Completely symmetrical biphenyl derivatives and their preparation and use

Abstract

The present invention relates to a completely symmetrical biphenyl derivative and its preparation and use. In particular, the present invention relates to a completely symmetrical biphenyl derivative having the structure of formula (I) and its preparation and a pharmaceutical composition containing the same. The series of compounds of the present invention can be widely applied to the preparation of drugs for preventing and / or treating cancer or tumor, immune-related disease and disorder, infectious disease, infectious disease or metabolic disease mediated by PD-1 / PD-L1 signal pathway, and are expected to be developed as a new generation PD-1 / PD-L1 inhibitor. [Formula 1] TIFF2025502993000045.tif36167

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention is in the field of drug synthesis, specifically, it relates to fully symmetrical biphenyl derivatives and their preparation and use. [Technical background] The immune system plays a crucial role in controlling and eliminating diseases such as cancer. However, tumor cells often develop strategies to evade or suppress the immune system's surveillance and promote their malignant growth. Here, one important mechanism is to alter the expression of costimulatory and co-inhibitory 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 therapeutic approach.

[0002] 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 one extracellular immunoglobulin variable region-like domain, one transmembrane domain and one intracellular domain, the latter of which contains two phosphorylation sites, located in an immunoreceptor tyrosine kinase-based inhibitory domain and an immunoreceptor tyrosine kinase-based transforming domain, suggesting that PD1 can negatively regulate the T cell receptor-mediated signaling pathway.

[0003] PD1 has two ligands, PD-L1 and PDL2, which have different expression spectra. PDL1 protein is elevated in macrophages and dendritic cells after treatment with lipopolysaccharide (LPS) or granulocyte-macrophage colony-stimulating factor (GM-CSF), and also after T cells and B cells are stimulated by the T cell receptor or B cell receptor signaling pathway. It is also highly expressed in most tumor cells, and its expression is elevated after interferon (IFN) gamma stimulation. In fact, the expression status of tumor PDL1 is thought to correlate with prognosis in many tumor types. Conversely, PD-L2 expression is relatively concentrated and is mainly expressed in dendritic cells.

[0004] Contact between T cells expressing PD-1 and cells expressing its ligand inhibits their functional activities after antigen stimulation, such as cell proliferation, cytokine release, and cell division activity. Thus, the interaction of PD1 and its ligand functions as an inherent negative feedback regulatory mechanism to prevent people from overactivating T cells during infection, immune tolerance, or tumor development, thereby reducing autoimmune diseases and promoting autoimmune tolerance. Prolonged antigen stimulation, such as that occurring during tumors or long-term infection, can cause T cells to express high levels of PD-1, and yet become inactive or nonfunctional in response to these long-term antigens, which is called T cell exhaustion. B cells are also subject to the inhibitory effect of PD1 and its ligand and the associated dysfunction.

[0005] Evidence from preclinical animal studies has revealed that PD-1 and its ligands can negatively regulate immune responses. PD-1-deficient mice develop lupus-like acute proliferative glomerulonephritis and dilated cardiomyopathy. Blocking the PD-1 / PDL1 interaction with PDL1 antibodies has already shown to restore and enhance the function of T cell activation in many systems. PDL1 monoclonal antibodies are also beneficial for patients with advanced cancer. Several preclinical animal tumor models have also shown that blocking the PD-1 / PD-L1 signaling pathway with monoclonal antibodies can enhance immune responses, and generate immune responses against a range of tumors that are clearly different in terms of histology. Using a long-term LCMV infection model, it has been found that PD-1 / PD-L1 interaction has already suppressed the activation, amplification, and acquisition of effector cell function of virus-specific CD8 T cells. In addition to being able to enhance immune responses to long-term antigens, it has also been found that blocking the PD-1 / PDL1 pathway can enhance responses to vaccines, such as the response to therapeutic vaccines in a long-term infection environment.

[0006] As described above, if a compound that blocks the interaction between PD1 and PDL1 proteins can be developed in addition to existing monoclonal antibodies, it can be an effective therapeutic method for blocking the signal pathway mediated by PD-1 / PDL1, thereby enhancing or restoring the function of T cells. Therefore, compounds that target blocking the PD-1 / PD-L1 interaction are believed to have a very good therapeutic effect in the immunotherapy of many types of cancer and other immune-related diseases.

[0007] [Summary of the Invention] The present invention aims to provide a completely symmetrical biphenyl derivative and its preparation and use, which is expected to contribute to the development of a new generation of PD-1 / PD-L1 inhibitors. In a first aspect of the present invention, there is provided a compound of formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof:

[0008] [ka]

[0009] However, the two R1 are the same or different and each independently represents hydrogen, deuterium, halogen, cyano group, C 1-4 Alkyl groups and C 3-6 cycloalkyl groups, 1-4 Alkyl groups and C 3-6 The cycloalkyl group may optionally be further substituted with deuterium, halogen, cyano, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Deuterated alkyl groups, cyclopropyl groups, hydroxy groups and C 1-4 may be substituted with one or more substituents selected from an alkoxy group; Two R2 are the same or different and each independently represents hydrogen, deuterium, C 1-4 Alkyl group, C 3-6 A cycloalkyl group and a hydroxy group are selected from the group consisting of C 1-4 Alkyl groups and C 3-6The cycloalkyl group may optionally be further substituted with deuterium, halogen, cyano, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Deuterated alkyl groups, cyclopropyl groups, hydroxy groups and C 1-4 may be substituted with one or more substituents selected from an alkoxy group; Two R3 are the same or different and each independently represents hydrogen, deuterium, C 1-10 Alkyl group, C 3-10 A cycloalkyl group and a 3- to 10-membered heterocyclic group are selected from the group consisting of C 1-10 Alkyl group, C 3-10 The cycloalkyl group and the 3- to 10-membered heterocyclic group may optionally further include deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Deuterated alkyl groups, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C 6-10 Aryl groups, 5-8 membered heteroaryl groups, C 3-6 Cycloalkoxy groups, 3- to 6-membered heterocyclic oxy groups and C 1-4 may be substituted with one or more substituents selected from an alkoxy group; two m's are identical or different and each independently represents 0, 1, 2, 3 or 4; The two n's are the same or different, and each independently is 0, 1, 2, 3, or 4.

[0010] In a preferred embodiment, two R1 in the compound represented by formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof are the same or different, and each independently represents hydrogen, deuterium, halogen, a cyano group, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Deuterated alkyl groups, cyclopropyl substituted C 1-4 Alkyl groups and C 3-6 It is selected from cycloalkyl groups.

[0011] In a more preferred embodiment, the two R1 in the compound represented by formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof are the same or different and are each independently selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, and a cyclopropyl group.

[0012] In a preferred embodiment, the two R2 in the compound represented by formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof are the same or different, and each independently represents hydrogen, deuterium, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Deuterated alkyl groups, cyclopropyl substituted C 1-4 Alkyl group, C 3-6 It is selected from a cycloalkyl group and a hydroxy group.

[0013] In a more preferred embodiment, the two R2 in the compound represented by formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof are the same or different and are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, a cyclopropyl group, and a hydroxy group.

