Compounds having benzyloxy aryl ether structure, and methods of making and uses thereof

Abstract

Disclosed are a compound having a benzyloxy aryl ether structure, a preparation method therefor, and use thereof. The compound having the benzyloxy aryl ether structure has a structure as shown in formula (I), wherein definitions of the substituents are as described in the specification and claims. The compound of the present application can be used to prepare a small molecule inhibitor of PD1 / PD-L1 interaction, for preventing and / or treating diseases related to PD1 / PD-L1 interaction, especially cancer.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a compound with a benzyloxy aryl ether structure, a stereoisomer, an enantiomer or a pharmaceutically acceptable salt thereof, a preparation method and use thereof. BACKGROUND

[0002] Under normal circumstances, immune cells in the human body, such as CD4 / CD8 + T cells have a killing effect on cancer cells, enabling immune function in normal people to be free from cancer. However, after the PD-1 (Programmed death 1) receptor on the surface of the T cell membrane is combined with the PD-L1 (Programmed death-ligand 1) protein expressed by the tumor cells, the immune function of the T cells is severely inhibited and cannot normally function, and the ability of the T cells to inhibit the proliferation of the cancer cells is severely weakened. The tumor cells achieve immune escape by combining the PD-L1 protein of the tumor cells with the PD-1 receptor of the T cells, and grow and survive. Biological and medical research has shown that the combination of an antibody drug with the PD-1 receptor or the PD-L1 protein can block the interaction between PD-1 and PD-L1, and can achieve good anti-tumor effects in the human body. For example, the PD-1 monoclonal antibody Pembrolizumab (Merck) and Nivolumab (BMS) can selectively bind to the PD-1 receptor of T cells, and the PD-L1 monoclonal antibody Atezolizumab (Genentech / Roche), Durvalumab (Medimmune / AstraZeneca) and Avelumab (Merck KGaA and Pfize) can selectively bind to the PD-1 receptor. These antibodies can all block the interaction between PD-1 and PD-L1, and have been used in the clinical treatment of various tumors, including non-small cell lung cancer, small cell lung cancer, melanoma, head and neck cancer, kidney cancer, bladder cancer, locally advanced or metastatic urothelial carcinoma, breast cancer, cervical cancer, metastatic Merkel cell carcinoma, prostate cancer, liver cancer, intestinal cancer, gastric cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma liver cancer, Hodgkin's lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma, etc. Blocking the interaction between PD-1 and PD-L1 can treat malignant tumors in patients, and this concept of drug research has been scientifically verified in clinical practice.

[0003] In another aspect, small molecule compounds and polypeptide compounds can also selectively bind to PD-1 or PD-L1. These compounds have the potential to block the interaction between PD-1 / PD-L1, activate T cell function, and have the activity of specifically killing tumor cells. Small molecule compounds CA-170, BMS-986189, CA-327, AUNP-12, and MAX-10129 can all act on the PD-1 / PD-L1 signaling pathway and have certain anti-tumor effects in animals.

[0004] In summary, if a small molecule compound can block the interaction between PD-1 / PD-L1, such a compound can block the binding between the PD-L1 protein of a tumor cell and the PD-1 of an immune cell, and can exhibit an anti-cancer effect in animals and humans and have potential drug use for treating malignant tumors in humans.

[0005] Currently, a number of marketed monoclonal antibody drugs targeting PD-1 or PD-L1 have confirmed that PD-1 / PD-L1 blockers can be used for the clinical treatment of various tumors. However, antibody drugs have their own characteristics, such as high production cost, poor stability, the need for injection administration, and the ease of immunogenicity. Small molecule drugs have the advantages of good tissue penetration, convenient storage and transportation, low production cost, no immunogenicity, and usually oral administration, so the research and development of small molecule inhibitors of PD-1 / PD-L1 has significant application value and social value. SUMMARY

[0006] The purpose of the present application is to provide a small molecule inhibitor for inhibiting the interaction of PD1-PD-L1.

[0007] In a first aspect of the present application, a compound represented by general formula (I), a stereoisomer, an enantiomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0008] wherein: W is

[0009] Y is absent or CH2; Z is CH2, O or NR; wherein R is hydrogen, C1-C4 alkyl or -CO(C1-C4 alkyl) (such as formyl, acetyl, propionyl, or butyryl);

[0010] X is CH or N; when X is N, R1 is -(CH2)n-CO2H; when X is CH, R1 is -NR2-(CH2)n-CO2H; wherein n is 1, 2, 3 or 4; R2 is hydrogen or C1-C4 alkyl;

[0011] R3 is C1-C4 alkyl or halogen;

[0012] R4 is selected from:

[0013]

[0014] wherein R5 is C1-C4 alkyl or halogen; R6 is hydrogen or C1-C6 alkyl; R7 is substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl or hydrogen, the substitution meaning one or more (e.g. 2, 3, 4 or 5) substituents selected from the group consisting of -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), hydroxy, C1-C6 alkoxy, 5-6 membered heteroaryl, halogen or CN;

[0015] or R6 and R7 and the nitrogen atom to which they are attached form a substituted or unsubstituted 4-9 membered heterocyclic ring, the substitution meaning one or more (e.g. 2, 3, 4 or 5) substituents selected from the group consisting of hydroxy, -N(C1-C6 alkyl)(C1-C6 alkyl), -NH(C1-C6 alkyl), halogen or CN;

[0016] R8 is C1-C4 alkyl, halogen or CN;

[0017] R9 is selected from the group consisting of C3-C8 cycloalkyl, C1-C6 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, C1-C5 acyl, the above groups being optionally substituted by one or more substituents selected from the group consisting of carboxy, hydroxy, -N(C1-C6 alkyl)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo (O=);

[0018] R 10 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or cyano.

[0019] In another preferred embodiment, the compound has the structure of Formula II: wherein X, Y, Z, R1, R3, R4 are as defined above.

[0020] In another preferred embodiment, the heteroaryl or heterocycle each independently comprises 1, 2 or 3 heteroatoms selected from N, O or S.

[0021] In another preferred embodiment, when X is N, R1 is -(CH2)n-CO2H; when X is CH, R1 is -NR2-(CH2)n-CO2H; wherein n is 1, 2, 3 or 4; R2 is hydrogen, methyl, ethyl, n-propyl or i-propyl.

[0022] In another preferred embodiment, R3 is methyl, ethyl, n-propyl, i-propyl, Cl, F or Br.

[0023] In another preferred embodiment, R5 is methyl, ethyl, n-propyl, isopropyl, Cl, F, or Br.

[0024] In another preferred embodiment, R6 is methyl, ethyl, n-propyl, isopropyl, or hydrogen; R7 is a substituted or unsubstituted 5-6-membered heteroaryl, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C4-C6 cycloalkyl, or hydrogen, wherein the substitution refers to one or more (e.g., 2, 3, 4, or 5) substituents selected from the group consisting of: -NH (C1-C4 alkyl), -N (C1-C4 alkyl), hydroxyl, C1-C4 alkoxy, 5-6-membered heteroaryl, Cl, F, Br, or CN;

[0025] Alternatively, R6 and R7, along with the nitrogen atom attached to them, form a substituted or unsubstituted 5-6 membered heterocycle, wherein the substitution refers to one or more (e.g., 2, 3, 4, or 5) substituents selected from the following group: hydroxyl, -N(C1-C4 alkyl), -NH(C1-C4 alkyl), Cl, F, Br, or CN.

[0026] R8 can be methyl, ethyl, n-propyl, isopropyl, Cl, F, Br, or CN.

[0027] In another preferred embodiment, the compound has the structure shown in Formula III, Formula IV, or Formula V:

[0028]

[0029] The definitions of R1, R3, R5, R6, R7, X, Y, and Z are the same as before.

[0030] In another preferred embodiment, the compound has the structure shown in Formula II-1:

[0031]

[0032] The definitions of R1, R3, R5, R6, R7, Y, and Z are the same as before.

[0033] In another preferred embodiment, the compound has the structure shown in Formula VI, Formula VI-1, or Formula VI-2:

[0034]

[0035] The definitions of R1, R3, R5, R6, R7, Y, and Z are the same as before.

[0036] In another preferred embodiment, the compound has the structure shown in Formula VII, Formula VII-1, or Formula VII-2:

[0037]

[0038] wherein R1, R3, R5, R6, R7 are as defined above.

[0039] In another preferred embodiment, the compound has the structure of Formula VIII, Formula VIII-1, or Formula VIII-2:

[0040]

[0041] wherein R1, R3, R5, R6, R7 are as defined above.

[0042] In another preferred embodiment, the compound has the structure of Formula IX, Formula IX-1, or Formula IX-2:

[0043]

[0044]

[0045] wherein R1, R3, R5, R6, R7 are as defined above.

[0046] In another preferred embodiment, the compound has the structure of Formula X, Formula X-1, or Formula X-2:

[0047]

[0048] wherein R1, R3, R5, R6, R7 are as defined above.

[0049] In another preferred embodiment, the compound has the structure of Formula XI:

[0050]

[0051] wherein R3, R5, R6, R7, R9, R 10 are as defined above.

[0052] In another preferred embodiment, R9 is substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl substituted C1-C4 alkyl, substituted or unsubstituted C1-C5 acyl, the substitution being with one or two substituents selected from the group consisting of carboxyl, hydroxyl, -N(C1-C4 alkyl)(C1-C4 alkyl), C1-C4 alkyl, C1-C4 alkoxy, halogen, oxo (O=).

[0053] In another preferred embodiment, R9 is substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, cyclopropyl-substituted C1-C4 alkyl, substituted or unsubstituted C1-C5 acyl, said substitution being with one or two substituents selected from the group consisting of carboxyl, hydroxyl, dimethylamino, oxo (O=).

[0054] In another preferred embodiment, R 10 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, or cyano, preferably R 10 is hydrogen, halogen, methyl, methoxy, cyano.

[0055] In another preferred embodiment, the compound is selected from the group consisting of compounds 1-89.

[0056] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a compound of the first aspect, a stereoisomer, an enantiomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0057] In another preferred embodiment, the pharmaceutical composition further comprises a second cancer therapeutic agent.

[0058] In another preferred embodiment, the second cancer therapeutic agent comprises a radiation agent, a cytotoxic agent, a kinase inhibitor, an immune-targeting inhibitor, and an angiogenesis inhibitor.

[0059] In another preferred embodiment, the second cancer therapeutic agent is one or more selected from the group consisting of:

[0060] PD-1 inhibitors (such as Nivolumab, Pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as Durvalumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311, or biosimilars of the above drugs, etc.), CD20 antibodies (such as Rituximab, Obinutuzumab, Ofatumumab, Tositumomab, Ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclacitinib), PI3K inhibitors (such as Idelalisib, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Egfrinib, Canertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Raveurbib, Cabozantinib, Sunitinib, Dornafinib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinostat, Dacsitst, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Oclacitinib, Linsitinib, BMS-754807, GSK1838705A, etc.), or combinations thereof.

[0061] In a third aspect, the present application provides the use of the compound, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof of the first aspect, or the pharmaceutical composition of the second aspect, for the preparation of a PD1-PDL1 interaction inhibitor; or for the preparation of a medicament for preventing and / or treating a disease associated with PD1 / PD-L1 interaction.

[0062] In another preferred embodiment, the disease associated with PD1 / PD-L1 interaction is cancer.

[0063] In another preferred embodiment, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, melanoma, head and neck cancer, renal cancer, bladder cancer, locally advanced or metastatic urothelial carcinoma, breast cancer, cervical cancer, metastatic Merkel cell carcinoma, prostate cancer, liver cancer, intestinal cancer, gastric cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma liver cancer, Hodgkin's lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma.

[0064] In another preferred embodiment, the compound, stereoisomer or pharmaceutically acceptable salt thereof is used in a combination regimen, such as a combination tumor chemotherapy regimen, other tumor immunotherapy agents (small molecule compounds and antibodies, etc.), a radiotherapy regimen, a tumor targeting drug, a tumor vaccine, etc., such as human papilloma virus (HPV), hepatitis virus (HBV and HCV) and Kaposi's herpes sarcoma virus (KHSV); can be administered before, after or simultaneously with the agent, or can be co-administered with other known therapies.

[0065] In another preferred embodiment, the compound, stereoisomer or pharmaceutically acceptable salt thereof is used alone or in combination for the treatment of patients exposed to specific toxins or pathogens; including but not limited to the treatment of various viruses, pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc.; such as HIV, hepatitis virus (A, B, C), influenza virus, herpes virus, Giardia, malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa, etc. established infections of pathogenic agents.

[0066] In another preferred embodiment, the compound, stereoisomer or pharmaceutically acceptable salt thereof is used to induce a therapeutic autoimmune response to treat patients with inappropriate accumulation of other autoantigens, such as amyloid deposits, including Αβ in Alzheimer's disease, cytokines such as TNFa and IgE.

[0067] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features specifically described below (such as in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0068] Figure 1 Tumor cell and T cell co-culture test results are shown.

[0069] Figure 2 Tumor volume and mouse weight changes. DETAILED DESCRIPTION

[0070] The present inventors have made extensive and intensive studies, and found a class of compounds having good inhibitory PD1 / PD-L1 interaction ability. In addition, the compounds of the present application have good effects of promoting T cell killing of cancer cells, good pharmacodynamic properties and lower toxicity. On this basis, the present application is completed.

[0071] Terminology

[0072] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs.

[0073] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value can vary from the recited value by not more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0074] As used herein, the term "comprising" or "including" can be open, semi-closed or closed.

[0075] Group Definitions

[0076] Definitions of standard chemical terminology can be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of the art are employed in practicing conventional methods, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods. Unless specific definitions are provided, the nomenclature utilized in connection with analytical chemistry, organic synthesis chemistry, and related descriptions herein are known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical formulation, and delivery, and treatment of patients. For example, reactions and purification methodologies can be performed by manufacturers' instructions or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be readily implemented by the skilled artisan by following the teachings of the present specification and the examples which follow. In the present specification, groups and substituents are chosen to provide stable moieties and compounds.

[0077] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0078] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0079] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to alkyl groups having a total of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0080] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0081] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0082] "Hydroxy" refers to the -OH group. "Hydroxyalkyl" refers to an alkyl group as defined below that has been replaced by a hydroxyl group (-OH).

[0083] "Carbonyl" refers to the -C(=O)- group. "Nitro" refers to -NO2. "Cyano" refers to -CN. "Amino" refers to -NH2.

[0084] "Substituted amino" refers to an amino group that is substituted by one or two alkyl, alkylcarbonyl, arylalkyl, or heteroarylalkyl groups as defined below, such as monoalkylamino, dialkylamino, alkylamide, arylalkylamino, or heteroarylalkylamino.

[0085] The "carboxyl group" refers to -COOH.

[0086] "(C1-C4)alkylsulfonyl" refers to (C1-C4)alkyl-SO2-, wherein the alkyl group is defined as follows.

[0087] "(C1-C4)alkylsulfinyl" refers to (C1-C4)alkyl-SO-, wherein the alkyl group is defined as follows.

[0088] "(C1-C4)alkylsulfonylamino" refers to: (C1-C4)alkyl-SO2-NH-, wherein the alkyl group is defined as described below.

[0089] "Aminosulfonyl" means -SO2-NH2.

[0090] "(C1-C5)acylamino" means (C1-C5 alkyl)(C=0)NH-, and "(C1-C5)acyl" means (C1-C5 alkyl)CO-, wherein the alkyl groups are as defined below.

[0091] In the present application, the term "alkyl" as a group or part of a group (for example in the groups halo-substituted alkyl and the like) refers to a straight or branched chain hydrocarbon group which is completely saturated, consisting solely of carbon and hydrogen atoms, having, for example, from 1 to 6 (preferably 1 to 4) carbon atoms, and being attached to the rest of the molecule by a single bond, such as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, and the like. In the present application, the alkyl group (as a group or part of a group) is also intended to include substituted alkyl groups, for example, substituted with a substituent selected from the group consisting of: halo, hydroxy, cyano, nitro, amino, carboxy, sulfonyl, and the like.

[0092] The term "cycloalkyl" means a fully saturated cyclic alkane, consisting solely of carbon and hydrogen atoms, having, for example, from 3 to 8 carbon atoms (i.e., C3-C8 cycloalkyl) or from 3 to 6 carbon atoms (i.e., C3-C6 cycloalkyl), and being attached to the rest of the molecule by a single bond, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. In the present application, the cycloalkyl group (as a group or part of a group) is also intended to include substituted cycloalkyl groups, for example, substituted with a substituent selected from the group consisting of: halo, hydroxy, cyano, nitro, amino, carboxy, sulfonyl, and the like. "Halo(C1-C4)alkyl" means a C1-C4 alkyl group substituted with one or two or three halo atoms, such as, for example, trifluoromethyl, difluoromethyl.

[0093] In the present application, the term "heterocyclyl" as a group or as part of another group means a stable 3- to 20-membered (i.e., 3- to 20-membered) non-aromatic ring radical consisting of two to fourteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur, preferably 4- to 11-membered heterocyclyl, more preferably 5- to 10-membered heterocyclyl. Unless otherwise specifically noted in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which can include fused, bridged, or spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclyl radical can be partially or fully saturated. The heterocyclyl radical can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl radicals comprising fused rings, one or more of the rings can be an aryl or heteroaryl group as defined below, provided the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, the heterocyclyl radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocyclyl radicals include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like. In the present application, the heterocyclyl radical (as a group or as part of another group) is also meant to include substituted heterocyclyl radicals, for example, substituted with halogen, hydroxy, cyano, nitro, amino, carboxy, sulfonyl, and the like.

[0094] In the present application, the term "aryl group (or aromatic ring)", as a group or part of other groups, means a conjugated hydrocarbon ring system group having from 6 to 18 carbon atoms, preferably having from 6 to 10 carbon atoms, i.e. C6-C10. For the purposes of the present application, the aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl group or a heterocyclic group as defined above, provided that the aryl group is linked to the rest of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-lH-isoindolyl, 2-benzoxazolinonyl, 2H-l,4-benzoxazin-3(4H)-on-7-yl, and the like. In the present application, the aryl group (or aromatic ring), as a group or part of other groups, is also intended to include substituted aryl groups (or aromatic rings), for example, substituted with a group selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, carboxy, sulfonyl, and the like.

[0095] In the present application, the term "heteroaryl (or heteroaromatic ring)" as a group or part of another group means a 5- to 16-membered conjugated ring system having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless specifically indicated otherwise in the present specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring ring system, and can also be fused with a cycloalkyl group or a heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present application, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthylidinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthrolinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthpyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, and the like. In the present application, the heteroaryl group (as a group or part of another group) is also intended to include substituted heteroaryl groups (or heteroaromatic rings), for example, the substitution is selected from halogen, hydroxyl, cyano, nitro, amino, carboxyl, sulfonyl, and the like.

[0096] In the present application, the plural means 2, 3, 4 or 5.

[0097] Active ingredient

[0098] As used herein, the term "compound of the present application" or "active ingredient of the present application" are used interchangeably to mean a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof of Formula I. The term also includes racemates, optical isomers, isotopically labeled compounds (such as deuterated compounds) or prodrugs.

[0099] The compound of formula (I) has the following structure:

[0100]

[0101] The definitions of the substituents are as previously described.

[0102] “Stereoisomers” refer to compounds which have the same atomic constituents, bonded by the same bonds, but which have different three-dimensional structures. The present invention will encompass all such stereo isomers and mixtures thereof.

[0103] “Tautomers” refer to isomers that differ in the protonation of an atom in the molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.

[0104] The compounds of the present invention, or their pharmaceutically acceptable salts, can contain one or more chiral carbon atoms and can therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined, based on its stereochemistry, as either the (R)- or (S)- isomer. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention can select the racemate, diastereomer or enantiomer as starting material or intermediate. The optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chromatography on chiral supports, among others.

[0105] Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gϋbitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A. M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0106] The present application also includes isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present application, or pharmaceutically acceptable salts or solvates thereof, wherein one or more atoms are replaced by isotopes of those atoms or other isotopes are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example, 3 H, and 14 C, are useful in drug and substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can result in greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. Isotopically-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent. The term "pharmaceutically acceptable salt" as used herein includes both acid addition salts and base addition salts.

[0107] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and non-toxicity of the free bases and which are, for example, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, 2,2-dichloroacetic acid, trifiuoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, octanoic acid, decanoic acid, undecylenic acid, glycolic acid, gluconic acid, lactic acid, sebacic acid, adipic acid, glutaric acid, malonic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, 4-amino salicylic acid, naphthalene-2-sulfonic acid and the like. These salts can be prepared by methods known to those skilled in the art.

[0108] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and non-toxicity of the free acids and which are, for example, formed with inorganic bases such as ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferric hydroxide, zinc hydroxide, copper hydroxide, manganese hydroxide, aluminum hydroxide and the like; or formed with organic bases such as primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as, for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known to those skilled in the art.

[0109] If a specific enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis, or by derivatization using a chiral auxiliary to produce a diastereomeric mixture, separation of the desired enantiomer from the mixture, and removal of the chiral auxiliary. Alternatively, if the molecule contains a basic functionality, such as an amino acid, or an acidic functionality, such as a carboxyl group, the pure enantiomer can be obtained by forming diastereomeric salts with an optically active acid or base, and then separating the resulting diastereomeric salts by conventional means, such as, for example, crystallization or chromatography.

[0110] As described herein, the compounds of the present application can be expanded to include any number of substituents or functional groups. In general, the term "substituted" whether preceded by the term "optionally" or not, is intended to refer to the general formula of the present application including substituents, is intended to mean that the indicated structure is replaced with the named substituent. When multiple instances of a particular structure are substituted with multiple instances of a particular substituent, each position can be the same or different. The term "substituted" as used herein includes all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present application, as for example with the heteroatom nitrogen, the hydrogen substituent or any permissible organic compound as described above can supplement the valence state. Furthermore, the present application is not intended to be limited in any way by any means of permissible substituents of organic compounds. The present application contemplates combinations of substituents and variables insofar as such combinations result in stable compounds useful in the treatment of disease. The term "stable" as used herein is intended to refer to compounds possessing stability sufficient to remain intact during treatment of a disease for a time sufficient to effect the intended biological or medicinal response, preferably for a time sufficient to allow the compound to be detected in the body, and as such is used herein for the above purpose.

[0111] Metabolites of compounds of the present application, which are within the scope of the present application, as well as prodrugs of compounds of the present application, which can be converted under metabolic conditions within the body to the compounds of the present application and their pharmaceutically acceptable salts, are also within the scope of the present application.

[0112] Pharmaceutical compositions and methods of administration

[0113] The pharmaceutical compositions of the present application are useful for the prevention and / or treatment of cancer, immunological diseases, metabolic diseases, and the like. In the present application, "pharmaceutical composition" refers to a preparation of a compound of the present application with a medium conventionally accepted in the art for the delivery of biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the biological agent, to aid in the absorption of the active ingredient, and to thereby effect biological activity. The term "pharmaceutically acceptable" as used herein means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0114] In the present application, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor approved by a regulatory agency of the relevant government for use in a human or an animal.

[0115] The term "cancer" or "tumor" as used herein includes, but is not limited to, non-small cell lung cancer, melanoma, head and neck cancer, renal cancer, urothelial cancer, locally advanced or metastatic urothelial cancer, metastatic Merkel cell carcinoma, prostate cancer, liver cancer, intestinal cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma liver cancer, Hodgkin's lymphoma, chronic lymphocytic leukemia, and the like.

[0116] The term "prevention" as used herein includes reducing the likelihood of the occurrence or worsening of a disease or condition in a subject.

[0117] The terms "treatment" and other similar terms as used herein include the following meanings:

[0118] (i) preventing the disease or condition from occurring in a subject, in particular, when such subject is predisposed to the disease or condition but has not yet been diagnosed as having it;

[0119] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0120] (iii) relieving the disease or condition, i.e., causing the condition to regress; or

[0121] (iv) alleviating the symptoms of the disease or condition.

[0122] The terms "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" as used herein refer to the amount of at least one agent or compound that, upon administration to a subject, is effective to alleviate to some extent one or more of the symptoms of the disease or condition being treated. As a consequence of such administration, there can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapy is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief of symptoms of a condition. Techniques for

[0123] The terms "administration", "administering" and the like, as used herein, refer to methods allowing delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusion), topical administration and transrectal

[0124] Intestinal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; *Pergamon*; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0125] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0126] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0127] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0128] In addition to these inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0129] In addition to the active compounds, the suspensions can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide gel, and agar-agar, or mixtures of these substances, and the like.

