were prepared by the synthetic method of Reference Example 88:

The NMR data of the compounds prepared in the above examples are as follows:

Example 95 (R, Z) -5-((5- (1-fluoro-2- (3 '-(3- (3-hydroxypyrrolidin-1-yl) propoxy) -2,2'- Preparation of dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2-hydroxyethyl) amino) methyl) phenoxy) methyl) nicotine nitrile

First step: (R, Z) -5-((5- (1-fluoro-2- (3 '-(3- (3-hydroxypyrrolidin-1-yl) propoxy) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile

In containing (R) -1- (3- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy (Propyl) propyl) pyrrolidin-3-ol (850 mg, 2.35 mmol) In a single-necked flask, 1,4-dioxane / water (3: 1, 28 mL) was added, and (Z) -5-(( 5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-formylphenoxy) methyl) nicotinenitrile (880 mg, 1.96 mmol), potassium phosphate (840 mg, 3.92 mmol) and chloro (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1 ' -Biphenyl)] Palladium (II) (154 mg, 0.2 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 90 ° C overnight. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 2: 1] to obtain (R, Z) -5 -((5- (1-fluoro-2- (3 '-(3- (3-hydroxypyrrolidin-1-yl) propoxy) -2,2'-dimethyl- [1,1'- Biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile (490 mg, yield 41%). ESI-MS 606.2 [M + H] ⁺ .

Second step: (R, Z) -5-((5- (1-fluoro-2- (3 '-(3- (3-hydroxypyrrolidin-1-yl) propoxy) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2-hydroxyethyl) amino) methyl) phenoxy) methyl) synthesis

Put (R, Z) -5-((5- (1-fluoro-2- (3 '-(3- (3-hydroxypyrrolidin-1-yl) propoxy) -2,2'-dimethyl -[1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile (100 mg, 0.17 mmol) dissolved in DMF / acetic acid (5: 1, 3 mL), ethanolamine (50 mg, 0.8 mmol) was added, and the reaction was stirred at room temperature for 1 hour, and sodium cyanoborohydride (52 mg, 0.8 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Reversed-phase chromatography [0.1% formic acid in water / acetonitrile] and lyophilization to obtain (R, Z) -5-((5- (1-fluoro-2- (3 '-(3- (3-hydroxypyrrolidine- 1-yl) propoxy) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2-hydroxyethyl) amino) Methyl) phenoxy) methyl) nicotyronitrile (5 mg). ESI-MS 651.3 [M + 1] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.02 (d, J = 2.1 Hz, 2 H), 8.47 (t, J = 2.2 Hz, 1 H), 8.35 (s, 3 H), 7.63 (d, J = 7.7Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 7.9, 1.6 Hz, 1H), 7.29 (t, J = 7.8Hz, 1H), 7.21 (t, J = 7.9Hz, 1H), 7.01 (dd, J = 7.7, 1.4Hz, 1H), 6.96 (d, J = 8.4Hz, 1H), 6.85 (d, J = 39.7Hz, 1H), 6.68 (d, J = 7.4Hz, 1H), 5.36 (s, 2H), 4.19 (dt, J = 6.6, 3.5Hz, 1H), 4.05 (dt, J = 11.1, 6.0Hz, 2H), 3.81 (s, 2H), 3.49 (t, J = 5.7Hz, 2H), 2.73 (dd, J = 9.6, 6.4Hz, 1H), 2.59 (dt, J = 16.8, 6.1Hz, 6H), 2.46 (d, J = 7.9 Hz, 1H), 2.35 (dd, J = 9.9, 3.6 Hz, 1H), 2.04 (s, 3H), 1.98 (dd, J = 13.1, 6.8 Hz, 1H), 1.94--1.90 (m, 2H), 1.85 (s, 3H), 1.54 (dt, J = 12.9, 7.7 Hz, 1H).

Examples 96 to 97 are prepared by the synthetic method of reference example 95:

The NMR data of the compounds prepared in the above examples are as follows:

Example 98 (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile

First step: (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl)- Synthesis of 2,2'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile

Add to a single-necked bottle containing (Z)-(4- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-methoxyphenyl) methanol (350 mg, 1 mmol) 1,4-dioxane / water (3: 1,14mL), and then add 5-((4-chloro-2-formyl-5-((2-methyl-3- (4,4,5) , 5-tetramethyl-1,3,2-dioxopentyl-2-yl) benzyl) oxo) phenoxy) methyl) nicotinenitrile (622mg, 1.2mmol), potassium phosphate (424mg , 2mmol) and chloro (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1 ' -Biphenyl)] Palladium (II) (79 mg, 0.1 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 90 ° C overnight. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 2: 1] to obtain (Z) -5- ( (4-chloro-5-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1 , 1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile (270 mg, yield 41%). ESI-MS 663.2 [M + H] ⁺ .

Second step: (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2 Synthesis of '-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile

Put (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2 '-Dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile (270mg, 0.4mmol) dissolved in dichloromethane (10 mL), Dess-Martin periodinane (345 mg, 0.8 mmol) was added at room temperature, and the reaction was stirred at room temperature for 15 minutes. The mixture was extracted and separated with ethyl acetate / saturated sodium bicarbonate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and separated by filtration and concentration column chromatography to obtain (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl- [ 1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile (260 mg, yield 96%). ESI-MS 661.1 [M + H] ⁺ .