[0014] In a preferred embodiment, the two R3 in the compound represented by formula (I), its stereoisomer, or its pharma- ceutically acceptable salt are the same or different, and each independently represents hydrogen, deuterium, C 1-4 Alkyl group, C 3-6 A cycloalkyl group and a 3- to 6-membered heterocyclic group are selected from the group consisting of C 1-4 Alkyl group, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group may further include deuterium, halogen, cyano, hydroxy, carboxy, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Deuterated alkyl groups, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C3-6 Cycloalkoxy groups and C 1-4 It may be substituted with one or more substituents selected from alkoxy groups.

[0015] In a more preferred embodiment, the two R3 in the compound represented by formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof are the same or different and are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetanyl group, and an azetidinyl group, and the methyl group, the ethyl group, the isopropyl group, the cyclopropyl group, the cyclobutyl group, the oxetanyl group, and the azetidinyl group may be optionally further substituted with one or more substituents selected from deuterium, a halogen, a cyano group, a hydroxy group, a carboxy group, a methyl group, a ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, an azetidinyl group, a cyclopropyloxy group, a cyclobutyloxy group, a methoxy group, an ethoxy group, and an isopropoxy group.

[0016] In a further preferred embodiment, the two R3 in the compound represented by formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof are the same or different and are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, and an azetidinyl group.

[0017] In a further preferred embodiment, the two R1 in the compound represented by formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof are identical and are selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, and a cyclopropyl group; two R2 are identical and selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, a cyclopropyl group, and a hydroxy group; two R3 are identical and selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group, and an azetidinyl group; The two m's are identical and are 0, 1 or 2; The two n's are identical and are 1 or 2.

[0018] In the most preferred embodiment, the compound represented by formula (I), its stereoisomer or its pharma- ceutically acceptable salt includes, but is not limited to, the following compounds:

[0019] [ka]

[0020] or

[0021] [ka]

[0022] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and a medicament carrier. In a third aspect of the present invention, there is provided a use of the compound represented by formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating an associated disease mediated by the PD-1 / PD-L1 signal pathway.

[0023] In a preferred embodiment, the associated disease mediated by the PD-1 / PD-L1 signal pathway is selected from cancer or tumor, immune-related disease and disorder, infectious disease, infectious disease, or metabolic disease. In a more preferred embodiment, the cancer or tumor is a 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), a sarcoma (Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma, or (including, but not limited to, lymphangiosarcoma), melanoma, glioblastoma, synovium, meningioma, bile duct tumor, thymic tumor, neural tumor, seminoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, spinal axis tumor, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma Cancer of the prostate, recurrent or resistant to existing drugs, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethra cancer, penile cancer, bladder cancer, ureter cancer, uterine cancer, ovarian cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia (including, but not limited to, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic granulocytic leukemia, and chronic lymphocytic leukemia) bronchial cancer, esophageal cancer, nasopharyngeal cancer, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, basal cell carcinoma, lung cancer, breast cancer, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, rectal cancer, colon cancer, rectal cancer selected from intestinal cancer, gastric cancer, pancreatic cancer, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, bone cancer, skin cancer, small intestine cancer, endocrine cancer, renal pelvic cancer, epidermoid carcinoma, abdominal wall carcinoma, renal cell carcinoma, transitional cell carcinoma or choriocarcinoma, and metastatic tumor; the immune-related disease and disorder is selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis; the infectious disease is selected from a bacterial infection, a viral infection, or a fungal infection; the contagious or infectious disease is selected from pyemia, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, or influenza; The metabolic disease is selected from diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, or osteoporosis.

[0024] In a fourth aspect of the present invention, there is provided a compound of formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof for use as a medicament for treating cancer or tumor, immune-related disease and disorder, infectious disease, infectious disease or metabolic disease mediated by the PD-1 / PD-L1 signaling pathway.

[0025] The present invention also provides a method for treating cancer or tumor, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signaling pathway, comprising administering to a patient in need thereof a clinically effective amount of a compound of formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof.

[0026] [Specific embodiment] As a result of intensive research, the inventors of the present application have developed a biphenyl-based compound having the structure of general formula (I) for the first time. The series of compounds according to the present invention have a strong inhibitory effect on the interaction of PD-1 / PD-L1, and can be widely applied to the manufacture of drugs for preventing and / or treating cancer or tumor, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases mediated by the PD-1 / PD-L1 signal pathway, and are expected to be developed as new generation PD-1 / PD-L1 inhibitors. Based on this, the present invention has been completed.

[0027] Special Note: Unless stated to the contrary or otherwise specified, the following terms used in the specification and claims have the following meanings. The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group, and is preferably a linear alkyl group or a branched alkyl group having 1 to 10 or 1 to 4 carbon atoms, and is particularly preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an s-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 5-methylpentyl group, a 6-methylpentyl group, a 7-methylpentyl group, a 8-methylpentyl group, a 9-methylpentyl group, a 10-methylpentyl group, a 11-methylpentyl group, a 12-methylpentyl group, a 13-methylpentyl group, a 14-methylpentyl group, a 15-methylpentyl group, a 16-methylpentyl group, a 17-methylpentyl group, a 18-methylpentyl group, a 21-methylpentyl group, a 22-methylpentyl group, a 23-methylpentyl group, a 24-methylpentyl group, a 25-methylpentyl group, a 26-methylpentyl group, a 27-methylpentyl group, a 28-methylpentyl group, a 29-methylpentyl group, a 30-methylpentyl group, a 31-methyl Examples of aryl groups include, but are not limited to, 2,3-dimethylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof. 1-10 "Alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms. 1-4 The term "alkyl group" refers to straight chain and branched chain alkyl groups containing 1 to 4 carbon atoms.

[0028] The alkyl group may be optionally substituted or unsubstituted, but if substituted, the substituents are independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0029] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the partially unsaturated cyclic hydrocarbon being a cyclic hydrocarbon that may contain one or more (preferably one, two or three) double bonds, but does not have any ring with a completely conjugated π-electron system. The cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, and is preferably a cycloalkyl group containing 3 to 10 or 3 to 6 carbon atoms, such as "C 3-10 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 10 carbon atoms. 3-6 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 6 carbon atoms, where Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0030] Polycyclic cycloalkyl groups include spiro, fused and bridged ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups that share one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more (preferably one, two or three) double bonds, but none of the rings has a completely conjugated pi-electron system.

[0031] Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups can be classified as monospirocycloalkyl groups, bisspirocycloalkyl groups or polyspirocycloalkyl groups, including but not limited to the following:

[0032] [ka]

[0033] "Fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, in which one or more rings may contain one or more (preferably one, two or three) double bonds, but in which none of the rings has a fully conjugated pi-electron system. Depending on the number of constituent rings, fused cycloalkyl groups may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, including, but not limited to, the following:

[0034] [ka]

[0035] "Bridged cycloalkyl groups" refer to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected, and these groups may contain one or more (preferably one, two or three) double bonds, but none of the rings has a completely conjugated pi-electron system. Depending on the number of constituent rings, bridged cycloalkyl groups may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, including but not limited to the following:

[0036] [ka]

[0037] The cycloalkyl group ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl group, including, but not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, and the like.