[0130] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0131] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed with a pharmaceutical carrier, which can be a sterile diluent or a solvent, and any preservatives, buffers, or the like, as can be required. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients are physically combined in one single entity or in one single dosage form. The term "non-fixed combination" means the active ingredients are provided in separate entities or in separate dosage forms which are packaged separately and used sequentially or simultaneously. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.

[0132] The drugs or active ingredients that can be combined with the compounds of general formula (I) include, but are not limited to, PD-1 inhibitors (such as Nivolumab, Pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as Durvalumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311, or biosimilars of the above drugs, etc.), CD20 antibodies (such as Rituximab, Obinutuzumab, Ofatumumab, Tositumomab, Ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclacitinib), PI3K inhibitors (such as Idelalisib, Dactolisib, Taselisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Egfrinib, Canertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Raveurbib, Cabozantinib, Sunitinib, Dornafinib, etc.), HDAC inhibitors (such as Givinostat, Droxinostat, Entinostat, Dacsitst, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212),

[0133] PD0325901, U0126, AS-703026, PD184352 (CI-1040), etc.), Akt inhibitors (such as MK-2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Oclacitinib, linsitinib, BMS-754807, GSK1838705A, etc.), or a combination thereof.

[0134] When the pharmaceutical composition is used, a safe and effective amount of the compound of the present application is applied to a mammal (such as a human) in need of treatment, wherein the dose is a pharmaceutically effective dose, and the daily dose for a 60 kg human is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dose should also consider the administration route, the health status of the patient, and other factors, which are within the skill of a skilled physician.

[0135] The present application also provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvate described in the present application, thereby forming a pharmaceutical composition.

[0136] The present application also provides a method for treatment, which comprises the step of administering the compound of general formula (I), its stereoisomer, enantiomer or its pharmaceutically acceptable salt described in the present application, or administering the pharmaceutical composition described in the present application to a subject in need of treatment for inhibiting PD1-PDL1 interaction.

[0137] Preparation of intermediates

[0138] 1. Synthesis of 7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[d]oxazole-5-carbaldehyde (ZK099)

[0139]

[0140] ZK105 (271 mg, 0.68 mmol, synthesis method see patent WO 2018 / 119224) was dissolved in dry dichloromethane (30 mL), then DMP (Dess-Martin periodinane) (575.6 mg, 1.36 mmol) was added to the reaction also, stirred at room temperature for 12 hours. After the reaction was completed, water was added to quench the reaction, dichloromethane was extracted, the organic phase was collected and rotary evaporated, and finally the target compound was obtained after separation and purification by column chromatography, yield: 220 mg, yield: 82%. 1 H NMR (400 MHz, Chloroform-d) δ 10.06 (s, 1H), 8.21 (dd, J = 7.4, 1.4 Hz, 2H), 8.11 - 7.82 (m, 2H), 7.37 (t, J = 7.6 Hz, 1H), 2.98 (s, 3H), 1.39 (s, 12H).

[0141] 2. Synthesis of 7-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzo[d]oxazole-5-carbaldehyde (EH056)

[0142]

[0143] EH050 (330 mg, 1.0 mmol, synthesis method see patent CN 113801111A) was dissolved in dry dichloromethane (30 mL), then DMP (800 mg, 2.0 mmol) was added to the reaction also, stirred at room temperature for 12 hours. After the reaction was completed, water was added to quench the reaction, dichloromethane was extracted, the organic phase was collected and rotary evaporated, and finally the target compound was obtained after separation and purification by column chromatography, yield: 120 mg, yield: 47%. 1 H NMR (500 MHz, Chloroform-d) δ 10.12 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H), 8.26 (dd, J = 7.9, 1.4 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.99 (dd, J = 7.5, 1.5 Hz, 1H), 7.40 (q, J = 7.7, 7.1 Hz, 1H), 3.00 (s, 3H), 1.40 (s, 12H).

[0144] 3. Synthesis of 5-formyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)picolinamide (ZZC034)

[0145]

[0146] Step 1: Synthesis of 5-hydroxymethyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridinecarboxamide (ZZC031)

[0147] Under nitrogen atmosphere, ZZC028 (1.0 g, 3.15 mmol), pinacol diboronate (1.6 g, 6.29 mmol), and potassium acetate (1.2 g, 12.59 mol) were suspended in dry 1,4-epoxyhexane (25 mL), degassed three times with dry nitrogen, and then [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (261.0 mg, 0.32 mmol) was added, degassed three times with dry nitrogen, and the reaction was heated and stirred at 100 °C for 12 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica gel column chromatography to give 1.1 g of the title compound (yield: 96%). 1 HNMR (500MHz, CD3OD) δ8.67(d,J=2.1Hz,1H),8.17(d,J=8.0Hz,1H),7.97(dd,J=8.0,2.1Hz,1H),7.92(dd,J= 8.0,1.4Hz,1H),7.60(dd,J=7.4,1.4Hz,1H),7.23(t,J=7.7Hz,1H),4.75(s,2H),2.55(s,3H),1.36(s,12H).

[0148] Step 2: Synthesize ZZC034

[0149] ZZC031 (1.1 g, 2.99 mmol) and DMP (2.5 g, 5.98 mmol) were suspended in dichloromethane (20 mL) and reacted with stirring at room temperature for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to adjust the pH to approximately 7.5. The mixture was extracted with dichloromethane (15 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography to give 782.0 mg of the title compound, yield: 92%. 1 H NMR (500MHz, CDCl3) δ10.22(s,1H),10.10(s,1H),9.11(d,J=2.1Hz,1H),8.49(d,J=7.9Hz,1H),8.38(dd,J=8.0,2.1 Hz,1H),8.32(dd,J=8.1,1.4Hz,1H),7.64(dd,J=7.5,1.4Hz,1H),7.29(t,J=7.8Hz,1H),2.63(s,3H),1.37(s,12H).

[0150] 4. Synthesis of N-methyl-N-(7-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)oxy)chroman-4-yl)glycine ethyl ester (ZK068)

[0151]

[0152] Step 1: Synthesis of 7-(3-bromo-2-methylbenzyl)oxy)chroman-4-one (ZK049)

[0153] To a solution of 1-bromo-3-(bromomethyl)-2-methylbenzene (1.21 g, 4.57 mmol) and ZK061 (0.9 g, 5.48 mmol) in acetonitrile (30 mL) was added potassium carbonate (1.26 g, 9.14 mmol) and stirred at room temperature for 12 h. After completion of the reaction, the solvent was evaporated and water was added. The organic layer was extracted with dichloromethane and purified by column chromatography to obtain the desired compound 1.1 g, yield: 70%. 1 HNMR (500 MHz, Chloroform-d) δ 7.86 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.1, 1.2 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 5.07 (s, 2H), 4.52 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.42 (s, 3H).

[0154] Step 2: Synthesis of 7-((3-bromo-2-methylbenzyl)oxy)-N-methylchroman-4-amine (ZK065)

[0155] To a solution of ZK049 (1.2 g, 3.47 mmol) and methylamine in methanol (37%, 2.39 g, 20.81 mmol) in tetrahydrofuran (50 mL) was added AcOH (0.8 mL) and stirred at room temperature for 15 min. Sodium cyanoborohydride (1.31 g, 20.81 mmol) was added and the reaction was stirred at 45 °C for 12 h. After completion of the reaction, the solvent was evaporated and water was added. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated and used directly for the next step. 1H NMR (500 MHz, Methanol-d4) δ 7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.67 (dd, J = 8.6, 2.5 Hz, 1H), 6.54 (d, J = 2.6 Hz, 1H), 5.05 (s, 2H), 4.37 (t, J = 4.6 Hz, 1H), 4.30 (dt, J = 8.8, 4.4 Hz, 1H), 4.27 - 4.17 (m, 1H), 2.77 (s, 3H), 2.39 (s, 3H), 2.30 (dt, J = 7.1, 4.6 Hz, 2H).

[0156] Step 3: Synthesis of N-(7-((3-bromo-2-methylbenzyl)oxy)chroman-4-yl)-N- methylglycine ethyl ester (ZK052)

[0157] ZK065 (1.05 g, 2.7 mmol), ethyl chloroacetate (0.83 g, 6.75 mmol) were dissolved in acetonitrile (50 mL) and then potassium carbonate (1.12 g, 8.1 mmol), KI (44.82 mg, 0.27 mmol) were added and the reaction was warmed to 80 °C and stirred for 12 h. After completion of the reaction, the solvent was evaporated, water was added and extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate and concentrated and purified to get the target compound 860 mg, yield: 55%. 1 H NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 7.6, 1.2 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.65 (dd, J = 8.7, 2.6 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 5.01 (s, 2H), 4.99 (t, J = 5.8 Hz, 1H), 4.42 (ddd, J = 12.1, 8.3, 3.8 Hz, 1H), 4.28 - 4.18 (m, 3H), 4.00 (d, J = 6.4 Hz, 2H), 2.95 (s, 3H), 2.42 (s, 4H), 2.38 - 2.27 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H).

[0158] Step 4: Synthesis of ZK068

[0159] To a solution of ZK052 (261.1 mg, 0.58 mmol), bis(pinacolato)diboron (370.8 mg, 1.46 mmol), KOAc (228.9 mg, 2.34 mmol) in anhydrous 1,4-dioxane (30 mL) was added palladium tetrakis(triphenylphosphine) (60 mg) under nitrogen atmosphere and the reaction was heated at 95 °C for 16 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, the solvent was evaporated and water was added. The mixture was extracted with ethyl acetate (3x) and the combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography to obtain the title compound 212 mg, yield: 74%. 1 H NMR (400 MHz, Chloroform-d) δ 7.74 (dd, J = 7.5, 1.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.56 (dd, J = 8.6, 2.6 Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 4.99 (s, 2H), 4.43 - 4.30 (m, 1H), 4.14 (dq, J = 14.6, 6.0, 5.0 Hz, 3H), 3.98 (t, J = 6.8 Hz, 1H), 3.32 (d, J = 16.6 Hz, 1H), 3.19 (d, J = 16.7 Hz, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 1.97 (q, J = 6.0 Hz, 2H), 1.35 (s, 12H), 1.31 - 1.21 (m, 3H).

[0160] 5. Synthesis of ethyl N-methyl-N-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)glycinate (ZL101).

[0161]

[0162] Step 1: Synthesis of 3,4-dihydronaphthalen-1-one (ZL122)

[0163] To a solution of 1-bromo-3-(bromomethyl)-2-methylbenzene (790 mg, 2.99 mmol), 6-hydroxy-3,4-dihydronaphthalen-1-one (534 mg, 3.29 mmol) in acetonitrile (30 mL) was added potassium carbonate (826.4 g, 5.98 mmol) and stirred at room temperature for 12 h. After completion of the reaction, the solvent was evaporated and water was added. The mixture was extracted with dichloromethane and the crude product was purified by column chromatography to obtain the title compound 970 mg, yield: 94%. 1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.90 (dd, J = 8.7, 2.5 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.10 (s, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.62 (t, J = 6.5 Hz, 2H), 2.44 (s, 3H), 2.13 (p, J = 6.3 Hz, 2H).

[0164] Step 2: Synthesis of 6-(3-bromo-2-methylbenzyloxy)-N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine (ZZD001)

[0165] To a solution of ZL122 (900.8 mg, 2.61 mmol) in tetrahydrofuran (20 mL) was added methylamine in methanol (37%, 2.70 g, 26.10 mmol), AcOH (0.90 mL), stirred at room temperature for 10 minutes. To the mixture was added sodium cyanoborohydride (493.2 mg, 7.83 mmol), the mixture was stirred at 45 °C for 12 hours. The reaction was concentrated, the pH was adjusted to ~12 with aqueous sodium hydroxide (1.5 M), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used in Step 3.

[0166] Step 3: Synthesis of N-(6-(3-bromo-2-methylbenzyloxy)-1,2,3,4- tetrahydronaphthalen-1-yl)-N-methylglycine ethyl ester (ZZC003)

[0167] To a solution of ZZD001 crude product (1.0 g, 2.78 mmol) in acetonitrile (20 mL) was added ethyl chloroacetate (847.2 mg, 6.94 mmol), potassium carbonate (1.15 g, 8.33 mmol), and potassium iodide (46.5 mg, 0.28 mmol), the mixture was stirred at 80 °C for 16 hours. After the reaction was completed, it was concentrated, diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to give the target compound 1.01 g (two-step yield: 81%). 1H NMR (500 MHz, Chloroform-d) δ 7.67 (dd, J = 8.7, 0.9 Hz, 1H), 7.54 (dd, J = 8.1, 1.3 Hz, 1H), 7.36 (dd, J = 7.6, 1.3 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.81 (dd, J = 8.6, 2.7 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 5.00 (s, 2H), 4.17 (q, J = 7.3 Hz, 2H), 3.90 (dd, J = 10.1, 4.7 Hz, 1H), 3.27 (d, J = 16.5 Hz, 1H), 3.15 (d, J = 16.5 Hz, 1H), 2.76 (ddd, J = 15.9, 10.9, 4.9 Hz, 1H), 2.72 - 2.63 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.03 - 1.94 (m, 2H), 1.73 - 1.60 (m, 1H), 1.59 - 1.50 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H).

[0168] Step 4: Synthesis of ZL101

[0169] ZZZC003 (400 mg, 0.90 mmol), bis(pinacolato)diboron (569 mg, 2.24 mmol), KOAc (313.6 mg, 3.2 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL) solution, and then palladium dichloride bis-triphenylphosphine (60 mg) was added under nitrogen atmosphere, and finally the reaction was heated at 95 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the solvent was evaporated, and then water was added, and then extracted with ethyl acetate three times, and the organic phase was combined and dried with anhydrous sodium sulfate, and then evaporated, and finally the target compound was separated and purified by column chromatography to obtain 320 mg, yield: 72%. 1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J = 7.4 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.82 (dd, J = 8.7, 2.8 Hz, 1H), 6.67 (s, 1H), 5.01 (s, 2H), 4.17 (q, J = 7.0 Hz, 1H), 3.89 (d, J = 8.6 Hz, 1H), 3.28 (d, J = 16.5 Hz, 1H), 3.15 (d, J = 16.6 Hz, 3H), 2.72 (d, J = 20.0 Hz, 3H), 2.56 (s, 4H), 2.40 (s, 3H), 1.98 (d, J = 10.2 Hz, 3H), 1.74 - 1.61 (m, 1H), 1.35 (s, 12H), 1.28 (m, J = 1.5 Hz, 3H). 6. Synthesis of N-(5-((3-bromo-2-methylbenzyl)oxy)-2,3-dihydro-1H-inden-1-yl)-N- methylglycine ethyl ester (ZL040).

[0170]

[0171] Step 1: Synthesis of 5-(3-bromo-2-methylbenzyloxy)-2,3-dihydro-1H-inden-1-one (ZK036)

[0172] 1-bromo-3-(bromomethyl)-2-methylbenzene (1.31 g, 5.0 mmol), 5-hydroxy-2,3- dihydroindenone (889 mg, 6.0 mmol) were dissolved in acetonitrile (30 mL), then potassium carbonate (1.38 g, 10 mmol) was added, stirred at room temperature for 12 hours, after the reaction was completed, the solvent was spin dried, then water, dichloromethane was extracted, and finally purified by column chromatography to obtain the target compound 1.15 g, yield: 72%. 1 H NMR (500 MHz, Chloroform-d) δ 7.75 - 7.69 (m, 1H), 7.58 (dd, J = 8.1, 1.2 Hz, 1H), 7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.3 Hz, 2H), 5.12 (s, 2H), 3.18 - 3.04 (m, 2H), 2.74 - 2.63 (m, 2H), 2.44 (s, 3H).

[0173] Step 2: Synthesis of 5-(3-bromo-2-methylbenzyloxy)-N-methyl-2,3-dihydroinden-1-amine (ZL039)

[0174] ZK036 (500 mg, 1.52 mmol), methylamine methanol solution (37%, 1.05 g, 9.09 mmol) were dissolved in tetrahydrofuran (50 mL), after stirring at room temperature for 15 minutes, AcOH (0.5 mL) was added, after stirring for 15 minutes, sodium cyanoborohydride (571 mg, 9.09 mmol) was added, the reaction was warmed to 45 °C, and stirring was continued for 12 hours. After the reaction was completed, the solvent was evaporated, water was added, and then extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated, which was directly used in the next step.

[0175] Step 3: Synthesis of ZL040

[0176] ZL039 crude (1.52 mmol), ethyl chloroacetate (465.7 mg, 3.8 mmol) were dissolved in acetonitrile (50 mL), then potassium carbonate (630.2 mg, 4.56 mmol), KI (25.2 mg, 0.15 mmol) were added, the reaction was warmed to 80 °C and stirred for 12 hours. After the reaction was completed, the solvent was evaporated, water was added, extracted with ethyl acetate, the organic phase was collected and dried with anhydrous sodium sulfate, concentrated and purified to obtain the target compound 334.2 mg, two-step yield: 51%. 1 H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.1, 1.3 Hz, 1H), 7.36 (dd, J = 7.6, 1.2 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.86 - 6.80 (m, 2H), 5.02 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.26 (d, J = 16.4 Hz, 1H), 3.18 - 3.10 (m, 1H), 2.93 (ddd, J = 14.3, 10.0, 5.0 Hz, 1H), 2.79 (dt, J = 15.9, 7.6 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 2.16 (dtd, J = 13.3, 8.3, 4.9 Hz, 1H), 2.01 (td, J = 13.9, 6.7 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H).

[0177] 7. Synthesis of (R)-1-(8-(3-bromo-2-chlorophenyl)amino)-1,7-naphthyridin-3-yl)methyl)pyrrolidin-3-ol (ZN041)

[0178]

[0179] Step 1: Synthesis of 3-bromo-2-chlorophenylamino-1,7-naphthyridine-3-methanol (ZZE053)

[0180] Into a sealed tube was added 3-bromo-2-chloroaniline (581.2 mg, 2.82 mmol), isopropyl alcohol (40 mL) and hydrochloric acid in 1,4-dioxane (4 M, 0.71 mL, 2.82 mmol) at room temperature. The tube was sealed and heated at 100 °C for 12 h. The reaction was concentrated and the residue was dissolved in ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (220.5 mg, 24%). 1 H NMR (500 MHz, CD3OD): δ 9.04 (dd, J = 8.4, 1.5 Hz, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.19 - 8.15 (m, 1H), 8.11 (d, J = 5.8 Hz, 1H), 7.35 (dd, J = 8.0, 1.5 Hz, 1H), 7.26 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 4.87 (d, J = 0.9 Hz, 2H).

[0181] Step 2: Synthesis of 3-bromo-2-chlorophenylamino-1,7-naphthyridine-3- carboxaldehyde (ZZE056)

[0182] Into a sealed tube was added 3-bromo-2-chlorophenylamino-1,7-naphthyridine-3- carboxaldehyde (60.1 mg, 0.16 mmol), methanol (5 mL) and sodium borohydride (20.6 mg, 0.54 mmol) at room temperature. The tube was sealed and heated at 60 °C for 12 h. The reaction was concentrated and the residue was dissolved in ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (60.1 mg, 78%). 1 H NMR (500 MHz, CD3OD): δ 9.04 (dd, J = 8.4, 1.5 Hz, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.19 - 8.15 (m, 1H), 8.11 (d, J = 5.8 Hz, 1H), 7.35 (dd, J = 8.0, 1.5 Hz, 1H), 7.26 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 4.87 (d, J = 0.9 Hz, 2H).

[0183] Step 3: Synthesis of ZN041

[0184] ZZE056 (120 mg, 0.33 mmol), B (50.1 mg, 0.67 mmol) were dissolved in dichloromethane (30 ml), after adding triethylamine (67.33 mg, 0.67 mmol) and stirring at room temperature for 2 hours. Finally, sodium triacetoxyborohydride (212 mg, 1.1 mmol) was added and the reaction was continued for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to quench, dichloromethane was extracted, the organic phase was collected and rotary evaporated, and the target compound was obtained after separation and purification by column chromatography. 140.1 mg, yield: 97%. 1 H NMR (400 MHz, Chloroform-d) δ 9.91 (s, 1H), 9.09 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 5.7 Hz, 1H), 8.03 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 4.41 (d, J = 6.0 Hz, 1H), 3.91 (d, J = 2.6 Hz, 2H), 3.01 (q, J = 8.1 Hz, 1H), 2.83 (d, J = 10.3 Hz, 1H), 2.69 (dd, J = 10.3, 5.1 Hz, 1H), 2.47 (q, J = 8.3 Hz, 1H), 2.26 (dq, J = 14.4, 7.2 Hz, 1H), 1.93 - 1.76 (m, 1H).

[0185] Example 1: Synthesis of N-(7-((3'-(5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridinamide)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK058N)

[0186]

[0187] Step 1: Synthesis of 5-formyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)picolinamide (ZK058)

[0188] ZK052 (50 mg, 0.11 mmol), ZZC034 (61.1 mg, 0.17 mmol) were dissolved in a mixed solution of ethylene glycol dimethyl ether (15 mL) and sodium carbonate (2M in H2O, 5 mL), Pd(pddf)Cl2-CH2Cl2(20 mg) was added under nitrogen atmosphere, then the reaction was heated to 75°C and continued to react under nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, then extracted with ethyl acetate (30 mL ╳3) and dichloromethane (30 mL ╳ 3) Each extraction was performed three times, and the organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude ZK058.

[0189] Step 2: Synthesis of ZK058N

[0190] The crude ZK058 (0.11 mmol) was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (28.7 mg, 0.33 mmol) was added, and stirred at room temperature for 15 minutes, and then AcOH (0.08 mL) was added. After stirring for 15 minutes, sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, water was added, and extraction was performed with dichloromethane, and the organic phase was combined and rotary evaporated. The obtained crude product was dissolved in a mixed solution of tetrahydrofuran and H2O, and then LiOH-H2O (22.6 mg, 0.55 mmol) was added, and stirred overnight at room temperature. After adjusting the pH to 1-2 with trifluoroacetic acid, the organic solvent was rotary evaporated, and then the target compound was separated and purified by HPLC to obtain 13.2 mg, yield: 18%. 1 H NMR (500 MHz, Methanol-d4) δ 8.85 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.22 (dd, J = 8.1, 2.2 Hz, 1H), 7.85 (dd, J = 8.1, 1.2 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.13 (dd, J = 7.7, 1.3 Hz, 1H), 7.03 (dd, J = 7.6, 1.3 Hz, 1H), 6.75 (dd, J = 8.7, 2.6 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 5.14 (d, J = 1.8 Hz, 2H), 4.85 (t, J = 6.5 Hz, 1H), 4.72 - 4.51 (m, 3H), 4.38 (dt, J = 11.6, 5.6 Hz, 1H), 4.29 - 4.17 (m, 1H), 4.13 (d, J = 17.0 Hz, 1H), 4.05 - 3.89 (m, 1H), 3.85 - 3.49 (m, 2H), 3.49 - 3.35 (m, 2H), 2.97 (s, 3H), 2.37 (tt, J = 6.1, 3.1 Hz, 2H), 2.08 (s, 3H), 2.05 (s, 3H).

[0191] Example 2: Synthesis of N-(7-((3'-(7-cyano-5-(((R)-3-hydroxypyrrolidin-l- yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)chroman-4- yl)-N-methylglycine (ZK073N)

[0192]

[0193] Step 1: Synthesis of N-(7-(3'-(7-cyano-5-formylbenzo[d]oxazol-2-yl)-2,2'- dimethyl-[l,l'-biphenyl]-3-yl)chroman-4-yl)-N-methylglycine ethyl ester (ZK070)

[0194] ZK052 (60 mg, 0.13 mmol), EH056 (68 mg, 0.21 mmol) were dissolved in a mixture of ethylene glycol dimethyl ether (15 mL) and sodium carbonate (2 M in H2O, 5 mL) under nitrogen atmosphere, Pd(pddf)Cl2-CH2Cl2(28 mg) was added, then the reaction was heated to 75 °C and continued to react for 12 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, water was added, then extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL ╳ 3) each three times, the organic phase was dried with anhydrous sodium sulfate and rotary evaporated to obtain the crude ZK070.