The third step: (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl) -3- Methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) -2-(((2-hydroxyethyl) amino ) Methyl) phenoxy) methyl) nicotine nitrile

Add (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-di Methyl- [1,1'-biphenyl] -3-yl) methoxy) -2-formylphenoxy) methyl) nicotinenitrile (60mg, 0.1mmol) was dissolved in DMF (3mL), Ethanolamine (37 mg, 0.6 mmol) and a catalytic amount of acetic acid were added. After the reaction was stirred at room temperature for 1 hour, sodium cyanoborohydride (63 mg, 1 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Reversed-phase chromatography [0.1% formic acid in water / acetonitrile], lyophilized to obtain (Z) -5-((4-chloro-5-((3 '-(2-fluoro-2- (4-(((2 -Hydroxyethyl) amino) methyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) 2-(((2-hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinenitrile (2 mg). ESI-MS 751.3 [M + H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 9.07 (dd, J = 16.9, 2.2 Hz, 2H), 8.51 (d, J = 2.2 Hz, 1H), 8.46 (s, 5H), 7.71 (d, J = 7.7Hz, 1H), 7.57 (d, J = 7.8Hz, 1H), 7.49–7.42 (m, 2H), 7.37 (dd, J = 15.6, 7.8Hz, 4H), 7.18 (d, J = 5.7 Hz, 2H), 7.11 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 39.6 Hz, 1H), 5.39 (s, 2H), 5.34 (s, 2H), 3.94 (s, 2H), 3.79 (s, 2H), 3.74 (s, 2H), 3.55 (d, J = 5.9 Hz, 7H), 2.63 (dt, J = 15.2, 5.7 Hz, 4H), 2.12 (d, J = 11.2 Hz, 6H ).

Examples 99 to 100 are prepared by the synthetic method of reference example 98:

The NMR data of the compounds prepared in the above examples are as follows:

Example 101 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4-(((2-hydroxyethyl) amino) methyl Yl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2-hydroxy Preparation of ethyl) amino) methyl) phenoxy) methyl) nicotyronitrile

First step: 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4- (hydroxymethyl) -3-methoxybenzene Synthesis of vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotyronitrile

In containing (Z)-(4- (1-fluoro-2- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2 -Yl) phenyl) vinyl) -2-methoxyphenyl) methanol (750mg, 1.9mmol) In a single-necked flask, 1,4-dioxane / water (3: 1,15mL) was added, followed by ( Z) -5-((5- (2- (3-bromo-2-methylphenyl) -1-fluorovinyl) -2-formylphenoxy) methyl) nicotinenitrile (600mg, 1.33mmol ), Potassium phosphate (565mg, 2.66mmol) and chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2 '-Amino-1,1'-biphenyl)] palladium (II) (105 mg, 0.13 mmol). After evacuation and nitrogen replacement, the reaction was stirred at 90 ° C overnight. Ethyl acetate / water extraction, the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated after column chromatography [petroleum ether / ethyl acetate = 3: 1] to obtain 5-((5- ( (Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'- Dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotyronitrile (550 mg, yield 41%, purity: 70%). ESI-MS 643.2 [M + H] ⁺ .

Second step: 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4-formyl-3-methoxyphenyl) ethylene (Synthesis) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile

5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) ethylene Yl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile (550 mg crude, 0.4 mmol ) Was dissolved in dichloromethane (15 mL), Dess-Martin periodinane (345 mg, 0.8 mmol) was added at room temperature, and the reaction was stirred at room temperature for 15 minutes. The mixture was extracted and separated with ethyl acetate / saturated sodium bicarbonate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered and concentrated by column chromatography to separate [petroleum ether / ethyl acetate = 3: 1] to obtain 5- ( (5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile (310 mg, yield 56%, purity 70%). ESI-MS 641.2 [M + H] ⁺ .

Step 3: 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4-(((2-hydroxyethyl) amino)) (Methyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-(((2- Synthesis of hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinenitrile

Add 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl)- 2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-formylphenoxy) methyl) nicotinenitrile (90mg, 0.1mmol) dissolved in DMF (3 mL), ethanolamine (37 mg, 0.6 mmol), and a catalytic amount of acetic acid were added. The reaction was stirred at room temperature for 1 hour, sodium cyanoborohydride (63 mg, 1 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Reversed-phase chromatography [0.1% formic acid in water / acetonitrile] and lyophilization gave 5-((5-((Z) -1-fluoro-2- (3 '-((Z) -2-fluoro-2- ( 4-(((2-hydroxyethyl) amino) methyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3- Yl) vinyl) -2-(((2-hydroxyethyl) amino) methyl) phenoxy) methyl) nicotinenitrile (3 mg). ESI-MS 731.3 [M + H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.02 (d, J = 1.9 Hz, 2 H), 8.47 (t, J = 2.2 Hz, 1 H), 8.29 (s, 1 H), 7.65 (d, J = 7.8Hz, 2H), 7.46 (d, J = 7.9Hz, 1H), 7.43–7.40 (m, 2H), 7.39–7.36 (m, 1H), 7.35–7.28 (m, 4H), 7.06 (dt, J = 7.7, 1.7Hz, 2H), 6.87 (dd, J = 39.7, 2.5Hz, 2H), 5.36 (s, 2H), 3.88 (s, 3H), 3.81 (s, 2H), 3.75 (s, 2H) , 3.49 (td, J = 5.7, 1.8 Hz, 6H), 2.61 (t, J = 5.7 Hz, 4H), 2.07 (s, 6H).