[0038] A "cycloalkyl group" or a "carbocycle" may be optionally substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0039] A "heterocyclic group" or "heterocycle" is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which the cyclic hydrocarbon group may contain one or more (preferably one, two or three) double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more (preferably one, two, three or four) ring atoms in the heterocyclic group are N, O, N.O or S(O). r (where r is an integer of 0, 1, or 2), but does not include a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Heterocyclic groups containing 3 to 10 or 3 to 6 ring atoms are preferred, and for example, a "3- to 6-membered heterocyclic group" refers to a heterocyclic group containing 3 to 6 ring atoms, and a "3- to 10-membered heterocyclic group" refers to a heterocyclic group containing 3 to 10 ring atoms.

[0040] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0041] Polycyclic heterocyclic groups include spiro, fused and bridged ring heterocyclic groups. A "spiro heterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, in which one or more (preferably one, two, three or four) ring atoms are N, O, N.O or S(O). r (where r is an integer 0, 1, 2) heteroatoms, with the remaining ring atoms being carbon. These groups may contain one or more double bonds (preferably one, two or three), but none of the rings has a fully conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, spiroheterocyclic groups are divided into monospiroheterocyclic groups, bisspiroheterocyclic groups or polyspiroheterocyclic groups. Spiroheterocyclic groups include, but are not limited to:

[0042] [ka]

[0043] A "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, and in which one or more (preferably one, two, three or four) of the rings may contain one or more (preferably one, two or three) double bonds, but none of the rings has a completely conjugated pi-electron system, and in which one or more (preferably one, two, three or four) of the ring atoms are N, O, N·O or S(O). r (wherein r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, the heterocyclic groups may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, including, but not limited to, the following:

[0044] [ka]

[0045] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly linked, and which may contain one or more (preferably one, two or three) double bonds, but none of the rings has a completely conjugated pi-electron system, and in which one or more (preferably one, two, three or four) ring atoms are N, O, N.O or S(O). r (where r is an integer 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, the bridged heterocyclic group may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, including, but not limited to, the following:

[0046] [ka]

[0047] The ring of the heterocyclic group may be fused to the ring of an aryl group, heteroaryl group, or cycloalkyl group, where the ring connected to the parent structure is a heterocyclic group, including, but not limited to, the following:

[0048] [ka]

[0049] A "heterocyclic group" or "heterocycle" may be optionally substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0050] An "aryl group" or "aryl ring" is an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6 to 10 carbons, e.g., "C 6-10 "Aryl group" refers to an all-carbon aryl group containing 6 to 10 carbons, including, but not limited to, phenyl and naphthyl groups. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring, including, but not limited to, the following:

[0051] [ka]

[0052] An "aryl group" or "aryl ring" may be substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0053] A "heteroaryl group" or "heteroaryl ring" refers to a heteroaromatic system containing one or more (preferably one, two, three or four) heteroatoms, said heteroatoms being N, O, N.O and S(O). r(where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5 to 10 or 5 to 8 ring atoms, For example, a "5-8 membered heteroaryl group" refers to a heteroaromatic system containing 5-8 ring atoms, and a "5-10 membered heteroaryl group" refers to a heteroaromatic system containing 5-10 ring atoms, including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The ring of the heteroaryl group may be fused to a ring of an aryl group, a heterocyclic group, or a cycloalkyl group, where the ring connected to the parent structure is the ring of the heteroaryl group, including, but not limited to, the following:

[0054] [ka]

[0055] A "heteroaryl" or "heteroaryl ring" may be optionally substituted or unsubstituted, and if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0056] The term "alkenyl group" refers to an alkyl group as defined above that consists of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably a straight-chain or branched-chain containing alkenyl group that contains 2 to 10 carbons. For example, "C 2-10The term "alkenyl group" refers to a straight or branched chain alkenyl group containing 2 to 10 carbons, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl groups.

[0057] The "alkenyl group" may be substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0058] The term "alkynyl group" refers to an alkyl group as defined above that consists of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably a straight-chain or branched-chain alkynyl group containing 2 to 10 carbons. For example, "C 2-10 The term "alkynyl group" refers to a straight or branched chain alkynyl group containing 2 to 10 carbons, including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0059] The "alkynyl group" may be substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0060] "Alkoxy group" refers to an -O-alkyl group, where alkyl is as defined above. For example, "C 1-4 "Alkoxy" refers to an alkyloxy group containing 1 to 4 carbons, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0061] The "alkoxy group" may be optionally substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0062] "Cycloalkoxy" or "cycloalkyloxy" refers to an -O-cycloalkyl group, where cycloalkyl is as defined above, e.g., "C 3-6 "Cycloalkoxy" refers to a cycloalkyloxy group containing 3 to 6 carbons, including, but not limited to, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like.

[0063] The "cycloalkoxy group" or "cycloalkyloxy group" may be optionally substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0064] "Heterocyclyloxy" or "heterocycleoxy" refers to the group --O-heterocycle, where heterocycle is defined above, including, but not limited to, azetidinyloxy, oxetanyloxy, azacyclopentyloxy, azacyclohexyloxy, oxacyclohexyloxy, and the like.

[0065] "Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted, but if substituted, the substituents are independently deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 1-10 Deuterated alkyl groups, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups, C 6-10 It is preferable that the alkyl group is one or more (preferably one, two, three or four) groups selected from an aryl group, a 5- to 10-membered heteroaryl group, =O, =S and -SF5.

[0066] "C 1-4 A "haloalkyl group" is an alkyl group of 1 to 4 carbon atoms in which a hydrogen atom in the alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom, and includes, but is not limited to, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a tribromomethyl group, and the like.

[0067] "C 1-4"Deuterated alkyl group" refers to an alkyl group of 1 to 4 carbon atoms in which a hydrogen atom in the alkyl group is optionally replaced with a deuterium atom. Examples include, but are not limited to, monodeuteromethyl groups, dideuteromethyl groups, trideuteromethyl groups, and the like.

[0068] "Halogen" refers to fluorine, chlorine, bromine, or iodine, "NaOH" refers to sodium hydroxide, "BH3·Me2S" refers to dimethylsulfide borane, "MeOH" refers to methanol, "NaBH3CN" refers to sodium cyanoborohydride, "HOAc" refers to acetic acid, "DMF" refers to N,N-dimethylformamide, "THF" refers to tetrahydrofuran, and "Dess-Martin reagent" refers to the Dess-Martin reagent.

[0069] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur, i.e., the two cases of substituted or unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0070] "Substitution" means that one or more "hydrogen atoms" in the group are replaced by a corresponding number of substituents independently of each other.Of course, the substituents are only in their chemically possible positions, and are in accordance with the chemical valence bond theory, and those skilled in the art can easily confirm (by experiment or theory) whether substitution is possible or not.For example, an amino group or a hydroxy group having free hydrogen may be unstable when it is bonded to a carbon atom having an unsaturated bond (e.g., olefin).