[0195] Step 2: Synthesis of ZK073N

[0196] The crude ZK070 (0.13 mmol) was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (35 mg, 0.4 mmol) was added, stirred at room temperature for 15 minutes, then AcOH (0.08 mL) was added, continued to stir for 15 minutes, then sodium triacetoxyborohydride (85.2 mg, 0.4 mmol) was added, and reacted at room temperature overnight. After the reaction was completed, water was added and extracted with dichloromethane, the organic phase was combined and rotary evaporated. The obtained crude product was dissolved in a mixture of tetrahydrofuran and H2O, then LiOH-H2O (27.5 mg, 0.67 mmol) was added, stirred at room temperature overnight, then trifluoroacetic acid was added to adjust pH = 1-2, the organic solvent was rotary evaporated, then the target compound was separated and purified by HPLC to obtain 18.3 mg, yield: 21%. 1H NMR (500 MHz, Methanol-d4) δ 8.28 (d, J = 1.6 Hz, 1H), 8.25 (dd, J = 7.9, 1.4 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.44 - 7.39 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.6, 1.4 Hz, 1H), 6.76 (dd, J = 8.8, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.16 (d, J = 2.0 Hz, 2H), 4.85 (d, J = 6.5 Hz, 1H), 4.60 (s, 3H), 4.39 (dt, J = 11.5, 5.2 Hz, 1H), 4.26 - 4.16 (m, 1H), 4.11 (d, J = 17.0 Hz, 1H), 3.93 (d, J = 17.0 Hz, 1H), 3.60 (s, 2H), 3.48 - 3.34 (m, 2H), 2.97 (s, 3H), 2.49 (s, 3H), 2.37 (tt, J = 6.9, 3.8 Hz, 3H), 2.09 (s, 4H).

[0197] Example 3: Synthesis of (3R)-1-((7-chloro-2-(3'-(((4-((2-hydroxyethyl)(methyl)amino)chroman-7-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3-ol (ZL015N)

[0198]

[0199] Step 1: Synthesis of 7-chloro-2-(3'-(4-(2-hydroxyethyl((methyl)amino)chroman-7-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde (ZL012)

[0200] ZK052 (200 mg, 0.45 mmol) was dissolved in anhydrous dichloromethane (20 mL) and anhydrous tetrahydrofuran (30 mL) and cooled to -78 °C, then diisobutylaluminum hydride (DIBAl-H, 1.0 mL, 1M in Hexane) was added dropwise to the reaction solution, after the addition was completed, it was slowly raised to 0 °C and continued to react for 12 hours. After the reaction was completed, the reaction solution was poured into ice water to quench, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate and rotary evaporated, finally separated by column chromatography to obtain the target compound 170 mg, yield: 93%. 1H NMR (500 MHz, Chloroform-d) δ 7.58 - 7.54 (m, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.65 (dd, J = 8.7, 2.6 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.01 (s, 2H), 4.97 (t, J = 6.0 Hz, 1H), 4.42 (ddd, J = 12.2, 8.4, 3.8 Hz, 1H), 4.21 - 4.18 (m, 1H), 4.05 - 3.92 (m, 2H), 3.82 (s, 1H), 2.93 (s, 3H), 2.42 (s, 5H), 2.32 (dddd, J = 14.7, 8.4, 6.1, 3.9 Hz, 1H).

[0201] Step 2 and 3: synthesis of ZL015N

[0202] Synthetic procedure: see example 2, steps 1 and 2, using the following starting materials ZL012 (170 mg, 0.41 mmol), ZK099 (218 mg, 0.55 mmol), Pd(pddf)Cl2-CH2Cl2(50 mg). Step 3 was performed using (R)-3-pyrrolidinol (28.7 mg, 0.33 mmol), AcOH (0.08 mL), sodium triacetoxyborohydride (70 mg, 0.33 mmol), LiOH-H2O (27.7 mg, 0.66 mmol). The target compound was obtained in 6.1 mg, 9% yield over two steps. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.7, 1.3 Hz, 1H), 6.76 (dd, J = 8.8, 2.5 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 5.16 (d, J = 1.7 Hz, 2H), 4.87 (t, J = 6.5 Hz, 1H), 4.59 (s, 3H), 4.39 (dt, J = 11.6, 5.6 Hz, 1H), 4.29 - 4.17 (m, 1H), 4.18 - 4.11 (m, 1H), 3.96 (d, J = 17.0 Hz, 1H), 3.66 (d, J = 50.7 Hz, 2H), 3.34 (d, J = 8.2 Hz, 2H), 3.28 - 3.19 (m, 1H), 2.98 (s, 3H), 2.46 (s, 3H), 2.37 (dq, J = 11.1, 5.5 Hz, 2H), 2.16 (s, 1H), 2.08 (s, 5H).

[0203] Example 4: Synthesis of N-(7-((3'-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK101N)

[0204]

[0205] Step 1: Synthesis of N-(7-(3'-(7-chloro-5-formylbenzo)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine ethyl ester (ZK101)

[0206] ZK052 (65 mg, 0.15 mmol), ZK099 (75 mg, 0.19 mmol) were dissolved in a mixture of ethyleneglycol dimethyl ether (15 mL) and sodium carbonate (2 M in H20, 3 mL) under nitrogen atmosphere, Pd(pddf)Cl2-CH2Cl2(30 mg, 0.015 mmol) was added and the reaction was continued at 75 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction was allowed to cool to room temperature, water was added and the reaction mixture was extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL)╳ 3) Each extraction was performed three times, and the organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude ZK101.

[0207] Step 2: Synthesis of ZK101N

[0208] The crude ZK101 (0.15 mmol) was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (39.2 mg, 0.45 mmol) was added. After stirring at room temperature for 15 minutes, AcOH (0.1 mL) was added and stirring was continued for 15 minutes. Then sodium triacetoxyborohydride (95.4 mg, 0.45 mmol) was added and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, water was added and extraction was performed with dichloromethane. The combined organic phase was rotary evaporated. The obtained crude product was dissolved in a mixture of tetrahydrofuran and H2O, then LiOH-H2O (30.8 mg, 0.75 mmol) was added and stirring was continued overnight at room temperature. After adjusting the pH to 1-2 with trifluoroacetic acid, the organic solvent was rotary evaporated, and then the target compound was separated and purified by HPLC to obtain 21.2 mg, yield: 22%. 1 H NMR (500 MHz, Methanol-d4) δ 8.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.7, 1.3 Hz, 1H), 6.76 (dd, J = 8.8, 2.5 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 5.16 (d, J = 1.7 Hz, 2H), 4.87 (t, J = 6.5 Hz, 1H), 4.59 (s, 3H), 4.39 (dt, J = 11.6, 5.6 Hz, 1H), 4.27 - 4.17 (m, 1H), 4.17 - 4.05 (m, 1H), 3.96 (d, J = 17.0 Hz, 1H), 3.66 (d, J = 50.7 Hz, 2H), 3.45 - 3.33 (m, 2H), 2.98 (s, 3H), 2.46 (s, 3H), 2.37 (dq, J = 11.1, 5.3, 4.7 Hz, 2H), 2.18 (d, J = 26.9 Hz, 1H), 2.08 (s, 3H).

[0209] Example 5: Synthesis of N-(6-((3'-(7-chloro-5-((((R)-3-hydroxypyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[1,1'-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydronaphthyl-1-yl)-N-methylglycine (ZZD012)

[0210]

[0211] Step 1: Synthesis of N-(6-(3'-(7-chloro-5-formylbenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydronaphth-1-yl)-N-methylglycine ethyl ester (ZZD009)

[0212] ZZD003 (300 mg, 0.67 mmol) and ZK099 (321.1 mg, 0.81 mmol) were dissolved in a mixed solution of ethylene glycol dimethyl ether (20 mL) and sodium carbonate (2 M in H2O, 10 mL). Pd(pddf)Cl2-CH2Cl2 (57 mg, 0.07 mmol) was added under a nitrogen atmosphere. The reaction solution was then heated to 75 °C and reacted under a nitrogen atmosphere for 12 hours. After the reaction was complete, the solution was allowed to return to room temperature, and water was added, followed by ethyl acetate (30 mL). ╳ 3) and dichloromethane (30mL) ╳ 3) Extract each phase three times, combine the organic phases, dry them with anhydrous sodium sulfate, and then evaporate to dryness to obtain 153.0 mg of the target compound. 1H NMR (500 MHz, CDC13) δ 10.05 - 10.00 (m, 1H), 8.23 - 8.16 (m, 2H), 7.96 - 7.90 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.86 (dd, J = 8.6, 2.6 Hz, 1H), 6.72 (br s, 1H), 5.07 (br s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.92 - 3.89 (m, 1H), 3.29 (dd, J = 16.5, 8.2 Hz, 1H), 3.17 (d, J = 16.5 Hz, 1H), 2.82 - 2.66 (m, 2H), 2.51 (s, 3H), 2.41 (s, 3H), 2.10 (s, 3H), 2.03 - 1.95 (m, 2H), 1.72 - 1.62 (m, 1H), 1.61 - 1.50 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H).

[0213] Step 2: Synthesis of ZZD012

[0214] ZZD009 (76.0 mg, 0.12 mmol) was dissolved in 1,2-dichloroethane (5 mL), then (R)-3-pyrrolidinol (21.3 mg, 0.24 mmol) was added, stirred at room temperature for 5 min, then AcOH (14.2 mg, 0.24 mmol) was added, stirred for 15 min, then sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction was completed, water was added for washing, and dichloromethane was used for extraction, and the organic phases were combined and rotary evaporated. The obtained crude product was dissolved in a mixed solution of tetrahydrofuran and H2O, then LiOH-H2O (32 mg, 0.76 mmol) was added, stirred at room temperature overnight, then trifluoroacetic acid was added to adjust pH = 1-2, then the organic solvent was rotary evaporated, and then HPLC separation and purification were carried out to obtain the target compound 31 mg, yield: 38%. ESI-MS C 40 H 42 ClN3O5[M+H] + = 680.28, found: 680.3.

[0215] Example 6: Synthesis of N-(5-((3'-(7-chloro-5-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)-N-methylglycine (ZL046N)

[0216]

[0217] Step 1: Synthesis of N-(5-(3'-(7-chloro-5-formylbenzo)-2,2'-dimethyl-[l,l'-biphenyl]-3-yl)- 2,3-dihydro-lH-inden-l-yl)-N-methylglycine (ZL044)

[0218] ZL040 (110 mg, 0.25 mmol), ZK099 (120 mg, 0.3 mmol) were dissolved in a mixture of ethylene glycol dimethyl ether (15 mL) and sodium carbonate (2 M in H2O, 3 mL) under nitrogen atmosphere, then Pd(pddf)Cl2-CH2Cl2(30 mg, 0.025 mmol) was added, and the reaction was continued at 75 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction was cooled to room temperature, water was added, and then the reaction was extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL ╳ 3) each three times, and the organic phase was dried over anhydrous sodium sulfate and then rotary evaporated to obtain the crude ZL044.

[0219] Step 2: Synthesis of ZL046 N

[0220] ZL044 (0.1 mmol) crude was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (25 mg, 0.3 mmol) was added, and the reaction was stirred at room temperature for 15 min, then AcOH (0.08 mL) was added, and the reaction was stirred for another 15 min, then sodium triacetoxyborohydride (62.6 mg, 0.3 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, water was added, and the reaction was extracted with dichloromethane, and the organic phase was combined and rotary evaporated. The obtained crude was dissolved in a mixture of tetrahydrofuran and H2O, then LiOH-H2O (21 mg, 0.5 mmol) was added, and the reaction was stirred at room temperature overnight, then trifluoroacetic acid was added to adjust pH = 1-2, and then the organic solvent was rotary evaporated, and then the target compound was separated and purified by HPLC to obtain 4.3 mg, yield: 6%. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 7.8 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.51 (t, J = 8.0 Hz, 3H), 7.39 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H), 7.05 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 5.04 (d, J = 8.2 Hz, 1H), 4.59 (s, 3H), 3.88 (d, J = 16.4 Hz, 1H), 3.74 (d, J = 16.7 Hz, 1H), 3.56 (s, 2H), 3.17 (dt, J = 15.9, 7.8 Hz, 2H), 3.08 - 2.95 (m, 2H), 2.82 (s, 3H), 2.57 (dt, J = 16.6, 8.7 Hz, 2H), 2.47 (d, J = 2.4 Hz, 4H), 2.10 (s, 4H).

[0221] Example 7: Synthesis of (R)-2-(6-((3'-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[1,1'-biphenyl]-3-yl)methoxy)-3,4-dihydroquinolin-1(2H)-yl)acetic acid (ZK152N)

[0222]

[0223] Step 1: Synthesis of 6-((3-bromo-2-methylbenzyl)oxy)-3,4-dihydroquinoline-1(2H)- carboxylic acid tert-butyl ester (ZK141)

[0224] Dissolve 1-bromo-3-(bromomethyl)-2-methylbenzene (800 mg, 3.05 mmol), 6-hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (835 mg, 3.35 mmol) in acetonitrile (30 mL), then add potassium carbonate (843 mg, 6.10 mmol), stir at room temperature for 12 hours, after the reaction is completed, spin dry the solvent, then add water, dichloromethane, and finally separate and purify with a chromatographic column to obtain the target compound 849 mg, yield: 92%. 1H NMR (500 MHz, Chloroform-d) δ 7.54 (dd, J = 8.1, 1.3 Hz, 2H), 7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.77 (dd, J = 9.0, 3.0 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 4.99 (s, 2H), 3.78 - 3.58 (m, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.91 (p, J = 6.6 Hz, 2H), 1.52 (s, 9H).

[0225] Step 2: Synthesis of 2-(6-((3-bromo-2-methylbenzyl)oxy)-3,4-dihydroquinolin-l(2H)- yl)acetic acid ethyl ester (ZK145)

[0226] ZK141 (849 mg, 1.97 mmol) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (2 mL) was added, and it was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate was added for quenching, and dichloromethane was used for extraction. The organic phase was washed with water, dried over anhydrous sodium sulfate, and then rotary evaporated. The obtained crude product was dissolved in MeCN (40 mL), and then ethyl chloroacetate (361.5 mg, 2.95 mmol) and Cs2CO3 (1.28 g, 3.94 mmol) were added. The reaction liquid was warmed to 40°C and stirred for 12 hours. After the reaction was completed, water was added for quenching, and dichloromethane was used for extraction. The organic phase was rotary evaporated, and then separated and purified by a chromatographic column to obtain the target compound 447 mg. Yield: 54%. 1 H NMR (500 MHz, Chloroform-d) δ 7.54 (dd, J = 8.1, 1.3 Hz, 2H), 7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.77 (dd, J = 9.0, 3.0 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 4.99 (s, 2H), 3.78 - 3.58 (m, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.91 (p, J = 6.6 Hz, 2H), 1.52 (s, 9H).

[0227] Step 3: Synthesis of ZK151

[0228] ZK145 (300 mg, 0.72 mmol), ZK099 (388 mg, 0.975 mmol) were dissolved in a mixture of ethyleneglycol dimethyl ether (30 mL) and sodium carbonate (2 M in H2O, 5 mL) under nitrogen atmosphere, Pd(pddf)Cl2-CH2Cl2(80 mg) was added, and the reaction was continued at 75 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction was cooled to room temperature, water was added, and the reaction was extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL ╳ 3) each, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give ZK151 as a crude product.

[0229] Step 4: Synthesis of (R)-2-(6-((3'-(7-chloro-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[1,1'-biphenyl]-3-yl)methoxy)-3,4-dihydroquinolin-1(2H)-yl)acetic acid (ZK152N)

[0230] ZK151 crude product (0.07 mmol, 40 mg) was dissolved in 1,2-dichloroethane (15 mL), and then (R)-3-pyrrolidinol (17.2 mg, 0.2 mmol) was added. After stirring at room temperature for 15 min, AcOH (0.06 mL) was added, and stirring was continued for 15 min. Then, sodium triacetoxyborohydride (41.8 mg, 0.2 mmol) was added, and the reaction was continued at room temperature overnight. After the reaction was completed, water was added, and the reaction was extracted with dichloromethane. The organic phase was combined and concentrated. The resulting crude product was dissolved in a mixture of tetrahydrofuran and H2O, and then LiOH-H2O (15 mg, 0.35 mmol) was added. After stirring at room temperature overnight, trifluoroacetic acid was added to adjust the pH to 1-2. The organic solvent was concentrated, and then the target compound was separated and purified by HPLC to give 15.3 mg, yield: 36%. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.2 Hz, 2H), 5.19 (s, 2H), 4.55 (d, J = 26.9 Hz, 3H), 3.65 (d, J = 43.0 Hz, 3H), 3.55 - 3.44 (m, 2H), 3.35 (s, OH), 2.96 (t, J = 6.5 Hz, 2H), 2.47 (s, 3H), 2.445 - 2.35 (m, 1H), 2.15 (q, J = 5.9 Hz, 2H), 2.10 (s, 3H).

[0231] Example 8: Synthesis of N-(7-((3'-(7-chloro-5-(((S)-3-hydroxypyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK157N)

[0232]

[0233] Synthesis method refers to Example 4 step 2, using the following raw materials: ZK101 (0.09 mmol) crude, (S)-3-pyrrolidinol (23.5 mg, 0.27 mmol), sodium triacetoxyborohydride (57.2 mg, 0.27 mmol), AcOH (0.06 mL), 1,2-dichloroethane (DCE, 20 mL), LiOH-H2O (18.5 mg, 0.45 mmol), tetrahydrofuran (THF, 8 mL), H2O (8 mL). The target compound 18.6 mg, yield: 30%. 1H NMR (500 MHz, Methanol-d4) δ 8.20 (dd, J = 7.9, 1.3 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.6, 1.3 Hz, 1H), 6.75 (dd, J = 8.8, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 4.86 (t, J = 6.5 Hz, 1H), 4.59 (s, 3H), 4.39 (dt, J = 11.5, 5.2 Hz, 1H), 4.25 - 4.14 (m, 1H), 4.10 (d, J = 16.9 Hz, 1H), 4.00 - 3.86 (m, 1H), 3.65 (d, J = 54.3 Hz, 2H), 3.35 (s, 1H), 2.97 (s, 3H), 2.46 (s, 3H), 2.37 (tt, J = 6.8, 3.9 Hz, 2H), 2.18 (d, J = 30.4 Hz, 1H), 2.08 (s, 4H).

[0234] Example 9: Synthesis of 3-((7-((3'-(7-chloro-5-(((R)-3-hydroxypyrrolidin-l- yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[l,r-biphenyl]-3-yl)methoxy)chroman-4- yl)(methyl)amino)propanoic acid (ZK114N)

[0235]

[0236] Step 1: Synthesis of 3-((7-((3-bromo-2-methylbenzyl)oxy)chroman-4-yl)amino)propanoic acid ethyl ester (ZK079)

[0237] ZK049 (250 mg, 0.72 mmol), alanine ethyl ester hydrochloride (665.9 mg, 4.34 mmol) were dissolved in tetrahydrofuran (30 mL) and stirred at room temperature for 15 minutes, then AcOH (0.12 mL) was added, and the stirring was continued at room temperature for 30 minutes, then sodium cyanoborohydride (272.7 mg, 4.34 mmol) was added, and the reaction was then warmed to 45 °C for 12 hours. After the reaction was completed, the solvent was rotary evaporated, water was added, and ethyl acetate was extracted, and the target compound was obtained after reverse phase column purification, 116 mg, yield: 36%. 1H NMR (500 MHz, Methanol-d4) δ 7.55 (dd, J = 8.1, 1.3 Hz, 1H), 7.37 (dd, J = 7.6, 1.2 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.69 (dd, J = 8.6, 2.6 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 5.11 (s, 2H), 4.51 (t, J = 4.5 Hz, 1H), 4.35 (dd, J = 12.0, 0.8 Hz, 1H), 4.29 - 4.23 (m, 1H), 4.23 - 4.17 (q, 2H), 3.47 (dd, J = 7.5, 6.5 Hz, 1H), 3.39 (d, J = 6.3 Hz, 1H), 2.92 - 2.70 (m, 2H), 2.42 (s, 3H), 2.35 (p, J = 4.7 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0238] Step 2: Synthesis of 3-((7-((3-bromo-2-methylbenzyl)oxy)chroman-4-yl)(methyl)amino)propanoic acid ethyl ester (ZK106)

[0239] ZK079 (116 mg, 0.26 mmol), formaldehyde (37%, 210.8 mg, 2.6 mmol) were dissolved in a mixture solution of tetrahydrofuran (10 mL) and methanol (10 mL) and stirred at room temperature for 15 minutes, then AcOH (0.08 mL) was added and the reaction was continued for 30 minutes, finally sodium triacetoxyborohydride (548 mg, 2.6 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated, water was added, and ethyl acetate was extracted. The organic phase was collected and dried with anhydrous sodium sulfate. After evaporation, 110 mg of the target compound was obtained. 1H NMR (500 MHz, Methanol-d4) δ 7.54 (dd, J = 8.1, 1.2 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.54 (dd, J = 8.6, 2.6 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 5.04 (s, 2H), 4.30 (ddd, J = 11.7, 5.4, 3.6 Hz, 1H), 4.13 (qd, J = 7.2, 2.8 Hz, 2H), 4.08 (ddd, J = 11.0, 9.7, 2.7 Hz, 1H), 3.96 (dd, J = 8.8, 5.7 Hz, 1H), 2.91 - 2.76 (m, 2H), 2.52 (td, J = 6.9, 3.8 Hz, 2H), 2.42 (s, 3H), 2.25 (s, 3H), 2.04 (dtd, J = 13.1, 9.4, 3.7 Hz, 1H), 1.98 (s, 1H), 1.97 - 1.91 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H).

[0240] Step 3: Synthesis of ZK114N

[0241] ZL106 (55 mg, 0.12 mmol), ZK099 (71 mg, 0.18 mmol) were dissolved in a mixture of ethyleneglycol dimethyl ether (15 mL) and sodium carbonate (2 M in H2O, 3 mL) under nitrogen atmosphere, Pd(pddf)Cl2-CH2Cl2(25 mg, 0.012 mmol) was added, then the reaction was heated to 75 °C and continued to react for 12 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, water was added, then extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL ╳ 3) each three times, the organic phase was dried with anhydrous sodium sulfate and rotary evaporated to obtain ZL110 crude product.

[0242] The crude ZL110 (0.11 mmol) was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (28.7 mg, 0.33 mmol) was added. After stirring at room temperature for 15 minutes, AcOH (0.06 mL) was added. After stirring at room temperature for 15 minutes, sodium triacetoxyborohydride (70 mg, 0.3 mmol) was added. After reaction at room temperature overnight, water was added to wash, and dichloromethane was used to extract. The organic phase was combined and concentrated. The obtained crude product was dissolved in a mixture of tetrahydrofuran and H2O, then LiOH-H2O (22.6 mg, 0.55 mmol) was added. After stirring at room temperature overnight, trifluoroacetic acid was added to adjust pH = 1-2. The organic solvent was concentrated, and then the target compound was separated and purified by HPLC to obtain 13.3 mg, yield: 17%. 1 H NMR (500 MHz, Methanol-d4) δ 8.20 (dd, J = 7.9, 1.4 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.39 (td, J = 5.0, 4.5, 2.7 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 7.6, 1.3 Hz, 1H), 6.76 (dd, J = 8.7, 2.6 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 5.16 (s, 2H), 4.83 (s, 1H), 4.67 - 4.48 (m, 3H), 4.35 (ddd, J = 11.8, 7.9, 3.8 Hz, 1H), 4.28 - 4.17 (m, 1H), 3.65 (d, J = 53.9 Hz, 2H), 3.48 (dt, J = 14.3, 7.7 Hz, 2H), 3.37 (dd, J = 11.9, 5.5 Hz, 2H), 2.89 (t, J = 6.9 Hz, 1H), 2.86 - 2.76 (m, 2H), 2.47 (s, 4H), 2.42 - 2.29 (m, 2H), 2.16 (s, 1H), 2.09 (s, 3H).

[0243] Example 10: Synthesis of N-(7-((3'-(7-chloro-5-(((3- (dimethylamino)propyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)chroman-4-yl)-N-methylglycine (ZK116N)

[0244]

[0245] The synthesis was performed according to the procedure described in Example 4, step 2, using the following starting materials: ZK101 (0.11 mmol) crude, 3-dimethylaminopropylamine (33.7 mg, 0.33 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol), AcOH (0.06 mL), 1,2-dichloroethane (20 mL). LiOH-H2O (27.7 mg, 0.66 mmol), THF (8 mL), H2O (8 mL) to give 17.5 mg of the target compound in 23% yield. 1 H NMR (500 MHz, Methanol-d4) δ 8.20 (dd, J = 8.0, 1.5 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.6, 1.3 Hz, 1H), 6.76 (dd, J = 8.7, 2.6 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 5.17 (d, J = 2.3 Hz, 2H), 4.86 (t, J = 6.6 Hz, 1H), 4.41 (s, 2H), 4.40 - 4.36 (m, 1H), 4.21 (dt, J = 11.6, 5.9 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H), 3.95 (d, J = 17.0 Hz, 1H), 3.28 - 3.23 (m, 2H), 3.23 - 3.18 (m, 2H), 2.97 (s, 3H), 2.92 (s, 6H), 2.46 (s, 3H), 2.38 (dp, J = 7.1, 3.6 Hz, 2H), 2.25 - 2.14 (m, 2H), 2.09 (s, 3H).