Examples 102 to 103 are prepared by the synthetic method of reference example 101:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 104 to 124 were prepared by referring to the synthetic method of Example 1:

The NMR data of the compounds prepared in the above examples are as follows:

Example 125 (4-((Z) -1-Fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxymethyl Of pyridylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine

First step: methyl (Z)-(4- (2- (3 '-(5- (dimethoxymethyl) -4-methoxymethylpyridylamino) -2,2'-di Synthesis of methyl- [1,1'-biphenyl] -3-yl) -1-fluorovinyl) -2-methoxybenzyl) -D-serine

Add (Z) -5- (dimethoxymethyl) -N- (3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2' -Dimethyl- [1,1'-biphenyl] -3-yl) -4-methoxymethylpyridamide (150 mg, 0.256 mmol) dissolved in N, N-dimethylformamide / acetic acid ( 2.0 mL / 0.4 mL), D-serine methyl ester hydrochloride (120 mg, 0.769 mmol) and triethylamine (77 mg, 0.769 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. Then add sodium cyanoborocyanide (48mg, 0.769mmol), continue stirring for 1 hour, and separate by reversed-phase column chromatography [eluent: 0.5% formic acid aqueous solution-0.5% formic acid aqueous solution / acetonitrile (40:60)] Methyl (Z)-(4- (2- (3 '-(5- (dimethoxymethyl) -4-methoxymethylpyridylamino) -2,2'-dimethyl- [1,1'-Biphenyl] -3-yl) -1-fluorovinyl) -2-methoxybenzyl) -D-serine (80 mg, yield 45.4%). ESI-MS345.0 [1 / 2M + H] ⁺ .

Second step: methyl (Z)-(4- (1-fluoro-2- (3 '-(5-formyl-4-methoxymethylpyridylamino) -2,2'-dimethyl -[1,1'-Biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine

Methyl (Z)-(4- (2- (3 '-(5- (dimethoxymethyl) -4-methoxymethylpyridinylamino) -2,2'-dimethyl- [1,1'-Biphenyl] -3-yl) -1-fluorovinyl) -2-methoxybenzyl) -D-serine (80 mg, 0.116 mmol) was dissolved in tetrahydrofuran (5 mL), A 4M aqueous hydrochloric acid solution (0.5 mL, 2 mmol) was added, and the reaction solution was stirred at 40 ° C for 2 hours. After concentration, methyl (Z)-(4- (1-fluoro-2- (3 '-(5-formyl-4-methoxymethylpyridinylamino) -2,2'-dimethyl- [1,1'-Biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine (70 mg, yield 94%), ESI-MS 642.3 [M + H] ⁺ .

The third step: methyl (4-((Z) -1-fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methyl Oxymethylpyridinylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine Synthesis

The methyl (Z)-(4- (1-fluoro-2- (3 '-(5-formyl-4-methoxymethylpyridinylamino) -2,2'-dimethyl- [1 , 1'-biphenyl) -3-yl) vinyl) -2-methoxybenzyl) -D-serine (70 mg, 0.11 mmol) dissolved in N, N-dimethylformamide / acetic acid ( (2.0 mL / 0.4 mL), (S) -pyrrolidin-3-ol (29 mg, 0.33 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. Then add sodium cyanoborocyanide (21 mg, 0.33 mmol), continue stirring for 1 hour, and separate by reversed-phase column chromatography [eluent: 0.5% formic acid aqueous solution-0.5% formic acid aqueous solution / acetonitrile (60:40)] Methyl (4-((Z) -1-fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxymethyl Pyridylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine acid ester (10mg, Yield: 12.75%). ESI-MS 357.4 [1 / 2M + H] ⁺ .

The fourth step: (4-((Z) -1-fluoro-2- (3 '-(5-(((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxy Synthesis of methylpyridylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine

Methyl (4-((Z) -1-fluoro-2- (3 '-(5-((((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxymethyl Pyridylamino) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine acid ester (10mg, 0.014 mmol) was dissolved in methanol / water (1 mL / 1 mL), lithium hydroxide monohydrate (3.0 mg, 0.07 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. Then reverse phase column chromatography [eluent: 0.5% formic acid in water solution to 0.5% formic acid in water solution / acetonitrile (60:40)] to obtain (4-((Z) -1-fluoro-2- (3'- (5-((((S) -3-hydroxypyrrolidin-1-yl) methyl) -4-methoxymethylpyridinylamino) -2,2'-dimethyl- [1,1'- Biphenyl] -3-yl) vinyl) -2-methoxybenzyl) -D-serine (3.4 mg, yield 34.75%). ESI-MS 699.4 [M + H] ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 8.48 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.7Hz, 1H), 7.45 (d, J = 7.9Hz, 1H), 7.33 (ddd, J = 12.1, 6.5, 3.2Hz, 4H), 7.06 (d, J = 7.5Hz, 1H), 6.98 ( d, J = 7.5 Hz, 1H), 6.90 (d, J = 39.6 Hz, 1H), 4.19 (dt, J = 6.6, 3.5 Hz, 1H), 3.98 (s, 3H), 3.89 (s, 5H), 3.66 (s, 2H), 3.59 (s, 2H), 3.00 (t, J = 5.7Hz, 1H), 2.69 (dd, J = 9.8, 6.0Hz, 1H), 2.63 (t, J = 7.6Hz, 1H ), 2.46--2.43 (m, 1H), 2.37 (dd, J = 9.7, 3.6Hz, 1H), 2.08 (s, 3H), 2.00 (s, 4H), 1.54 (dd, J = 8.6, 5.3Hz, 1H).

Examples 126 to 188 were prepared by the synthesis method of reference example 125:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 189 to 198 were prepared by the synthetic method of Reference Example 30:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 199 to 201 are prepared by the synthetic method of reference example 62:

The NMR data of the compounds prepared in the above examples are as follows:

Example 202: (S) -1-((8-((3 '-((Z) -2-fluoro-2- (4-(((R) -3-hydroxypyrrolidin-1-yl) methyl Yl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene- Preparation of 3-yl) methyl) piperidine-2-carboxylic acid

First step: (Z) -8-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl -[1,1'-Biphenyl] -3-yl) amino) -1,7-Diazanaphthalene-3-carbaldehyde

In 8-((3'-bromo-2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3-carboxaldehyde ( 1.1 g, 2.5 mmol) in a solution of 1,4-dioxane / water (100 mL / 20 mL), and (Z)-(4- (1-fluoro-2- (4,4,5,5-tetrahydrofuran) Methyl-1,3,2-dioxopentyl-2-yl) vinyl) -2-methoxyphenyl) methanol (2.2 g, 7.1 mmol), potassium carbonate (1.0 g, 7.5 mmol) and [ 1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (365 mg, 0.5 mmol). The reaction solution was stirred at 95 ° C for 1 hour, and then the mixture was layered with ethyl acetate and water. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated and separated by column chromatography [petroleum ether / ethyl acetate = 1/2] to obtain (Z) -8-((3 '-(2 -Fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino ) -1,7-Diazanaphthalene-3-carboxaldehyde (1.0 g, yield 74%). ESI-MS 534.2 [M + H] ⁺ .