[0071] The English name for "stereoisomer" is stereoisomer, which refers to an isomer formed by the difference in the spatial arrangement of atoms in a molecule. It may be divided into two types, cis-trans isomers and enantiomers, or into two types, enantiomers and diastereomers. Stereoisomers formed by the rotation of a single bond are called conformational stereoisomers, and sometimes called rotamers. For example, stereoisomers formed by bond length, bond angle, double bonds or rings in the molecule are called configuration stereoisomers, which are further divided into two types. Here, isomers formed because the double bonds or single bonds of the ring carbon atoms cannot rotate freely are geometric isomers, also called cis-trans isomers, and are divided into two types of configurations, Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical rotations formed due to the lack of antiaxial symmetry in the molecule are called optical isomers, and are divided into R and S configurations. The "stereoisomer" described in the present invention may be understood to include one or more of the enantiomers, configurational isomers, and conformational isomers, unless otherwise specified.

[0072] "Pharmaceutically acceptable salts" in the present invention refer to pharma-ceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art. A "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, and other components, such as physiologically / pharmaceutical acceptable carriers and excipients, to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert biological activity. The present invention will be described in more detail and comprehensively below in conjunction with examples, but the present invention is in no way limited to the contents of the examples.

[0073] The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) or / and liquid chromatography mass spectrometry (LC-MS). The chemical shifts (δ) of NMR are expressed in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 nuclear magnetic resonance instrument, with the solvents used being deuterated dimethylsulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0074] Liquid chromatography-mass spectrometry (LC-MS) measurements were performed using an Agilent 6120 mass spectrometer, and HPLC measurements were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters II695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0075] Thin layer chromatography silica gel plates used were Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with the specifications used for TLC being 0.15 mm to 0.20 mm, and the specifications used for product separation and purification by thin layer chromatography being 0.4 mm to 0.5 mm. For column chromatography, Yantai Yellow Sea silica gel with 200 to 300 mesh was generally used as the carrier.

[0076] The starting materials in the examples of the present invention are known and commercially available or can be synthesized by or according to methods known in the art. Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon gas atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius (°C).

[0077] [Preparation of compounds of specific examples] Example 1: Preparation of 4-(((6-((3'-(5-(((4-carboxybicyclo[2.2.2]octan-1-yl)amino)methyl)-4-cyclopropylpyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid

[0078] [ka]

[0079] First step: synthesis of methyl 4-(((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(((4-(methoxycarbonyl)bicyclo[2.2.2]octan-1-yl)amino)methyl)pyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

[0080] [ka]

[0081] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-formylpyridinecarboxamide) [prepared with reference to the synthesis method of WO2021008491A1] (200 mg, 0.358 mmol) was placed in DMF (5 mL), then 4-aminobicyclo[2.2.2]octane-1-carboxylate methyl (656.1 mg, 3.58 mmol) and HOAc (1.5 mL) were added and stirred at room temperature for 1 hour. Sodium cyanoborohydride (225.0 mg, 3.58 mmol) was added and stirred at room temperature overnight. After completion of the reaction, separation was performed by reverse phase column chromatography to obtain methyl 4-(((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(((4-(methoxycarbonyl)bicyclo[2.2.2]octan-1-yl)amino)methyl)pyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (180 mg, 0.20 mmol, yield: 56.3%). MS m 2 / z (ESI): 893.6 [M+H] + . Second step: synthesis of 4-(((6-((3'-(5-(((4-carboxybicyclo[2.2.2]octan-1-yl)amino)methyl)-4-cyclopropylpyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid

[0082] [ka]

[0083] Methyl 4-(((4-cyclopropyl-6-((3'-(4-cyclopropyl-5-(((4-(methoxycarbonyl)bicyclo[2.2.2]octan-1-yl)amino)methyl)pyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (350 mg, 0.39 mmol) was added to a mixture of MeOH (5 mL), THF (5 mL) and water (5 mL), then NaOH (314 mg, 7.84 mmol) was added and heated to 50° C. under nitrogen gas protection and stirred overnight. After completion of the reaction, the reaction solution was adjusted to pH=6 with formic acid and the reaction solution was concentrated. The crude product was separated by reverse phase column chromatography to give 4-(((6-((3'-(5-(((4-carboxybicyclo[2.2.2]octan-1-yl)amino)methyl)-4-cyclopropylpyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (180 mg, 0.187 mmol, yield: 47.8%). MS m 2 / z (ESI): 865.6 [M+H] + .

[0084] 1 HNMR (400 MHz, DMSO-d6) δ 10.31 (s, 2H), 8.55 (s, 2H), 7.89 (d, J =8.0 Hz, 2H), 7.57 (s, 2H), 7.31 (t, J= 7.8 Hz, 2H), 6.97 (d, J = 7.5Hz, 2H), 3.87 (s, 4H), 2.28 (td, J= 8.3, 4.2Hz, 2H), 2.00 (s, 6H), 1.77 (dd, J= 10.5, 5.3Hz, 12H), 1.60 (dd, J= 10.3, 5.5Hz, 12H), 1.12 (dt, J= 7.7, 4.9Hz, 4H), 0.84 (q, J= 5.2 Hz, 4H). Example 2: Preparation of 4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid)

[0085] [ka]

[0086] First step: Synthesis of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid

[0087] [ka]

[0088] Dimethylbicyclo[2.2.1]heptane-1,4-dicarboxylate (2.0 g, 9.42 mmol) was dissolved in THF (40 mL) and a solution of NaOH (377 mg, 9.42 mmol) in methanol (8 mL) was added dropwise and stirred at room temperature overnight. After completion of the reaction, the reaction solution was carefully concentrated until the solvent was completely removed. The solid was washed with petroleum ether and then filtered, the filter cake was dissolved in water (50 mL), and the aqueous solution was acidified with 2M hydrochloric acid to pH=4, then extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (1.49 g, yield: 80.0%). Second step: Synthesis of methyl 4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0089] [ka]

[0090] 4-(Methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (700 mg, 3.53 mmol) was dissolved in toluene (30 mL), then diphenyl phosphate azide (0.91 mL, 4.24 mmol) and triethylamine (0.98 mL, 7.06 mmol) were added, and the mixture was heated to 120° C. under nitrogen gas protection for 2 hours. The reaction mixture was cooled to room temperature, then benzyl alcohol (0.73 mL, 7.06 mmol) was added, and the mixture was reacted at 100° C. under nitrogen gas protection for 18 hours. After the reaction was completed, the reaction mixture was concentrated, and the crude product was separated by column chromatography to obtain methyl 4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (1000 mg, 3.30 mmol, yield: 93.4%). MS m 2 / z (ESI): 304.0 [M+H] + . Third step: Synthesis of methyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate

[0091] [ka]

[0092] Methyl 4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (1000 mg, 3.30 mmol) was dissolved in methanol (30 mL), then 10% Pd / C (100 mg) was added and stirred overnight at room temperature under normal pressure and hydrogen atmosphere. After completion of the reaction, it was filtered and the filtrate was concentrated to give methyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (500 mg, 2.955 mmol, yield: 89.6%). MS m 2 / z (ESI): 170.0 [M+H] + . Fourth step: Synthesis of dimethyl 4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylate)

[0093] [ka]

[0094] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-formylpyridinecarboxamide) (200 mg, 0.358 mmol) was dissolved in DMF (5 mL), followed by the addition of methyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (484.7 mg, 2.864 mmol) and HOAc (1.5 mL) and stirring at room temperature for 60 min, followed by the addition of NaBH3CN (225.0 mg, 3.58 mmol) and stirring overnight at room temperature under nitrogen gas protection. After completion of the reaction, the reaction mixture was separated by column chromatography (water / acetonitrile / formic acid) to obtain dimethyl 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylate) (230 mg, 0.266 mmol, yield: 74.3%). MS m 2 / z (ESI): 865.4 [M+H] + . Fifth step: Synthesis of 4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid)

[0095] [ka]

[0096] Dimethyl 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylate) (230 mg, 0.266 mmol) was added to a mixture of MeOH (5 mL), THF (5 mL) and water (5 mL), followed by NaOH (212.7 mg, 5.317 mmol) and stirring at 50° C. for 1 h under nitrogen gas protection. After completion of the reaction, the reaction was adjusted to pH=6 with formic acid and the reaction was concentrated. The crude product was separated by reverse phase column chromatography to give 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) (160 mg, 0.181 mmol, yield: 67.9%). MS m 2 / z (ESI): 837.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 2H), 8.69 (s, 2H), 7.86 (d, J = 8.2Hz, 2H), 7.63 (s, 2H), 7.32 (t, J= 7.8 Hz, 2H), 6.99 (dd, J = 7.6, 1.3 Hz, 2H), 4.38 - 4.02 (m, 4H), 2.31 - 2.24 (m, 2H), 2.12 - 1.46 (m, 26H), 1.15 (d, J= 7.9 Hz, 4H), 0.95 -0.78 (m, 4H). Example 3 Preparation of 4,4'-(((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(methylazanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid)

[0097] [ka]

[0098] 4,4'-(((((2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) (50 mg, 0.060 mmol) was dissolved in DMF (3 mL), followed by addition of HOAc (1 mL) and 35% aqueous formaldehyde solution (37.5 mg, 0.597 mmol). The mixture was stirred at room temperature for 0.5 h, followed by addition of NaBH3CN (37.5 mg, 0.597 mmol) and stirring overnight at room temperature under nitrogen gas protection. After completion of the reaction, the reaction mixture was separated by reverse phase column chromatography to obtain 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(methylazanediyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) (12 mg, 0.013 mmol, yield: 21.6%). MS m 2 / z (ESI): 865.6 [M+H] + .

[0099] 1HNMR (400 MHz, DMSO-d6) δ 10.30 (s, 2H), 8.52 (s, 2H), 7.90 (d, J= 8.0 Hz, 2H), 7.59 (s, 2H), 7.31 (t, J = 7.8Hz, 2H), 6.97 (d, J= 7.5 Hz, 2H), 3.81 (s, 4H), 2.40 (td, J = 8.2, 4.2 Hz, 2H), 2.11(s, 6H), 2.05 - 1.95 (m, 10H), 1.87 - 1.57 (m, 16H), 1.12 (d, J= 8.1 Hz, 4H), 0.84 (d, J = 5.2Hz, 4H). Example 4 Preparation of 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(methylene))bis(bicyclo[2.2.1]heptane-1-carboxylic acid)

[0100] [ka]

[0101] First step: Synthesis of methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0102] [ka]

[0103] 4-(Methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (800 mg, 4.04 mmol) was dissolved in dry THF (40 mL), and BH3·Me2S / THF solution (5.25 mL, 5.25 mmol) was slowly added dropwise with cooling in an ice-water bath. After completion of the addition, the mixture was stirred at room temperature overnight. MeOH (10 mL) was added dropwise to the reaction solution, and the mixture was quenched by refluxing for 4 hours. Ethyl acetate and water were added for extraction, and the organic phase was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was separated by column chromatography to obtain methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate (600 mg, yield: 80.7%).

[0104] 1 HNMR (400 MHz, CDCl3) δ 3.70 (s, 2H), 3.67 (s, 3H), 2.06 - 1.93 (m, 2H), 1.73 - 1.62 (m, 4H), 1.58 - 1.54 (m, 2H), 1.43 - 1.34 (m, 2H). Second step: Synthesis of methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate

[0105] [ka]

[0106] Methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate (600 mg, 3.27 mmol) was dissolved in CHCl(20 mL) and then Dess-Martin reagent (1.66 g, 3.91 mmol) was added. The reaction was stirred at room temperature and monitored by TLC until the raw material was consumed. The mixture was filtered through diatomaceous earth and the filtrate was concentrated and separated by column chromatography to give methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate (500 mg, yield: 84.3%).

[0107] 1HNMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 3.70 (s, 3H), 2.13 - 2.00 (m,4H),1.86 - 1.82 (m, 2H), 1.79 - 1.68 (m, 2H), 1.60 - 1.52 (m, 2H). Third step: Synthesis of methyl 4-((benzylamino)methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0108] [ka]

[0109] Methyl 4-formylbicyclo[2.2.1]heptane-1-carboxylate (200 mg, 1.10 mmol) and benzylamine (235 mg, 2.20 mmol) were added to a mixture of MeOH (20 mL) and HOAc (0.2 mL) and stirred at room temperature for 30 min under nitrogen gas protection, then NaBH(OAc)3 (465 mg, 2.20 mmol) was added and stirring was continued at room temperature overnight. After completion of the reaction, saturated aqueous NaHCO3 was added and extracted with CHCl2. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by column chromatography to give methyl 4-((benzylamino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (300 mg, yield: 100%). MS m 2 / z (ESI): 274.2 [M+H] + . Fourth step: Synthesis of methyl 4-(aminomethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0110] [ka]

[0111] Methyl 4-((benzylamino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (300 mg, 1.10 mmol) and 10% Pd / C (50 mg) were added to methanol (30 mL) and stirred overnight at room temperature under atmospheric pressure and hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give methyl 4-(aminomethyl)bicyclo[2.2.1]heptane-1-carboxylate (194 mg, yield: 96.5%). MS m 2 / z (ESI): 184.1 [M+H] + . Fifth step: Synthesis of methyl 4-({[(4-cyclopropyl-6-{[3-(3-{4-cyclopropyl-5-[({[4-(methoxycarbonyl)bicyclo[2.2.1]heptan-1-yl]methyl}amino)methyl]pyridin-2-amido}-2-methylphenyl)-2-methylphenyl]carbamoyl}pyridin-3-yl)methyl]amino}methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0112] [ka]

[0113] N,N'-(2,2'-Dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-formylpyridinecarboxamide) (115 mg, 0.206 mmol) and methyl 4-(aminomethyl)bicyclo[2.2.1]heptane-1-carboxylate (189 mg, 1.03 mmol) were placed in a mixture of DMF (3 mL) and HOAc (0.75 mL) and stirred under nitrogen gas at room temperature for 1 h, then NaBH3CN (65 mg, 1.03 mmol) was added and stirring was continued at room temperature overnight. After completion of the reaction, the reaction mixture was separated by reverse phase column chromatography to give methyl 4-({[(4-cyclopropyl-6-{[3-(3-{4-cyclopropyl-5-[({[4-(methoxycarbonyl)bicyclo[2.2.1]heptan-1-yl]methyl}amino)methyl]pyridin-2-amido}-2-methylphenyl)-2-methylphenyl]carbamoyl}pyridin-3-yl)methyl]amino}methyl)bicyclo[2.2.1]heptane-1-carboxylate (124 mg, yield: 67.5%). MS m 2 / z (ESI): 893.5 [M+H] + . Sixth step: Synthesis of 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(methylene))bis(bicyclo[2.2.1]heptane-1-carboxylic acid)

[0114] [ka]

[0115] Methyl 4-({[(4-cyclopropyl-6-{[3-(3-{4-cyclopropyl-5-[({[4-(methoxycarbonyl)bicyclo[2.2.1]heptan-1-yl]methyl}amino)methyl]pyridin-2-amido}-2-methylphenyl)-2-methylphenyl]carbamoyl}pyridin-3-yl)methyl]amino}methyl)bicyclo[2.2.1]heptane-1-carboxylate (124 mg, 0.139 mmol) was placed in a mixture of MeOH (3 mL), THF (3 mL) and water (1.5 mL), and NaOH (83 mg, 2.08 mmol) was added. Under nitrogen gas protection, the mixture was heated to 50° C. and stirred for 1 h. After completion of the reaction, the reaction solution was adjusted to pH=6 with formic acid, the reaction solution was concentrated, and the crude product was separated by reverse phase column chromatography to obtain 4,4'-(((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(methylene))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) formate (45.5 mg, yield: 34.1%). MS m 2 / z (ESI): 865.5 [M+H] + .

[0116] 1 HNMR (400 MHz, DMSO-d6) δ 10.30 (s, 2H), 8.57 (s, 2H), 7.88 (d, J = 8.0Hz, 2H), 7.60 (s, 2H), 7.31 (t, J= 7.8 Hz, 2H), 6.98 (m, 2H), 3.98 (s, 4H), 2.67 (s, 4H), 2.28 (m, 2H), 2.01 (m, 6H), 1.90 -1.82 (m, 4H), 1.65 - 1.58 (m, 4H), 1.54 (t, J= 10.3 Hz, 4H), 1.45 (m, 4H), 1.32 (m, 4H), 1.15 -1.09 (m, 4H), 0.88 - 0.82 (m, 4H). Example 5: Preparation of 4-((((6-((3'-(5-(((4-carboxybicyclo[2.2.1]heptyl-1-yl)ethyl)aminomethyl)-4-cyclopropylmethylpyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)amino)ethyl)bicyclo[2.2.1]heptyl-1-carboxylic acid

[0117] [ka]

[0118] First step: Synthesis of methyl 4-(2-(benzylamino)ethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0119] [ka]

[0120] Methyl 4-(2-carbonylethyl)bicyclo[2.2.1]heptane-1-carboxylate (350 mg, 1.78 mmol) and benzylamine (382 mg, 3.57 mmol) were added to a mixture of MeOH (20 mL) and HOAc (0.2 mL) and stirred at room temperature for 30 minutes under nitrogen gas protection, then NaBH(OAc)3 (756 mg, 3.57 mmol) was added and stirring was continued at room temperature overnight. After the reaction was completed, saturated aqueous NaHCO3 was added and extracted with CHCl2. The organic phase was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, it was separated by column chromatography to obtain methyl 4-(2-(benzylamino)ethyl)bicyclo[2.2.1]heptane-1-carboxylate (425 mg, yield: 82.9%). MS m 2 / z (ESI): 288.2 [M+H] + . Second step: Synthesis of methyl 4-(2-aminoethyl)bicyclo[2.2.1]heptane-1-carboxylate

[0121] [ka]

[0122] 4-(2-(benzylamino)ethyl)bicyclo[2.2.1]heptane-1-methyl carboxylate (425 mg, 1.48 mmol) and 10% Pd / C (50 mg) were added to methanol (30 mL) and stirred overnight at room temperature under atmospheric pressure and hydrogen atmosphere. After completion of the reaction, it was filtered and the filtrate was concentrated to give 4-(2-aminoethyl)bicyclo[2.2.1]heptane-1-methyl carboxylate (246 mg, yield: 84.3%). MS m 2 / z (ESI): 198.1 [M+H] + . Third step: Synthesis of dimethyl 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethyl-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylate)

[0123] [ka]

[0124] N,N'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(4-cyclopropyl-5-formylpyridinecarboxamide) (110 mg, 0.197 mmol) and methyl 4-(2-aminoethyl)bicyclo[2.2.1]heptane-1-carboxylate (233 mg, 1.18 mmol) were placed in a mixture of DMF (3 mL) and HOAc (0.75 mL) and stirred under nitrogen gas at room temperature for 1 h, then NaBH3CN (74 mg, 1.18 mmol) was added and stirring was continued at room temperature overnight. After completion of the reaction, the reaction mixture was separated by reverse phase column chromatography to give dimethyl 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethyl-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylate) (100 mg, yield: 55.1%). MS m 2 / z (ESI): 921.5 [M+H] + . Fourth step: synthesis of 4-((((6-((3'-(5-(((4-carboxybicyclo[2.2.1]heptyl-1-yl)ethyl)aminomethyl)-4-cyclopropylmethylpyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)amino)ethyl)bicyclo[2.2.1]heptyl-1-carboxylic acid

[0125] [ka]

[0126] Dimethyl 4,4'-((((((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(azanediyl))bis(carbonyl))bis(4-cyclopropylpyridine-6,3-diyl))bis(methylene))bis(azanediyl))bis(ethyl-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylate) (100 mg, 0.108 mmol) was added to a mixture of methanol (3 mL), THF (3 mL) and water (1.5 mL), and NaOH (90 mg, 2.25 mmol) was added. The mixture was heated to 50°C and stirred for 1 h. After completion of the reaction, the reaction solution was adjusted to pH=6 with formic acid, concentrated, and separated by reverse phase column chromatography to obtain 4-((((6-((3'-(5-(((4-carboxybicyclo[2.2.1]heptyl-1-yl)ethyl)aminomethyl)-4-cyclopropylmethylpyridinamido)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)carbamoyl)-4-cyclopropylpyridin-3-yl)methyl)amino)ethyl)bicyclo[2.2.1]heptyl-1-carboxylic acid (45.5 mg, yield: 34.1%). MS m 2 / z (ESI): 893.5 [M+H] + .

[0127] 1 HNMR (400 MHz, DMSO-d6) δ 10.30 (s, 2H), 8.55 (s, 2H), 7.88 (m, 2H), 7.58 (s, 2H), 7.31 (t, J= 7.8 Hz, 2H), 6.98 (m, 2H), 3.96 (s, 4H), 2.63 (t, J = 7.8Hz, 4H), 2.29 (m, 2H), 2.00(s, 6H), 1.86 (m, 4H), 1.69 (t, J= 7.8 Hz, 4H), 1.56 -1.30 (m, 16H), 1.16 - 1.10 (m, 4H), 0.87 - 0.82 (m, 4H).

[0128] [Biological measurements and evaluation] 1. PD1-PDL1 HTRF binding activity test The effect of the compounds according to the embodiments of the present invention on PD-1 / PD-L1 protein interaction was measured by Cisbio's PD-1 / PD-L1 binding assay kit (#64ICP01PEG or 64ICP01PEH), and the specific experimental method is as follows: 1) Add diluted compounds, 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 2 hours of incubation at room temperature or overnight at 4°C, the readings were read on a Pelkin Elmer Envision. Readings were taken at 665 nm and 620 nm, respectively, and the ratio of the two was used as the reading for each well. 4) The readings from each well after compound treatment were compared to the readings from DMSO treated wells to give the percentage inhibition of the compound. 5) The IC of the compounds according to the present invention was calculated by analyzing the inhibition percentage at different compound concentrations by nonlinear regression. 50 The specific experimental results are shown in Table 1.

[0129] II. Jurkat reporter gene cell activity test Jurkat reporter gene cell activity test was used to measure the effect of the compounds according to the embodiments of the present invention on the interaction of PD-1 / PD-L1 protein expressed on the cell surface and the resulting effect on T cell function. In short, the reporter plasmid of NF-κB-luc and the plasmid of human PD-1 were transfected into Jurkat cells to establish a stable expression line that simultaneously and stably expresses PD-1 and NF-κB-luc reporter genes, and the surface expression level of PD-1 was identified by flow cytometry, and the OKT-3 and Raji cells were stimulated to identify the expression level of the reporter gene by the reaction of the reporter gene. In addition, human PD-L1 expression plasmid was transfected into Raji cells to obtain a cell line that stably expressed PD-L1. Then, Jurkat / NF-κB-luc / PD1 cells were co-cultured with Raji-PD-L1 cells and stimulated with OKT-3. Compounds were added, and the reporter gene response readings reflected the inhibitory effects of the compounds on PD-1 / PD-L1 interaction and enhancement of T cell activation signal pathway. The specific experimental method is as follows: 1) 30 μL of compound or antibody at different dilutions was added to a white 96-well plate (corning, 3610), and 10 μL of OKT3 (Biolegend, 317326) (final concentration of OKT3 was 1 μg / mL) was added. 2) Add 20 μL of Raji-PD-L1 cell suspension to each well, ensuring that each well contains 5 × 10 4 cells and incubated in an incubator for 20 minutes. 3) Add 20 μL of Jurkat / NF-κb-luc / PD-1 cell suspension to each well, ensuring that each well contains 5 × 10 4 The cells were mixed homogenously and Bright-glo (Promega, E2620) was measured 6 hours later. 4) The readings from each well after compound treatment were compared to the readings from DMSO-treated wells to obtain the fold activation of compound effect. 5) The EC of the compounds according to the present invention was determined by analyzing the activation fold at different compound concentrations using nonlinear regression. 50 The specific experimental results are shown in Table 1:

[0130] [Table 1]

[0131] The biological activity data of the compounds in the specific examples show that a series of compounds of the present invention have strong inhibitory effects on PD-1 / PD-L1 protein interaction, and this inhibitory effect can enhance or restore T cell activation at the cellular level. 3. Pharmacokinetic evaluation (evaluation of membrane permeability and intestinal absorption potential of candidate drugs using Caco-2 cell line) The Caco-2 cells used in this test are human colon cancer cells, and under appropriate culture conditions, Caco-2 cells can form differentiated monolayer cells with many characteristics, such as tight junctions, microvilli, and expression of brush border enzymes, similar to normal intestinal epithelium. The permeability of compounds in the Caco-2 cell model is closely related to their absorption in the human body, and the Caco-2 cell model has been widely applied to evaluate the intestinal permeability and spontaneous transport process of compounds. This test evaluated the permeability and efflux ratio of the compounds according to the examples of the present invention and the comparative compounds using the Caco-2 cell model. The specific method is as follows: 1) The Caco-2 cell culture medium was modified Eagle's medium (MEM) containing 10% inactivated fetal bovine serum and 1% non-essential amino acids. The cells were seeded on polycarbonate filters and cultured at 37°C in a 5% CO2 incubator.

[0132] 2) After seeding, the cells can be used for transport experiments when cultured for 21 to 28 days. The density of the cell monolayer is such that the apparent permeability coefficient (P app ) was characterized and verified. 3) In the experiment, the compounds were dissolved in DMSO to prepare 10 mM stock solutions, and the reference compounds for evaluating permeability in this test were metoprolol, atenolol and erythromycin, which were respectively high and low permeability positive compounds and positive substrates of P-gp. The apparent permeability coefficients measured by the reference compounds obtained according to this test method are as follows:

[0133] [Table 2]

[0134] Hanks' Balanced Salt Solution (HBSS, Invitrogen) containing 25 mM HEPES (pH 7.4) was used for dilution to obtain the working solution. The detection concentration of the test compound was 10 μM. This study was a bidirectional permeation experiment from the top membrane side to the substrate side (AB) and from the substrate side to the top membrane side (BA), which required incubation at 37°C for 90 min. After the incubation, the samples diluted with buffer were detected by LC-MS / MS. The concentration of the compound was quantified using a standard curve. 4) Apparent permeability coefficient P app Value(cm / s): P app = (VA / (Area × time)) × ([drug]accepter / (([drug]initial, donor) ×Dilution Factor) Here, "VA" refers to the volume of the receptor pore, "Area" refers to the surface area of ​​the membrane, and "time" is the total transport time in seconds.

[0135] 5) The apparent membrane permeability coefficient value P of the corresponding compound app and the outflow ratio ER=P app (BA) / P app (AB) was determined according to the above formula, and the results are shown in Table 2.

[0136] [Table 3]

[0137] [Table 4]

[0138] The membrane permeability test data in Table 2 shows that the membrane permeability of the AB terminal of the compound according to the embodiment of the present invention is significantly improved by modifying the terminal linking groups on both sides of the compound, while the comparative compounds 2, 4, and 6 have similar symmetrical diacid structures, but all have very low AB and very low membrane permeability. Furthermore, the inventors have further found through in vivo pharmacokinetic experiments in mice that such compounds are hardly absorbed when directly administered orally, and can only be administered orally in the form of prodrugs (comparative compounds 1, 3, and 5), which are different in metabolic pathway from the compounds according to the embodiment of the present invention.

[0139] 4. Pharmacokinetic evaluation in mice and rats

[0140] 1. Research purpose The purpose of this study was to investigate the pharmacokinetic behavior of some compounds according to the present invention, administered by single oral (PO) or intravenous injection (IV) to ICR mice or rats, respectively.

[0141] 2. Test Proposal

[0142] 2.1 Study Drugs The compounds used in this study are derived from the specific example compounds of the present invention and the comparative compounds listed.

[0143] 2.2 Test animals ICR mice, male, N=9. Source: Shanghai Xipur-Bikai Laboratory Animal Co., Ltd. ICR rats, male, N=3. Source: Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.

[0144] 2.3 Drug production and administration The compounds were weighed out, dissolved in the corresponding solvent, swirled to homogenize, and sonicated to obtain a clear, colorless solution. Nine mice and three rats were orally administered after an overnight fast. Mice were administered a dose of 10 mg / kg (or IV 2 mg / kg), and rats were administered a dose of 5 mg / kg (or IV 1 mg / kg).

[0145] 2.4 Sample collection Blood was collected via the submandibular vein at approximately 90 μL time points, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged for plasma within 1 hour (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). Blood collection time points were 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored in a refrigerator at -20°C. 40 μL of plasma sample was taken, and 160 μL of ice-cold acetonitrile containing internal standard was added, swirled for 3 minutes, and centrifuged at 11000 rpm for 5 minutes. 100 μL of the supernatant was taken and added to 100 μL of water, and 5 μL of the sample was taken and analyzed by LC / MS / MS. Comparative compounds 1, 3, and 5 were simultaneously analyzed with prodrug compounds and corresponding prototype compounds 2, 4, and 6, and the specific analytical results are shown in Table 4.

[0146] 2.5 Measurement results

[0147] [Table 5]

[0148] It has been demonstrated through experiments that the compounds according to the embodiments of the present invention have significantly improved oral exposure and good oral availability compared to the comparative compounds, and can be well supported in the development of subsequent oral administration.

[0149] [Table 6]

[0150] It has been demonstrated through experiments that the compounds according to the embodiments of the present invention have significantly improved oral exposure and good oral availability compared to the comparative compounds, and can be well supported in the development of subsequent oral administration. All documents related to the present invention are incorporated herein by reference as if each document was individually incorporated by reference. Furthermore, after reading the above content of the present invention, one skilled in the art may make various changes and modifications to the present invention, and it should be understood that equivalent forms thereof are within the scope of the claims of the present invention.

Claims

1. A compound represented by formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 However, two R １ are the same or different and each independently represents hydrogen, deuterium, a halogen, a cyano group, C １－４ Alkyl group and C ３－６ cycloalkyl group, １－４ Alkyl group and C ３－６ The cycloalkyl group may optionally further include deuterium, halogen, cyano group, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Deuterated alkyl groups, cyclopropyl groups, hydroxy groups and C １－４ may be substituted with one or more substituents selected from an alkoxy group; Two R's ２ are identical or different and each independently represents hydrogen, deuterium, C １－４ Alkyl group, C ３－６ A cycloalkyl group and a hydroxy group are selected from the group consisting of C １－４ Alkyl group and C ３－６ The cycloalkyl group may optionally further include deuterium, halogen, cyano group, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Deuterated alkyl groups, cyclopropyl groups, hydroxy groups and C １－４ may be substituted with one or more substituents selected from an alkoxy group; Two R's ３ are identical or different and each independently represents hydrogen, deuterium, C １－１０ Alkyl group, C ３－１０ A cycloalkyl group and a 3- to 10-membered heterocyclic group are selected from the group consisting of C １－１０ Alkyl group, C ３－１０ The cycloalkyl group and the 3- to 10-membered heterocyclic group may optionally further include deuterium, halogen, cyano, hydroxy, carboxy, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Deuterated alkyl groups, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclic group, C ６－１０ Aryl group, 5- to 8-membered heteroaryl group, C ３－６ Cycloalkoxy group, 3- to 6-membered heterocyclic oxy group and C １－４ may be substituted with one or more substituents selected from an alkoxy group; Two m's are the same or different, and each independently represents 0, 1, 2, 3, or 4; Two n's are the same or different, and each independently is 0, 1, 2, 3, or 4; A compound represented by formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

2. Two R's １ are the same or different and each independently represents hydrogen, deuterium, a halogen, a cyano group, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Deuterated alkyl group, cyclopropyl substituted C １－４ Alkyl group and C ３－６ cycloalkyl groups, Preferably, two R １ are identical or different and are each independently selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group and a cyclopropyl group.

3. Two R's ２ are identical or different and each independently represents hydrogen, deuterium, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Deuterated alkyl group, cyclopropyl substituted C １－４ Alkyl group, C ３－６ selected from cycloalkyl groups and hydroxy groups; Preferably, two R ２ are identical or different and are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, a cyclopropyl group and a hydroxy group.

4. Two R's ３ are identical or different and each independently represents hydrogen, deuterium, C １－４ Alkyl group, C ３－６ A cycloalkyl group and a 3- to 6-membered heterocyclic group are selected from the group consisting of C １－４ Alkyl group, C ３－６ The cycloalkyl group and the 3- to 6-membered heterocyclic group may optionally further include deuterium, halogen, cyano, hydroxy, carboxy, C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Deuterated alkyl groups, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclic group, C ３－６ Cycloalkoxy groups and C １－４ may be substituted with one or more substituents selected from an alkoxy group; Preferably, two R ３ are identical or different and are each independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl and azetidinyl, and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl groups may be optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, carboxy, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, cyclopropyloxy, cyclobutyloxy, methoxy, ethoxy and isopropoxy; More preferably, two R ３ are identical or different and are each independently selected from hydrogen, deuterium, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a trideuteromethyl group, a cyclopropylmethyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group and an azetidinyl group.

5. Two R's １ are identical and are selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl and cyclopropyl; Two R's ２ are identical and are selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, cyclopropyl, and hydroxy; Two R's ３ are identical and are selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; two m's are identical and are 0, 1 or 2; The compound represented by formula (I) according to claim 1, characterized in that the two n's are identical and are 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Request 6】 【Chemical 2】 or 【Chemistry 3】 The compound represented by formula (I) according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which is selected from the following:

7. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 6, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof and a pharmaceutical carrier.

8. Use of a compound of formula (I) according to any one of claims 1 to 6, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a related disease mediated by the PD-1 / PD-L1 signal pathway.

9. The use according to claim 8, wherein the associated disease mediated by the PD-1 / PD-L1 signal pathway is selected from cancer or tumor, immune-related diseases and disorders, infectious diseases, infectious diseases or metabolic diseases.

10. The cancer or tumor may be a 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), a sarcoma (including, but not limited to, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma, or lymphangiosarcoma). but are not limited to), melanoma, glioblastoma, synovium, meningioma, bile duct tumor, thymus tumor, nerve tumor, seminoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, spinal axis tumor, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, prostate cancer, Recurrent or resistant to existing drugs: 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, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia (including, but not limited to, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic granulocytic leukemia, and chronic lymphocytic leukemia), bronchial carcinoma, esophageal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, basal cell carcinoma, lung cancer, breast cancer, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, rectal cancer, colon cancer, colorectal cancer , gastric cancer, pancreatic cancer, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal tract cancer, bone cancer, skin cancer, small intestine cancer, endocrine system cancer, renal pelvis cancer, epidermoid carcinoma, abdominal wall carcinoma, renal cell carcinoma, transitional cell carcinoma or choriocarcinoma, and metastatic tumor, the immune-related disease and disorder is selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis and multiple sclerosis; The infectious disease is selected from a bacterial infection, a viral infection, or a fungal infection; the infectious or contagious disease is selected from pyemia, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papilloma virus, or influenza; 10. The use according to claim 9, characterized in that the metabolic disease is selected from diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency or osteoporosis.

11. A compound of formula (I) according to any one of claims 1 to 6, its stereoisomer or a pharma- ceutically acceptable salt thereof for use as a drug for treating cancer or tumor, immune-related disease and disorder, infectious disease, infectious disease or metabolic disease mediated by the PD-1 / PD-L1 signal pathway.

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