[0246] Example 11: Synthesis of N-(7-((3'-(7-chloro-5-(((2- (dimethylamino)ethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)methoxy)chroman-4-yl)-N-methylglycine (ZK115N)

[0247]

[0248] The synthesis was carried out according to the procedure described in Example 4, Step 2 using the following starting materials: ZK101 (0.11 mmol) crude, N,N-dimethylethylenediamine (29.1 mg, 0.33 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol), AcOH (0.06 mL), 1,2-dichloroethane (20 mL). LiOH-H2O (27.7 mg, 0.66 mmol), THF (8 mL), H2O (8 mL). The target compound was obtained in 21.4 mg, yield: 29%. 1 H NMR (500 MHz, Methanol-d4) δ 8.19 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.54 - 7.44 (m, 2H), 7.40 (dd, J = 19.4, 8.1 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.75 (dd, J = 8.7, 2.5 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 4.86 (t, J = 7.4 Hz, 1H), 4.45 (s, 2H), 4.39 (dt, J = 11.6, 5.6 Hz, 1H), 4.20 (dt, J = 11.6, 5.6 Hz, 1H), 4.13 (d, J = 16.9 Hz, 1H), 3.95 (d, J = 17.2 Hz, 1H), 3.67 - 3.59 (m, 2H), 3.59 - 3.52 (m, 2H), 2.98 (d, J = 6.0 Hz, 9H), 2.45 (s, 3H), 2.43 - 2.32 (m, 2H), 2.08 (s, 3H).

[0249] Example 12: Synthesis of N-(7-((3'-(7-chloro-5-(((3-hydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1))'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK118N)

[0250]

[0251] The synthesis was carried out according to the procedure described in Example 4, Step 2 using the following starting materials: ZK101 (0.11 mmol) crude, 3-amino-1-propanol (25 mg, 0.33 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol), AcOH (0.06 mL), 1,2-dichloroethane (20 mL). LiOH-H2O (27.7 mg, 0.66 mmol), THF (8 mL), H2O (8 mL). The target compound was obtained in 23.3 mg, yield: 32%. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 8.7, 2.5 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.16 (s, 2H), 4.86 (t, J = 6.7 Hz, 1H), 4.45 - 4.32 (m, 3H), 4.20 (dt, J = 11.7, 5.1 Hz, 1H), 4.08 (d, J = 16.9 Hz, 1H), 3.98 - 3.86 (m, 1H), 3.71 (t, J = 5.7 Hz, 2H), 3.22 (t, J = 7.4 Hz, 2H), 2.97 (s, 3H), 2.43 (s, 3H), 2.37 (td, J = 6.6, 3.2 Hz, 2H), 2.08 (s, 3H), 1.94 (p, J = 6.4 Hz, 2H).

[0252] Example 13: Synthesis of N-(7-((3'-(7-chloro-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1))'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK117N)

[0253]

[0254] The synthesis method is described in Example 4, step 2, using the following starting materials: ZK101 (0.11 mmol) crude, ethanolamine (0.1 mg, 0.33 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol), AcOH (0.06 mL), 1,2-dichloroethane (20 mL). LiOH-H2O (27.7 mg, 0.66 mmol), THF (8 mL), H2O (8 mL) to give the target compound 9.7 mg, yield: 15%. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (dd, J = 7.9, 1.4 Hz, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.7, 1.3 Hz, 1H), 6.76 (dd, J = 8.7, 2.6 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 5.16 (d, J = 2.0 Hz, 2H), 4.86 (t, J = 6.5 Hz, 1H), 4.41 (s, 2H), 4.40 - 4.35 (m, 1H), 4.24 - 4.16 (m, 1H), 4.13 (d, J = 17.1 Hz, 1H), 3.95 (d, J = 17.1 Hz, 1H), 3.88 - 3.79 (m, 2H), 3.24 - 3.16 (m, 2H), 2.97 (s, 3H), 2.46 (s, 3H), 2.38 (dd, J = 8.9, 4.8 Hz, 2H), 2.09 (s, 3H).

[0255] Example 14: Synthesis of N-(7-((3'-(7-chloro-5-(((2-methoxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1))'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK125N)

[0256]

[0257] Synthesis was performed according to the procedure described in Example 4, step 2, using the following starting materials: ZK101 (0.074 mmol) crude, 2-methoxyethylamine (16.7 mg, 0.22 mmol), sodium triacetoxyborohydride (46 mg, 0.22 mmol), AcOH (0.05 mL), 1,2-dichloroethane (20 mL). LiOH-H2O (16 mg, 0.37 mmol), THF (8 mL), H2O (8 mL) to give the target compound 11.7 mg, yield: 24%. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (dd, J = 7.9, 1.4 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.19 - 7.12 (m, 1H), 6.73 (dd, J = 8.7, 2.6 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.81 (t, J = 7.1 Hz, 1H), 4.38 (s, 3H), 4.22 - 4.10 (m, 1H), 3.72 (d, J = 16.2 Hz, 1H), 3.69 - 3.65 (m, 2H), 3.63 - 3.56 (m, 1H), 3.29 - 3.25 (m, 3H), 2.93 (s, 3H), 2.46 (s, 3H), 2.37 (dt, J = 10.3, 3.3 Hz, 1H), 2.30 (d, J = 3.9 Hz, 0H), 2.08 (s, 3H).

[0258] Example 15: Synthesis of N-(7-((3'-(7-chloro-5-(((3-methoxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1))'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK126N)

[0259]

[0260] Synthesis was performed according to the procedure described in Example 4, step 2, using the following starting materials: ZK101 (0.074 mmol) crude, 3-methoxypropylamine (19.6 mg, 0.22 mmol), sodium triacetoxyborohydride (46 mg, 0.22 mmol), AcOH (0.05 mL), 1,2-dichloroethane (20 mL), LiOH-H20 (16 mg, 0.37 mmol), THF (8 mL), H20 (8 mL), to give the target compound 13.6 mg, yield: 27%. 1H NMR (500 MHz, Methanol-d4) δ 8.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.87 (dd, J = 3.9, 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 7.6, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.7, 1.3 Hz, 1H), 6.73 (dd, J = 8.8, 2.6 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.81 (t, J = 7.1 Hz, 2H), 4.39 (dd, J = 7.0, 4.4 Hz, 1H), 4.16 (ddd, J = 11.8, 8.7, 3.1 Hz, 1H), 3.67 (d, J = 16.3 Hz, 1H), 3.58 - 3.50 (m, 3H), 3.36 (s, 3H), 3.20 (t, J = 7.2 Hz, 2H), 2.92 (s, 3H), 2.46 (d, J = 1.2 Hz, 3H), 2.41 - 2.32 (m, 1H), 2.29 (dd, J = 10.6, 6.7 Hz, 1H), 2.08 (s, 3H), 1.99 (ddd, J = 12.7, 7.2, 5.6 Hz, 3H).

[0261] Example 16: Synthesis of N-(7-((3'-(7-chloro-5-((methylamino)methyl)benzo[d]oxazol-2-yl)-2,2'- dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK137N)

[0262]

[0263] The synthesis was performed according to the procedure described in Example 4, step 2, using the following starting materials: ZK101 (0.063 mmol) crude, methylamine (22 mg, 0.19 mmol, 27% in MeOH), sodium triacetoxyborohydride (40.3 mg, 0.19 mmol), AcOH (0.05 mL), 1,2-dichloroethane (15 mL), LiOH-H20 (13 mg, 0.32 mmol), THF (8 mL), H20 (8 mL), to give 15.2 mg of the target compound in 39% yield. 1H NMR (500 MHz, Methanol-d4) δ 8.20 (dd, J = 7.9, 1.4 Hz, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 7.5, 1.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.6, 1.3 Hz, 1H), 6.76 (dd, J = 8.8, 2.5 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 5.16 (d, J = 2.3 Hz, 2H), 4.85 (t, J = 6.6 Hz, 1H), 4.39 (dt, J = 11.5, 5.6 Hz, 1H), 4.34 (s, 2H), 4.20 (dt, J = 11.6, 5.6 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 3.94 (d, J = 17.1 Hz, 1H), 2.97 (s, 3H), 2.77 (s, 3H), 2.46 (s, 3H), 2.37 (d, J = 4.7 Hz, 2H), 2.09 (s, 3H).

[0264] Example 17: Synthesis of N-(7-((3'-(7-chloro-5-(((S)-3-hydroxypiperidin-l- yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)chroman-4- yl)-N-methylglycine (ZK135N)

[0265]

[0266] The synthesis method is described in Example 4, step 2, using the following starting materials: ZK101 (0.063 mmol) crude, (S)-3-hydroxypiperidine hydrochloride (26.2 mg, 0.19 mmol), sodium triacetoxyborohydride (40.3 mg, 0.19 mmol), AcOH (0.05 mL), 1,2-dichloroethane (15 mL), LiOH-H20 (13 mg, 0.32 mmol), THF (8 mL), H20 (8 mL), to give the target compound 11.2 mg, yield: 26%. 1H NMR (500 MHz, Methanol-d4) δ 8.20 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 4.8 Hz, 1H), 7.69 (d, J = 4.3 Hz, 1H), 7.56 - 7.46 (m, 2H), 7.40 (dd, J = 16.7, 8.1 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 8.8, 2.7 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 5.17 (d, J = 10.1 Hz, 2H), 4.86 (t, J = 6.6 Hz, 1H), 4.52 (d, J = 14.5 Hz, 2H), 4.46 - 4.32 (m, 2H), 4.20 (dt, J = 11.8, 5.8 Hz, 1H), 4.12 (d, J = 16.5 Hz, 2H), 4.04 - 3.84 (m, 1H), 3.61 - 3.42 (m, 2H), 3.25 (d, J = 12.3 Hz, 1H), 3.09 (d, J = 11.9 Hz, 2H), 2.98 (d, J = 7.0 Hz, 3H), 2.45 (s, 3H), 2.38 (t, J = 6.6 Hz, 2H), 2.18 - 2.06 (m, 3H), 1.93 - 1.63 (m, 2H).

[0267] Example 18: Synthesis of N-(7-((3'-(7-chloro-5-((4-hydroxypiperidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK134N)

[0268]

[0269] The synthesis method refers to Example 4 step 2, using the following raw materials: ZK101 (0.063 mmol) crude product, 4-hydroxypiperidine (19.2 mg, 0.19 mmol), sodium triacetoxyborohydride (40.3 mg, 0.19 mmol), AcOH (0.05 mL), 1,2-dichloroethane (15 mL). LiOH-H2O (13 mg, 0.32 mmol), THF (8 mL), H2O (8 mL). The target compound 1.8 mg, yield: 4%. ESI-MS C 40 H 42 ClN3O6[M+H] + = 696.28, found: 696.4.

[0270] Example 19: Synthesis of N-(7-((3'-(7-chloro-5-((((R)-3-(dimethylamino)pyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2)'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK133N)

[0271]

[0272] The synthesis method is described in step 2 of Example 4, using the following raw materials: crude ZK101 (0.063 mmol), (S)-3-hydroxypiperidine hydrochloride (26.2 mg, 0.19 mmol), sodium triacetoxyborohydride (40.3 mg, 0.19 mmol), AcOH (0.05 mL), 1,2-dichloroethane (15 mL), LiOH-H2O (13 mg, 0.32 mmol), THF (8 mL), and H2O (8 mL). 13.8 mg of the target compound was obtained, with a yield of 31%. 1 H NMR (500MHz, Methanol-d4) δ8.17(d,J=7.7Hz,1H),7.81(s,1H),7.60(d,J=1.5Hz,1H),7.54–7.45(m,2H),7.42(d,J=8.8Hz, 1H),7.38(d,J=7.4Hz,1H),7.31(t,J=7.6Hz,1H),7.19–7.11(m,1H),6.75(dd,J=8.7,2.6Hz,1H),6.62(d,J=2.5Hz,1H),5.1 6(d,J=2.4Hz,2H),4.84(t,J=6.6Hz,1H),4.38(dt,J=11.5,5.3Hz,1H),4.18(s,3H),4.04–3.93(m,2H),3.82(d,J=16.8Hz,1 H),3.35(d,J=9.7Hz,1H),2.95(s,3H),2.89(s,6H),2.45(s,2H),2.44(s,2H),2.41–2.27(m,2H),2.20(s,1H),2.08(s,3H).

[0273] Example 20: Synthesis of N-(7-((3'-(5-((((1H-pyrazol-4-yl)amino)methyl)-7-chlorobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZL017N)

[0274]

[0275] The synthesis method is described in step 2 of Example 4, using the following raw materials: crude ZK101 (0.09 mmol), 4-aminopyrazole (22.4 mg, 0.27 mmol), sodium triacetoxyborohydride (40.3 mg, 0.27 mmol), AcOH (0.06 mL), 1,2-dichloroethane (20 mL), LiOH-H2O (18.5 mg, 0.45 mmol), THF (8 mL), and H2O (8 mL). 12.4 mg of the target compound was obtained, yield: 20%. 1 H NMR(500MHz, Methanol-d4)δ8.20(dt,J=8.0,2.8Hz,1H),7.82(d,J=1.7Hz,2H),7.60(d,J=1.6Hz,1H),7.52–7.46(m,2H) ,7.43–7.37(m,2H),7.31(t,J=7.6Hz,1H),7.18–7.13(m,1H),6.76(dd,J=8.8,2.6Hz,1H),6.63(d,J=2.6Hz,1H),5.16(d, J=2.4Hz,2H),4.85(q,J=6.3Hz,1H),4.68(d,J=4.4Hz,2H),4.39(dt,J=11.7,5.7Hz,1H),4.20(dt,J=11.6,5.5Hz,1H),4. 11(dd,J=13.5,6.4Hz,1H),3.98(s,1H),2.97(s,3H),2.45(d,J=8.7Hz,3H),2.37(s,2H),2.09(s,3H),2.04–1.99(m,1H).

[0276] Example 21: Synthesis of N-(7-((3'-(7-chloro-5-(((((S)-2,3-dihydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZK127N)

[0277]

[0278] The synthesis method is described in step 2 of Example 4, using the following raw materials: crude ZK101 (0.074 mmol), (S)-3-amino-1,2-propanediol (21 mg, 0.23 mmol), sodium triacetoxyborohydride (46 mg, 0.23 mmol), AcOH (0.05 mL), 1,2-dichloroethane (15 mL), LiOH-H2O (16 mg, 0.37 mmol), THF (8 mL), and H2O (8 mL). 12.4 mg of the target compound was obtained, with a yield of 24%.1 H NMR (500 MHz, Methanol-d4) δ 8.26 - 8.20 (m, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.76 (dd, J = 8.7, 2.5 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.83 (t, J = 7.2 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.22 - 4.14 (m, 1H), 4.00 - 3.93 (m, 1H), 3.63 (dd, J = 11.2, 4.6 Hz, 1H), 3.60 (s, 1H), 3.57 (dd, J = 11.2, 5.7 Hz, 1H), 3.52 (s, 1H), 3.50 - 3.45 (m, 1H), 3.26 (dd, J = 12.7, 3.2 Hz, 1H), 3.20 (p, J = 1.6 Hz, 1H), 3.09 (dd, J = 12.7, 9.3 Hz, 1H), 2.95 (s, 3H), 2.49 (d, J = 2.1 Hz, 3H), 2.38 (s, 1H), 2.31 (s, 1H), 2.11 (s, 3H).

[0279] Example 22: Synthesis of N-(7-((3'-((3-(((R)-3-hydroxypyrrolidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZK119N)

[0280]

[0281] Step 1: Synthesis of N-(7-(3'-(3-formyl-l,7-naphthyridin-8-ylamino)-2,2'-dimethyl- [l,l'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine ethyl ester (ZK119)

[0282] ZK068 (50 mg, 0.1 mmol), ZL106 (26 mg, 0.075 mmol, synthesis method see patent WO2018119286) were dissolved in a mixed solution of ethylene glycol dimethyl ether (15 mL) and sodium carbonate (2M in H2O, 3 mL), Pd(pddf)Cl2-CH2Cl2(12 mg, 0.01 mmol) was added under nitrogen atmosphere, then the reaction solution was heated to 75°C and continued to react under nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, then extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL ╳ 3) each three times, the organic phase was dried with anhydrous sodium sulfate and rotary evaporated to obtain ZK119 crude product.

[0283] Step 2: synthesis of ZK119N

[0284] ZK119 (0.075 mmol) crude product was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (19.6 mg, 0.23 mmol) was added, stirred at room temperature for 15 minutes, then AcOH (0.08 mL) was added, stirred for 15 minutes, then sodium triacetoxyborohydride (48.8 mg, 0.23 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction was completed, water was added and extracted with dichloromethane, the organic phase was combined and rotary evaporated. The obtained crude product was dissolved in a mixed solution of tetrahydrofuran and H2O, then LiOH-H2O (15.4 mg, 0.38 mmol) was added, stirred at room temperature overnight, then trifluoroacetic acid was added to adjust pH = 1-2, the organic solvent was rotary evaporated, then HPLC separation and purification were carried out to obtain the target compound 32.3 mg, yield: 64%. 1H NMR (400 MHz, Methanol-d4) δ 9.21 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 5.5, 3.5 Hz, 1H), 7.31 (dd, J = 9.5, 7.3 Hz, 2H), 7.19 (dd, J = 7.7, 1.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.85 (d, J = 6.6 Hz, 1H), 4.79 (d, J = 6.5 Hz, 2H), 4.62 (s, 1H), 4.38 (dt, J = 11.5, 5.7 Hz, 1H), 4.25 - 4.18 (m, 1H), 4.15 (d, J = 16.9 Hz, 1H), 3.97 (d, J = 17.1 Hz, 1H), 3.70 (s, 1H), 3.57 (s, 2H), 3.43 (s, 1H), 2.97 (s, 3H), 2.37 (q, J = 6.1 Hz, 3H), 2.14 (s, 4H), 2.05 (s, 3H).

[0285] Example 23: Synthesis of N-(7-((3'-((3-((((S)-2,3-dihydroxypropyl)amino)methyl)-1,7- naphthyridin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZL116N)

[0286]

[0287] The synthesis method is shown in Example 22 step 2, using the following raw materials: ZK119 (0.1 mmol) crude product, (S)-3-amino-1,2-propanediol (27.3 mg, 0.3 mmol), sodium triacetoxyborohydride (63.6 mg, 0.3 mmol), AcOH (0.09 mL), 1,2-dichloroethane (20 mL), LiOH-H2O (25 mg, 0.37 mmol), THF (10 mL), H2O (10 mL), to obtain 18.3 mg of the target compound, yield: 27%. 1H NMR (500 MHz, Methanol-d4) δ 9.18 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.47 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.19 (dd, J = 7.6, 1.5 Hz, 1H), 6.75 (dd, J = 8.7, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.85 (t, J = 6.6 Hz, 1H), 4.62 (d, J = 1.7 Hz, 2H), 4.38 (dt, J = 11.5, 5.1 Hz, 1H), 4.19 (dt, J = 11.6, 5.7 Hz, 1H), 4.09 (d, J = 17.1 Hz, 1H), 3.99 (dq, J = 8.9, 4.6 Hz, 1H), 3.91 (d, J = 20.7 Hz, 1H), 3.63 (dd, J = 11.3, 4.5 Hz, 1H), 3.56 (dd, J = 11.2, 5.6 Hz, 1H), 3.34 - 3.32 (m, 1H), 3.21 - 3.14 (m, 1H), 2.96 (s, 3H), 2.36 (t, J = 5.1 Hz, 2H), 2.14 (s, 3H), 2.05 (s, 3H).

[0288] Example 24: Synthesis of N-(6-((3'-((3-(((R)-3-hydroxypyrrolidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)-l,2,3,4- tetrahydronaphthalen-l-yl)-N-methylglycine (ZL111N)

[0289]

[0290] Step 1: Synthesis of N-(6-(3'-(3-formyl-l,7-naphthyridin-8-yl)amino)-2,2'- dimethyl-[l,l'-biphenyl]-3-yl)methoxy)-l,2,3,4-tetrahydronaphthalen-l-yl)-N- methylglycine ethyl ester (ZL108)

[0291] ZL101 (140 mg, 0.28 mmol), ZL106 (75 mg, 0.22 mmol) were dissolved in a mixture of ethyleneglycol dimethyl ether (20 mL) and sodium carbonate (2 M in H20, 3 mL) under nitrogen atmosphere, Pd(pddf)Cl2-CH2Cl2(30 mg) was added, then the reaction was heated to 75 °C and continued to react for 12 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, water was added, then extracted with ethyl acetate (30 mL ╳ 3) and dichloromethane (30 mL ╳ 3) each three times, the organic phase was dried with anhydrous sodium sulfate and then rotary evaporated to obtain the crude ZL108.

[0292] Step 2: Synthesis of ZL111N

[0293] ZL108 (0.11 mmol) crude was dissolved in 1,2-dichloroethane (20 mL), then (R)-3-pyrrolidinol (28.7 mg, 0.33 mmol) was added, stirred at room temperature for 15 minutes, then AcOH (0.09 mL) was added, continued to stir for 15 minutes, then sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added, and reacted at room temperature overnight. After the reaction was completed, water was added, extracted with dichloromethane, and the organic phase was combined and rotary evaporated. The obtained crude was dissolved in a mixture of tetrahydrofuran (10 mL) and H20 (10 mL), then LiOH-H20 (25 mg, 0.55 mmol) was added, stirred at room temperature overnight, then trifluoroacetic acid was added to adjust pH = 1-2, the organic solvent was rotary evaporated, then HPLC separation and purification were carried out to obtain the target compound 8.7 mg, yield: 12%. 1 H NMR (400 MHz, Methanol-d4) δ 9.20 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.54 (d, J = 4.4 Hz, 2H), 7.50 (t, J = 8.4 Hz, 2H), 7.35 (t, J = 4.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 9.3 Hz, 1H), 6.94 (s, 1H), 5.18 (s, 2H), 4.83 - 4.70 (m, 2H), 4.62 (s, 1H), 4.21 - 3.96 (m, 2H), 3.95 - 3.78 (m, 2H), 3.71 (s, 2H), 3.56 (s, 2H), 3.46 (d, J = 17.5 Hz, 2H), 2.87 (d, J = 12.1 Hz, 3H), 2.80 (d, J = 17.0 Hz, 2H), 2.32 (s, 2H), 2.15 (s, 3H), 2.05 (s, 3H), 1.76 (s, 1H).

[0294] Example 25: Synthesis of N-(7-((3'-((3-(((S)-3-hydroxypyrrolidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZL127N)

[0295]

[0296] Synthesis method see Example 22 step 2, using the following raw materials: ZK119 (0.08 mmol) crude, (S)-3-pyrrolidinol (20.9 mg, 0.24 mmol, 27% in MeOH), sodium triacetoxyborohydride (50.9 mg, 0.24 mmol), AcOH (0.07 mL), tetrahydrofuran (20 mL), LiOH-H2O (16.4 mg, 0.4 mmol), THF (8 mL), H2O (8 mL), to get the target compound 15.6 mg, yield: 29%. 1 H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.60 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.54 (t, J = 3.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.32 (q, J = 9.4, 8.7 Hz, 3H), 7.19 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.62 (d, J = 2.9 Hz, 1H), 5.16 (s, 2H), 4.79 (d, J = 6.5 Hz, 2H), 4.62 (s, 1H), 4.46 - 4.32 (m, 1H), 4.27 - 4.16 (m, 1H), 4.13 (d, J = 17.1 Hz, 1H), 4.02 - 3.86 (m, 1H), 3.71 (s, 1H), 3.56 (s, 2H), 3.43 (s, 1H), 2.97 (s, 3H), 2.37 (d, J = 7.1 Hz, 3H), 2.21 (s, 1H), 2.14 (s, 4H), 2.05 (d, J = 2.1 Hz, 3H).

[0297] Example 26: Synthesis of N-(7-((3'-((3-(((2-hydroxyethyl)amino)methyl)-l,7- naphthyridin-8-yl)amino)-2,2'-dimethyl-[l,l'))-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZL129N)

[0298]

[0299] The synthesis was carried out according to the procedure described in Example 22, Step 2, using the following starting materials: ZK119 (0.08 mmol) crude, ethanolamine (14.7 mg, 0.24 mmol), sodium triacetoxyborohydride (50.9 mg, 0.24 mmol), AcOH (0.07 mL), tetrahydrofuran (20 mL), LiOH-H2O (16.4 mg, 0.4 mmol), THF (8 mL), H2O (8 mL), to give the target compound 11.2 mg, yield: 22%. 1 H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 8.51 (s, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.30 (t, J = 7.2 Hz, 3H), 7.18 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.61 (s, 1H), 5.15 (s, 2H), 4.94 (s, 1H), 4.81 - 4.70 (m, 2H), 4.60 (s, 2H), 4.38 (s, 1H), 4.16 (d, J = 11.7 Hz, 1H), 3.93 (s, 1H), 3.89 (s, 2H), 3.76 (d, J = 16.4 Hz, 1H), 2.95 (s, 3H), 2.35 (s, 2H), 2.13 (s, 3H), 2.04 (s, 3H).