Second step: (S, Z) -1-((8-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2, Synthesis of 2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) methyl) piperidine-2-carboxylic acid

(Z) -8-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1 , 1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene-3-carboxaldehyde (150 mg, 0.28 mmol) in methylene chloride / N, N-diisopropylethylamine (20 mL / 5 mL), (S) -piperidine-2-carboxylic acid (180 mg, 1.4 mmol) was added. The reaction was stirred at reflux for 16 hours, and then sodium acetate borohydride (296 mg, 1.4 mmol) was added. The reaction solution was stirred under reflux for 2 hours. After spin-drying, column chromatography separated [0.05% formic acid / acetonitrile) to give (S, Z) -1-((8-((3 '-(2-fluoro-2- (4- (hydroxymethyl))-3 -Methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) Methyl) piperidine-2-carboxylic acid (60 mg, yield 33%). ESI-MS 647.2 [M + H] ⁺ .

Third step: (S, Z) -1-((8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'- Synthesis of dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) methyl) piperidine-2-carboxylic acid

(S, Z) -1-((8-((3 '-(2-fluoro-2- (4- (hydroxymethyl) -3-methoxyphenyl) vinyl) -2,2'- Dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) methyl) piperidine-2-carboxylic acid (60 mg, 0.092 mmol ) To a solution of N, N-dimethylformamide (4 mL) was added 2,2,6,6-tetramethylpiperidino oxo (24 mg, 0.185 mmol) and cuprous chloride (27 mg, 0.276 mmol). After evacuation, the reaction solution was stirred at room temperature for 2 hours. Then column chromatography separated [0.05% formic acid / acetonitrile] to obtain (S, Z) -1-((8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl)) (Vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) methyl) piperidine- 2-carboxylic acid (35 mg, yield 59%). ESI-MS 645.2 [M + H] ⁺ .

The fourth step: (S) -1-((8-((3 '-((Z) -2-fluoro-2- (4-(((R) -3-hydroxypyrrolidin-1-yl) methyl Yl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphthalene- Synthesis of 3-yl) methyl) piperidine-2-carboxylic acid

(S, Z) -1-((8-((3 '-(2-fluoro-2- (4-formyl-3-methoxyphenyl) vinyl) -2,2'-dimethyl -[1,1'-biphenyl] -3-yl) amino) -1,7-diazanaphth-3-yl) methyl) piperidine-2-carboxylic acid (35 mg, 0.05 mmol) of N To a solution of N-dimethylformamide / acetic acid (4 mL / 1.5 mL), (R) -pyrrolidin-3-ol (43 mg, 0.5 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (31 mg, 0.5 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. Column chromatography (0.05% formic acid / acetonitrile) gave (S) -1-((8-((3 '-((Z) -2-fluoro-2- (4-(((R) -3-hydroxy Pyrrolidin-1-yl) methyl) -3-methoxyphenyl) vinyl) -2,2'-dimethyl- [1,1'-biphenyl] -3-yl) amino) -1 , 7-Diazanaphthalen-3-yl) methyl) piperidine-2-carboxylic acid (11 mg, yield 30%). ESI-MS 716.3 [M + H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.90 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 8.06 (d, J = 5.8Hz, 1H), 7.65 (d, J = 7.8Hz, 1H), 7.41 (d, J = 7.9Hz, 1H), 7.37-7.28 (m, 4H) , 7.18 (d, J = 5.9 Hz, 1H), 7.11–7.06 (d, J = 7.9 Hz, 1H), 6.95–6.89 (d, J = 16 Hz, 1H), 6.87–6.83 (d, J = 16 Hz, 1H), 4.72 (s, 1H), 4.20 (s, 1H), 4.01 (d, J = 14.3Hz, 1H), 3.87 (s, 3H), 3.70 (d, J = 14.3Hz, 1H), 3.62 ( d, J = 7.2Hz, 2H), 2.90–2.86 (m, 1H), 2.75–2.70 (m, 1H), 2.68–2.60 (m, 2H), 2.41–2.37 (m, 1H), 2.33 (p, J = 1.9 Hz, 1H), 2.29–2.23 (m, 1H), 2.02–1.96 (m, 1H), 1.85–1.74 (m, 2H), 1.59–1.39 (m, 4H).

Examples 203 to 212 are prepared by the synthetic method of reference example 202:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 213 to 217 were prepared by the synthesis method of Reference Example 38:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 218 to 219 were prepared by the synthetic method of Reference Example 62:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 220 to 225 were prepared by the synthetic method of Reference Example 38:

The NMR data of the compounds prepared in the above examples are as follows:

Examples 226 to 230 are prepared by the synthetic method of Reference Example 62:

The NMR data of the compounds prepared in the above examples are as follows:

Evaluation of biological tests

I. PD1-PDL1 HTRF binding activity test

The effect of the compound of the embodiment of the present invention and the positive compound on the PD-1 / PD-L1 protein interaction was determined by Cisbio's PD-1 / PD-L1 binding assay kit (# 64ICP01PEG or 64ICP01PEH). The specific experimental method is as follows:

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

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

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

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

5) The IC ₅₀ values of the compounds of the examples and the positive compounds of the present invention were determined by analyzing the percentage inhibition at different compound concentrations by non-linear regression analysis. The specific experimental results are shown in Table 1.