[0300] Example 27: Synthesis of N-(7-((2,2'-dimethyl-3'-((3-((methylamino)methyl)-1,7- naphthyridin-8-yl)amino)-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZL128N)

[0301]

[0302] The synthesis was carried out according to the procedure described in Example 22, Step 2, using the following starting materials: ZK119 (0.08 mmol) crude, methylamine (27.6 mg, 0.24 mmol, 27% in MeOH), sodium triacetoxyborohydride (50.9 mg, 0.24 mmol), AcOH (0.07 mL), tetrahydrofuran (20 mL), LiOH-H2O (16.4 mg, 0.4 mmol), THF (8 mL), H2O (8 mL), to give the target compound 12 mg, yield: 24%. 1H NMR (400 MHz, Methanol-d4) δ 9.15 (s, 1H), 8.50 (s, 1H), 7.67 - 7.61 (m, 1H), 7.57 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 7.7 Hz, 3H), 7.18 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 5.15 (s, 2H), 4.95 (d, J = 2.1 Hz, 1H), 4.55 (s, 2H), 4.46 - 4.31 (m, 1H), 4.19 (s, 1H), 4.00 (d, J = 16.8 Hz, 1H), 3.83 (d, J = 16.8 Hz, 1H), 2.96 (s, 3H), 2.87 (d, J = 2.2 Hz, 3H), 2.39 (d, J = 25.3 Hz, 2H), 2.14 (s, 3H), 2.04 (d, J = 2.1 Hz, 3H).

[0303] Example 28: Synthesis of N-(7-((3'-((3-(((R)-3-hydroxypiperidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZL131N)

[0304]

[0305] Synthesis method refers to example 22 step 2, using the following raw materials: ZK119 (0.08 mmol) crude product, (R)-piperidin-3-ol (24.3 mg, 0.24 mmol), sodium cyanoborohydride (15.1 mg, 0.24 mmol), AcOH (0.07 mL), tetrahydrofuran (20 mL), LiOH-H2O (16.4 mg, 0.4 mmol), THF (8 mL), H2O (8 mL), to get the target compound 19.8 mg, yield: 36%. 1H NMR (400 MHz, Methanol-d4) δ 9.19 (s, 1H), 8.59 (s, 1H), 7.65 - 7.58 (m, 1H), 7.54 (t, J = 3.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.33 (dq, J = 14.4, 7.9, 6.5 Hz, 3H), 7.19 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 3.0 Hz, 1H), 5.16 (s, 2H), 4.94 (s, 2H), 4.86 (d, J = 9.8 Hz, 2H), 4.69 (t, J = 14.4 Hz, 2H), 4.45 - 4.31 (m, 1H), 4.24 - 4.07 (m, 2H), 3.96 (d, J = 17.0 Hz, 1H), 3.53 (d, J = 38.9 Hz, 2H), 3.13 (s, 2H), 2.97 (s, 3H), 2.43 - 2.31 (m, 3H), 2.22 (s, 2H), 2.14 (s, 3H), 2.04 (d, J = 2.2 Hz, 3H), 1.82 (d, J = 14.8 Hz, 2H).

[0306] Example 29: Synthesis of N-(6-((3'-((3-(((R)-3-hydroxypiperidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2,2'-dimethyl)-[l,l'-biphenyl]-3-yl)methoxy)-l,2,3,4- tetrahydronaphthalen-l-yl)-N-methylglycine (ZL124N)

[0307]

[0308] ZL108 (0.11 mmol) crude product was dissolved in 1,2-dichloroethane (20 mL), then (R)-piperidin-3-ol (33.4 mg, 0.33 mmol) was added, stirred at room temperature for 15 minutes, then AcOH (0.1 mL) was added, stirred for 15 minutes, then sodium triacetoxyborohydride (33.4 mg, 0.33 mmol) was added, and reacted at room temperature overnight. After the reaction was completed, water was added for washing, and dichloromethane was used for extraction, and the organic phases were combined and concentrated. The obtained crude product was dissolved in a mixed solution of tetrahydrofuran (10 mL) and H2O (10 mL), then LiOH-H2O (25 mg, 0.55 mmol) was added, stirred at room temperature overnight, then trifluoroacetic acid was added to adjust pH = 1~2, the organic solvent was concentrated, and then the target compound was separated and purified by HPLC to obtain 11.4 mg, yield: 15%. 1H NMR (400 MHz, Methanol-d4) δ 9.19 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.54 (d, J = 4.6 Hz, 2H), 7.53 - 7.44 (m, 2H), 7.33 (ddd, J = 16.6, 9.3, 5.9 Hz, 3H), 7.19 (d, J = 7.6 Hz, 1H), 7.01 (dd, J = 8.7, 2.6 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 4.86 - 4.81 (m, 1H), 4.69 (t, J = 14.1 Hz, 2H), 4.10 (s, 2H), 3.89 (s, 1H), 3.48 (s, 1H), 3.46 - 2.36 (m, 1H), 3.13 (s, 2H), 3.00 - 2.70 (m, 5H), 2.25 (d, J = 38.5 Hz, 2H), 2.15 (s, 3H), 2.07 (s, 1H), 2.05 (s, 3H), 2.03 (s, 1H), 1.90 - 1.65 (m, 3H).

[0309] Example 30: Synthesis of N-(7-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZZE060)

[0310]

[0311] Step 1: Synthesis of 3-bromo-2-chlorophenylamino-1,7-naphthyridine-3-methanol (ZZE053)

[0312] Into a sealed tube was added 8-chloro-1,7-naphthyridine-3-methanol (500.0 mg, 2.56 mmol, refer to the synthesis method of patent CN110950865) and 3-bromo-2-chloroaniline (581.2 mg, 2.82 mmol) in isopropanol (40 mL) and hydrochloric acid in 1,4-dioxane solution (4 M, 0.71 mL, 2.82 mmol) at room temperature, the tube was sealed, heated and stirred at 100 °C for 12 hours. The reaction was concentrated, and sodium bicarbonate saturated aqueous solution (100 mL) and ethyl acetate (100 mL) were added to the residue, mixed and dissolved, the organic phase was separated, and then extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium carbonate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (220.5 mg, 24%). 1H NMR (500MHz, CD3OD): δ9.04(dd,J=8.4,1.5Hz,1H),8.90(d,J=2.0Hz,1H),8.19–8.15(m,1H),8.11(d,J=5. 8Hz,1H),7.35(dd,J=8.0,1.5Hz,1H),7.26(t,J=8.2Hz,1H),7.22(d,J=5.8Hz,1H),4.87(d,J=0.9Hz,2H).

[0313] Step 2: Synthesis of 3-bromo-2-chlorophenylamino-1,7-naphthidine-3-carboxaldehyde (ZZE056)

[0314] 3-Bromo-2-chlorophenylamino-1,7-naphthidine-3-methanol (78.2 mg, 0.21 mmol, ZZE053) and Dys-Martin oxidant (136.3 mg, 0.32 mmol) were suspended in dichloromethane (5 mL) and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to adjust the pH to approximately 7.5. The mixture was extracted with dichloromethane (15 mL × 3), the organic phases were combined, dried over anhydrous sodium carbonate, filtered, concentrated, and the product was purified by silica gel column chromatography to give the title compound (60.1 mg, 78%). 1 H NMR (500MHz, CDCl3): δ10.31(s,1H),9.96(s,1H),9.33(d,J=1.9Hz,1H),9.06(dd,J=8.3,1.5Hz, 1H),8.54(d,J=2.0Hz,1H),8.28(d,J=5.8Hz,1H),7.34(dd,J=8.0,1.4Hz,1H),7.26–7.21(m,2H).

[0315] Steps 3-1 to 3-3: Synthesis of N-(2-chloro-3-(3-((R)-3-hydroxypyrrolidone-1-ylmethyl)-1,7-naphthidin-8-ylamino)-2-methyl-[1,1'-biphenyl]-3-yl)chromo-4-yl)-N-methylglycine (ZZE060)

[0316] ZZE056 (50.3 mg, 0.14 mmol) and ZK068 (81.1 mg, 0.17 mmol) were suspended in a suspension of sodium carbonate in water (2 M, 1 mL) and ethylene glycol dimethyl ether (4 mL) under nitrogen. The reaction was degassed with dry nitrogen three times, and then palladium [1,1'-bis(diphenylphosphino)ferrocene] dichloride (20.0 mg, 0.02 mmol) was added. The reaction was degassed with dry nitrogen three times, and then stirred at 80 °C for 13 h. The reaction was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was combined, dried over anhydrous sodium carbonate, filtered, and concentrated to give crude compound ZZE057.

[0317] ZZE057 (135 mg) was dissolved in 1,2-dichloroethane (5 mL), and 3-(R)-hydroxypyrrolidine (36.1 mg, 0.41 mmol) was added. The reaction was stirred at room temperature for 2 h. Acetic acid (37.5 mg, 0.63 mmol) and sodium triacetoxyborohydride (134.2 mg, 0.63 mmol) were added, and the reaction was stirred at room temperature for 1 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution to pH ~ 7.5, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was combined, dried over anhydrous sodium carbonate, filtered, and concentrated. The compound was purified by silica gel column chromatography to give ZZE059.

[0318] ZZE059 (67 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide monohydrate (40.2 mg, 0.93 mmol) was added. The reaction was stirred at room temperature for 48 h. The reaction was concentrated under reduced pressure, diluted with water, and acidified with trifluoroacetic acid (pH ~ 2.0). The acidified solution was purified by high-performance liquid chromatography to give the title compound (22.0 mg, 23% yield over three steps). 1H NMR (500 MHz, CD3OD) δ 9.18 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (d, J = 6.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.49 (dd, J = 7.6, 1.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (dd, J = 7.8, 1.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.6 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 5.15 (br s, 2H), 4.86 (t, J = 6.5 Hz, 1H), 4.83 - 4.83 (m, 2H), 4.62 (br s, 1H), 4.38 (dt, J = 11.6, 5.6 Hz, 1H), 4.20 (dt, J = 11.6, 5.6 Hz, 1H), 4.17 - 4.09 (m, 1H), 4.00 - 3.92 (m, 1H), 3.64 - 3.49 (m, 2H), 3.46 - 3.38 (m, 1H), 2.97 (s, 3H), 2.42 - 2.32 (m, 2H), 2.17 (s, 3H), 2.16 - 2.07 (m, 1H).

[0319] Example 36: N-(7-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-l-yl)methyl)-l,7- naphthyridin-8-yl)amino)-2')-methyl-[l,l'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N- methylglycine (ZM015)

[0320]

[0321] Step 1: Synthesis of 7-((3-bromo-2-chlorobenzyl)oxy)chroman-4-one (ZL155)

[0322] Compound 7-hydroxychroman-4-one (1.5 g, 12.78 mmol), 1-bromo-3-(bromoethyl)-2- chlorobenzene (3.2 g, 10.65 mmol) were dissolved in acetonitrile (50 ml) and after addition of cesium carbonate (4 g, 21.3 mmol) the reaction mixture was heated to 80 °C for 3 h. After completion of the reaction the organic phase was collected by filtration and dried under vacuum. The product was purified by column chromatography to obtain the target compound 3.7 g, yield: 95%. 1HNMR(500MHz,Chloroform-d)δ7.87(d,J=8.8Hz,1H),7.62(dd,J=8.1,1.4Hz,1H),7.47(dd,J=7.8,1.4Hz,1H),7.18(t,J= 7.9Hz,1H),6.67(dd,J=8.8,2.4Hz,1H),6.48(d,J=2.4Hz,1H),5.20(s,2H),4.52(t,J=6.5Hz,2H),2.76(t,J=6.4Hz,2H).

[0323] Step 2: Synthesis of 7-((3-bromo-2-chlorobenzyl)oxy)-N-methylbenzopyran-4-amine (ZL157)

[0324] ZL155 (2.5 g, 6.8 mmol) was dissolved in tetrahydrofuran (35 ml), and methylamine (4.72 g, 41.0 mmol, 27% in MeOH) was added. After stirring at room temperature for 2 hours, AcOH (2.46 g, 41.0 mmol) was added, and stirring continued for 0.5 hours. Finally, sodium cyanoborohydride (2.55 g, 41.0 mmol) was added, and the temperature was raised to 45 °C, and the reaction continued for 12 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated to dryness for use in the next step.

[0325] Step 3: Synthesis of N-(7-((3-bromo-2-chlorobenzyl)oxy)chroman-4-yl)-N-methylglycine ethyl ester (ZM003)

[0326] Compound ZL157 (6.8 mmol) and ethyl chloroacetate (1.67 g, 13.66 mmol) were dissolved in acetonitrile (50 mL), followed by the sequential addition of K₂CO₃ (2.36 mg, 17.08 mmol) and KI (112.9 mg, 0.68 mmol). The reaction was heated to 80 °C and continued for 12 hours. After the reaction was completed, the solvent was evaporated to dryness, and the mixture was extracted with water and ethyl acetate. The organic phase was collected, evaporated to dryness, and purified by column chromatography to obtain 1.85 g of the target compound, yield: 58%. 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 9.1 Hz, 2H), 5.03 (s, 2H), 4.43 (s, 1H), 4.25 - 4.14 (m, 2H), 3.25 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 16.4 Hz, 1H), 2.90 (d, J = 8.6 Hz, 1H), 2.79 (q, J = 8.1 Hz, 1H), 2.56 (d, J = 2.1 Hz, 3H), 2.39 (s, 3H), 2.15 (s, 1H), 2.00 (s, 1H), 1.36 (d, J = 2.1 Hz, 12H).

[0327] Step 4: Synthesis of N-(7-((2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)chroman-4-yl)-N-methylglycine ethyl ester (ZM005)

[0328] Step 4: Synthesis of N-(7-((2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)chroman-4-yl)-N-methylglycine ethyl ester (ZM005)

[0329] ZM003 (467 mg, 1.0 mmol), pinacol diboronic acid (634.85 mg, 2.5 mmol), AcOK (392.56 mg, 4.0 mmol) were dissolved in anhydrous 1,4-dioxane (50 mL) solution, and then bis(triphenylphosphine)palladium dichloride (70.2 mg, 0.1 mmol) was added under a nitrogen atmosphere, and finally the reaction was heated at 80°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, and after the solvent was spin-dried, water was added, and then extracted with ethyl acetate three times, and the organic phase was combined and dried with anhydrous sodium sulfate and spin-dried, and finally the target compound was isolated and purified with a chromatography column to obtain 329.7 mg, yield: 64%. 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (t, J = 5.8 Hz, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.30 - 7.27 (m, 1H), 6.56 (d, J = 8.5 Hz, 1H), 6.41 (d, J = 2.8 Hz, 1H), 5.13 (s, 2H), 4.39 - 4.29 (m, 1H), 4.22 - 4.12 (m, 2H), 3.96 (d, J = 7.1 Hz, 1H), 3.31 (d, J = 16.6 Hz, 1H), 3.19 (d, J = 16.6 Hz, 1H), 2.43 (s, 3H), 1.96 (q, J = 6.2 Hz, 2H), 1.38 (s, 12H), 1.27 (d, J = 6.9 Hz, 3H).

[0330] Step 5: Synthesis of ZM015

[0331] ZM005 (85.87 mg, 0.17 mmol), ZL106 (68.2 mg, 0.2 mmol) were dissolved in a mixture of ethyleneglycol dimethyl ether (15 ml) and aqueous Na2CO3(2 ml, 2M) solution. After purging oxygen with nitrogen, Pd(dppf)Cl2-CH2Cl2(70 mg, 0.08 mmol) was added. Finally, the reaction mixture was heated to 75 °C under nitrogen atmosphere for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was used directly in the next step.

[0332] The crude product from the above reaction, (R)-3-pyrrolidinol (43.6 mg, 0.50 mmol) was dissolved in 1,2-dichloroethane (30 ml) and stirred at room temperature for 4 h. AcOH (0.18 ml) was added and the mixture was stirred for another 0.5 h. Then, sodium triacetoxyborohydride (106.2 mg, 0.5 mmol) was added. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was dissolved in a mixture of tetrahydrofuran (8 ml) and water (8 ml), and LiOH-H2O (42.04 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 12 h. After the reaction was completed, trifluoroacetic acid was added to adjust the pH to acidic, and the organic solvent was removed by evaporation. Finally, the target compound was purified by reverse phase column to give 22.8 mg, total yield: 19%. 1H NMR (400 MHz, Methanol-d4) δ 9.21 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.58 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.34 (td, J = 7.6, 2.8 Hz, 2H), 6.76 (dd, J = 8.7, 2.6 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H), 4.84 (d, J = 6.9 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 4.62 (s, 1H), 4.38 (dt, J = 11.6, 5.7 Hz, 1H), 4.20 (dt, J = 11.8, 5.6 Hz, 1H), 4.13 (d, J = 17.3 Hz, 1H), 4.03 - 3.87 (m, 1H), 3.70 (s, 1H), 3.56 (s, 2H), 3.46 (d, J = 17.9 Hz, 1H), 2.97 (s, 3H), 2.37 (d, J = 6.1 Hz, 3H), 2.10 (s, 3H).

[0333] Example 37: N-(7-((2,2'-dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino))[1,1'-biphenyl]-3-yl)methoxy)chroman-4-yl)-N-methylglycine (ZM019)

[0334]

[0335] ZM005 (78.3 mg, 0.15 mmol), ZN041 (59.6 mg, 0.14 mmol), K2CO3 (48.4 mg, 0.35 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), and Ruphos Pd G4 (20 mg, 0.02 mmol) was added under a nitrogen atmosphere, and then the mixture was heated to 80°C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The product was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and water (4 ml), and then LiOH-H2O (34.8 mg, 0.83 mmol) was added, and stirred at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to adjust the pH to be acidic, and then the organic solvent was spin-dried, and finally purified by reverse phase column separation to obtain 53.2 mg of the target compound. Yield: 52%.1 H NMR (400 MHz, Methanol-d4) δ 9.06 (d, J = 2.1 Hz, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 6.1 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.38 - 7.33 (m, 1H), 7.31 (d, J = 6.2 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.77 (dd, J = 8.7, 2.6 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 5.25 (s, 2H), 4.73 (d, J = 6.9 Hz, 2H), 4.61 (s, 1H), 4.44 - 4.34 (m, 1H), 4.26 - 4.15 (m, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.96 - 3.81 (m, 2H), 3.69 (s, 1H), 3.60 - 3.46 (m, 2H), 3.42 (s, 1H), 2.96 (s, 3H), 2.37 (s, 3H), 2.11 (s, 1H).

[0336] Example 38: N-(6-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl

[0337] - [1,1'-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-N-methylglycine (ZM020)

[0338]

[0339] ZL101 (75.2 mg, 0.15 mmol), ZN041 (59.6 mg, 0.14 mmol), K2CO3 (48.4 mg, 0.35 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), and Ruphos Pd G4 (20 mg, 0.02 mmol) was added under a nitrogen atmosphere. Finally, it was heated to 80°C for 5 hours under a nitrogen atmosphere. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The above product was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and water (4 ml), and then LiOH-H2O (34.8 mg, 0.83 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to adjust the pH to be acidic, and then the organic solvent was spin-dried. Finally, it was separated and purified by a reverse phase column to obtain 46.2 mg of the target compound. Yield: 42%.1 H NMR (400 MHz, Methanol-d4) δ 9.18 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.12 - 8.02 (m, 1H), 7.82 (d, J = 6.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.3, 3.8 Hz, 2H), 7.42 - 7.35 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.01 (dd, J = 8.7, 2.6 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 4.77 (t, J = 9.8 Hz, 2H), 4.62 (q, J = 4.2, 3.4 Hz, 1H), 4.25 - 3.98 (m, 1H), 3.85 (s, 1H), 3.70 (s, 1H), 3.56 (s, 2H), 3.43 (s, 1H), 2.84 (dt, J = 33.1, 10.8 Hz, 5H), 2.32 (s, 2H), 2.18 (s, 3H), 2.16 - 1.95 (m, 3H), 1.86 - 1.68 (m, 1H).

[0340] Example 40: N-(6-((2,2'-Dichloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino))[1,1'-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-N- methylglycine (ZM045)

[0341]

[0342] Step 1: Synthesis of 6-((3-bromo-2-chlorobenzyl)oxy)-3,4-dihydronaphthalen-1(2H)-one (ZM023)

[0343] Compound 7-hydroxychroman-4-one (2.30 g, 14.32 mmol), 1-bromo-3-(bromoethyl)-2- chlorobenzene (3.66 g, 13.02 mmol) were dissolved in acetonitrile (50 ml) and after addition of cesium carbonate (8.48 g, 26.04 mmol) the reaction mixture was heated to 80 °C for 3 hours. After completion of the reaction the organic phase was collected by filtration and dried under vacuum. The product was purified by column chromatography to obtain 3.93 g of the target compound in 83% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8.1, 1.5 Hz, 1H), 7.57 (dd, J = 8.0, 1.5 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.17 (td, J = 7.9, 4.4 Hz, 2H), 6.90 (dd, J = 8.7, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 5.22 (s, 2H), 4.81 (s, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.66 - 2.57 (m, 2H), 2.12 (p, J = 6.4 Hz, 3H).

[0344] Step 2: Synthesis of 6-((3-bromo-2-chlorobenzyl)oxy)-N-methyl-1,2,3,4- tetrahydronaphthalen-1-amine (ZM26)

[0345] ZM023 (800 mg, 2.2 mmol) was taken in a sealed tube and dissolved in tetrahydrofuran (20 ml), methyl amine (1.52 g, 13.2 mmol, 27% in Alcohol) was added, stirred at room temperature for 5 hours, then AcOH (2.46 g, 41.0 mmol) was added and stirred for 3 hours, finally sodium cyanoborohydride (828.86 mg, 13.2 mmol) was added and the temperature was raised to 45 °C and the reaction was continued for 12 hours. After completion of the reaction, water was added and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate and evaporated to dryness directly for the next step.

[0346] Step 3: Synthesis of N-(6-((3-bromo-2-chlorobenzyl)oxy)-1,2,3,4- tetrahydronaphthalen-1-yl)-N-methylglycine ethyl ester (ZM029)

[0347] Compound ZM026 (1.76 mmol), ethyl chloroacetate (431.4 mg, 3.52 mmol) was dissolved in acetonitrile (30 ml), then K2CO3(608.12 mg, 4.4 mmol), KI (29.2 mg, 0.18 mmol) was added sequentially, the reaction was raised to 80 °C and the reaction was continued for 12 hours. After completion of the reaction, the solvent was evaporated to dryness, water was added, extracted with ethyl acetate, the organic phase was collected, evaporated to dryness and purified by column chromatography to obtain the target compound 604 mg, two-step yield: 59%. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.54 (dd, J = 7.8, 1.4 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.81 (dd, J = 8.6, 2.7 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 5.13 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.27 (d, J = 16.5 Hz, 1H), 3.15 (d, J = 16.5 Hz, 1H), 2.71 (ddd, J = 22.2, 13.4, 8.5 Hz, 2H), 2.40 (s, 3H), 2.03 - 1.92 (m, 2H), 1.60 (dddd, J = 33.1, 21.8, 11.3, 7.6 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0348] Step 4: Synthesis of N-(6-((2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyloxy)-l,2,3,4-tetrahydronaphthalen-l-yl)-N-methylglycine ethyl ester (ZM031)

[0349] ZM029 (290 mg, 0.62 mmol), bis(pinacolato)diboron (395.9 mg, 1.56 mmol), AcOK (244.96 mg, 2.5 mmol) were dissolved in anhydrous 1,4-dioxane (25 mL) solution, and bis(triphenylphosphine)palladium dichloride (43.8 mg, 0.06 mmol) was added under a nitrogen atmosphere, and finally the reaction was heated at 80°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, and the solvent was evaporated, and then water was added, and then extracted with ethyl acetate three times, and the organic phase was combined and dried with anhydrous sodium sulfate and evaporated, and finally the target compound was separated and purified with a column to obtain 281.4 mg, yield: 88%. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 14.7 Hz, 1H), 6.83 (dd, J = 8.6, 2.7 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 5.16 (s, 2H), 4.24 - 4.16 (m, 2H), 4.14 (d, J = 7.2 Hz, 1H), 3.91 (d, J = 5.4 Hz, 1H), 3.29 (d, J = 16.5 Hz, 1H), 3.16 (d, J = 16.5 Hz, 1H), 2.42 (s, 3H), 1.99 (d, J = 9.9 Hz, 2H), 1.68 (dd, J = 11.0, 5.7 Hz, 1H), 1.61 (s, 3H), 1.59 - 1.51 (m, 1H), 1.41 (s, 12H).

[0350] Step 5: Synthesis of ZM045

[0351] ZM031 (93.8 mg, 0.18 mmol), B (60 mg, 0.17 mmol) were dissolved in a mixed solution of ethylene glycol dimethyl ether (18 ml) and aqueous Na2C03 solution (2 ml, 2 M) and Pd(dppf)Cl2-CH2Cl2 (60 mg, 0.07 mmol) was added after the oxygen was replaced by nitrogen. Finally, the reaction was heated to 75 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the temperature was returned to room temperature, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and rotary evaporated directly for the next step.

[0352] The above reaction crude product, (R)-3-pyrrolidinol (43.4 mg, 0.50 mmol) was dissolved in 1,2-dichloroethane (30 ml) and stirred at room temperature for 4 h. AcOH (0.18 ml) was added and stirred for another 0.5 h. Finally, sodium triacetoxyborohydride (105.6 mg, 0.5 mmol) was added. After the reaction was completed, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and rotary evaporated. Then, the above product was dissolved in a mixed solution of tetrahydrofuran (8 ml) and water (8 ml), and LiOH-H20 (40.9 mg, 1.0 mmol) was added and reacted at room temperature for 12 h. After the reaction was completed, trifluoroacetic acid was added to adjust the pH to be acidic, and the organic solvent was rotary evaporated. Finally, the target compound was purified by a reverse phase column to obtain 31.9 mg, three-step yield: 25%. 1H NMR (400 MHz, Methanol-d4) δ 9.06 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 6.1 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 8.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 6.1 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.95 (s, 1H), 5.28 (s, 2H), 4.72 (d, J = 6.7 Hz, 2H), 4.61 (s, 1H), 4.11 - 3.94 (m, 1H), 3.91 - 3.62 (m, 3H), 3.63 - 3.37 (m, 4H), 3.00 - 2.78 (m, 4H), 2.32 (s, 2H), 2.03 (d, J = 31.2 Hz, 3H), 1.83 - 1.69 (m, 1H).

[0353] Example 56: N-(7-((2-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-ylamino)-2'-methyl

[0354] -[1,1'-biphenyl]-3-ylmethoxy)chroman-4-yl)-N-ethylglycine (ZM065)

[0355]

[0356] Step 1: Synthesis of 7-((3-bromo-2-chlorobenzyl)oxy)-N-ethylbenzopyran-4-amine (CC152)

[0357] ZL155 (1.54 g, 4.2 mmol) was dissolved in tetrahydrofuran (50 ml), methylamine (2.9 g, 25.2 mmol, 27% in MeOH) was added, stirred at room temperature for 2 hours, then AcOH (1.51 g, 25.2 mmol) was added, stirred for another 0.5 hour, finally sodium cyanoborohydride (1.57 g, 25.2 mmol) was added and the reaction was continued at 45 °C for 12 hours. After the reaction was completed, water was added and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate and rotary evaporated directly for the next step.

[0358] Step 2: Synthesis of N-(7-((3-bromo-2-chlorobenzyl)oxy)chroman-4-yl)-N-ethylglycine ethyl ester (ZM035)

[0359] Compound CC152 (4.1 mmol), ethyl chloroacetate (1.0 g, 8.2 mmol) was dissolved in acetonitrile (35 ml), then K2CO3(1.42 mg, 10.25 mmol), KI (68.1 mg, 0.41 mmol) were added successively, the reaction was heated to 80 °C and continued to react for 12 hours. After the reaction was completed, the solvent was spin-dried, water was added, and ethyl acetate was extracted. The organic phase was spin-dried and then separated and purified by a chromatographic column to obtain the target compound 1.07 g, two-step yield: 55%. 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.55 (dd, J = 8.6, 2.6 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 5.12 (s, 2H), 4.42 - 4.30 (m, 1H), 4.21 - 4.02 (m, 4H), 3.28 (q, J = 17.0 Hz, 2H), 2.69 (qt, J = 7.1, 3.6 Hz, 2H), 2.07 - 1.82 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).

[0360] Step 3: Synthesis of N-(7-((2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)chroman-4-yl)-N-ethylglycine ethyl ester (ZM036)

[0361] ZM035 (480 mg, 1.0 mmol), pinacol diboronic acid (634.85 mg, 2.5 mmol), AcOK (392.56 mg, 4.0 mmol) were dissolved in anhydrous 1,4-dioxane (50 mL) solution, and under nitrogen atmosphere, dichlorobis(triphenylphosphine)palladium (70.2 mg, 0.1 mmol) was added, and finally the reaction was heated to 80 °C for 12 hours under nitrogen atmosphere. After the reaction was completed, it was restored to room temperature, and the solvent was spin-dried, then water was added, and then extracted with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, then spin-dried, and finally separated and purified by a chromatographic column to obtain the target compound 445.8 mg, yield: 84%. 1H NMR (400 MHz, Chloroform-d) δ 7.61 (dd, J = 7.4, 2.4 Hz, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 7.0 Hz, 1H), 6.56 (dd, J = 8.6, 2.6 Hz, 1H), 6.40 (d, J = 2.6 Hz, 1H), 5.12 (s, 2H), 4.35 (dt, J = 11.0, 4.4 Hz, 1H), 4.20 - 4.00 (m, 4H), 3.28 (q, J = 17.0 Hz, 2H), 2.68 (tt, J = 7.0, 3.8 Hz, 2H), 1.94 (ddd, J = 22.5, 8.9, 4.5 Hz, 2H), 1.38 (s, 12H), 1.26 (d, J = 3.9 Hz, 6H).

[0362] Step 4: Synthesis of ZM065

[0363] ZM036 (80 mg, 0.15 mmol), ZL106 (46.7 mg, 0.14 mmol) were dissolved in a mixture of ethyleneglycol dimethyl ether (20 ml) and aqueous Na2C03(2 ml, 2M), after purging oxygen with nitrogen, Pd(dppf)Cl2-CH2Cl2(50 mg, 0.07 mmol) was added. Finally, the reaction was heated to 75 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and rotary evaporated to dryness for use in the next step.

[0364] The above reaction crude, (R)-3-pyrrolidinol (44.5 mg, 0.41 mmol, 3.0 eq) was dissolved in 1,2-dichloroethane (20 ml) and stirred at room temperature for 5 hours. AcOH (0.15 ml) was added and stirred for 1 hour. Finally, sodium triacetoxyborohydride (104.6 mg, 0.41 mmol) was added. After the reaction was completed, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and rotary evaporated to dryness. Then, the above product was dissolved in a mixture of tetrahydrofuran (8 ml) and water (8 ml), and LiOH-H20 (34.5 mg, 0.82 mmol, 6.0 eq) was added and reacted at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to adjust the pH to be acidic, and the organic solvent was rotary evaporated to dryness. Finally, the target compound was purified by a reverse phase column to obtain 44.6 mg, three-step yield: 42%. 1H NMR (400 MHz, Methanol-d4) δ 9.20 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.47 (dd, J = 8.4, 5.8 Hz, 2H), 7.39 (dd, J = 7.2, 1.8 Hz, 1H), 7.37 - 7.30 (m, 2H), 6.72 (dd, J = 8.8, 2.6 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 5.24 (s, 2H), 4.79 (d, J = 6.6 Hz, 2H), 4.62 (s, 1H), 4.50 - 4.38 (m, 1H), 4.14 (t, J = 10.7 Hz, 1H), 3.98 (d, J = 17.3 Hz, 1H), 3.76 (d, J = 17.7 Hz, 2H), 3.56 (s, 2H), 3.44 (dd, J = 7.3, 4.0 Hz, 3H), 2.41 (d, J = 12.8 Hz, 2H), 2.30 - 2.19 (m, 2H), 2.10 (s, 4H), 1.39 (t, J = 7.2 Hz, 3H).

[0365] Example 57: (R)-3-(6-((2'-chloro-3'-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-3,4-dihydroquinolin-1(2H)- yl)propanoic acid (ZN044)

[0366]

[0367] Step 1: Synthesis of 6-((3-bromo-2-methylbenzyl)oxy)-3,4-dihydroquinoline-1(2H)- carboxylic acid tert-butyl ester (ZN018)

[0368] Compound 6-hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (640 mg, 2.44 mmol), 1-bromo-3-(bromoethyl)-2-methylbenzene (670 mg, 2.69 mmol) were dissolved in acetonitrile (30 ml) and after addition of cesium carbonate (1.59 g, 4.89 mmol) the reaction mixture was heated to 80 °C for 3 hours. After completion of the reaction the organic phase was collected by filtration and dried in vacuo. The product was isolated and purified by column chromatography to yield 1.02 g of the target compound in 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.60 - 7.51 (m, 2H), 7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.77 (dd, J = 9.0, 3.0 Hz, 1H), 6.70 - 6.68 (m, 1H), 4.99 (s, 2H), 3.73 - 3.64 (m, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.96 - 1.86 (m, 2H), 1.52 (s, 9H).

[0369] Step 2: tert-Butyl 3-(6-(3-bromo-2-methylbenzyloxy)-3,4-dihydroquinolin- 1(2H)-yl)propanoate (ZN151)

[0370] Compound ZN018 (1.05 g) was dissolved in dichloromethane (10 ml), then trifluoroacetic acid (2 ml) was added dropwise, stirred at room temperature for 2 hours, after the reaction was completed, quenched with water, extracted with dichloromethane, the organic phase was collected and rotary evaporated to obtain ZN019. ZN019 (662 mg, 2.0 mmol), (627.2 mg, 3.0 mmol) were dissolved in acetonitrile (60 ml), then K2CO3 (691.1 mg, 5.0 mmol), KI (166 mg, 1.0 mmol) were added in turn, the reaction was continued to react at 80°C for 12 hours. After the reaction was completed, the solvent was rotary evaporated, and the target compound 350 mg was obtained by column separation and purification, yield: 38%. 1 H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.65 (s, 1H), 6.56 (d, J = 9.0 Hz, 1H), 4.94 (s, 2H), 3.53 (t, J = 7.3 Hz, 2H), 3.22 (t, J = 5.4 Hz, 2H), 2.73 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.94 (p, J = 6.1 Hz, 2H), 1.45 (s, 9H).

[0371] Step 3: tert-Butyl 3-(6-((2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)-3,4-dihydroquinolin-l(2H)-yl)propanoate (ZN038)

[0372] ZN151 (120 mg, 0.28 mmol), bis(pinacolato)diboron (176.7 mg, 0.70 mmol), AcOK (109.1 mg, 1.12 mmol) were dissolved in anhydrous 1,4-dioxane (25 mL) solution, bis(triphenylphosphine)palladium dichloride (20 mg, 0.03 mmol) was added under nitrogen atmosphere, and finally the reaction was heated at 80 °C for 12 hours under nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, the solvent was evaporated, water was added, and then extracted with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate and evaporated, and finally the target compound was separated and purified with a column to obtain 127.8 mg, yield: 88%. 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (dd, J = 7.5, 1.5 Hz, 1H), 7.48 (dd, J = 7.6, 1.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.73 (dd, J = 8.8, 3.0 Hz, 1H), 6.66 (d, J = 3.0 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 4.95 (s, 2H), 3.53 (t, J = 7.2 Hz, 2H), 3.21 (t, J = 5.5 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.56 (s, 3H), 2.48 (t, J = 7.2 Hz, 2H), 1.93 (p, J = 6.2 Hz, 2H), 1.45 (s, 9H), 1.35 (s, 12H).

[0373] Step 4: Synthesis of ZN044

[0374] ZN038 (63.9 mg, 0.12 mmol), ZN041 (52.96 mg, 0.12 mmol), K2CO3 (42.5 mg, 0.31 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), RuphosPd G4 (20 mg, 0.02 mmol) was added under nitrogen atmosphere, and finally heated to 80 °C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was evaporated, water was added, and then extracted with ethyl acetate, the organic phase was collected, dried with anhydrous sodium sulfate, and evaporated to obtain the product 33.8 mg. The product was dissolved in dichloromethane (9 ml), and then trifluoroacetic acid (3 ml) was added dropwise, and stirred at room temperature for 2 hours. After the reaction was completed, water was added, and then the organic solvent was evaporated, and finally separated and purified with a reverse phase column to obtain the target compound 24 mg. Two-step yield: 30%. 1H NMR (400 MHz, Methanol-d4) δ 9.17 (s, 1H), 8.58 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 6.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.43 - 7.27 (m, 5H), 7.22 (d, J = 7.7 Hz, 1H), 7.01 (s, 2H), 5.15 (s, 2H), 4.78 (d, J = 6.2 Hz, 2H), 4.62 (s, 1H), 3.91 - 3.37 (m, 7H), 2.83 (m, 4H), 2.34 (s, 1H), 2.18 (s, 6H).

[0375] Example 58: (R)-4-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-3,4-dihydroquinolin-1(2H)- yl)butanoic acid (ZN067)

[0376]

[0377] Step 1: Synthesis of 4-(6-((3-bromo-2-methylbenzyl)oxy)-3,4-dihydroquinolin-1(2H)- yl)butanoic acid ethyl ester (ZN056)

[0378] ZN019 (166 mg, 0.37 mmol), 4-iodobutanoic acid ethyl ester (242.1 mg, 1.0 mmol) were dissolved in acetonitrile (20 ml), then K2CO3 (138.2 mg, 1.0 mmol), KI (8 mg, 0.05 mmol) were added successively, the reaction was continued to react at 80 °C for 12 hours. After the reaction was completed, the solvent was spin dried, and the target compound was obtained after separation and purification by column chromatography. 67.3 mg, yield: 41%. ESI-MS C 23 H 28 BrNO3[M+H] + = 446.13, found: 446.8.

[0379] Step 2: Synthesis of 4-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)- 3,4-dihydroquinolin-1(2H)-yl)butanoic acid ethyl ester (ZN058)

[0380] ZN056 (67 mg, 0.15 mmol), bis(pinacolato)diboron (95.6 mg, 0.38 mmol), AcOK (58.88 mg, 0.6 mmol) were dissolved in anhydrous 1,4-dioxane (25 mL) solution, and bis(triphenylphosphine)palladium dichloride (15 mg, 0.02 mmol) was added under a nitrogen atmosphere, and the reaction was finally heated at 80°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, and the solvent was evaporated, and then water was added, followed by extraction with ethyl acetate three times, and the organic phase was combined and dried with anhydrous sodium sulfate and then evaporated, and finally, the target compound was separated and purified by column chromatography to obtain 65.7 mg, yield: 89%. 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.66 (s, 1H), 6.55 (d, J = 8.9 Hz, 1H), 4.95 (s, 2H), 4.13 (q, J = 7.4 Hz, 2H), 3.23 (dd, J = 15.1, 7.1 Hz, 4H), 2.73 (d, J = 7.1 Hz, 2H), 2.56 (s, 3H), 2.36 (t, J = 7.3 Hz, 2H), 1.91 (d, J = 16.8 Hz, 4H), 1.59 (d, J = 2.2 Hz, 15H).

[0381] Step 3: Synthesis of ZN067

[0382] ZN058 (65.7 mg, 0.13 mmol), ZN041 (56.2 mg, 0.13 mmol), K2CO3 (44.9 mg, 0.33 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), and Ruphos Pd G4 (20 mg, 0.02 mmol) was added under a nitrogen atmosphere, and finally heated to 80°C for 5 hours under a nitrogen atmosphere. After the reaction was completed, the organic solvent was evaporated, water was added, and ethyl acetate was extracted, and the organic phase was collected and dried with anhydrous sodium sulfate and then evaporated. The above product was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and water (4 ml), and stirred at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to adjust the pH to be acidic, and then the organic solvent was evaporated, and finally, the target compound was separated and purified by reverse phase column to obtain 36.2 mg. Yield: 40%. ESI-MS Theoretical value: C 40 H 42 ClN5O4[M+H]+ = 692.29, measured: 692.5.

[0383] Example 59: Synthesis of (R)-3-(6-((2'-chloro-3'-((3-((3- hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3- yl)methoxy)-1H-benzo[de]isoquinolin-2(3H)-yl)propanoic acid (ZN106)

[0384]

[0385] Step 1: Synthesis of tert-butyl 6-bromo-1H-benzo[de]isoquinoline-2(3H)- carboxylate (ZN082)

[0386] Compound ZN080 (247 mg, 1.0 mmol) was dissolved in dichloromethane, then Et3N (404 mg, 4.0 mmol) was added and stirred at room temperature for 15 minutes, and finally Boc20 (654 mg, 3.0 mmol) was added. The reaction was monitored by TLC, and stopped after complete reaction. The solvent was evaporated and the residue was purified by silica gel column to give the target compound 206 mg, 1 H NMR (500 MHz, Chloroform-d) δ 8.14 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.57 (dd, J = 8.6, 7.0 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 4.92 (s, 2H), 4.88 (s, 2H), 1.50 (s, 9H).

[0387] Step 2: Synthesis of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[de]isoquinoline-2(3H)-carboxylate (ZN090)

[0388] ZN082 (520 mg, 1.5 mmol), bis(pinacolato)diboron (884.8 mg, 3.75 mmol), AcOK (588.84 mg, 6 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL) solution, and then dichlorobis(triphenylphosphine)palladium (70 mg) was added under nitrogen atmosphere. Finally, the reaction was heated at 95 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the solvent was evaporated. Then, water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was combined and dried over anhydrous sodium sulfate, and then evaporated. Finally, the target compound was obtained by purification using a chromatography column, and the yield was 500 mg, 84%. 1H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.50 (dd, J = 8.5, 7.0 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 6.62 (q, J = 5.8 Hz, 1H), 5.02 (d, J = 11.5 Hz, 2H), 4.96 (s, 1H), 1.42 (s, 12H), 1.26 (s, 9H). Step 3: Synthesis of tert-butyl 6-hydroxy-lH-benzo[de]isoquinoline-2(3H)- carboxylate (ZN096)

[0389] ZN090 (500 mg, 1.26 mmol) was dissolved in DMF (4 ml), then H202 (30% in H20, 5 ml) was added. After stirring at room temperature for 3 h, water was added to the reaction system, and a solid precipitated. After standing for some time, the solid was filtered, and the target compound was obtained, 341.3 mg, yield: 95%. 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.76 (s, 1H), 4.88 (s, 2H), 4.82 (s, 2H), 1.48 (s, 9H).

[0390] Step 4: Synthesis of tert-butyl 6-((3-bromo-2-methylbenzyl)oxy)-lH- benzo[de]isoquinoline-2(3H)-carboxylate (ZN097)

[0391] ZN096 (341 mg, 1.2 mmol), 1-bromo-3-(bromoethyl)-2-methylbenzene (345.8 g, 1.3 mmol) were dissolved in acetonitrile (30 ml), then Cs2C03(782 mg, 2.4 mmol) was added, and the reaction was warmed to 85 °C for 3 h. After the reaction was completed, the solvent was spin-dried, and then separated and purified by column chromatography to obtain the target compound, 472.7 mg, yield: 84%. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.44 (q, J = 7.9 Hz, 2H), 7.31 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.21 (s, 2H), 4.88 (s, 2H), 4.84 (s, 2H), 2.48 (d, J = 2.2 Hz, 3H), 1.48 (s, 9H).

[0392] Step 5: Synthesis of 6-((3-bromo-2-methylbenzyl)oxy)-2,3-dihydro-1H- benzo[de]isoquinoline (ZN099)

[0393] ZN097 (472.7 mg) was dissolved in dichloromethane (10 ml), then trifluoroacetic acid (2 ml) was added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate was added to quench, and dichloromethane was used for extraction. The organic phase was rotary evaporated and directly used for the next step. 1 H NMR (400 MHz, Chloroform-d) δ 8.16 - 8.10 (m, 1H), 7.60 - 7.55 (m, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.22 (dd, J = 7.0, 1.1 Hz, 1H), 7.10 (dt, J = 7.8, 3.8 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 5.21 (s, 2H), 4.32 (s, 2H), 4.28 (s, 2H), 2.48 (s, 3H).

[0394] Step 6: Synthesis of 3-(6-((3-bromo-2-methylbenzyl)oxy)-1H- benzo[de]isoquinolin-2(3H)-yl)propanoic acid tert-butyl ester (ZN101)

[0395] ZN099 (400 mg, 1.09 mmol), K2CO3 (301.3 mg, 2.18 mmol) were dissolved in acetonitrile (50 ml) and stirred at room temperature for 20 minutes, then 3-bromopropionic acid tert-butyl ester (341.72 mg, 1.63 mmol), KI (18.26 mg, 0.11 mmol) were added, and then the temperature was raised to 80°C for 12 hours. After the reaction was completed, the solvent was rotary evaporated and separated and purified by column chromatography to obtain the target compound 280.5 mg, yield: 52%. ESI-MS Theoretical value: C 27 H 30 BrNO3[M+H] + = 496.14, measured: 496.2.

[0396] Step 7: Synthesis of tert-butyl 3-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)-yl)propanoate (ZN102)

[0397] ZN101 (280.5 mg, 0.56 mmol), pinacol diboronic acid (334.15 mg, 1.42 mmol), AcOK (222.39 mg, 2.27 mmol) were dissolved in anhydrous 1,4-dioxane (25 mL) solution, under nitrogen atmosphere, palladium dichloride bis-triphenylphosphine (39.76 mg, 0.06 mmol) was added, finally the reaction was heated at 85 °C for 12 hours under nitrogen atmosphere. After completion of the reaction, it was brought to room temperature, the solvent was evaporated, then water was added, followed by extraction with ethyl acetate three times, the organic phase was combined and dried over anhydrous sodium sulfate and evaporated, finally the target compound was isolated and purified by column chromatography to obtain 285.3 mg, yield: 93%. 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 10.0 Hz, 3H), 7.11 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 5.21 (s, 2H), 4.22 (q, J = 7.2 Hz, 3H), 4.15 - 4.08 (m, 3H), 3.41 (t, J = 6.2 Hz, 2H), 3.11 (t, J = 12.9 Hz, 1H), 2.91 - 2.71 (m, 1H), 2.60 (s, 3H), 1.37 (d, J = 2.1 Hz, 12H).

[0398] Step 8: Synthesis of ZN106

[0399] ZO102 (54.3 mg, 0.1 mmol), ZN041 (43.2 mg, 0.1 mmol), K2CO3 (34.55 mg, 0.25 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), and Ruphos Pd G4 (8.5 mg, 0.01 mmol) was added under a nitrogen atmosphere, and then the reaction was heated to 80°C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The spin-dried product was dissolved in dichloromethane (20 ml), and then trifluoroacetic acid (2 ml) was added dropwise, and the reaction was allowed to proceed at room temperature for 1.5 hours. After the reaction was completed, water was added to the reaction system, and then the organic solvent was spin-dried and separated and purified by reverse phase column to obtain 22.6 mg of the target compound, with a yield of 32%. 1 H NMR (500 MHz, Methanol-d4) δ 9.18 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.32 - 8.26 (m, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 6.7 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.59 - 7.54 (m, 1H), 7.53 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.36 (s, 1H), 7.27 (dd, J = 7.7, 1.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.47 - 5.36 (m, 2H), 4.77 (t, J = 11.2 Hz, 4H), 4.62 (s, 1H), 3.68 (d, J = 23.4 Hz, 1H), 3.60 (t, J = 7.1 Hz, 3H), 3.57 - 3.48 (m, 1H), 3.44 (d, J = 1.7 Hz, 1H), 2.94 (t, J = 7.1 Hz, 2H), 2.36 (s, 1H), 2.24 (s, 3H), 2.13 (s, 1H), 2.03 (s, 2H).

[0400] Example 60: (R)-1-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1H-benzo[de]isoquinolin- 2(3H)-yl)methyl)cyclopropane-1-carboxylic acid (ZN137)

[0401]

[0402] Step 1: Synthesis of methyl 1-((6-((3-bromo-2-methylbenzyl)oxy)-1H-benzo[de]isoquinoline-2(3H)-yl)methyl)cyclopropane-1-carboxylic acid (ZN122)

[0403] ZN099 (410 mg, 1.12 mmol) and K₂CO₃ (385.61 mg, 2.79 mmol) were dissolved in acetonitrile (50 mL). Finally, methyl-1-(bromomethyl)cyclopropane-1-carboxylic acid ester (536.02 mg, 2.79 mmol) and KI (20 mg, 0.01 mmol) were added, and the mixture was heated to 80 °C and reacted for 12 hours. After the reaction, the solvent was evaporated, and the mixture was purified by column chromatography to obtain 380.1 mg of the target compound, yield: 71%. ESI-MS theoretical value: C 26 H 26 BrNO3[M+H] + =480.11, measured: 480.4.

[0404] Step 2: Synthesis of methyl 1-((6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)benzyl)oxy)-1H-benzo[de]isoquinoline-2(3H)-yl)methyl)cyclopropane-1-carboxylic acid (ZN128)

[0405] ZN122 (380.1 mg, 0.79 mmol), pinacol diborate (467.96 mg, 1.98 mmol), and AcOK (311.3 mg, 3.17 mmol) were dissolved in anhydrous 1,4-dioxane (30 mL). Under a nitrogen atmosphere, palladium dichloride bis(triphenylphosphine) (56.15 mg, 0.08 mmol) was added. The reaction was then heated at 95 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was allowed to return to room temperature, the solvent was evaporated, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness. Finally, the mixture was purified by column chromatography to obtain 366.3 mg of the target compound (yield: 88%). 1H NMR (400 MHz, Methanol-d4) δ 8.08 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.40 (q, J = 8.4, 8.0 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H), 7.19 (dd, J = 12.1, 7.7 Hz, 2H), 6.97 (d, J = 7.8 Hz, 1H), 5.23 (s, 2H), 4.10 (s, 2H), 4.06 (s, 2H), 3.67 (d, J = 2.3 Hz, 3H), 2.93 (s, 2H), 2.58 (d, J = 2.2 Hz, 3H), 1.77 (d, J = 5.4 Hz, 1H), 1.36 (d, J = 2.2 Hz, 12H), 1.24 (d, J = 2.2 Hz, 2H), 1.20 (d, J = 2.2 Hz, 2H).

[0406] Step 3: Synthesis of ZN137

[0407] ZN128 (105.5 mg, 0.2 mmol), ZN041 (86.4 mg, 0.2 mmol), K2CO3 (69.1 mg, 0.5 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), and Ruphos Pd G4 (17 mg, 0.02 mmol) was added under a nitrogen atmosphere, and then the mixture was heated to 80 °C for 5 hours under a nitrogen atmosphere. After the reaction was completed, the organic solvent was evaporated, water was added, and ethyl acetate was extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, and evaporated. The obtained reaction crude product (ZN132) was dissolved in water (5 ml) and tetrahydrofuran (5 ml), and then LiOH-H2O (50.35 mg, 1.2 mmol) was added, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the organic solvent was evaporated by adjusting the pH to be acidic with trifluoroacetic acid, and the target compound was separated and purified by a reverse phase column to obtain 58.3 mg, yield: 39%. ESI-MS Calcd for C 44 H 42 ClN5O4[M+H] + = 740.29, Found: 740.5.

[0408] Example 61: (R)-2-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1H-benzo[de]isoquinoline- 2(3H)-acetic acid (ZN124)

[0409]

[0410] Step 1: Synthesis of 2-(6-((3-bromo-2-methylbenzyl)oxy)-lH- benzo[de]isoquinolin-2(3H)-yl)ethyl acetate (ZN114)

[0411] ZN099 (367.1 mg, 1.0 mmol), K2CO3 (414.6 mg, 3.0 mmol) were dissolved in acetonitrile (40 ml) and stirred at room temperature for 20 minutes, then ethyl chloroacetate (269.61 mg, 2.2 mmol), KI (16.6 mg, 0.1 mmol) were added, then the reaction was heated to 80 °C for 12 hours. After the reaction was completed, the solvent was evaporated and purified by column chromatography to obtain the target compound 203 mg, yield: 45%. 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.24 (s, 1H), 7.10 (q, J = 8.0, 7.3 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 5.21 (s, 2H), 4.24 - 4.20 (d, J = 7.4 Hz, 2H), 4.11 (d, J = 7.4 Hz, 2H), 2.47 (s, 3H), 1.28 (q, J = 9.2, 8.2 Hz, 4H), 1.20 (t, J = 7.2 Hz, 3H).

[0412] Step 2: Synthesis of 2-(6-((2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)-lH-benzo[de]isoquinolin-2(3H)-yl)ethyl acetate (ZN117)

[0413] ZN114 (128.2 mg, 0.28 mmol), bis(pinacolato)diboron (166.9 mg, 0.71 mmol), AcOK (111.07 mg, 1.13 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL) solution, and under a nitrogen atmosphere, dichlorobis(triphenylphosphine)palladium (20 mg) was added, and finally the reaction was heated to 95 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, and after the solvent was evaporated, water was added, then extracted with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, then evaporated, and finally purified by column chromatography to obtain the target compound 112 mg, yield: 80%. 1H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 7.0 Hz, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 5.21 (s, 2H), 4.22 (q, J = 7.2 Hz, 3H), 4.11 (q, J = 7.2 Hz, 3H), 2.59 (s, 3H), 1.53 (d, J = 2.0 Hz, 2H), 1.37 (d, J = 2.1 Hz, 12H), 1.23 - 1.16 (m, 3H).

[0414] Step 3: Synthesis of ZN124

[0415] ZN117 (104 mg, 0.21 mmol), ZN041 (89.68 mg, 0.21 mmol), K2CO3 (71.87 mg, 0.52 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), and RuphosPd G4 (17.85 mg, 0.02 mmol) was added under a nitrogen atmosphere, and then the temperature was raised to 80°C under nitrogen protection for 5 hours. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The crude product was obtained, dissolved in water (5 ml) and tetrahydrofuran (5 ml), and then LiOH-H2O (51.2 mg, 1.22 mmol) was added, and the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, the pH was adjusted to be acidic with trifluoroacetic acid, the organic solvent was spin-dried, and the target compound was separated and purified by a reverse phase column to obtain 38.6 mg, yield: 26%. 1 H NMR (400 MHz, Methanol-d4) δ 9.07 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.64 - 7.56 (m, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.21 (dd, J = 15.1, 7.7 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 5.41 (s, 2H), 4.73 (s, 2H), 4.61 (s, 1H), 4.48 (s, 1H), 3.70 (s, 2H), 3.60 - 3.38 (m, 4H), 3.26 - 3.08 (m, 3H), 2.44 - 2.29 (m, 1H), 2.22 (s, 3H), 2.12 (s, 1H).

[0416] Example 62: (R)-3-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1H- benzo[de]isoquinolin-2(3H)-yl)-3-oxopropanoic acid (ZO053)

[0417]

[0418] Step 1: Synthesis of 3-(6-((3-bromo-2-methylbenzyl)oxy)-1H- benzo[de]isoquinolin-2(3H)-yl)-3-oxopropanoic acid ethyl ester (ZO045)

[0419] ZN099 (300 mg, 0.6 mmol) was dissolved in dry dichloromethane (25 ml), triethylamine (133.6 mg, 1.32 mmol) was added after stirring for 15 minutes, monochloroacetic acid ethyl ester (117.44 mg, 0.78 mmol) was added dropwise after cooling in an ice water bath, and the reaction was monitored with a TLC plate after slowly warming to room temperature. After the reaction was completed, water was added to quench the reaction, dichloromethane was added for extraction, the organic phase was collected and dried, and the target compound was obtained after separation and purification with a chromatography column. The yield was 274.2 mg, and the yield was 95%. 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (t, J = 8.9 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.44 (t, J = 6.5 Hz, 2H), 7.28 (d, J = 5.4 Hz, 1H), 7.23 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.86 (dd, J = 13.3, 7.8 Hz, 1H), 5.22 (d, J = 2.4 Hz, 2H), 5.08 (d, J = 17.6 Hz, 2H), 4.88 (d, J = 17.9 Hz, 2H), 4.09 (p, J = 7.1 Hz, 2H), 3.60 (s, 2H), 2.48 (s, 3H), 1.11 (q, J = 7.1 Hz, 3H).

[0420] Step 2: Synthesis of 3-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)-yl)-3-oxopropanoic acid ethyl ester (ZO048)

[0421] ZO045 (0.66 mmol), bis(pinacolato)diboron (422.77 mg, 1.66 mmol), AcOK (261.16 mg, 2.66 mmol) were dissolved in anhydrous 1,4-dioxane (25 mL) solution, under nitrogen atmosphere, bis(triphenylphosphine)palladium dichloride (46.3 mg, 0.07) was added, finally the reaction was heated at 95 °C for 12 hours under nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, the solvent was spin-dried, then water was added, followed by extraction with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, then spin-dried, finally the target compound (ZO048) 303.6 mg, yield: 87% was obtained by column separation and purification. 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (t, J = 9.0 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.42 (q, J = 7.7 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.25 (m, 2H), 6.90 - 6.83 (m, 1H), 5.22 (d, J = 3.3 Hz, 2H), 5.07 (d, J = 17.6 Hz, 2H), 4.88 (d, J = 18.1 Hz, 2H), 4.09 (dd, J = 7.6, 6.3 Hz, 2H), 3.60 (s, 2H), 2.60 (s, 3H), 1.37 (s, 12H), 1.10 (td, J = 7.1, 5.0 Hz, 3H).

[0422] Step 3: Synthesis of ZO053

[0423] ZO048 (80 mg, 0.151 mmol), ZN041 (71.8 mg, 0.166 mmol), K2CO3 (52.2 mg, 0.378 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), under nitrogen atmosphere, RuphosPd G4 (12.8 mg, 0.015 mmol) was added, finally heated to 80 °C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was spin-dried, water was added, extracted with ethyl acetate, the organic phase was collected, dried with anhydrous sodium sulfate, then spin-dried, the spin-dried product was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (8 ml), then LiOH-H2O (63.4 mg, 1.51 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to the reaction system to adjust the pH to acidic, then the organic solvent was spin-dried and purified by reverse phase column to obtain the target compound 33.5 mg, yield: 31%. 1H NMR (500 MHz, Methanol-d4) δ 9.18 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.12 - 8.04 (m, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.44 (dt, J = 7.7, 2.0 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.36 - 7.29 (m, 3H), 7.24 (dt, J = 13.5, 8.1 Hz, 2H), 7.00 (dd, J = 19.9, 7.9 Hz, 1H), 5.29 (d, J = 11.9 Hz, 2H), 4.74 (t, J = 10.8 Hz, 2H), 4.67 - 4.53 (m, 1H), 3.65 (dd, J = 8.0, 3.4 Hz, 3H), 3.55 (s, 2H), 3.47 - 3.34 (m, 1H), 2.33 (d, J = 4.1 Hz, 1H), 2.20 (d, J = 4.0 Hz, 3H), 2.12 (s, 1H).

[0424] Example 63: (R)-4-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1H- benzo[de]isoquinolin-2(3H)-yl)-4-oxobutanoic acid (ZO052)

[0425]

[0426] Step 1: Synthesis of 4-(6-((3-bromo-2-methylbenzyl)oxy)-1H- benzo[de]isoquinolin-2(3H)-yl)-4-oxobutanoic acid ethyl ester (ZO046)

[0427] ZN099 (320 mg, 0.665 mmol) was dissolved in dry dichloromethane (25 ml), triethylamine (148.07 mg, 1.46 mmol) was added after stirring for 15 minutes, and monosuccinic acid chloride (142.32 mg, 0.865 mmol) was added dropwise after cooling in an ice water bath. The reaction was monitored using a TLC plate after slowly warming to room temperature. After the reaction was completed, water was added to quench the reaction, dichloromethane was used for extraction, and the organic phase was collected and rotary evaporated. The target compound was obtained after separation and purification using a chromatographic column, 326.7 mg, yield: 98%. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (t, J = 9.7 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.43 (ddd, J = 13.8, 8.1, 4.6 Hz, 2H), 7.32 (dd, J = 18.8, 7.5 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.86 (t, J = 6.9 Hz, 1H), 5.22 (d, J = 3.5 Hz, 2H), 5.04 (d, J = 17.9 Hz, 2H), 4.92 (d, J = 18.2 Hz, 2H), 4.13 (d, J = 7.1 Hz, 2H), 2.80 (q, J = 7.0 Hz, 2H), 2.70 - 2.64 (m, 2H), 2.48 (s, 3H), 1.25 - 1.20 (m, 3H).

[0428] Step 2: Synthesis of ethyl 4-(6-((2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)-lH-benzo[de]isoquinolin-2(3H)-yl)-4-oxobutanoate (ZO049)

[0429] ZO046 (0.66 mmol), pinacol diboronic acid (422.77 mg, 1.66 mmol), AcOK (261.16 mg, 2.66 mmol) were dissolved in anhydrous 1,4-dioxane (25 mL) solution, under nitrogen atmosphere, palladium dichloride bis-triphenylphosphine (46.3 mg, 0.07) was added, finally the reaction was heated at 95 °C for 12 hours under nitrogen atmosphere. After the end of the reaction, it was brought to room temperature, the solvent was evaporated, then water was added, then it was extracted with ethyl acetate three times, the organic phases were combined and dried with anhydrous sodium sulfate, then evaporated, finally the target compound was isolated and purified by column chromatography, 311.7 mg, yield: 87%. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (t, J = 9.9 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.31 (dd, J = 16.8, 5.2 Hz, 1H), 7.25 - 7.20 (m, 2H), 6.87 (t, J = 7.3 Hz, 1H), 5.22 (d, J = 4.1 Hz, 2H), 5.04 (d, J = 17.9 Hz, 2H), 4.92 (d, J = 18.1 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H), 2.67 (t, J = 6.9 Hz, 2H), 2.60 (s, 3H), 1.37 (s, 12H), 1.23 (t, J = 7.2 Hz, 3H).

[0430] Step 3: Synthesis of ZO052

[0431] ZO049 (82 mg, 0.151 mmol), ZN041 (71.8 mg, 0.166 mmol), K2CO3 (52.2 mg, 0.378 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), RuphosPd G4 (12.8 mg, 0.015 mmol) was added under nitrogen atmosphere, and finally heated to 80 °C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The spin-dried product was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (8 ml), and then LiOH-H2O (63.4 mg, 1.51 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to the reaction system to adjust the pH to be acidic, and then the organic solvent was spin-dried and separated and purified by a reverse phase column to obtain the target compound 36.2 mg, yield: 32%. 1H NMR (400 MHz, Methanol-d4) δ 9.16 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.28 (dd, J = 8.2, 1.4 Hz, 1H), 8.25 - 8.18 (m, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.58 - 7.46 (m, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.1, 2.1 Hz, 3H), 7.26 (dd, J = 7.7, 1.4 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 5.39 (d, J = 2.2 Hz, 2H), 4.77 (d, J = 6.3 Hz, 2H), 4.72 (s, 2H), 4.67 (s, 2H), 4.62 (s, 1H), 3.70 (m, 2H), 3.55 (m, 2H), 3.43 (m, 2H), 2.34 (s, 1H), 2.24 (s, 3H), 2.14 (m, 2H), 2.03 (s, 1H).

[0432] Example 64: (R)-1-((8-((2-chloro-3'-(((2-(3-(dimethylamino)propyl)-2,3-dihydro-1H- benzo[de]isoquinolin-6-yl)oxy)methyl)-2'-methyl-[1,1'-biphenyl]-3-ylamino)-1,7- naphthyridin-3-yl)methyl)pyrrolidin-3-ol (ZO072)

[0433]

[0434] Step 1: Synthesis of 3-(6-((3-bromo-2-methylbenzyl)oxy)-1H- benzo[de]isoquinolin-2(3H)-yl)-N,N-dimethyl-1-propanamine (ZO068)

[0435] ZN099 (100 mg, 0.207 mmol) was dissolved in DMF (3 ml), after cooling in ice water bath, NaH (65.4 mg, 1.64 mmol) was added and reacted for 20 minutes, then 3-bromo-N,N-dimethyl-1-propanamine hydrobromide (105 mg, 0.545 mmol) was added, and the reaction was continued to room temperature for 4 hours. After the reaction was completed, ice water was added to quench, extracted with ethyl acetate, the organic phase was collected and rotary evaporated. Then the target compound was obtained by separation and purification with a chromatographic column, 63 mg, yield: 67%. 1H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 10.0, 5.5 Hz, 1H), 7.28 (s, 2H), 7.17 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 5.21 (s, 2H), 4.00 (s, 2H), 3.97 (s, 2H), 3.11 - 3.04 (m, 2H), 2.77 (t, J = 6.6 Hz, 2H), 2.71 (s, 6H), 2.47 (s, 3H), 2.20 (p, J = 6.7 Hz, 2H).

[0436] Step 2: Synthesis of N,N-dimethyl-3-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)-yl)propan-1-amine (ZO069)

[0437] ZO068 (160 mg, 0.354 mg), bis(pinacolato)diboron (224.6 mg, 0.885 mmol), AcOK (139 mg, 1.42 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL) solution, palladium dichloride bis-triphenylphosphine (24.8 mg, 0.035) was added under nitrogen atmosphere, finally the reaction was heated at 95 °C for 12 hours under nitrogen atmosphere. After completion of the reaction, it was brought to room temperature, the solvent was evaporated, then water was added, followed by extraction with ethyl acetate three times, the organic phase was combined and dried over anhydrous sodium sulfate and evaporated, finally the target compound (ZO069) 138 mg, yield: 78% was isolated and purified by column chromatography. ESI-MS Theoretical value: C 31 H 41 BN2O3[M+H] + = 501.32, Found: 501.5.

[0438] Step 3: Synthesis of ZO072

[0439] ZO069 (100 mg, 0.2 mmol), ZN041 (86.41 mg, 0.2 mmol), K2CO3 (69.1 mg, 0.5 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), and Ruphos Pd G4 (17 mg, 0.02 mmol) was added under a nitrogen atmosphere, and finally heated to 80°C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. Finally, the target compound was obtained by reverse phase column separation and purification, and the yield was 51.8 mg, 36%. 1 H NMR (400 MHz, Methanol-d4) δ 9.10 (d, J = 2.2 Hz, 1H), 8.57 - 8.50 (m, 2H), 8.33 - 8.28 (m, 1H), 8.02 (d, J = 6.2 Hz, 1H), 7.60 (dd, J = 8.6, 7.2 Hz, 2H), 7.54 (dd, J = 7.4, 5.6 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.27 - 7.19 (m, 3H), 5.47 - 5.34 (m, 2H), 4.84 - 4.68 (m, 5H), 4.61 (s, 1H), 3.62 (m, 3H), 3.50 - 3.37 (m, 3H), 3.28 - 3.19 (m, 2H), 2.94 (s, 6H), 2.38 (qd, J = 10.8, 9.4, 6.6 Hz, 3H), 2.23 (s, 3H), 2.13 (m, 1H).

[0440] Example 65: (R)-3-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1H-benzo[de]isoquinolin- 2(3H)-yl)cyclobutane-1-carboxylic acid (ZO074)

[0441]

[0442] Step 1: Synthesis of 3-(6-((3-bromo-2-methylbenzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)- yl)cyclobutane-1-carboxylic acid methyl ester (ZO067)

[0443] ZN099 (289 mg, 0.6 mmol), 3-oxo-cyclobutane carboxylic acid methyl ester (153.76, 1.2 mmol) was dissolved in dichloromethane (30 ml), after adding triethylamine (212.5 mg, 2.1 mmol) and stirring for 30 minutes, sodium triacetoxyborohydride (381.6 mg, 1.8 mmol) was added and the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, water was added and dichloromethane was extracted, the organic phase was collected and dried after rotary evaporation, and the target compound was obtained by column separation and purification, 213.5 mg, yield: 74%. 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J = 8.5 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 5.21 (s, 2H), 3.94 (d, J = 14.8 Hz, 4H), 3.68 (s, 4H), 3.07 (m, 1H), 2.81 (q, J = 9.0 Hz, 1H), 2.47 (s, 3H).

[0444] Step 2: Synthesis of 3-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-1H- benzo[de]isoquinolin-2(3H)-yl)cyclobutane-1-carboxylic acid methyl ester (ZO070)

[0445] ZN067 (213.5 mg, 0.446 mg), pinacol diboronic acid (283 mg, 1.11 mmol), AcOK (175.1 mg, 1.78 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL) solution, and dichlorobis(triphenylphosphine) palladium (31.6 mg, 0.045 mmol) was added under a nitrogen atmosphere, and finally the reaction was heated at 95°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was allowed to return to room temperature, the solvent was dried by rotary evaporation, then water was added, followed by extraction with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, and then rotary evaporation was performed, and finally the target compound was obtained by column separation and purification, 228.4 mg, yield: 97%. ESI-MS Theoretical value: C 32 H 38 BNO5[M+H] + = 528.28, measured: 528.6.

[0446] Step 3: Synthesis of ZO074

[0447] ZO070 (105 mg, 0.2 mmol), ZN041 (86.4 mg, 0.2 mmol), K2CO3 (69.1 mg, 0.5 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), and Ruphos Pd G4 (17 mg, 0.02 mmol) was added under a nitrogen atmosphere, and then the reaction was heated to 80°C for 5 hours under a nitrogen atmosphere. After the reaction was completed, the organic solvent was evaporated, water was added, and ethyl acetate was extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated. The above product was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (8 ml), and then LiOH-H2O (50.4 mg, 1.2 mmol) was added, and the reaction was performed at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to the reaction system to adjust the pH to be acidic, and then the organic solvent was evaporated and separated and purified by a reverse phase column to obtain 44.8 mg of the target compound with a yield of 30%. 1 H NMR (400 MHz, Methanol-d4) δ 9.13 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.30 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 (d, J = 6.5 Hz, 1H), 7.61 (dd, J = 7.6, 1.3 Hz, 1H), 7.59 - 7.51 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 9.2, 7.0 Hz, 2H), 7.28 (dd, J = 7.7, 1.6 Hz, 1H), 7.25 (dd, J = 7.7, 1.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.40 (d, J = 2.4 Hz, 2H), 4.75 (t, J = 9.9 Hz, 4H), 4.62 (d, J = 4.5 Hz, 2H), 3.97 - 3.85 (m, 1H), 3.70 (s, 1H), 3.51 (d, J = 26.7 Hz, 2H), 3.42 (s, 1H), 3.02 (tt, J = 9.7, 8.0 Hz, 1H), 2.83 - 2.72 (m, 2H), 2.58 (qd, J = 9.6, 2.7 Hz, 2H), 2.37 (d, J = 17.1 Hz, 1H), 2.23 (s, 3H), 2.13 (s, 1H).

[0448] Example 66: (1R)-3-(6-((2'-chloro-3'-((3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7- naphthyridin-8-yl)amino)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1H-benzo[de]isoquinolin- 2(3H)-yl)cyclopentane-1-carboxylic acid (ZO093)

[0449]

[0450] Step 1: Synthesis of (1R)-3-(6-((3-bromo-2-methylbenzyl)oxy)-1H- benzo[de]isoquinolin-2(3H)-yl)cyclopentane-1-carboxylate (ZO087)

[0451] ZN099 (289 mg, 0.6 mmol), (R)-3-oxocyclopentanecarboxylic acid methyl ester (187.42, 1.2 mmol) were dissolved in dichloromethane (30 ml), after adding triethylamine (212.5 mg, 2.1 mmol) and stirring for 30 minutes, sodium triacetoxyborohydride (381.6 mg, 1.8 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, water was added and dichloromethane was extracted, the organic phase was collected and dried by rotary evaporation, and then separated and purified by a chromatography column to obtain 163.6 mg of the target compound, yield: 55%. 1 H NMR (500 MHz, Chloroform-d) δ 8.15 (d, J = 8.4 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.47 - 7.41 (m, 2H), 7.15 (d, J = 7.5 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.21 (s, 2H), 4.20 (d, J = 20.5 Hz, 4H), 3.68 (d, J = 1.8 Hz, 3H), 3.07 - 2.92 (m, 2H), 2.76 (t, J = 9.1 Hz, 2H), 2.48 (d, J = 2.8 Hz, 3H), 2.32 (dt, J = 13.2, 6.7 Hz, 2H), 1.88 (t, J = 10.1 Hz, 1H).

[0452] Step 2: Synthesis of (1R)-3-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)-yl)cyclopentane-1-carboxylate (ZO091)

[0453] ZN087 (163.6 mg, 0.332 mg), bis(pinacolato)diboron (210.6 mg, 0.83 mmol), AcOK (130.3 mg, 1.33 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL) solution, under nitrogen atmosphere, palladium dichloride bis-triphenylphosphine (23.2 mg, 0.033 mmol) was added, finally the reaction was heated at 95 °C for 12 hours under nitrogen atmosphere. After the reaction was completed, it was brought to room temperature, the solvent was evaporated, then water was added, followed by extraction with ethyl acetate three times, the organic phase was combined and dried over anhydrous sodium sulfate and evaporated, finally the target compound was obtained by column separation and purification, 114.3 mg, yield: 64%. ESI-MS Theoretical value: C 33 H 40 BNO5[M+H] + = 542.30, measured: 542.5.

[0454] Step 3: Synthesis of ZO093

[0455] ZO091 (80 mg, 0.148 mmol), ZN041 (70 mg, 0.163 mmol), K2CO3 (51.14 mg, 0.37 mmol) were dissolved in a mixed solution of 1,4-dioxane (16 ml) and water (4 ml), under nitrogen atmosphere, Ruphos Pd G4 (12.8 mg, 0.015 mmol) was added, finally heated to 80 °C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was evaporated, water was added, extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate and evaporated. The above evaporated product was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and water (10 ml), then LiOH-H2O (58.7 mg, 1.41 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to the reaction system to adjust the pH to acidic, then the organic solvent was evaporated and purified by reverse phase column to obtain the target compound 46.7 mg, yield: 42%. 1H NMR (400 MHz, Methanol-d4) δ 9.19 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.28 (dd, J = 6.7, 3.0 Hz, 1H), 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 2H), 7.58 - 7.52 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 7.7, 1.6 Hz, 1H), 7.36 (dd, J = 8.8, 7.1 Hz, 2H), 7.27 (dd, J = 7.8, 1.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.49 (s, 4H), 5.40 (d, J = 1.6 Hz, 2H), 4.83 - 4.70 (m, 2H), 4.66 - 4.56 (m, 1H), 3.84 (p, J = 8.2 Hz, 1H), 3.70 (s, 1H), 3.54 (d, J = 17.9 Hz, 2H), 3.43 (s, 1H), 3.05 - 2.93 (m, 1H), 2.62 (dt, J = 14.0, 7.5 Hz, 1H), 2.37 (q, J = 11.0, 8.6 Hz, 2H), 2.24 (d, J = 2.9 Hz, 4H), 2.21 - 2.16 (m, 1H), 2.16 - 2.11 (m, 1H), 2.11 - 2.05 (m, 2H), 2.03 (s, 6H).

[0456] Example 67: (R)-4-(6-((2'-chloro-3'-((3-((3-hydroxypyrrolidin-l- yl)methyl)-l,7-naphthyridin-8-yl)amino)-2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-lH- benzo[de]isoquinolin-2(3H)-yl)cyclohexane-l-carboxylic acid (ZO080)

[0457]

[0458] Step 1: Synthesis of methyl 4-(6-((3-bromo-2-methylbenzyl)oxy)-lH- benzo[de]isoquinolin-2(3H)-yl)cyclohexane-l-carboxylate (ZO075)

[0459] ZN099 (190 mg, 0.52 mmol), 4-cyclohexanone carboxylic acid methyl ester (161.7, 1.04 mmol) were dissolved in dichloromethane (30 ml), after adding triethylamine (131.6 mg, 1.3 mmol) and stirring for 30 minutes, sodium triacetoxyborohydride (330.7 mg, 1.6 mmol) was added and the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, water was added and dichloromethane was extracted, the organic phase was collected and dried, and then purified by column chromatography to obtain 99 mg of the target compound, yield: 38%. 1 H NMR (500 MHz, Chloroform-d) δ 8.17 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 8.1, 1.2 Hz, 1H), 7.45 (dt, J = 8.8, 1.7 Hz, 2H), 7.29 (dd, J = 6.3, 2.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.22 (s, 2H), 4.35 (d, J = 20.5 Hz, 4H), 3.72 (s, 3H), 2.77 (s, 2H), 2.62 - 2.55 (m, 2H), 2.48 (s, 3H), 2.30 - 2.24 (m, 2H), 1.92 (d, J = 15.7 Hz, 2H), 1.83 (dd, J = 9.5, 4.8 Hz, 2H), 1.52 - 1.48 (m, 1H).

[0460] Step 2: Synthesis of 4-(6-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)oxy)-1H-benzo[de]isoquinolin-2(3H)-yl)cyclohexane-1-carboxylic acid methyl ester (ZO077)

[0461] ZN075 (94 mg, 0.185 mg), pinacol diboronic acid (117.7 mg, 0.464 mmol), AcOK (72.76 mg, 0.741 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL) solution, and palladium dichloride bis-triphenylphosphine (13 mg, 0.018 mmol) was added under a nitrogen atmosphere, and finally the reaction was heated at 95°C for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was returned to room temperature, the solvent was dried and then water was added, followed by extraction with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, and then dried, and finally purified by column chromatography to obtain 44.6 mg of the target compound, yield: 43%. 1H NMR (500 MHz, Chloroform-d) δ 8.31 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.58 - 7.53 (m, 1H), 7.52 - 7.46 (m, 2H), 7.38 (d, J = 7.3 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.29 - 5.22 (m, 2H), 4.80 (d, J = 22.1 Hz, 2H), 4.61 (d, J = 13.7 Hz, 2H), 3.75 (s, 3H), 2.96 (s, 1H), 2.62 (s, 3H), 2.56 (s, 1H), 2.30 (d, J = 14.3 Hz, 4H), 2.01 (s, 4H), 1.37 (s, 12H).

[0462] Step 3: Synthesis of ZO080

[0463] ZO077 (44.6 mg, 0.08 mmol), ZN041 (38.2 mg, 0.08 mmol), K2CO3(27.6 mg, 0.2 mmol) were dissolved in a mixed solution of 1,4-dioxane (12 ml) and water (3 ml), and Ruphos Pd G4 (8.5 mg, 0.01 mmol) was added under a nitrogen atmosphere, and then the mixture was heated to 80°C for 5 hours under nitrogen protection. After the reaction was completed, the organic solvent was spin-dried, water was added, and ethyl acetate was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The spin-dried product was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (8 ml), and then LiOH-H2O (20.1 mg, 0.48 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, trifluoroacetic acid was added to the reaction system to adjust the pH to be acidic, and then the organic solvent was spin-dried and separated and purified by a reverse phase column to obtain 18.8 mg of the target compound, with a yield of 31%. 1H NMR (400MHz, Methanol-d4) δ9.20(d,J=2.0Hz,1H),8.60(d,J=2.0Hz,1H),8.29(dd,J=7.4,2.3Hz,1H),8.15(dd,J=8.0,1.6Hz,1H),7.86(d,J=6.7Hz,1H ),7.64(ddd,J=7.9,4.6,3.3Hz,2H),7.59–7.52(m,2H),7.49(d,J=7.9Hz,1H ),7.41(dd,J=7.7,1.6Hz,1H),7.38(t,J=7.5Hz,2H),7.29(dd,J=7.8,1.3Hz ,1H),7.21(d,J=8.0Hz,1H),5.42(d,J=1.9Hz,2H),4.87(s,2H),4.81(t,J= 8.0Hz,4H),4.64(q,J=3.8,3.2Hz,1H),3.72(s,1H),3.58(s,2H),3.49(tt,J =12.3,3.7Hz,2H),2.75(dp,J=5.0,2.5Hz,1H),2.40(d,J=13.9Hz,3H),2.26 (s,3H),2.25–2.09(m,3H),1.99–1.85(m,2H),1.71(tt,J=13.5,4.1Hz,2H).

[0464] The above embodiments are summarized as follows:

[0465] Table 1

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476] Biological test example 1

[0477] HTRF method for detecting the activity of compounds inhibiting PD1 / PD-L1 protein interaction

[0478] The PD1 / PD-L1 Binding Assay Kit used in the experiment was purchased from Cisbio (#64PD1PEG), and the 96-well plate was purchased from Cisbio Company (white, #66PL96025). The multifunctional enzyme labeler is a product of TECAN Company, model: SPARK 10M. The specific experimental scheme is as follows:

[0479] 1) The compound to be tested was dissolved in DMSO to form a standard stock solution of 10 mM. Then, in an EP tube, the standard stock solution of the test compound was diluted with the diluent buffer provided by the kit to form a working sample solution, and 12 concentration gradients were set according to the experimental plan, with a 5-fold dilution between adjacent concentrations. The prepared working sample solution concentration = 10 times the required sample concentration on the test plate (10x test compound solution), ready for use.

[0480] 2) Dilute Tag1-PD-L1 protein and Tag2-PD1 protein with diluent buffer to working protein solution concentration, and the required working protein solution concentration = 5 times the required sample concentration on the test plate (5x test compound solution), ready for use.

[0481] 3) Dilute Anti-Tag1-Eu3+ 100 times with the detection buffer provided by the kit, and dilute Anti-Tag2-XL665 25 times with the detection buffer provided by the kit, ready for use.

[0482] 4) Add 2 uL of the diluted test compound 1 to the corresponding wells of A1-A12, B1-B12, respectively, add 2 uL of the diluted test compound 2 to the corresponding wells of C1-C12, D1-D12, respectively, and add 2 uL of the diluted test compound 3 to the corresponding wells of E1-E12, F1-F12, respectively.

[0483] 5) Add 4 uL of Tag1-PD-L1 protein to each well containing the test compound.

[0484] 6) Add 4 uL of Tag2-PD1 protein to each well containing the test compound, and incubate at room temperature for 15 minutes.

[0485] 7) Take 400 uL of the diluted Anti-Tag1-Eu3+ and Anti-Tag2-XL665, mix them evenly in a 1:1 ratio, and then take 10 uL and add it to each well containing the test compound.

[0486] 8) The experiment designed 4 groups of control, respectively: positive control group (2uL diluent buffer + 4uL Tag1-PD-L1 + 4uL Tag2-PD1 + 5uL Anti-Tag1-Eu3++ 5uL Anti-Tag2-XL665), negative control group (6uL diluent buffer + 4uL Tag2-PD1 + 5uL Anti-Tag1-Eu3++ 5uL Anti-Tag2-XL665), Anti-Tag1-Eu3+ control group (10uL diluent buffer + 5uL Anti-Tag1-Eu3+ 5uL detection buffer) and buffer control group (10uL diluent buffer + 10uL detection buffer).

[0487] 9) After the 96-well plate was sealed with a sealing film, it was incubated at room temperature for 2h.

[0488] 10) After removing the sealing film, the signal values of Ex320nm / Em612nm and Ex320nm / Em650nm were read by a microplate reader, respectively. The ratio of donor and acceptor emission signals in each well was calculated by the formula 10 4 ×Signal665nm / Signal612nm. The calculated ratio was plotted against the compound concentration gradient, and the median of the maximum and minimum values corresponded to the IC 50 value of the compound.

[0489]

[0490] Compound BMS-1266 is a compound of WO2015160641A2 patented by BMS company, which can inhibit the interaction of PD-1 / PD-L1 protein.

[0491] The results of the activity test of the compound are shown in Table 2:

[0492] Table 2

[0493]

[0494]

[0495] ***** indicates <1nM; **** indicates IC 50 <25nM; *** indicates IC 50 =25-100nM; ** indicates IC 50 =100-1000

[0496] nM; * indicates IC50 >1000nM

[0497] Biological test example 2

[0498] Pharmacokinetic properties of compounds in mice

[0499] ICR mice were weighed before dosing, and the dosing amount was calculated according to the body weight. The mice were dosed once by intravenous injection or oral gavage on the dosing day. The blood sampling time points were as follows: intravenous group: 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing; oral group: 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Blood was collected from the submandibular vein or other suitable ways, 0.03 mL / time point, and the blood samples were anticoagulated with K2-EDTA. The blood samples were centrifuged (centrifugation conditions: 6800 g, 6 minutes, 2-8°C) within 1 hour after collection to obtain plasma, which was stored in a -80°C refrigerator before analysis. 20 uL of the plasma sample was added to 400 uL of methanol (containing 100 ng / mL of an internal standard) solvent and centrifuged to extract the sample, and the obtained compound methanol solution was detected by LC-MS / MS method. The obtained compound content information was used to calculate the concentration of the target compound in the extraction solution by a standard curve. The pharmacokinetic parameters such as AUC(0-t), T 1 / 2 , Cmax, Tmax, and MRT were calculated by WinNonlin using the blood drug concentration data at different time points.

[0500] Table 3: Pharmacokinetic parameters of compound 22 (ZK119N) in mice

[0501]

[0502] Table 4: Pharmacokinetic parameters of compound 57 (ZN044) in mice

[0503]

[0504] Table 5: Pharmacokinetic parameters of compound 67 (ZO080) in mice

[0505]

[0506] The experimental data show that compounds 22 (ZK119N), 57 (ZN044), and 67 (ZO080) have good oral absorption and bioavailability.

[0507] Biological test example 3

[0508] Compounds promote T cell killing of cancer cells

[0509] Step one. ① Take OT-I transgenic mouse spleen, put it in a culture dish containing 1640 medium, use the syringe seat to grind the spleen tissue until no visible tissue. ② Transfer the tissue turbidity liquid to a 15 mL centrifuge tube, filter with a 40 μm filter before transfer, centrifuge at 1200 rpm for 5 minutes. ③ Discard the supernatant, add 2 mL of red blood cell lysis solution, stand for 6 minutes, then add 8 mL of 1640 complete medium and mix well, centrifuge at 1200 rpm for 5 minutes. ④ Remove the supernatant to obtain immune cells. Resuspend the immune cells with 1640 complete medium, add SIINFEKL OVA peptide (OVA257-264, Shanghai Sungene), the final concentration is 10-100 ug / mL, and add mIL-2 (R&D, 402-ML-020), the final concentration is 10-100 ng / mL. ⑤ Transfer the immune cells to a 12-well plate for culture, the system in each well is 2 mL. Culture in vitro for 5-7 days, change the liquid 1-2 times, and add different drugs for treatment at a concentration of 1 / 10 μM in the last 48 h of the culture process. After the culture ends, T cells are obtained for the next step experiment.

[0510] Step two. ① Take EL4 lymphoma cells in logarithmic growth state, add different drugs for 48 h, the concentration is 1 / 10 μM, and set up a solvent blank control. ② Collect the cells into 1.5 mL centrifuge tubes respectively, centrifuge at 1200 rpm for 5 minutes. ③ Discard the supernatant, wash the cells with 1 mL of sterile PBS, centrifuge at 1200 rpm for 5 minutes, discard the supernatant, repeat 2 times, and then resuspend with 1 mL of 1640 complete medium. ④ Divide each group of cells, add or do not add OVA peptide, the treatment concentration is 10-100 ug / mL, and incubate at 37°C for 2 h. The OVA peptide-treated group finally obtains EL4+OVA cells, which are used as target cells. The untreated EL4 cells are used as non-target cell controls. ⑤ Centrifuge at 1200 rpm for 5 minutes, discard the supernatant, wash the cells with 1 mL of sterile PBS, centrifuge again and discard the supernatant, repeat 2 times, then resuspend with 1 mL of sterile PBS. ⑥ The obtained cells are treated with high / low concentration CFSE (Invitrogen, 65-0850), wherein 10 μM CFSE is used to label the target cell group EL4+OVA cells, and 1 μM CFSE is used to label the non-target cell control group EL4 cells. After incubation at 37°C for 10 minutes in the dark, quench the remaining label in an ice bath for 5 minutes. After centrifugation, resuspend with 1640 complete medium.

[0511] Step three. Co-culture target cells and non-target cells with the same drug-treated T cells at different ratios. The effector-target ratio (T cells: target cells) is 16:1, 2:1, respectively, and the T cells and the same drug-treated target cells are co-cultured in a round-bottom 96-well plate. Different drugs are added to the culture system, and the types and concentrations of the drugs are the same as the original treatment conditions of the cells in the system. Referring to the above operation, T cells and the same drug-treated non-target cells are used as a blank control. After incubation at 37°C for 24 h, the specific killing percentage is calculated by FACS analysis (Beckman, CytoFlex S). PDL1 antibody (Bio X Cell, BE0101) and PD-1 / PD-L1 Inhibitor 3 (Selleck #S8158) are used as positive controls.

[0512]

[0513] PD-1 / PD-L1 Inhibitor 3 (Selleck #S8158) (protein level inhibition of PD-1 / PD-L1 interaction IC 50 = 5.6 nM)

[0514] The test results are shown in Table 1. Figure 1 The experimental results show that compounds 9 (ZK114N), 22 (ZK119N), 37 (ZM109), 57 (ZN044), 65 (ZO074), and 67 (ZO080) all have the activity of activating T cells and specifically killing target cells. And the specific killing effect of target cells of 22, 37, 57, and 67 is higher than that of the literature compound ZE132 (CAS No. 2566710-63-0), PD-L1 antibody (a-PDL1, BioXcell, BE0101), and cyclic peptide compound PD-1 / PD-L1 Inhibitor 3 (Selleck #S8158).

[0515] Biological test example 4: Anti-tumor efficacy of the compounds in a mouse syngeneic tumor model

[0516] The animal experiment operation steps are as follows:

[0517] 1. Culture B16F10 melanoma cells, and when they reach the logarithmic phase, centrifuge them at 800 rpm for 5 min, resuspend them in PBS, and the cell concentration is 5 x 10 6 cells / mL, and inoculate them subcutaneously in the right groin of C57BL / 6 mice as soon as possible. The cell suspension can be placed in an ice water bath during the operation.

[0518] 2. When the tumor volume grows to 50 mm 3Afterwards, mice were randomly grouped according to tumor volume and tumor growth curve was recorded. Compound 22 (ZK119) was administered at (a) 20 mg / kg i.v. once daily; (b) 50 mg / kg i.v. once daily; (c) 50 mg / kg p.o. once daily; (d) 100 mg / kg p.o. once daily. PD-1 antibody (BioXcell, BE0146) was administered at 10 mg / kg i.v. once every 3 days. Tumor volume was measured every two to three days. Tumor volume formula: V = L*W*W*1 / 2. The experiment was terminated when the tumor volume reached about 2000 mm3. 3 The results of the tumor volume experiment are shown in Table 1. Figure 2 Table 1. Tumor volume experiment results.

[0519] 3. Compound 22 (ZK119) and PD-1 antibody were administered in B16F10 mouse syngeneic tumor model at the following conditions: (a) Compound 22 i.v. 20 mg / kg once daily; (b) Compound 22 i.v. 50 mg / kg once daily; (c) Compound 22 p.o. 50 mg / kg once daily; (d) Compound 22 p.o. 100 mg / kg once daily; (e) PD-1 antibody (BioXcell, BE0146) was administered at 10 mg / kg i.v. once every 3 days. Figure 2 Figure 2B shows the body weight change of mice inoculated with B16F10 cancer cells after administration of Compound 22 (ZK119) and PD-1 antibody at different dosages.

[0520] The results of the experiment show that Compound 22 (ZK119) has anti-tumor efficacy in a mouse tumor model. Among them, Compound 22 i.v. 20 mg / kg, Compound 22 i.v. 50 mg / kg, and Compound 22 p.o. 100 mg / kg all have a significant effect on inhibiting tumor growth compared with the blank control. Compared with the positive compound PD-1 antibody (BioXcell, BE0146), Compound 22 i.v. 20 mg / kg and Compound 22 i.v. 50 mg / kg show more significant efficacy in inhibiting tumor growth. The above data show that Compound 22 has significant anti-cancer effect and certain advantages compared with antibodies.

[0521] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without the specific details that are set forth herein. Further, it should be noted that, in this application, "exemplary" or "for example" is used on a purely illustrative basis to aid the reader in understanding the application. Any process steps, or sequences of steps, or examples, or embodiments, or materials, or components, or compounds, or elements, or techniques described herein are understood not to be limiting, but are exemplary.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in, W is Y represents either non-existent or CH2; Z is CH2 or O; X is CH or N; when X is N, R1 is -(CH2)m-CO2H, where m is 1, 2, 3 or 4; when X is CH, R1 is -NR2-(CH2)n-CO2H, where n is 1, 2 or 3; R2 is a C1-C4 alkyl group. R3 is a C1-C4 alkyl group or a halogen; R4 is selected from: R5 is a C1-C4 alkyl group or a halogen; R6 is hydrogen or a C1-C6 alkyl group; R7 is selected from: 5-6-membered heteroaryl, substituted or unsubstituted C1-C6 alkyl; the substitution refers to substitution by one or more substituents selected from the group below: -NH (C1-C6 alkyl), -N (C1-C6 alkyl), hydroxyl, C1-C6 alkoxy; Alternatively, R6 and R7, along with the nitrogen atom attached to them, can form a substituted or unsubstituted 4- to 9-membered heterocycle, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, -N(C1-C6 alkyl)(C1-C6 alkyl), -NH(C1-C6 alkyl); R8 is either halogen or CN; R9 is selected from: C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkyl substituted by C3-C8 cycloalkyl, C1-C5 alkylCO-, and the above groups may be optionally substituted by one or more substituents selected from the following group: carboxyl, -N(C1-C6 alkyl)(C1-C6 alkyl); R 10 It is hydrogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound has the structure shown in Formula II: Where Y represents either non-existent or CH2; Z is CH2 or O; X is CH or N; when X is N, R1 is -(CH2)m-CO2H, where m is 1, 2 or 3; when X is CH, R1 is -NR2-(CH2)n-CO2H, where n is 1 or 2; R2 is a C1-C4 alkyl group. R3 is a C1-C4 alkyl group or a halogen; R4 is selected from: R5 is a C1-C4 alkyl group or a halogen; R6 is hydrogen; R7 is selected from 5- to 6-membered heteroaryl groups, substituted or unsubstituted C1-C6 alkyl groups; the substitution refers to substitution by one or more substituents selected from the group consisting of: -N(C1-C6 alkyl), hydroxyl, C1-C6 alkoxy. Alternatively, R6 and R7, along with the nitrogen atom attached to them, can form substituted or unsubstituted 4- to 9-membered heterocycles, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, -N(C1-C6 alkyl)(C1-C6 alkyl); R8 is either halogen or CN.

3. The compound according to claim 2, characterized in that, The compound has the structure shown in Formula III, Formula IV or Formula V: The definitions of R1, R3, R5, R6, R7, X, Y, and Z are the same as in claim 2.

4. The compound according to claim 2, characterized in that, The compound has the structure shown in formula VI, formula VI-1 or formula VI-2: The definitions of R1, R3, R5, R6, R7, Y, and Z are the same as in claim 2.

5. The compound according to claim 2, characterized in that, The compound has the structure shown in formula VII, formula VII-1, or formula VII-2: The definitions of R1, R3, R5, R6, and R7 are the same as in claim 2.

6. The compound according to claim 2, characterized in that, The compound has the structure shown in formula VIII, formula VIII-1, or formula VIII-2: The definitions of R1, R3, R5, R6, and R7 are the same as in claim 2.

7. The compound according to claim 2, characterized in that, The compound has the structure shown in Formula IX, Formula IX-1, or Formula IX-2: The definitions of R1, R3, R5, R6, and R7 are the same as in claim 2.

8. The compound according to claim 2, characterized in that, The compound has the structure shown in formula X, formula X-1, or formula X-2: The definitions of R, R1, R3, R5, R6, and R7 are the same as in claim 2.

9. The compound according to any one of claims 2-8, characterized in that, R6 is hydrogen; R7 is selected from: 5-6-membered heteroaryl, substituted or unsubstituted C1-C6 alkyl; the substitution refers to substitution by 1, 2 or 3 substituents selected from the group below: -N(C1-C4 alkyl)(C1-C4 alkyl), hydroxyl, C1-C4 alkoxy; Alternatively, R6 and R7, along with the nitrogen atom attached to them, can form a substituted or unsubstituted 5-6 membered heterocycle, wherein the substitution refers to the substitution of 1, 2, or 3 of the selected group of 5 substituents: hydroxyl, -N(C1-C4 alkyl)(C1-C4 alkyl); R8 can be Cl, F, Br, or CN.

10. The compound according to claim 1, characterized in that, The compound has the structure shown in Formula XI: The definitions of R3, R5, R6, R7, R9, and R10 are the same as those in claim 1.

11. The compound according to claim 10, characterized in that, R9 is a substituted C3-C6 cycloalkyl, a substituted C1-C4 alkyl, a cyclopropyl-substituted C1-C4 alkyl, a substituted or unsubstituted C1-C5 alkyl CO-, wherein the substitution refers to one or two substituents selected from the group below: carboxyl, dimethylamino.

12. A compound, characterized in that, The compound is selected from:

13. A pharmaceutical composition comprising the compound of any one of claims 1-12, its stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

14. The use of the compound according to any one of claims 1-12, its stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, characterized in that, Used for the preparation of PD1-PDL1 interaction inhibitors; or for the preparation of drugs for the prevention and / or treatment of diseases related to PD1 / PD-L1 interaction.

15. The use as described in claim 14, characterized in that, The diseases associated with PD1 / PD-L1 interaction are cancers.

16. The use as described in claim 15, characterized in that, The cancers mentioned are selected from the following group: non-small cell lung cancer, small cell lung cancer, melanoma, head and neck cancer, kidney cancer, bladder cancer, locally advanced or metastatic urothelial carcinoma, breast cancer, cervical cancer, metastatic Merkel cell carcinoma, prostate cancer, liver cancer, colorectal cancer, stomach cancer, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, and squamous cell carcinoma.

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