2. Jurkat reporter gene cell activity test

The effect of the compound of the embodiment of the present invention and the positive compound on the PD-1 / PD-L1 protein interaction expressed on the cell surface and the effect of the T cell function brought about by it are determined by the Jurkat reporter gene cell activity test.

In short, the NF-kB-luc reporter gene plasmid and human PD-1 plasmid were transfected into Jurkat cells to establish a stable transgenic cell line that stably expresses both PD-1 and NF-kB-Luc reporter genes. Flow cytometry was used to identify the surface expression level of PD-1, and reporter gene response after stimulation with OKT-3 and Raiji cells was used to identify the expression level of the reporter gene.

In addition, human PD-L1 expression plasmid was transfected into Raji cells to obtain a cell line stably expressing PD-L1. Then Jurkat / NF-kB-luc / PD1 cells and Raji-PD-L1 cells were co-cultured and stimulated with OKT-3. Compounds were added on this basis, and the readings of the gene response were reported to reflect the compounds' response to PD-1 / PD. Inhibition of -L1 interaction enhances T cell activation signaling pathway. The specific experimental methods are as follows:

1) In a white 96-well plate (corning, 3610), add 30 μL of the compound or antibody at different dilution concentrations, and then add 10 μL of OKT3 (Biolegend, 317326) (the final concentration of OKT3 is 1 μg / mL);

2) Add 20 μL of Raji-PD-L1 cell suspension to each well, 5 * 10 ^ 4 cells per well, and incubate in the incubator for 20 minutes;

3) Add 20μL Jurkat / NFkb-luc / PD-1 cell suspension to each well, mix 5 * 10 ^ 4 cells per well, mix well, and detect Bright-glo (Promega, E2620) after 6h;

4) Compare the readings of each well obtained after the compound treatment with the DMSO-treated wells to obtain the activation multiple of the compound action;

EC ₅₀ values were determined and positive example compounds of the present invention compound 5) Analysis fold activation at different concentrations of the compound by nonlinear regression. The specific experimental results are shown in Table 1:

Table 1: Biological test results

From the biological activity data of the compounds of the specific examples, the 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 T cell at the cellular level. activation.

All documents mentioned in the present invention are incorporated by reference in this application, as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching 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 appended claims of the present application.

Claims (17)

Compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof:

Wherein X and Y are each independently selected from N or C (R ₈ ); R ₁ and R ₂ 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 Heterocyclic group, C _5-10 aryl group or 5-10 membered heteroaryl group, or R ₁ and R ₂ together with the nitrogen atom to which it is directly attached form a 3-10 membered heterocyclic group. The above group is optionally further Is selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkane Group, 3-10 membered heterocyclic group, C _5-10 aryl group, 5-10 membered heteroaryl group, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from the group consisting of deuterium, halogen, cyano, nitro, Azide, 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 ring alkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered _{Aryl, = O, -C 0-8 -S (} O) r R 19, -C 0-8 -OR 20, -C 0-8 -C (O) OR 20, -C 0-8 -C ( O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8- Substitution of N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ Superseded by R ₃ and R ₈ are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered _{heteroaryl, -C 0-8 -S (O) r} R 19, -C 0- 8 - OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more selected from the group consisting of 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or- C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; R ₄ and R ₅ are each independently selected from hydrogen or fluorine, or R ₅ and R ₆ and the directly connected group together form a 4-10 membered carbocyclic group or a 4-10 membered heterocyclic group, with the proviso that R _4. R _{5 is} not selected from hydrogen at the same time; R _{6 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, 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, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _{0 -8} -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _{0 -8} -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl , C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkyl substituted with halo, deuterium substituted C _{1- 10} alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl , C _5-10 aryl, 5-10 membered _{heteroaryl, = O, -C 0-8 -S (} O) r R 19, -C 0- 8 -OR 20, -C 0-8 -C ( O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C ( = NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; Each R _{7 is} independently selected from the following groups:

Each R _{9 is} independently selected from -C _0-4 -NR ₁₇ R ₁₈ , and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _{1- 10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkyl substituted with halo, deuterium substituted C _{1- 10} alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered _{heteroaryl, = O, -C 0-8 -S (} O) r R 19, -C 0- 8 -OR 20, -C 0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _{0- 8} -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; Each R ₁₀ , R _{11 is} independently selected from hydrogen, fluorine, cyano or methyl; Each R _{12 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered _{heteroaryl, -C 0-8 -S (O) r} R 19, -C 0- 8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ 、 -C _0-8 -C (= NR ₂₂ ) R ₂₁ 、 -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ 、 -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _{0 -8} -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _{0 -8} -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ substituted with a substituent; Each of R ₁₃ , R ₁₄ , and R _{15 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 Alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S (O) _r R ₁₉ ,- C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _{0 -8} -NR ₂₂ R ₂₃ , -C _{0- 8} -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8- C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro , Azide, 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 heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8- OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; R _{16 is} selected from hydrogen, deuterium, halogen, cyano, C _1-10 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl , -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ or -C _0-8 -OC (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 heterocyclyl, C _{5- 10} aryl, 5-10 membered heteroaryl, = O, -C _0-8 -S (O) _r R ₁₉ , -C _0-8 -OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further further substituted by one or more selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _{2 -10} alkenyl, C _2-10 alkynyl, C _1-10 alkyl substituted with halo, deuterium substituted C _{1- 10} alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered _{heteroaryl, = O, -C 0-8 -S (} O) r R 19, -C 0- 8 -OR 20, -C 0-8 -C (O ) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ 、 -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ 、 -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N ( R ₂₂ ) -C (O) R ₂₁ substituted with a substituent; Each R _17, R ₁₈ are each independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, 3 A -10 membered heterocyclic group, a C _5-10 aryl group or a 5-10 membered heteroaryl group, or R ₁₇ and R ₁₈ together with its directly attached nitrogen atom form a 3-10 membered heterocyclic group. Is further selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = 0, -C _0-8 -S (O) _r R ₁₉ , -C _0-8- OR ₂₀ , -C _0-8 -C (O) OR ₂₀ , -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, cyano, nitrate group, azido group, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkyl substituted with halo, deuterium substituted C _{1- 10} alkyl, C _{3- 10} cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl , 5-10 membered _{heteroaryl, = O, -C 0-8 -S (} O) r R 19, -C 0- 8 -OR 20, -C 0-8 -C (O) OR 20, -C _0-8 -C (O) R ₂₀ , -C _0-8 -OC (O) R ₂₁ , -C _0-8 -NR ₂₂ R ₂₃ , -C _0-8 -C (= NR ₂₂ ) R ₂₁ , -C _0-8 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-8 -C (O) NR ₂₂ R ₂₃ or -C _0-8 -N (R ₂₂ ) -C ( O) substituted by a substituent of R ₂₁ ; Each R _{19 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, 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 heterocyclic Aryloxy or -NR ₂₂ R ₂₃ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, 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 heterocyclic Substituted with aryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ substituents; Each R _{20 is} independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl Or 5- to 10-membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of 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 Substituted by heteroaryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ substituents; Each R _{21 is} 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 heterocyclic Aryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, cyano, C _1-10 alkyl, C _{1- 10} alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 Substituted with aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR ₂₂ R ₂₃ ; Each R _22, R ₂₃ are each independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkoxy, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl group, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C _1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium , Halogen, hydroxyl, 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 _1-10 Alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclooxy, C _5-10 aryl, C _5-10 aromatic Substituted by oxo, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents; Alternatively, R ₂₂ and R ₂₃ and the directly connected nitrogen atom together form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, and hydroxyl group. , Carboxyl, 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 _1-10 alkoxy Group, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents; (Z) / (E) means cis, trans isomers or a mixture of cis and trans isomers thereof; m is 0, 1 or 2; Each p is independently 0, 1, 2 or 3; Each n, q is independently 0, 1, 2, 3 or 4; Each r is independently 0, 1, or 2. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein R _{6 is} selected from hydrogen, deuterium, halogen, cyano, nitro, and Nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5 -8-membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , The aforementioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Halo-substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ )-C (= NR ₂₃ ) R ₂₁ 、 -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ substituted with R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , r As claimed in claim 1; Preferably, R _{6 is} selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, bromine, cyano, nitro, azide, methyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, methoxy, methoxyl, carboxyl, acetyl , Acetoxy, amino, dimethylamino, aminoacyl, or acetamino, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, Substituted with cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl or amino substituents; More preferably, R _{6 is} selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, hydroxyl, bromine, cyano, nitro, azide, methyl, cyclopropyl, phenyl, pyridyl, diazole and triazole. , Methoxy or carboxyl, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methyl Substituted by a sulfonyl, methoxy, carboxyl or amino substituent. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ and R ₂ are each independently selected from hydrogen, deuterium, and C _{1- 4-} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl or 5-8 membered heteroaryl Or, R ₁ and R ₂ and the nitrogen atom directly connected together form a 3-8 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, and azide. Alkyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5- 8-membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _{0 -4} -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R _{21 is} a substituted group substituted with the above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _{1- 4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl , 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ Or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ substituted with R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , r as described in claim 1; Preferably, R _{1 is} selected from hydrogen, deuterium or methyl; R _{2 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5- 6-membered heteroaryl, or R ₁ and R ₂ and its directly attached nitrogen atom together form a 3-8-membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more selected from deuterium, halogen, cyano, C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _5-6 aryl, 5-6 membered heteroaryl, = 0, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R _23, or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, the above-mentioned group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, C _3-8 cycloalkyl, 3 -8-membered heterocyclyl, C _5-6 aryl, 5-6-membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O ) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ are substituted with R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in claim 1; More preferably, R _{1 is} selected from hydrogen, deuterium or methyl; R _{2 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, or, R ₁ Forms a 3-6 membered heterocyclic group together with R ₂ and a nitrogen atom directly connected thereto, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, isopropyl , Cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl, pyridyl, diazole, triazole, = O, methanesulfonyl, aminosulfonyl, methoxy, Methoxy, ethoxy, isopropoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl, acetylamino, or

The aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methoxy , Formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein R _{3 is} selected from hydrogen, deuterium, halogen, cyano, nitro, and Nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5 -8-membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , The aforementioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Halo-substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ 、 -C _0-4- C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , r as Claim 1. Preferably, R _{3 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC ( O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C (O) NR ₂₂ R _23, or -N ( R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in claim 1. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that it is selected from a compound of formula (IIa) or a compound of formula (IIb) :

among them, X and Y in the compound of the formula (IIa) are each independently selected from N or C (R ₈ ), and R _{8 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _{0- 4} -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, halogen, cyano, nitro, azide, 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, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = 0, -C _0-4 -S (O ) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ generation; In the compound of formula (IIb), X and Y are each independently selected from N or C (R ₈ ). R ₅ and R ₆ and the directly connected group together form a 5-6 membered carbocyclic group or a 5-6 membered heterocyclic group. Cyclic group, R _{8 is} selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _{0- 4} -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ Or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3-8 member Heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R _{7 are} as described in claim 1. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 5, wherein each R _{7 is} independently selected from the following groups:

among them, Each R _{9 is} independently selected from -CH ₂ -NR ₁₇ R ₁₈ , and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _1-4 alkane , C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-8 aryl, 5-8 membered heteroaryl, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4- N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; Each R ₁₀ , R _{11 is} independently selected from hydrogen, fluorine, cyano or methyl; Each R _{12 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _{0- 4} -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3- 8-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, = 0, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _{0 -4} -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _{0 -4} -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ substituted with a substituent; Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S (O) _r R ₁₉ , -C _{0- 4} -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4- NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O ) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide Alkyl, 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 , 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, = O, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ Or substituted by -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ substituents; Each of R ₁₇ and R _{18 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 Heterocyclic group, C _5-8 aryl group or 5-8 membered heteroaryl group, or R ₁₇ and R ₁₈ together with the nitrogen atom to which it is directly attached form a 3-8 membered heterocyclic group. The above group is optionally further Is selected from one or more of deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkane Group, 3-8 membered heterocyclic group, C _5-8 aryl group, 5-8 membered heteroaryl group, = 0, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4 -OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from the group consisting of deuterium, halogen, cyano, nitro, Azide, 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 ring Alkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = 0, -C _0-4 -S (O) _r R ₁₉ , -C _0-4 -OR ₂₀ , -C _0-4 -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₁ , -C _0-4- OC (O) R ₂₁ , -C _0-4 -NR ₂₂ R ₂₃ , -C _0-4 -C (= NR ₂₂ ) R ₂₁ , -C _0-4 -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C _0-4 -C (O) NR ₂₂ R ₂₃ or -C _0-4 -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; R _22a and R _23b are each independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkoxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 10} cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, P-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C _1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium, halogen , Hydroxyl, 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 _1-10 alkoxy Group, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents, Alternatively, R _22a and R _23b together with the directly connected nitrogen atom form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more selected from the group consisting of deuterium, halogen, and hydroxyl group. , Carboxyl, 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 _1-10 alkoxy Group, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents; R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in claim 5. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 6, wherein each R _{12 is} independently selected from hydrogen, deuterium, fluorine, chlorine, Hydroxyl, bromo, cyano, nitro, azide, methyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azatidine , Phenyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, methoxy, methoxyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl, or Acetamino, the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methyl Substituted with oxo, carboxyl or amino substituents; Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ ,- C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C ( O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ , the above-mentioned groups are optionally further selected from one or more of 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 _3-8 cycloalkyl, 3-8 -Membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (= NR ₂₂ ) R ₂₁ , -N (R ₂₂ ) -C (= NR ₂₃ ) R ₂₁ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ substituents; R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in claim 6. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that each R _{9 is} independently selected from -CH ₂ -NR ₁₇ R ₁₈ The above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azide, 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, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₁ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O ) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ substituents; Each of R ₁₇ and R _{18 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, Alternatively, R ₁₇ and R ₁₈ and its directly attached nitrogen atom together form a 3-6 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, and C _1-4 alkyl , C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, = O, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C _0-4 -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R _23, or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, and deuterium-substituted C _{1- 4-} alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, = 0, -S (O) _r R ₁₉ , -OR ₂₀ , -C ( O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R _23, or -N (R ₂₂ ) -C (O) R ₂₁ R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in claim 6; preferably, R _{17 is} selected from hydrogen or deuterium; R _{18 is} selected from hydrogen, deuterium, C _{1 -4} alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, or R ₁₇ and R ₁₈ together with its directly attached nitrogen atom form a 3-6 membered heterocyclic group, The above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl , Phenyl, pyridyl, diazole, triazole, = O, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, ethoxyl, isopropoxyl, carboxyl, acetyl, acetoxy Amino, dimethylamino, aminoacyl, acetylamino or

The above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, = 0, methanesulfonyl, Substituted by methoxy, formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 5 to 8, characterized in that it is selected from a compound of formula (IIIa) or a compound of formula (IIIb) :

among them, X in the compound of formula (IIIa) is selected from N or CH; X in the compound of formula (IIIb) is selected from N or CH; R _{1 is} selected from hydrogen, deuterium or methyl; R _{2 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclic group, or R ₁ and R ₂ and The directly connected nitrogen atoms together form a 3-6 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, isopropyl, and cyclopropyl. , 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, = O, methanesulfonyl, aminosulfonyl, methoxy, methoxyacyl, Ethoxyl, isopropoxyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl, acetylamino or

The aforementioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, and methoxy , Formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents; Each R _{3 is} independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, benzene Group, 5-6 membered heteroaryl group, -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ or -NR ₂₂ R ₂₃ , the above-mentioned group is optionally further Is substituted by one or more selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 -Membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, = O, -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ or -NR ₂₂ Substituted by a substituent of R ₂₃ ; R _{6 is} selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine With hydroxy, cyano, methyl, cyclopropyl, phenyl or methoxy substituents; Each R _{7 is} independently selected from the following groups:

Each of R ₁₀ and R _{11 is} independently selected from hydrogen or fluorine; Each R _{9 is} independently selected from -CH ₂ -NR ₁₇ R ₁₈ , and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C _1-4 alkane , C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterated C _1-4 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-8 aryl, 5-8 membered heteroaryl, = 0, -S (O) _r R ₁₉ , -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₁ ,- OC (O) R ₂₁ , -NR ₂₂ R ₂₃ , -C (O) NR ₂₂ R ₂₃ or -N (R ₂₂ ) -C (O) R ₂₁ is substituted by a substituent; R _{17 is} selected from hydrogen or deuterium; R _{18 is} selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, Alternatively, R ₁₇ and R ₁₈ and the directly connected nitrogen atom together form a 3-6 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, and methyl , Isopropyl, cyclopropyl, 3-oxetanyl, 3-azacyclobutyl, phenyl, pyridyl, diazole, triazole, = 0, methanesulfonyl, aminosulfonyl, Methoxy, methoxy, ethoxy, isopropoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl, acetylamino, or

The above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, = 0, methanesulfonyl, Substituted with methoxy, formyloxy, acetoxy, propionyloxy, isobutyryloxy, carboxyl or amino substituents; Each R _{12 is} independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the above-mentioned groups are optionally further selected from one or more Substituted with deuterium, fluorine, chlorine, hydroxy, cyano, methyl, cyclopropyl, phenyl or methoxy; Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 Heteroaryl, -OR ₂₀ , -C (O) OR ₂₀ , -C (O) R ₂₀ , -OC (O) R ₂₁ or -NR ₂₂ R ₂₃ , the above-mentioned groups are optionally further substituted by one or more Substituted with a substituent selected from deuterium, fluorine, chlorine, hydroxy, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, methoxy, carboxyl or amino; R _22a , R _23b and the directly connected nitrogen atom together form a 4- to 10-membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, 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 _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C _5-10 aryl group, C _5-10 aryloxy group, 5-10 membered heteroaryl group, 5 -10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-10 alkanoyl substituents; R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , and r are as described in claim 5. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 9, characterized in that: Each R _{19 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heterocyclic Aryloxy, amino, monoalkylamino, dialkylamino, the above groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, C _1-4 alkyl, C _1-4 alkoxy Group, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy , 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino substituents; Each R _{20 is} independently selected from hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _{5- 8} aryl Or 5-8 membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _{3 -6} cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, diazole , Triazole, pyridine, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino substituents; Each R _{21 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heterocyclic Aryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxy, cyano, C _1-4 Alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclooxy, C _5-8 aromatic With C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino substituents; Each of R ₂₂ and R _{23 is} independently selected from hydrogen, deuterium, hydroxyl, C _1-4 alkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C _1-4 alkanoyl, the above-mentioned groups are optionally further selected from one or more of deuterium , Halogen, hydroxy, 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 _1-4 Alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclooxy, C _5-8 aryl, C _5-8 aromatic Aryl, 5- to 8-membered heteroaryl, 5- to 8-membered heteroaryloxy, amino, monoalkylamino, dialkylamino, or a C _1-4 alkanoyl substituent; or R ₂₂ , R ₂₃ and its directly attached nitrogen atom together form a 4- to 6-membered heterocyclyl or 4- to 6-membered heteroaryl, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, 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 _1-4 alkoxy, C _3-6 Cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heterocyclic Substituted by aryl, 5-8 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C _1-4 alkanoyl substituents. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 9, wherein each R _{3 is} independently selected from hydrogen, deuterium, halogen, and cyano , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl C _{1- 4} alkyl, benzyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, cyano-substituted phenyl, C _1-4 alkoxyphenyl, 5- to 6-membered heteroaryl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterated C _1-4 alkoxy, carboxyl, methoxyacyl, ethoxyacyl, isopropoxyacyl , Acetyl, acetoxy, amino, monomethylamino, dimethylamino, or

Each R _{12 is} independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano, methyl, cyclopropyl, methoxy, or carboxyl, and the methyl, cyclopropyl, methoxy is Optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, hydroxyl, cyano, methyl, cyclopropyl, phenyl or methoxy; Each of R ₁₃ and R _{14 is} independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _1-4 Alkoxy C _1-4 alkyl, C _3-6 cycloalkyl C _1-4 alkyl, benzyl, C _2-4 alkenyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl , Phenyl, cyano-substituted phenyl, C _1-4 alkoxyphenyl, 5-6 membered heteroaryl, C _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _{1 -4} alkoxy, carboxy, methoxy, ethoxy, isopropoxy, acetyl, acetoxy, amino, monomethylamino, dimethylamino or

R _22a , R _23b and its directly connected nitrogen atom together form a 4- to 6-membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, halogen, hydroxyl, carboxyl, _C1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl, phenyl, phenoxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, Substituted by amino, monoalkylamino, dialkylamino, or C _1-4 alkanoyl substituents. The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, characterized in that it is selected from the following compounds:

The method for preparing a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that it comprises the following steps:

Where R ₇ 'is

Alternatively, R ₇ 'is selected from the group:

Where R ₉ ′ is -C _0-3 -CHO; X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , m, n, p, q are as described in claim 1. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-12, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compound of formula (I) according to any one of claims 1-12, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 in the preparation of a preventive and / or therapeutic agent. Application of a PD-1 / PD-L1 signal pathway-related disease drug; preferably, the related disease mediated by the PD-1 / PD-L1 signal pathway is selected from cancer or tumor, immune-related disease, and A disorder, an infectious disease, an infectious disease, or a metabolic disease; more preferably, the infectious disease is selected from a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease. The application according to claim 15, wherein the cancer or tumor is selected from the group consisting of lymphoma (including but not limited to lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, follicular central lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma), sarcomas (including but not limited to Kaposi's sarcoma, fibrosarcoma, fat Sarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma), melanoma, glioblastoma, synovial tumor, meningioma, biliary tumor, thymic tumor, neurotumor, Seminoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyomas, hemangioma, lymphangioma, Osteoma, chondroma, lipoma, fibroma, central nervous system tumor, spinal axoma, brainstem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or Dermatoma, prostate cancer, prostate cancer that has relapsed or is resistant to existing drugs, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethral cancer, penile cancer, bladder cancer, ureter cancer, uterine cancer, ovaries Cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, Merkel cell cancer, embryo cancer, chronic or acute leukemia (including but not limited to acute myeloid leukemia, chronic myeloid leukemia, Acute lymphocytic leukemia, chronic myelogenous 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 cancer, 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 cancer, abdominal wall cancer, renal cell cancer, transitional cell cancer or chorionic cancer, and metastasis Tumors, especially PD-L1 expression in metastatic tumors; 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, atherosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple Sclerosis The infectious disease or infectious disease is selected from the group consisting of sepsis, liver infection, HTV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus or influenza; The metabolic disease is selected from diabetes, diabetic ketoacidosis, hyperglycemia and hypertonic syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, or osteoporosis . A compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, or a pharmaceutical composition according to claim 14, which is used for prevention and / Or drugs for the treatment of cancer or tumors, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway.