A small molecule immunomodulatory inhibitor and its drug combination and use

Abstract

The present invention relates to the field of medicine, and specifically to a small molecule immunomodulatory inhibitor and a drug combination and use thereof. More specifically, the small molecule compound described in the present invention can be used as a PD-L1 inhibitor and has anti-tumor use.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and specifically to a class of small molecule compounds used as immunomodulatory inhibitors. More specifically, the small molecule compounds described in the present invention can be used as PD-L1 inhibitors for anti-tumor purposes. Background Art

[0002] Programmed cell death protein 1 (PDCD1 or CD279) is a type I transmembrane protein composed of 288 amino acid residues encoded by the gene PDCD1. It belongs to the B7-CD28 receptor superfamily. Its structure consists of four parts: immunoglobulin variable region (IgV), transmembrane region, immunoreceptor tyrosine-based inhibitory motif (ITIM), immunoreceptor tyrosine-based switch motif (ITIM), and immunoreceptor tyrosine-based inhibitory motif (ITIM). motif, ITSM, is expressed on the surface of various immune cells such as bone marrow cells, dendritic cells, natural killer cells (NK), monocytes, regulatory T cells, B cells, and antigen-presenting cells. PD-1 has two ligands, PD-L1 (CD274) and PD-L2 (CD273), which belong to the B7 family of molecules and have 37% homologous sequences. PD-L1 consists of three parts: IgV and IgC-like extracellular regions, transmembrane regions, and short cytoplasmic tail regions. PD-L1 is expressed on antigen-presenting cells, non-lymphoid organs, and various tumor cells. Although PD-L1 and PD-L2 are both ligands of PD-1, PD-L2 has a narrow expression range and is mainly expressed on immune cells such as dendritic cells and monocytes. Studies have found that PD-L1 plays a major role in the immune escape of tumors.

[0003] Under normal physiological conditions, T cells do not express PD-1 in large quantities. Only when T cells are exposed to antigen stimulation for a long time will PD-1 expression be upregulated. At the same time, activated T cells will further induce other cells to overexpress PD-L1 by releasing cytokines such as interferon-γ (TNF-γ) and interleukin. After PD-L1 binds to PD-1, the immunoreceptor tyrosine inhibitory motif (ITIM) and immunoreceptor tyrosine switch motif (ITSM) in the intracellular domain of PD-1 are phosphorylated, thereby recruiting tyrosine phosphatases SHP-1 and SHP-2. These phosphatases can dephosphorylate multiple key proteins in the T cell antigen receptor (TCR) signaling pathway, inhibit TCR downstream signaling pathways, such as PI3K / AKT / mTOR, RAS / MEK / ERK, c-Myc, etc., and then inhibit the transcription of related genes, hinder the progression of the T cell cell cycle, and the expression of related proteins, which will inhibit the proliferation and differentiation of T cells and the production of cytokines. This regulatory mechanism can prevent T cells from being overactivated, enable the human immune system to maintain immune tolerance to self-antigens, and reduce the damage of the immune response to surrounding normal tissues.

[0004] Tumor cells overexpress PD-L1 and continuously activate the PD-1 / PD-L1 signaling pathway, causing various immunosuppression. Currently, these mechanisms can be roughly divided into the following three categories: 1) promoting apoptosis of tumor-specific T cells;

[0005] 2) It can convert T cells in peripheral and lymphoid tissues into dysfunctional regulatory T cells (Treg) and "exhausted" T cells (TEX); 3) It can inhibit the activation of effector T cells and naive T cells, and PD-L1 expressed on the surface of immune cells can also affect the response of anti-tumor CD8+T cells. Through such an immune escape mechanism, tumor cells can easily avoid recognition and attack by the immune system. Therefore, blocking the binding of PD-1 and PD-L1 can reverse the above-mentioned immunosuppressive mechanism, which will help improve the body's immune system's ability to kill tumors, and this also provides a reliable theoretical basis for blocking PD-1 / PD-L1-mediated tumor immunotherapy.

[0006] At present, several monoclonal antibody drugs targeting PD-1 or PD-L1 have been launched on the market, which prove that PD-1 / PD-L1 blockers can be used for the clinical treatment of various tumors. Compared with antibody drugs, small molecule drugs have unique advantages. Low development and production costs, relatively mature production technology; oral administration can improve the ease of use of patients; antibody drugs have large immune-related side effects, mainly immune enteritis, immune myocarditis, immune hepatitis, and immune pneumonia, and small molecule drugs are safer; small molecule drugs can not only target immunosuppressive mechanisms similar to mAb, but also stimulate intracellular pathways downstream of checkpoint proteins in innate or adaptive immune cells that mAb cannot reach. Small molecule drugs can be used alone or in a complementary or synergistic treatment with extracellular checkpoint mAbs to solve the problems of low clinical response and drug resistance; small molecule drugs can also provide better pharmacokinetic and pharmacodynamic parameters, such as oral administration and more flexible clinical doses, and can also induce relatively acute anti-tumor efficacy, thereby avoiding the systemic immunogenicity of monoclonal antibodies. Therefore, the research and development of small molecule blockers of PD-L1 has significant application value and social value.

[0007] The present invention provides a novel small molecule compound that can be used as an inhibitor of PD-1, PD-L1 or PD-1 / PD-L1 interaction, which exhibits exciting anti-tumor effects, and some compounds even exhibit unexpected pharmacokinetic properties. Summary of the invention

[0008] In view of this, the present invention provides a small molecule compound that can be used as an inhibitor of PD-1, PD-L1 or PD-1 / PD-L1 interaction, which has a tumor-suppressing effect. Therefore, the compounds of the present invention can be used for, but not limited to, treating tumor diseases.

[0009] To achieve the above object, the present invention provides a compound represented by formula (I) or its stereoisomers and pharmaceutically acceptable salts:

[0010]

[0011] in,

[0012] R1 is hydrogen, CHF2, CH3, CF3, F, Cl, -NH2;

[0013] R2 is -NR 2a R 2b , -C 1-6 Alkyl NR 2a R 2b 、-OC 1-6 Alkyl NR 2a R 2b , -C 1-6 Alkyl-OC1-6 Alkyl NR 2a R 2b 、-NR 2c -C 1-6 Alkyl NR 2a R 2b , -SC 1-6 Alkyl NR 2a R 2b 、-C(O)NR 2a R 2b 、-S(O)2R 2a , -C 1-6 Alkyl S(O)2NR 2a R 2b , -C 1-6 Alkyl NR 2c S(O)2NR 2a R 2b 、-S(O)2NR 2c C 1-6 Alkyl NR 2a R 2b 、-NR 2c S(O)2C 1-6 Alkyl NR 2a R 2b , -C 1-6 Alkyl C(O)NR 2c S(O)2NR 2a R 2b and -OH;

[0014] Each R 2a , R 2b and R 2c Independently selected from: hydrogen, -OR f , -C 1-8 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-6 Alkyl aryl, -C 1-6 Alkylheteroaryl, -C 1-6 Alkyl heterocyclic group, -C 1-6 Alkyl C(O)OR f , -C 2-6 Alkenyl C(O)OR f 、-S(O)2R f 、-S(O)2NR f R g 、-C(O)NR f S(O)2R f and -C 1-6 Alkyl C 3-8 Cycloalkyl; or R2a and R 2b to form a 3-10 membered heterocyclyl optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C(O)R f , -C 1-6 Alkyl C(O)R f 、-C(O)OR f , -C 1-6 Alkyl C(O)OR f 、-NR f R g , -C 1-6 Alkyl NR f R g 、-C(O)NR f R g , -C 1-6 Alkyl C(O)NR f R g 、-S(O)2R f , -C 1-6 Alkyl S(O)2R f 、-S(O)2NR f R g , -C 1-6 Alkyl S(O)2NR f R g 、-C(O)NR f S(O)2R g and-NR f C(O)R g ;

[0015] The alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R2 is optionally substituted by 1 to 3 substituents independently selected from the following: -NR f R g , halogen, cyano, oxo, -OR f , -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Cyanoalkyl, -C 1-6 Alkyl NR f R g , -C 1-6 Hydroxyalkyl, -C 3-8 Cycloalkyl and -C 1-3Alkyl C 3-8 Cycloalkyl;

[0016] X is N or CH;

[0017] Each R3 is independently halogen, -OR 3a 、-NO2、cyano、-NR 3a R 3b 、-N3、-S(O)2R 3a , -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 3-8 Cycloalkyl or -C 1-6 Alkyl C 3-8 Cycloalkyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -NO2, -N3, -OR 3a , halogen and cyano, each R 3a and R 3b are independently selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Cyanoalkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C 1-6 Alkyl aryl, -C 1-6 Alkylheteroaryl and -C 1-6 Alkyl heterocyclic group;

[0018] Each m is independently 0, 1 or 2;

[0019] p is 1 or 2;

[0020] L1 is a single bond, -NH-, -C(O)-NH-, -O-CH2-, -CH2=CH2-;

[0021] L2 is a single bond, -NH-, -C(O)-NH-, -O-CH2-, -CH2=CH2-;

[0022] Y and Z are independently N or CH;

[0023] Each R4 is independently hydrogen, halogen, -OH, -N3, -NO2, cyano, -NR 4a R 4b 、-S(O)2R 4a 、-S(O)2NR4a R 4b 、-NR 4a S(O)2R 4b 、-NR 4a C(O)R 4b 、-C(O)R 4a 、-C(O)OR 4a 、-C(O)NR 4a R 4b 、-NR 4a C(O)OR 4b 、-NR 4c C(O)NR 4a R 4b 、-OC(O)NR 4a R 4b 、-NR 4c S(O)2NR 4a R 4b 、-C(O)NR 4c S(O)2NR 4a R 4b , -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-6 Alkyl C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclic groups, and wherein the alkyl, alkenyl, alkynyl, C 3-8 The cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -OH, -NO2, -N3, -OR 4a , halogen, cyano, -NR 4a R 4b 、-C(O)R 4a 、-C(O)OR 4a 、-OC 1-6 Cyanoalkyl, -C(O)NR 4a R 4b 、-NR 4a C(O)R 4b 、-NR 4a C(O)OR 4b 、-S(O)2R 4a 、-NR 4a S(O)2R 4b 、-SO2NR 4a R 4b 、-NR 4c S(O)2NR4a R 4b 、-C(O)NR 4c S(O)2NR 4a R 4b and -C 3-8 Cycloalkyl;

[0024] Each R 4a , R 4b and R 4c are independently selected from: hydrogen, -OH, -C 1-8 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-6 Alkyl aryl, -C 1-6 Alkylheteroaryl, -C 1-6 Alkyl heterocyclic group and -C 1-6 Alkyl C 3-8 Cycloalkyl; or R 4a and R 4b to form a 3-10 membered heterocyclyl optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl OR f , -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C(O)R f , -C 1-6 Alkyl C(O)R f 、-C(O)OR f , -C 1-6 Alkyl C(O)OR f 、-NR f R g , -C 1-6 Alkyl NR f R g 、-C(O)NR f R g , -C 1-6 Alkyl C(O)NR f R g 、-S(O)2R f , -C 1-6 Alkyl S(O)2R f 、-S(O)2NR f R g , -C 1-6 Alkyl S(O)2NR f R g 、-C(O)NRf S(O)2R g and-NR f C(O)R g ;

[0025] n is independently 0, 1 or 2;

[0026] R5 is -NR 5a R 5b , -C 1-6 Alkyl NR 5a R 5b 、-OC 1-6 Alkyl NR 5a R 5b , -C 1-6 Alkyl-OC 1-6 Alkyl NR 5a R 5b 、-NR 5c -C 1-6 Alkyl NR 5a R 5b , -SC 1-6 Alkyl NR 5a R 5b 、-C(O)NR 5a R 5b 、-S(O)2R 5a , -C 1-6 Alkyl S(O)2NR 5a R 5b , -C 1-6 Alkyl NR 5c S(O)2NR 5a R 5b 、-S(O)2NR 5c C 1-6 Alkyl NR 5a R 5b 、-NR 5c S(O)2C 1-6 Alkyl NR 5a R 5b , -C 1-6 Alkyl C(O)NR 5c S(O)2NR 5a R 5b and -OH;

[0027] Each R 5a , R 5b and R 5c Independently selected from: hydrogen, -OR f , -C 1-8 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-6 Alkyl aryl, -C 1-6 Alkylheteroaryl, -C 1-6 Alkyl heterocyclic group, -C 1-6 Alkyl C(O)OR f , -C 2-6 Alkenyl C(O)OR f 、-S(O)2R f 、-S(O)2NR f R g 、-C(O)NR f S(O)2R f and -C 1-6 Alkyl C 3-8 Cycloalkyl; or R 5a and R 5b to form a 3-10 membered heterocyclyl optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C(O)R f , -C 1-6 Alkyl C(O)R f 、-C(O)OR f , -C 1-6 Alkyl C(O)OR f 、-NR f R g , -C 1-6 Alkyl NR f R g 、-C(O)NR f R g , -C 1-6 Alkyl C(O)NR f R g 、-S(O)2R f , -C 1-6 Alkyl S(O)2R f 、-S(O)2NR f R g , -C 1-6 Alkyl S(O)2NR f R g 、-C(O)NR f S(O)2R g and-NR f C(O)R g;

[0028] The R5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 3 substituents independently selected from the following: -NR f R g , halogen, cyano, oxo, -OR f , -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Cyanoalkyl, -C 1-6 Alkyl NR f R g , -C 1-6 Hydroxyalkyl, -C 3-8 Cycloalkyl and -C 1-3 Alkyl C 3-8 Cycloalkyl;

[0029] Each R f and R g are independently selected from hydrogen, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C 1-6 Alkyl aryl, -C 1-6 Alkylheteroaryl and -C 1-6 Alkyl heterocyclic group.

[0030] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or CHF2.

[0031] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, provided that when X is N, R1 is CHF2, and when X is CH, R1 is hydrogen.

[0032] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein p is preferably 1.

[0033] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Y and Z are preferably N.

[0034] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the following substructures of formula (IIA) or (IIB):

[0035] wherein R1, R2, R3, R4, R5, X, L1, L2, p and n are as defined herein.

[0036] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R2 is -NR 2a R 2b 、-CH2NR 2a R 2b ; Each R 2a and R 2b Independently selected from: hydrogen, -OR f , -C 1-8 Alkyl, -C 3-6 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-2 Alkyl aryl, -C 1-2 Alkylheteroaryl, -C 1-2 Alkyl heterocyclic group, -C 1-3 Alkyl C(O)OR f , and -C 1-2 Alkyl C 3-8 Cycloalkyl; or R 2a and R 2b to form a 3-10 membered heterocyclyl optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C(O)R f , -C 1-2 Alkyl C(O)R f 、-C(O)OR f , -C 1-2 Alkyl C(O)OR f 、-NR f R g , -C 1-2 Alkyl NR f R g 、-C(O)NR f R g , -C 1-2 Alkyl C(O)NR f R g ;

[0037] The alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R2 is optionally substituted by 1 to 3 substituents independently selected from the following: -NR f R g , halogen, cyano, oxo, -ORf , -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Cyanoalkyl, -C 1-6 Alkyl NR f R g , -C 1-6 Hydroxyalkyl, -C 3-8 Cycloalkyl and -C 1-3 Alkyl C 3-8 Cycloalkyl;

[0038] R f and R g As defined herein.

[0039] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R2 is -CH2NR 2a R 2b , R 2a and R 2b to form a 3-10 membered heterocyclyl optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C(O)R f , -C 1-2 Alkyl C(O)R f 、-C(O)OR f , -C 1-2 Alkyl C(O)OR f 、-NR f R g , -C 1-2 Alkyl NR f R g 、-C(O)NR f R g , -C 1-2 Alkyl C(O)NR f R g ;

[0040] The R2 alkyl and cycloalkyl groups are optionally substituted by 1 to 3 substituents independently selected from the following: -NR f R g , halogen, cyano, oxo, -OR f , -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Cyanoalkyl, -C1-6 Alkyl NR f Rg, -C 1-6 Hydroxyalkyl, -C 3-8 Cycloalkyl and -C 1-3 Alkyl C 3-8 Cycloalkyl;

[0041] R f and R g As defined herein.

[0042] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R2 is R 2d , R 2e , R 2f , R 2g They are independently hydrogen, C1-C4 alkyl, C1-C4 carboxyl, hydroxyl, and oxo, and the C1-C4 alkyl is optionally further substituted with 1-3 halogens, hydroxyl, carboxyl, and oxo.

[0043] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R2 is

[0044] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt, R3 and m together with the groups to which they are attached form the following fragment: p and R3 are as defined herein.

[0045] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R3 is independently halogen, -OH, -NO2, cyano, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 The halogen is preferably fluorine, chlorine, bromine, C 1-6 The alkyl group is preferably methyl, -C 1-6 The alkyl halide is preferably trifluoromethyl.

[0046] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, wherein each R4 is independently halogen, -OH, -N3, -NO2, cyano, -C1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -NR 4a R 4b ; and wherein the alkyl, C 3-8 The cycloalkyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, -OH, -NO2, -OR 4a , halogen, cyano, -NR 4a R 4b 、-C(O)R 4a 、-C(O)OR 4a 、-C(O)NR 4a R 4b 、-NR 4a C(O)R 4b 、-NR 4a C(O)OR 4b and -C 3-8 Cycloalkyl;

[0047] R 4a and R 4b are independently selected from: hydrogen, -OH, -C 1-8 Alkyl, -C 3-6 Cycloalkyl; or R 4a and R 4b to form a heterocyclic group optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl OR f , -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C(O)R f , -C 1-6 Alkyl C(O)R f 、-C(O)OR f , -C 1-6 Alkyl C(O)OR f 、-NR f R g , -C 1-6 Alkyl NR f R g 、-C(O)NR f R g , -C 1-6 Alkyl C(O)NR f R g and-NR fC(O)R g ;

[0048] R f and R g As defined herein.

[0049] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5 is -CH2-NR 5a R 5b , R 5a and R 5b As defined herein.

[0050] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 5a and R 5b Independently selected from: hydrogen, -OR f , -C 1-8 Alkyl, -C 3-6 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C 1-2 Alkyl aryl, -C 1-2 Alkylheteroaryl, -C 1-2 Alkyl heterocyclic group, -C 1-3 Alkyl C(O)OR f , and -C 1-2 Alkyl C 3-8 Cycloalkyl; or R 5a and R 5b to form a 3-10 membered heterocyclyl optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, -OR f , cyano, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-3 Alkyl C 3-8 Cycloalkyl, -C(O)R f , -C 1-2 Alkyl C(O)R f 、-C(O)OR f , -C 1-2 Alkyl C(O)OR f 、-NR f R g , -C 1-2 Alkyl NR f R g 、-C(O)NR f R g , -C 1-2 Alkyl C(O)NR f R g ;

[0051] The R5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 to 3 substituents independently selected from the following: -NR f R g , halogen, cyano, oxo, -OR f , -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Cyanoalkyl, -C 1-6 Alkyl NR f R g , -C 1-6 Hydroxyalkyl, -C 3-8 Cycloalkyl and -C 1-3 Alkyl C 3-8 Cycloalkyl;

[0052] R f and R g As defined herein.

[0053] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5 is R 5d , R 5e , R 5f , R 5g They are independently hydrogen, C1-C4 alkyl, C1-C4 carboxyl, hydroxyl, and oxo, and the C1-C4 alkyl is optionally further substituted with 1-3 halogens, hydroxyl, carboxyl, and oxo.

[0054] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R5 is

[0055] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L1 is -NH-.

[0056] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein L2 is -NH-.

[0057] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the following substructures of formula (IIIA) or (IIIB):

[0058] wherein R2, R3, R4, R5 and p are as defined herein, and wherein each R4 exists independently.

[0059] In some embodiments of the present invention, the present invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the following substructures of formula (IVA) or (IVB):

[0060]

[0061] , where R2, R3, R4, R 5a , R 5b As defined herein.

[0062] In some embodiments of the present invention, the present invention provides the following specific compounds or stereoisomers or pharmaceutically acceptable salts thereof,

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] All the structural aspects mentioned above are preferred embodiments of the corresponding aspects. The structural aspects related to the compound (I) of the present invention can be combined with each other as needed to obtain preferred compounds. Each combination represents and defines an individual embodiment or a general subset of the compound (I) of the present invention, and the combination of substituents and / or variables is allowed as long as such a combination produces a stable compound or a useful synthetic intermediate.

[0071] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, isomers and prodrugs of compounds of formula (I) (including all embodiments thereof).

[0072] The present invention further relates to pharmaceutically acceptable salts of compounds of formula (I) (including all embodiments thereof) including pharmaceutically acceptable salts of compounds of formula (I) (including all embodiments thereof) with inorganic or organic acids or bases. Pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates and similar salts; and salts with organic acids, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoates such as acetate, HOOC-(CH2)n-COOH (wherein n is 0-4) and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium.

[0073] In addition, pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0074] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. When they have multiple asymmetric stereocenters, their stereocombination forms and their mixtures are all included within the scope of the present invention, and the selected forms of stereocompounds can be obtained by conventional technical means of those skilled in the art, such as the introduction of chiral raw materials, chiral separation and other means.

[0075] Cis and trans, or "Z" or "E" indicates that a compound exists as cis and trans isomers, generally but not limited to the different configurations involved in the double bond-containing moieties of the compound.

[0076] In another aspect, the compounds as described herein can be formulated into pharmaceutical compositions with human acceptable carriers and administered to a mammalian host (such as a human patient) in a variety of forms suitable for the selected route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal, intrathecal, ocular, intranasal, intraperitoneal or subcutaneous routes.

[0077] The compounds described herein can be administered systemically, for example, orally or intravenously in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, can be compressed into tablets, or can be directly admixed with the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0078] On the other hand, the present invention relates to a compound of formula (I) (including all embodiments thereof), which can be used in a kit for treating a disease or condition treated by inhibiting PD-1, PD-L1 and / or PD-1 / PDL1 interaction, comprising: a method for treating an inhibitor-related disease, the method comprising administering an effective amount of one or more of the above-mentioned compounds, stereoisomers or salts, metabolites or prodrugs thereof to an individual in need thereof.

[0079] On the other hand, the present invention relates to a compound of formula (I) (including all embodiments thereof) or a pharmaceutical composition, which can be used in the preparation of a drug for treating and / or preventing cancer. On the other hand, the present invention relates to a compound of formula (I) (including all embodiments thereof) or a pharmaceutical composition, for the preparation of a drug for preventing and / or treating a disease associated with the activity or expression of PD-1 / PD-L1. In another preferred embodiment, the disease is selected from the group consisting of tumors, pathogen infection, autoimmune response-related diseases, and the relevant disease is treated with an effective dose of the compound of the present invention. The "effective amount" refers to a drug dose that can prevent, alleviate, delay, inhibit or cure the subject's condition. The size of the dosage is determined by the drug administration method, the pharmacokinetics of the agent, the severity of the disease, the subject's individual signs (sex, weight, height, age), etc.

[0080] Anti-tumor drugs include: melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer). Bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastrointestinal cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia) leukemia, chronic lymphocytic leukemia), solid tumors of childhood, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, neoplasms / tumors of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including those induced by asbestos), and combinations of said cancers. Metastatic cancers, particularly metastatic cancers expressing PD-L1.

[0081] In another aspect, the present invention relates to a kit comprising a compound described herein or a pharmaceutically acceptable salt thereof, and instructions for administering the compound or a pharmaceutically acceptable salt thereof to a subject suffering from cancer.

[0082] In another aspect, the present invention relates to compounds of formula (I) (including all embodiments thereof), which can be used in combination with other anti-tumor drugs.

[0083] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.

[0084] Where appropriate, the various starting materials, intermediates and compounds described herein can be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. The characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrometry, nuclear magnetic resonance and a variety of other spectral analyses.

[0085] Some embodiments of the compounds of the present invention can be realized by the following reaction scheme:

[0086] Reaction Scheme 1

[0087]

[0088] Reaction Scheme 2

[0089]

[0090] R1, R2, R3, R4, R5, X, L1, L2, p, m, n are as defined herein.

[0091] The beneficial effects of the present invention are as follows: This new type of small molecule inhibitor can be used as an inhibitor of PD-1, PD-L1 or PD-1 / PD-L1 interaction, showing exciting anti-tumor effects, and some compounds even show unexpected pharmacokinetic properties.

[0092] Glossary

[0093] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs, as well as instances where the event or circumstance does not occur. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein. One skilled in the art will understand that for any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically unfeasible, synthetically unfeasible, and / or inherently unstable.

[0094] "Alkyl" includes straight and branched chains having a specified number of carbon atoms (usually 1-20 carbon atoms, for example 1-8 carbon atoms, such as 1-6 carbon atoms). 1-6 Alkyl includes straight and branched chain alkyl groups of 1-6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, etc. Alkylene is another subset of alkyl, referring to the same residue as alkyl, but it has two points of attachment, and when two points of attachment are claimed for certain alkyl groups in the present invention, alkylene is also represented. Alkylene typically has 2-20 carbon atoms, for example, 2-8 carbon atoms, such as 2-6 carbon atoms. When naming an alkyl residue with a specific number of carbons, all geometric isomers with that number of carbons are intended to be included, for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" means an alkyl group with 1-4 carbons.

[0095] "Alkenyl" means a straight or branched hydrocarbon radical having a specified number of carbon atoms (usually 1-8 carbon atoms, e.g. 2-4 carbon atoms) and at least 1 and preferably 1-2 sites of vinyl (>C=C<) unsaturation. Examples of such radicals are, for example, vinyl, allyl and but-3-en-1-yl. Both cis and trans isomers or mixtures of these isomers are included within the term. "Lower alkenyl" means an alkenyl radical having 1-4 carbon atoms, which may be substituted by C 2-4 The alkylene group is represented by alkylene.

[0096] Haloalkyl (haloalkenyl, haloalkynyl) are all derived from the previously defined alkyl (alkenyl, alkynyl) groups by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If the haloalkyl (haloalkenyl, haloalkynyl) groups are to be further substituted, the substitutions may be carried out independently of one another in each case in the form of mono- or poly-substitutions on all the carbon atoms carrying hydrogen. Examples of haloalkyl (haloalkenyl, haloalkynyl) groups are -CF3, -CHF2, -CH2F, -CF2CF3-CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡CCF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0097] "Cycloalkyl" means a non-aromatic partially saturated or fully saturated carbon ring having a specified number of carbon ring atoms (e.g., 3-10, or 3-8, or 3-6 ring carbon atoms). Cycloalkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well as bridged ring groups and caged ring groups (e.g., bicyclo[2.2.2]octane). Lower cycloalkanes generally refer to C 3-6 In the case where there is no special explanation, the lower cycloalkyl group is generally preferably a fully saturated carbon ring.

[0098] "Hydroxyalkyl (hydroxycycloalkyl)" includes straight-chain and branched alkyl (cycloalkyl) groups having the specified number of carbon atoms (usually 1-20 carbon atoms, e.g. 1-8 carbon atoms, such as 1-6 carbon atoms) replaced by one or more hydroxy groups, and combinations of substituents and / or variables are permissible as long as such combinations result in stable compounds or useful synthetic intermediates.

[0099] "Halo-hydroxyalkyl" includes straight and branched chain alkyl groups having the specified number of carbon atoms (usually 1-20 carbon atoms, e.g. 1-8 carbon atoms, such as 1-6 carbon atoms) replaced by one or more hydroxy and halogen groups. Combinations of substituents and / or variables are permissible as long as such combinations result in stable compounds or useful synthetic intermediates.

[0100] "Aryl" means an aromatic carbocyclic ring with a specified number of carbon atoms (e.g., 6-12 or 6-10 carbon atoms) in the ring. Aryl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of polycyclic aromatic groups are aromatic (e.g., naphthyl). In other cases, polycyclic aromatic groups may include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to aromatic rings, as long as the polycyclic aromatic groups are bound to the parent structure via the atoms in the aromatic ring. Thus, 1,2,3,4-tetrahydronaphthalene-5-yl (wherein the part is bound to the parent structure via aromatic carbon atoms) is considered to be an aryl, while 1,2,3,4-tetrahydronaphthalene-1-yl (wherein the part is bound to the parent structure via non-aromatic carbon atoms) is not considered to be an aryl. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not include "heteroaryl" as defined herein or does not overlap with "heteroaryl" as defined herein, regardless of the point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl groups). In some cases, unless otherwise specified, the aryl ring may be further substituted with functional groups well known in the art without affecting the definition of the number of carbon atoms on the aromatic ring. In some cases, the aryl group is phenyl or naphthyl. In some cases, the aryl group is phenyl. Other examples of aryl groups containing aromatic carbocyclic rings fused to non-aromatic rings are described below. The C0-C1 alkylene-C0-C1 alkylene described herein 6-10 Aryl, generally refers to when C0 alkane-C 6-10 Aryl refers to the corresponding aromatic group, C1 alkylene-C 6-10 When it is an aryl group, it generally refers to an aryl group with a methylene group adjacent to it, such as a benzyl group.

[0101] "Carboxy" or "carboxyl" means -COOH or a salt thereof.

[0102] "Heteroaryl" means an aromatic ring (e.g., 5-12 or 5-10 membered heteroaryl) containing a specified number of ring atoms, the ring atoms being composed of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S, and the remaining ring atoms being carbon. A 5-membered heteroaryl is a heteroaryl having 5 ring atoms. A 6-membered heteroaryl is a heteroaryl having 6 ring atoms. In some embodiments, the total number of S and O atoms in the heteroaryl is no more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl is no more than 1. Unless otherwise indicated, a heteroaryl can be bonded to the parent structure through a carbon or nitrogen atom, as long as valence permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl. When nitrogen is present in a heteroaryl ring, it may be present in an oxidized state (i.e., N+-O-) if the nature of adjacent atoms and groups permits. In addition, when sulfur is present in a heteroaryl ring, it may be present in an oxidized state (i.e., S+-O- or SO2) if the nature of adjacent atoms and groups permits. A heteroaryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0103] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

[0104] In other cases, polycyclic heteroaryl groups may include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, as long as the polycyclic heteroaryl group is bound to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0105] "Heterocycloalkyl" means a non-aromatic partially saturated or fully saturated ring (e.g., 3-10 or 3-7 membered heterocycloalkyl) with a specified number of ring atoms, sometimes also referred to as a heterocyclyl in this article, which is a unified meaning, wherein the ring atoms are composed of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S, and the remaining ring atoms are carbon. A 5-membered heterocycloalkyl is a heterocycloalkyl with 5 ring atoms. A 6-membered heterocycloalkyl is a heterocycloalkyl with 6 ring atoms. Heterocycloalkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl include oxacyclopropyl, aziridine, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. When nitrogen is present in a heterocycloalkyl ring, the nitrogen may be present in an oxidized state (i.e., N+-O-) where the properties of the adjacent atoms and groups permit. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. In addition, when sulfur is present in the heterocycloalkyl ring, the sulfur may be present in an oxidized state (i.e., S+-O- or -SO2-) when the properties of adjacent atoms and groups permit. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of a polycyclic heterocycloalkyl may be aromatic (e.g., aryl or heteroaryl) as long as the polycyclic heterocycloalkyl is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinolin-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl, while 1,2,3,4-tetrahydroquinolin-8-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl. Lower heterocycloalkanes generally refer to C 3-6 In the case where there is no special explanation, the lower heterocycloalkyl group is generally preferably a fully saturated carbon ring.

[0106] "Alkoxy" refers to an alkyl group of a specified number of carbon atoms connected by an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc. Alkoxy is also intended to include cycloalkyl groups as defined above that are also connected by an oxygen bridge. Alkoxy groups typically have 1-6 carbon atoms connected by an oxygen bridge. "Lower alkoxy" means an alkoxy group with 1-4 carbons, which is sometimes described in this article using -O-alkyl.

[0107] The term "halo" includes fluoro, chloro, bromo and iodo.

[0108] The term "substituted" as used herein refers to any one or more hydrogens on a designated atom or group are replaced by a selection from a designated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is an oxo (i.e., =O), then 2 hydrogens on the atom are replaced. Combinations of substituents and / or variables are allowed, as long as such combinations produce stable compounds or useful synthetic intermediates. Stable compounds or stable structures are intended to imply that the compound is robust enough to survive separation from a reaction mixture and subsequently formulated as a reagent with at least practical utility. Unless otherwise noted, substituents are named into the core structure. For example, it should be understood that when (cycloalkyl) alkyl is listed as a possible substituent, the point of attachment of the substituent to the core structure is in the alkyl portion.

[0109] R x and R y The heterocyclic group formed by combining is generally referred to as R x and R y The atoms commonly linked to it form a heterocyclic group, and the heterocyclic group heteroatom includes the commonly linked atoms, and may further include other atoms such as O, S, and N; for example, NR 2a and R 2b The heterocyclic group formed by the combination may include only piperidinyl containing only N, or may contain additional heteroatoms such as morpholinyl. DETAILED DESCRIPTION

[0110] Preparation of liquid phase method used in some examples of this article

[0111] Instrument: Shimadzu preparative liquid phase SIL-10AP;

[0112] Acid method: Column: Welch Ultimate XB-C18, 21.2*250mm, 10um,

[0113] Mobile phase: A: 0.05% TFA aqueous solution B: acetonitrile;

[0114] Alkali method: Column: Welch Xtimate C18, 21.2*250mm, 10um,

[0115] Mobile phase: A: 10mmol / L aqueous solution B: acetonitrile;

[0116] Column temperature: room temperature;

[0117] Flow rate: 25ml / min;

[0118] Detection wavelength: 214 / 254nm.

[0119] In order to further illustrate the present invention, the compounds provided by the present invention, their preparation methods and applications are described in detail below in conjunction with examples.

[0120] Example 1

[0121] N-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methylglycine

[0122] first step

[0123] (S)-3-Methoxy-5-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indan-1-(yl)amino)-6-(trifluoromethyl)pyrazine-2-carbaldehyde

[0124]

[0125] (S)-5-((4-bromo-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 1a (1.0 g, 2.4 mmol, 1.0 eq, synthesis method reference WO2020014643 A1), biboronic acid pinacol ester (1.52 g, 6.0 mmol, 2.50 eq), potassium acetate (0.47 g, 4.8 mmol, 2.0 eq) were dissolved in DMF (15 mL), and then dichloro[1,1'-bis(tert-butylphosphino)ferrocenepalladium(II) (0.16 g, 0.24 mmol, 0.1 eq) was added. Nitrogen was replaced three times, the reaction mixture was reacted at 85°C for 3 hours, and water and dichloromethane (3×50 mL) were added for extraction. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=0-100%, dichloromethane: ), to give (S)-3-methoxy-5-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indan-1-(yl)amino)-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1b (1.0 g, 89.9%). LCMS m / z (ESI): 463.26 [M+1] + .

[0126] Step 2

[0127] N-(3-Bromo-2-chlorophenyl)-2-(difluoromethyl)-7-vinylpyridin[3,2-d]pyrimidin-4-amine

[0128]

[0129] 4-Chloro-2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine 1c (1.90 g, 7.40 mmol, 1.0 eq) and 3-bromo-2-chloroaniline (1.83 g, 8.88 mmol, 1.2 eq) were dissolved in tert-butyl alcohol (20.0 mL), and the reaction mixture was reacted at 80°C for 4 hours, then cooled to room temperature, filtered, and the filter cake was spin-dried to obtain N-(3-bromo-2-chlorophenyl)-2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine 1d (2.30 g, 75.5%). LCMS m / z (ESI): 411.63 [M+1] + .

[0130] Step 3

[0131] 4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde

[0132]

[0133] N-(3-bromo-2-chlorophenyl)-2-(difluoromethyl)-7-vinylpyridino[3,2-d]pyrimidin-4-amine 1d (1.00 g, 2.43 mmol, 1.0 eq) was dissolved in tetrahydrofuran (7.0 mL) and water (2.0 mL), and then sodium periodate (1.56 g, 7.29 mmol, 3.0 eq), N,N-dimethylaniline (0.59 g, 4.86 mmol, 2.0 eq) were added, and finally potassium osmate (0.09 g, 0.24 mmol, 0.1 eq) was added, followed by reaction at 19°C for 16 hours. The reaction was monitored by LCMS. The mixture was then concentrated under reduced pressure, and a large amount of solid precipitated, which was then separated by column chromatography (petroleum ether: Dichloromethane:methanol=10%) gave 4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde 1e (1.07 g, 93.43%). LCMS m / z (ESI): 413.61 [M+1] + .

[0134] Step 4

[0135] (R)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol

[0136]

[0137] 4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde 1e (1.07 g, 2.45 mmol, 1.0 eq) and (R)-pyrrolidin-3-ol (426.8 mg, 4.90 mmol, 2.0 eq) were dissolved in dichloromethane (20 mL) and reacted at room temperature for 30 minutes. Then, sodium cyanoborohydride (1.03 g, 4.90 mmol, 2.0 eq) was added and the reaction mixture was reacted at 20°C for 3 hours. Water and dichloromethane (3×30 mL) were added for extraction. The combined organic phase was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: Dichloromethane:methanol=10%), to give (R)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol 1f (0.90 g, 65.30%). LCMS m / z (ESI): 484.73 [M+1] + .

[0138] Step 5

[0139] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde

[0140]

[0141] (R)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol 1f (200.0 mg, 0.36 mmol, 1.0 eq), (S)-3-methoxy-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene -1-yl)amino)-6-(trifluoromethyl)pyrazine-2-carboxaldehyde 1b (250.1 mg, 0.54 mmol, 1.5 eq), potassium carbonate (99.5 mg, 0.72 mmol, 2.0 eq) were dissolved in dioxane (4 mL) and water (1 mL), and then 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (23.4 mg, 0.04 mmol, 0.1 eq) was added. Nitrogen was replaced three times, and the reaction mixture was reacted at 75°C for 4 hours. Part of the solvent was concentrated, and then water and dichloromethane (3×30 mL) were added for extraction. The combined organic phase was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: Dichloromethane:methanol=10%), to obtain 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1g (200mg, 75.0%). LCMSm / z(ESI): 741.12[M+1] + .

[0142] Step 6

[0143] N-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methylglycine

[0144]

[0145] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1g (50 mg, 0.05 mmol, 1.0 eq) and methylglycine (22.2 mg, 0.25 mmol, 4.98 eq) were dissolved in a methanol solution (2 mL), stirred at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (6.1 mg, 6.1 mmol, 1.97 eq) was added. The reaction mixture was reacted at 0°C for 4 hours. After antisense post-treatment, the product was concentrated and prepared by Prep-HPLC (NH4CO3) to give N-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methylglycine 1 (white solid, 5.5 mg, 13.28%). LCMS m / z (ESI): 814.25 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.15(s,1H),8.59(s,1H),8.36-8.20(m,1H),7. 63-7.51(m,2H),7.32(t,J=7.6Hz,1H),7.28–7.16(m,4H),6.86(t,J=54.4Hz,1H),5.95 -5.80(m,1H),5.60-5.40(m,1H),4.80-4.60(m,2H),4.50-4.40(m,1H),4.29(s,2H),4. 10-4.00(m,2H),3.85(s,3H),2.90-2.70(m,5H),2.34-2.18(m,4H),2.02-1.86(m,3H).

[0146] Example 2

[0147] N-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine

[0148]

[0149] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1 g (50 mg, 0.05 mmol, 1.0 eq) and methyl-L-alanine (25.7 mg, 0.25 mmol, 4.98 eq) were dissolved in methanol solution (2 mL), reacted at room temperature for 30 minutes, cooled to 0°C, and sodium cyanoborohydride (6.1 mL) was added. g, 6.1mmol, 1.97eq), the reaction mixture was reacted at 0°C for 3 hours, and the reaction mixture was post-treated and subjected to Prep-HPLC (NH4CO3) to prepare N-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine 2 (white solid, 5.5mg, 11.86%). LCMS m / z(ESI): 828.24[M+1] + . 1 H NMR(400MHz, DMSO-d6)δ10.36(s,1H),9.00(d,J=1.6Hz,1H),8.50-8.38(m,1H),8.25(s,1H),7.55(s ,1H),7.31(t,J=7.2Hz,1H),7.28-7.08(m,5H),6.86(t,J=54.4Hz,1H),5.90-5.70(m,1H),4.76(brs, 1H),4.28-4.18(m,1H),3.89(q,J=14.0Hz,2H),3.81(s,3H),3.74(s,1H),3.65(s,1H),3.62(s,1H),3 .10(s,1H),2.78–2.64(m,5H),2.46-2.41(m,3H),2.28(s,3H),2.10-1.95(m,3H),1.65-1.55(m,1H).

[0150] Example 3

[0151] (R)-1-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0152]

[0153] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1 g (50 mg, 0.05 mmol, 1.0 eq) and (R)-pyrrolidine-3-carboxylic acid (28.7 mg, 0.25 mmol, 4.99 eq) were dissolved in methanol solution (5 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (6.1 The reaction mixture was reacted at 0°C for 4 hours. After post-treatment, the reaction mixture was purified by Prep-HPLC (TFA) to obtain (R)-1-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid (trifluoroacetate) 3 (white solid, 11.0 mg, 26.04%). LCMS m / z(ESI): 840.25[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.02(d,J=1.6Hz,1H),8.50-8.35(m,1H),8.30(s, 1H),7.60-7.50(m,1H),7.31(t,J=7.6Hz,1H),7.28-7.13(m,3H),6.86(t,J=54.4Hz,1H) ,5.83(s,1H),4.85(brs,1H),4.26(s,1H),4.10-3.95(m,2H),3.90-3.75(m,5H),3.10-2 .98(m,3H),2.90-2.74(m,6H),2.30-2.14(m,1H),2.12–1.92(m,4H),1.70-1.58(m,1H).

[0154] Example 4

[0155] (3R,5R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-5-methylpyrrolidin-3-ol

[0156]

[0157] The compound 5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 1g (60.0mg, 0.04mmol, 1.0eq) and (3R,5R)-5-methylpyrrolidin-3-ol (24.28mg, 0.24mmol, 6.0eq) were dissolved in methanol solution (2mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (4.95mg, 0.08mmol, 2.0eq) was added. The reaction mixture was reacted at 0°C for 2.5 hours, the reaction was monitored by LCMS, filtered and then subjected to Prep-HPLC (TFA) to prepare (3R,5R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-5-methylpyrrolidin-3-ol (trifluoroacetate) 4 (white solid, 15.3 mg, 45.72%). LCMS m / z (ESI): 826.20 [M+1] + . 1H NMR (400MHz, DMSO) δ10.79(s,1H),10.55(s,1H),9.83(s,1H),9.16(s,1H),8.59(s,1H),8.33-8.20(m,1H),7.65-7.4 5(m,2H),7.31(q,J=7.6Hz,1H),7.25-7.16(m,2H),6.87(t,J=54.4Hz,1H),5.95-5.80(m,1H),5.70-5.35(m,2H),4.7 1(brs,2H),4.56-4.40(m,2H),4.35(s,1H),4.23(dd,J=13.6,5.6Hz,1H),3.93-3.81(m,4H),3.77–3.67(m,1H),3.18 (d,J=12.0Hz,2H),2.90-2.70(m,2H),2.47–2.40(m,1H),2.36-2.20(m,2H),2.13–1.71(m,4H),1.39(d,J=6.0Hz,3H).

[0158] Example 5

[0159] (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)piperidine-2-carboxylic acid

[0160]

[0161] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1g (50 mg, 0.05 mmol, 1.0 eq) and (R)-piperidine-2-carboxylic acid (38.7 mg, 0.30 mmol, 5.99 eq) were dissolved in a methanol solution (5 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (6.1 mg, 6.1 mmol, 0.1 eq) was added. The reaction mixture was reacted at 0°C for 4 hours. The reaction system was filtered and then subjected to Prep-HPLC (TFA) to obtain (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)piperidine-2-carboxylic acid (trifluoroacetate) 5 (white solid, 14.0 mg, 32.8%). LCMS m / z (ESI): 854.28 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ10.37(s,1H),9.00(d,J=1.2Hz,1H),8.50-8.35(m,1H),8.25(s,1H),7.60-7.50(m,1H),7 .31(t,J=7.6Hz,1H),7.27-7.11(m,3H),6.86(t,J=54.4Hz,1H),5.90-5.70(m,1H),4.77(brs,1H),4.30-4.19(m,1 H),3.89(q,J=14.0,14.2Hz,2H),3.85-3.70(m,5H),3.18(t,J=4.8Hz,1H),3.07–2.97(m,1H),2.88–2.63(m,4H), 2.48–2.37(m,3H),2.30-2.15(m,1H),2.09–1.86(m,2H),1.80-1.65(m,2H),1.63-1.55(m,1H),1.50-1.30(m,4H).

[0162] Example 6

[0163] 2-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid

[0164]

[0165] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1 g (75 mg, 0.05 mmol, 1.0 eq) and 2-azaspiro[3.3]heptane-6-carboxylic acid (35.2 mg, 0.25 mmol, 4.99 eq) were dissolved in DMF solution (3 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (6.1 mL) was added. g, 6.1 mmol, 1.97 eq), the reaction mixture was reacted at 0°C for 2.5 hours, the reaction system was filtered and then subjected to Prep-HPLC (NH4CO3) to prepare 2-((5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid 6 (white solid, 6.9 mg, 15.62%). LCMS m / z(ESI): 866.29[M+1] + . 1H NMR(400MHz, DMSO-d6)δ10.37(s,1H),9.00(d,J=1.6Hz,1H),8.50-8.35(m,1H),8.25(s,1H),7.60-7.50 (m,1H),7.30(t,J=7.2Hz,1H),7.26-7.06(m,4H),6.86(t,J=54.4Hz,1H),5.79(brs,1H),4.76(d,J=4.0H z,1H),4.22(brs,1H),3.95-3.80(m,2H),3.78(s,3H),3.45(s,2H),3.23(s,2H),3.12(s,2H),2.94-2.8 3(m,1H),2.79–2.63(m,4H),2.47–2.37(m,2H),2.30-2.14(m,5H),2.09-1.97(m,1H),1.66–1.52(m,1H).

[0166] Example 7

[0167] (R)-1-((4-((2-chloro-3-((S)-1-((5-(((2-hydroxyethyl)amino)methyl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)

[0168] 2-(amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol

[0169]

[0170] 5-(((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 1g (31.0 mg, 0.02 mmol, 1.0 eq) and ethanolamine (14.6 mg, 0.24 mmol, 11.95 eq) were dissolved in methanol solution (2.0 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (4. 9mg, 0.08mmol, 3.96eq), the reaction mixture was reacted at 0°C for 3 hours, filtered and then subjected to Prep-HPLC (TFA) to prepare (R)-1-((4-((2-chloro-3-((S)-1-((5-(((2-hydroxyethyl)amino)methyl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)phenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)pyrrolidin-3-ol (trifluoroacetate) 7 (white solid, 4.4mg, 27.05%). LCMS m / z(ESI): 786.25[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.16(s,1H),8.88(s,2H),8.58(s,1H),8.35-8.20(m,1H),7.79(s ,1H),7.57(s,1H),7.50-7.38(m,1H),7.32(t,J=7.6Hz,1H),7.20(s,2H),6.86(t,J=54.4Hz,1H),5.85(s ,1H),5.55(brs,1H),5.36-5.12(m,1H),4.69(s,2H),4.46(s,1H),4.16(s,2H),3.85(s,3H),3.70(t,J= 4.8Hz,2H),3.58(t,J=5.2Hz,1H),3.12(s,3H),2.90-2.70(m,3H),2.35-2.15(m,2H),1.95-1.80(m,1H).

[0171] Example 8

[0172] (3R)-1-((5-((1S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0173]

[0174] first step

[0175] (R)-1-((3-methoxy-5-((S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0176]

[0177] (S)-3-Methoxy-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 1b (260.0 mg, 0.56 mmol, 1.0 eq) and (R)-pyrrolidine-3-carboxylic acid (129.0 mg, 1.12 mmol, 2.0 eq) were dissolved in methanol solution (10.0 mL), and sodium triacetylborohydride (236.0 mg, 1.12 mmol, 2.0 eq) was added at room temperature and reacted for 3 hours. The solvent was removed by concentration under reduced pressure and purified by column chromatography to give (R)-1-((3-methoxy-5-((S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid 8a (light yellow solid, 156 mg, 51.0%). LCMS m / z (ESI): 563.26 [M+1] + .

[0178] Step 2

[0179] 1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol

[0180]

[0181] 4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-aminocarbaldehyde 1e (60.0 mg, 0.15 mmol, 1.0 eq) and 3-methyl-3-hydroxy-pyrrolidine (30.3 mg, 0.3 mmol, 2.0 eq) were dissolved in 5 mL of dichloromethane, sodium cyanoborohydride (18.6 mg, 0.3 mmol, 2.0 eq) was added, and the mixture was reacted at room temperature for 6 hours. The solvent was removed by concentration under reduced pressure, and 1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol 8b (light yellow solid, 30.0 mg, 40.1%) was obtained by column chromatography purification. LCMS m / z(ESI): 498.04[M+1] + .

[0182] Step 3

[0183] (3R)-1-((5-((1S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0184]

[0185] 1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)-3-methylpyrrolidin-3-ol 8b (20.0 mg, 0.04 mmol, 1.0 eq), (R)-1-((3-methoxy-5-((S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid 8a (27.0 mg, 0.05 mmol, 1.0 eq), di-tert-butylphosphinoferrocenepalladium dichloride (2.6 mg, 0.004 mmol, 0.1 eq), potassium carbonate (11.06 mg, 0.08 mmol, 2.0 eq) was dissolved in 2 mL of dioxane and 0.5 mL of water, replaced with nitrogen three times, reacted at 95 ° C for 6 hours, and purified by Prep-HPLC (TFA) to give (3R)-1-((5-((1S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid (trifluoroacetate) 8 (yellow solid, 5 mg, 14.6%) LCMS m / z (ESI): 854.29 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ10.53(s,1H),9.14(s,1H),8.56(s,1H),8.27(s,1H),7.63-7.5 1(m,2H),7.32(t,J=7.6Hz,1H),7.28-7.16(m,2H),6.86(t,J=54.4Hz,1H),5.95-5.80(m, 1H),5.40-5.30(m,1H),4.80-4.60(m,2H),4.50-4.30(m,2H),4.29(s,2H),4.10-4.00(m ,2H),3.86(s,3H),3.30-3.10(m,3H),2.90-2.70(m,3H),2.34-1.90(m,4H),1.34(s,3H).

[0186] Example 9

[0187] (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0188]

[0189] first step

[0190] 1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyridin[3,2-d]pyrimidin-7-yl)methyl)-3-methylazetidinol

[0191]

[0192] 4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-aminocarbaldehyde 1e (60.0 mg, 0.15 mmol, 1.0 eq) and 3-methylazepine-3-ol (26.2 mg, 0.3 mmol, 2.0 eq) were dissolved in 5 mL of dichloromethane, sodium cyanoborohydride (18.6 mg, 0.3 mmol, 2.0 eq) was added, and the mixture was reacted at room temperature for 6 hours. The solvent was removed by concentration under reduced pressure, and 1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-yl)methyl)-3-methylazetidinol 9a was purified by column chromatography (light yellow solid, 30.0 mg, 41.3%). LCMS m / z(ESI): 483.03[M+1] + .

[0193] Step 2

[0194] (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0195]

[0196] (S)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyridin[3,2-d]pyrimidin-7-yl)methyl)-3-methylazetidinol 9a (20.0 mg, 0.04 mmol, 1.0 eq), (R)-1-((3-methoxy-5-((S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid 8a (27.0 mg, 0.05 mmol, 1.0 eq), di-tert-butylphosphinoferrocenepalladium dichloride (2.6 mg, 0.004 mmol, 0. 1eq), potassium carbonate (11.06 mg, 0.08 mmol, 2.0 eq) was dissolved in 2 mL of dioxane and 0.5 mL of water, replaced with nitrogen three times, reacted at 95 ° C for 6 hours, and purified by Prep-HPLC (TFA) to obtain (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid (trifluoroacetate) 9 (yellow solid, 5.0 mg, 14.6%). LCMS m / z (ESI): 840.20 [M+1] + . 1 HNMR(400MHz,MeOD)δ10.53(s,1H),9.05(s,1H),8.80(s,1H),8.45(s,1H),7.54(t ,J=8.0Hz,1H),7.33-7.31(m,2H),7.25-7.16(m,2H),6.86(t,J=54.4Hz,1H),5.95- 5.80(m,1H),4.80-4.60(m,3H),4.46(s,2H),4.27-4.24(m,2H),4.20-4.10(m,2H), 3.97(s,3H),2.85-2.82(m,3H),2.63-2.61(m,2H),2.38-2.15(m,4H),1.58(s,3H).

[0197] Example 10

[0198] (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0199]

[0200] first step

[0201] (3R,5R)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyridin[3,2-d]pyrimidin-7-yl)methyl)-5-methylpyrrolidin-3-ol

[0202]

[0203] 4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-aminocarbaldehyde 1e (60.0 mg, 0.15 mmol, 1.0 eq) and (3R,5R)-5-methylpyrrolidin-3-ol (41.3 mg, 0.3 mmol, 2.0 eq) were dissolved in 5 mL of dichloromethane, and sodium cyanoborohydride (18.6 mg, 0.3 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 6 hours, and the solvent was removed by concentration under reduced pressure. The mixture was purified by column chromatography to obtain (3R,5R)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-7-yl)methyl)-5-methylpyrrolidin-3-ol 10a (30.0 mg, 40.1%). LCMS m / z(ESI):497.04[M+1] + .

[0204] Step 2

[0205] (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0206]

[0207] (3R,5R)-1-((4-((3-bromo-2-chlorophenyl)amino)-2-(difluoromethyl)pyridin[3,2-d]pyrimidin-7-yl)methyl)-5-methylpyrrolidin-3-ol 10a (20.0 mg, 0.04 mmol, 1.0 eq), (R)-1-((3-methoxy-5-((S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid 8a (27.0 mg, 0.05 mmol, 1.0 eq), di-tert-butylphosphinoferrocenepalladium dichloride (2.6 mg, 0.004 mmol, 0.1 eq), potassium carbonate (11.06 mg, 0.08 mmol, 2.0 eq) was dissolved in 2 mL of dioxane and 0.5 mL of water, replaced with nitrogen three times, reacted at 95 ° C for 6 hours, and purified by Prep-HPLC (TFA) to obtain (R)-1-((5-((S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((2R, 4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid (trifluoroacetate) 10 (yellow solid, 5.0 mg, 14.6%) LCMS m / z (ESI): 854.25 [M+1] + . 1 H NMR (400MHz, MeOD) δ10.53(s,1H),9.12(s,1H),8.79(s,1H),8.52(s,1H),7.54(t,J=8. 0Hz,1H),7.33-7.31(m,2H),7.25-7.16(m,2H),6.86(t,J=54.4Hz,1H),5.95-5.80(m,1H ),4.80-4.60(m,3H),4.46(s,2H),4.27-4.24(m,2H),4.20-4.10(m,2H),3.98(s,3H),3 .35(s,3H),2.85-2.82(m,3H),2.63-2.61(m,2H),2.38-2.15(m,4H),1.50-1.49(m,3H).

[0208] Embodiment 11

[0209] (R)-1-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0210]

[0211] first step

[0212] (S)-N-(4-bromo-2,3-dihydro-1H-inden-1-yl)-5-(1,3-dioxan-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-amine

[0213]

[0214] The reactant (S)-5-((4-bromo-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 1a (10.46 g, 25 mmol, 1.0 eq), ethylene glycol (3.10 g, 50.00 mmol, 2.0 eq) and solvent toluene (200 mL) were added to a 500 mL single-mouth bottle to obtain a yellow solution, which was protected by N2 and reacted at 135° C. for 8 hours. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether: ), to give (S)-N-(4-bromo-2,3-dihydro-1H-inden-1-yl)-5-(1,3-dioxane-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-amine 11a (light yellow oil, 11.51 g, crude product). LCMS m / z (ESI): 461.15 [M+1] + .

[0215] Step 2

[0216] (S)-5-(1,3-dioxacyclyl-2-yl)-6-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclyl-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(trifluoromethyl)pyrazin-2-amine

[0217]

[0218] The reactants (S)-N-(4-bromo-2,3-dihydro-1H-inden-1-yl)-5-(1,3-dioxane-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-amine 11a (11.51 g, 25.0 mmol, 1.0 eq), biboronic acid pinacol ester (9.52 g, 37.50 mmol, 1.5 eq), 1,1'-bis( [diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (1.03 g, 1.25 mmol, 0.05 eq), potassium acetate (7.36 g, 75.00 mmol, 3.0 eq,) and solvent 1,4-dioxane (150 mL) were added to obtain a yellow solution, which was reacted at 100 ° C for 2 hours under N2 protection, and then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ), to give (S)-5-(1,3-dioxacyclyl-2-yl)-6-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclyl-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(trifluoromethyl)pyrazin-2-amine 11b (light yellow solid, 10.05 g, 79.3%). LCMS m / z (ESI): 508.25 [M+1] + .

[0219] Step 3

[0220] (S)-8-((3-(1-((5-(1,3-dioxacyclohexane-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-2-chlorophenyl)amino)-1,7-naphthyridine-3-carbaldehyde

[0221]

[0222] 8-[(3-bromo-2-chlorophenyl)amino]-1,7-naphthyridine-3-carbaldehyde 11c (279.21 mg, 0.77 mmol, 1.0 eq, reference CN110582493 for the synthetic route), (S)-5-(1,3-dioxolan-2-yl)-6-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-2,3-dihydro-1H-indene-1-yl)-3-(trifluoromethyl)-1-[(3-bromo-2-chlorophenyl)amino]-1,7-naphthyridine-3-carbaldehyde 11c (279.21 mg, 0.77 mmol, 1.0 eq, reference CN110582493 for the synthetic route), 1,1'-bis(tert-butylphosphino)ferrocenepalladium(II) (25.09 mg, 0.04 mmol, 0.05 eq) was added, and the nitrogen was replaced three times. The reaction mixture was reacted at 30°C for 2 hours. The reaction was monitored by LCMS, and part of the solvent was concentrated. Then, water and dichloromethane (3×30 mL) were added for extraction. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ), to give (S)-8-((3-(1-((5-(1,3-dioxocyclohexane-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-2-chlorophenyl)amino)-1,7-naphthyridine-3-carboxaldehyde 11d (light yellow solid, 350 mg, crude product). LCMS m / z(ESI): 664.15[M+1] + .

[0223] Step 4

[0224] N-(2-Chloro-3-[(1S)-1-[(5-(1,3-dioxolan-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino]-2,3-dihydro-1H-inden-4-yl]phenyl)-3-{[(3R)-3-methylpyrrolidin-1-yl]-}-1,7-naphthyl-8-amine

[0225]

[0226] (S)-8-((3-(1-((5-(1,3-dioxacyclohexane-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino)-2,3-dihydro-1H-inden-4-yl)-2-chlorophenyl)amino)-1,7-naphthyridine-3-carboxaldehyde 11d (464.13 mg, 0.70 mmol, 1.0 eq) and (R)-pyrrolidin-3-ol (91.48 mg, 1.05 mmol, 1.5 eq) were dissolved in dichloromethane (35 mL) and reacted at room temperature for 30 minutes, and then sodium cyanoborohydride (87.98 mg, 1.40 mmol, 2.0 eq) was added and the reaction mixture was reacted at 20°C for 3 hours. The reaction was monitored by LCMS. Water and dichloromethane (3×30 mL) were added for extraction. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane: ), to give N-(2-chloro-3-[(1S)-1-[(5-(1,3-dioxolan-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino]-2,3-dihydro-1H-inden-4-yl]phenyl)-3-{[(3R)-3-methylpyrrolidin-1-yl]-}-1,7-naphthyl-8-amine 11e (light yellow solid, 320 mg, crude product). LCMS m / z (ESI): 733.15 [M+1] + .

[0227] Step 5

[0228] 5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-yl

[0229] Aminoformaldehyde

[0230]

[0231] The compound N-(2-chloro-3-[(1S)-1-[(5-(1,3-dioxolan-2-yl)-6-methoxy-3-(trifluoromethyl)pyrazin-2-yl)amino]-2,3-dihydro-1H-inden-4-yl]phenyl)-3-{[(3R)-3-methylpyrrolidin-1-yl]-}-1,7-naphthyl-8-amine 11e (293.67 mg, 0.40 mmol, 1.0 eq) was dissolved in acetonitrile (8 mL) to obtain a colorless solution. 2N hydrochloric acid (2 mL, 4.0 mmol, 10.0 eq) was added at 0°C, reacted at 20°C for 2 hours, and water and dichloromethane (3×30 mL) were added for extraction. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: ), to obtain compound 5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 11f (light yellow solid, 200 mg, 72.5%). LCMS m / z (ESI): 691.15 [M+1] + .

[0232] Step 6

[0233] (R)-1-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0234]

[0235] Compound 5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 11f (48.31 mg, 0.07 mmol, 1.0 eq) and (3R)-pyrrolidine-3-carboxylic acid (12.1 mg, 0.11 mmol, 1.5 eq) were dissolved in a methanol solution (3 mL), and then reacted at room temperature for 30 minutes, and then cooled to 0°C and sodium cyanoborohydride (8.8 mg, 0.14 mmol, 2.0 eq) was added. The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were performed to give (R)-1-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid (trifluoroacetate) 11 (white solid, 8 mg, 14.5%). LCMS m / z (ESI): 789.20 [M+1] + . 1H NMR(400MHz,DMSO)δ10.36(s,1H),9.09(s,1H),8.42(s,1H),8.26(s,1H),7.55(s,1H),7.31-6.86(m,7H),5.81-5.76 (m,1H),4.23(s,1H),3.81-3.62(m,7H),2.74-2.66(m,6H),2.48-2.30(m,5H),2.04-1.97(m,4H),1.70-1.58(m,2H).

[0236] Example 12

[0237] (S)-2-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)amino)-3-hydroxy-2-methylpropanoic acid

[0238]

[0239] 5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-amethoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 11f (50.0 mg, 0.07 mmol, 1.0 eq) and (2s)-2-amino-3-hydroxy-2-methylpropanoic acid (12.2 mg, 0.11 mmol, 1.5 eq) were dissolved in methanol solution (3 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (8.8 mg, 0.14 mmol, 2.0 eq) was added. The reaction mixture was reacted at 0°C for 4 hours, the reaction was monitored by LCMS, filtered and then subjected to Prep-HPLC (TFA) to give (S)-2-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)amino)-3-hydroxy-2-methylpropanoic acid 12 (white solid, 6.0 mg, 11.2%). LCMS m / z (ESI): 793.20 [M+1] + . 1H NMR(400MHz,DMSO)δ9.92(s,1H),9.09(s,1H),8.92(d,J=1.6Hz,1H),8.26(s,1H),8 .19(d,J=5.6Hz,1H),7.49(m,1H),7.39-7.13(m,5H),6.98(m,1H),5.82(m,1H),4.7 4(s,1H),4.22(s,1H),3.96-3.77(m,7H),3.62(d,J=10.8Hz,1H),3.50(d,J=10.8Hz ,1H),2.85–2.61(m,4H),2.44–2.14(m,4H),2.02(m,1H),1.58(m,1H),1.24(s,3H).

[0240] Embodiment 13

[0241] N-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine

[0242]

[0243] 5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 11f (50.0 mg, 0.07 mmol, 1.0 eq) and (2s)-2-(methylamino)propionic acid (11.3 mg, 0.11 mmol, 1.5 eq) were dissolved in a methanol solution (3 mL), and then reacted at room temperature for 30 minutes, and then cooled to 0°C and sodium cyanoborohydride (8.8 mg, 0.14 mmol, 2.0 eq) was added. The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were performed to give N-((5-((S)-4-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine (trifluoroacetate) 13 (white solid, 12.0 mg, 22.0%). LCMS m / z (ESI): 777.20 [M+1] + . 1H NMR (400MHz, DMSO) δ9.93(s,1H),9.09(s,1H),8.92(s,1H),8.26(s,1H),8.18(s,1H),7.48(s 1H),7.39-6.95(m,7H),5.95-5.80(m,1H),4.25(s,1H),3.89-3.75(m,7H),3.67-3.62(m,2H ),2.84-2.63(m,7H),2.45-2.32(m,2H),2.29(s,3H),2.09-1.94(s,3H),1.64-1.53(m,1H).

[0244] Embodiment 14

[0245] N-((5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine

[0246] -2-yl)methyl)-N-methylglycine

[0247]

[0248] 5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 11f (48.3 mg, 0.07 mmol, 1.0 eq) and 2-(methylamino)acetic acid (9.8 mg, 0.11 mmol, 1.5 eq) were dissolved in methanol solution (3 mL), followed by reaction at room temperature for 30 minutes, followed by cooling to 0°C and adding sodium cyanoborohydride (8.8 mg, 0.14 mmol, 2.0 eq). The reaction mixture was reacted at 0°C for 4 hours, and the reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were performed to give N-((5-((S)-4-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methylglycine (trifluoroacetate) 14 (white solid, 5.0 mg, 9.3%). LCMS m / z (ESI): 763.20 [M+1] + . 1H NMR (400MHz, DMSO) δ9.92(s,1H),9.09(s,1H),8.92(s,1H),8.26(s,1H),8.19(d,J=5.6Hz,1H),7.49(s,1H),7.39-6.86(m,7H),5.95-5.80(m,1 H),4.26(s,1H),3.86-3.76(m,7H),3.25(m,2H)2.75-2.63(m,4H),2.44 -2.28(m,5H),2.27-2.20(m,1H),2.13-1.85(m,2H),1.58-1.54(m,1H).

[0249] Embodiment 15

[0250] 3-Hydroxy-2-((5-(((S)-4-(3-(((R)-3-(3-((R)-3-hydroxypyrrolidinone-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-ylamino)-3-methoxy-6-(trimethoxy)-2-pyridinylmethylamino)-2-methylpropanoic acid

[0251]

[0252] first step

[0253] 5-((1S)-4-(3-(3-((3R)-3-hydroxycyclopentyl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-ylamino)-3-methoxy-6-(trimethylpyrazine)-2-carbaldehyde

[0254]

[0255] 5-(1,3-dioxol-2-yl)-6-methoxy-N-[(1S)-4-(tetramethyl-1,3,2-dioxol-2-yl)-2,3-dihydro-1H-inden-1-yl]-3-(trifluoromethyl)pyrazin-2-amine 15a (51.7 mg, 0.13 mmol, 1.0 eq, synthesis method see WO2018119286 A1), 8-[(3-bromo-2-chlorophenyl)amino]-1,7-naphthyridine-3-carboxaldehyde 1b (69.5 mg, 0.15 mmol, 1.2 eq), sodium carbonate (26.5 mg, 0.26 mmol, 2.0 eq) were dissolved in tetrahydrofuran (3 mL) and water (1 mL), and then dichloro[1,1'-bis(tert-butylphosphino)ferrocenepalladium(II) (8.15 mg, 0.01 mmol, 0.1 eq) was added. Nitrogen was replaced three times, and the reaction mixture was reacted at 50°C for 2 hours. The reaction was monitored by LCMS. Part of the solvent was concentrated, and then water and dichloromethane (3×30 mL) were added for extraction. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ), to give 5-((1S)-4-(3-(3-((3R)-3-hydroxycyclopentyl)methyl)-1,7-naphthyridin-8-ylamino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-ylamino)-3-methoxy-6-(trimethylpyrazine)-2-carbaldehyde 15b (light yellow solid, 67.0 mg, 81%). LCMS m / z (ESI): 669.25 [M+1] + .

[0256] Step 2

[0257] 4-Hydroxy-2-((5-(((S)-4-(3-(((R)-3-(3-((R)-3-hydroxypyrrolidinone-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-ylamino)-3-methoxy-6-(trimethoxy)-2-pyridinylmethylamino)-2-methylpropanoic acid

[0258]

[0259] Compound 2 5-{[(1S)-4-(2-chloro-3-(3-{[(3R)-3-hydroxypyrrolidinone-1-yl]methyl}-1,7-naphthyridin-8-yl]amino]phenyl)-2,3-dihydro-1H-inden-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 15b (67.0 mg, 0.1 mmol, 1.0 eq) and (2S)-2-amino-3-hydroxy-2-methylpropionic acid (17.8 mg, 0.15 mmol, 1.5 eq) were dissolved in methanol solution (3 mL) and reacted at room temperature for 30 minutes. Then, the temperature was lowered to 0°C and sodium cyanoborohydride (12.57 mg, 0. 14mmol, 2.0eq). The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were performed to give white solid 3-hydroxy-2-((5-(((S)-4-(3-(((R)-3-(3-((R)-3-hydroxypyrrolidinone-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-ylamino)-3-methoxy-6-(trimethoxy)-2-pyridylmethylamino)-2-methylpropanoic acid (trifluoroacetate) 15 (white solid, 15.5mg, 20.5%). LCMS m / z (ESI): 772.45 [M+1] + . 1 H NMR(400MHz,DMSO)δ10.69(s,1H),9.76(s,1H),9.07(s,1H),8.51(s,1H),8.17-8.04(m,2H),7.30-6.97(m,7H),5.88-5.82(m,1H) ,4.66(s,1H),4.45(s,1H),4.22(s,2H),3.90-3.78(m,6H),3.32-3.31(m,4H),2.83-2.60(m,2H),2.35-1.89(m,7H),1.51(s,3H).

[0260] Example 16

[0261] (R)-1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-

[0262] (Trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0263]

[0264] first step

[0265] (S)-5-Bromo-1,2,3,4-tetrahydronaphthalene-1-amine hydrochloride

[0266]

[0267] Add reactants 5-bromo-3,4-dihydronaphthalene-1(2H)-one 16a (9.08 g, 40.0 mmol, 1.0 eq), (S)-2-methylpropane-2-sulfenamide (5.33 g, 44.0 mmol, 1.1 eq), and tetraethoxytitanium (13.69 g, 60.0 mmol, 1.05 eq) to a 500 mL single-mouth bottle and dissolve in 100 mL of toluene to obtain a yellow solution, which is heated at 90°C for 6 hours. The reaction is monitored by LCMS, and the temperature of the reaction system is reduced to -70°C. Sodium borohydride (4.45 g, 120.0 mmol, 3.0 eq) is added in four batches at this temperature, and the temperature is slowly raised to room temperature for 2 hours. The reaction is complete as monitored by LCMS. Add 3L ethyl acetate and 1L saturated sodium bicarbonate, stir overnight, filter on diatomaceous earth, wash the filter cake with 200mL*3 ethyl acetate, separate the layers, dry the organic layer, filter, spin dry, add 80mL methanol to dissolve, add 40mL 4mol / L dioxane hydrochloride, react at room temperature for 2 hours, and monitor the reaction completion by LCMS. Spin dry, add 20mL ethyl acetate and stir for 0.5 hour. Filter, wash the filter cake with ethyl acetate (5mL*2) and dry to obtain (S)-5-bromo-1,2,3,4-tetrahydronaphthalene-1-amine hydrochloride 16b (brown solid 7.0g, 66.2%). LCMS m / z(ESI): 226.20,228.20[M+1] + .

[0268] Step 2

[0269] (S)-5-(5-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl)amino-3-methoxypyrazine-2-carbonitrile

[0270]

[0271] Add the reactant (S)-5-bromo-1,2,3,4-tetrahydronaphthalene-1-amine hydrochloride 16b (7.01 g, 27.0 mmol, 1.0 eq) and ethylenediisopropylamine (6.98 g, 54.0 mmol, 2.0 eq) to a 250 mL single-mouth bottle and dissolve in 50 mL of N,N-dimethylformamide to obtain a yellow solution. Add 3,5-dichloropyrazine-2-carbonitrile (4.93 g, 28.35 mmol, 1.05 eq) at 0°C and react at room temperature for 0.5 hours. Add 50 mL of 30% sodium methoxide solution and reflux for 1.5 hours. 100 mL of ice water was slowly added under ice bath and stirred for 0.5 hours, filtered, the filter cake was washed with 10 mL*3 of water, and the filter cake was dried to obtain (S)-5-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)amino-3-methoxypyrazine-2-carbonitrile 16c (brown solid, 6.82 g, 70.3%). LCMS m / z (ESI): 359.20, 361.20 [M+1] + .

[0272] Step 3

[0273] 5-{[(1S)-5-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-iodo-3-methoxypyrazine-2-carbonitrile

[0274]

[0275] To a 50 mL single-necked bottle, add the reactant (S)-5-(5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)amino-3-methoxypyrazine-2-carbonitrile 16c (6.83 g, 19.0 mmol, 1.0 eq) and potassium acetate (4.66 g, 47.5 mmol, 2.5 eq) dissolved in 80 mL of acetic acid to obtain a yellow suspension. Add N-iodosuccinimide (4.71 g, 20.9 mmol, 1.1 eq) within 10 min and react at 50 ° C for 3 hours. The reaction is complete when LCMS is detected. 100 mL of ice water was slowly added under ice bath and stirred for 0.5 hours, filtered, the filter cake was washed with 10 mL*3 of water, and the filter cake was dried to obtain 5-{[(1S)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-iodo-3-methoxypyrazine-2-carbonitrile 16d (earth-yellow solid, 9.22 g, 100%). LCMS m / z (ESI): 485.05, 487.05 [M+1] + .

[0276] Step 4

[0277] 5-{[(1S)-5-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbonitrile

[0278]

[0279] The reactants 5-{[(1S)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-iodo-3-methoxypyrazine-2-carbonitrile 16d (9.22 g, 19.0 mmol, 1.0 eq) and cuprous iodide (4.34 g, 22.8 mmol, 1.2 eq) were added to a 50 mL single-mouth bottle. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (7.30 g, 38.0 mmol, 2.0 eq) was dissolved in 50 mL of N,N-dimethylformamide to obtain a yellow suspension. Under N2 protection, the mixture was reacted at 100 °C for 2.5 hours, filtered, and the filter cake was washed with 5 mL*2 DMF. The mother liquor was slowly added with 100 mL of ice water under an ice bath and stirred for 0.5 hours. The mixture was filtered, and the filter cake was washed with 10 mL*3 water. The filter cake was dried and purified by column chromatography (petroleum ether: ) to give 5-{[(1S)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbonitrile 16e (light yellow solid, 7.0 g, 86.2%). LCMS m / z (ESI): 427.20, 429.20 [M+1] + .

[0280] Step 5

[0281] {[(1S)-5-Bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)(hydrogenated)carbaldehyde

[0282]

[0283] 5-{[(1s)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbonitrile 16e (1.07 g, 2.5 mmol, 1.0 eq) was added to a 50 mL single-necked bottle and dissolved in 15 mL of dichloromethane. Schwarz reagent (1.29 g, 5.0 mmol, 2.0 eq) was added in batches at 0°C to maintain the internal temperature <3°C. After 45 min, 5 mL of acetonitrile was added and stirred for 0.5 hour. 1 mL of water and 10 g of silica gel were stirred for 0.5 hour. The mixture was spin-dried and passed through a column to obtain (5-{[(1s)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-yl)(hydrogenated)formaldehyde 16f (light yellow solid, 0.76 g, 71.5%). LCMS m / z(ESI): 430.20,432.20[M+1] + .

[0284] Step 6

[0285] 3-Methoxy-5-{[(1s)-5-(tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-(trifluoromethyl)pyrazin-2-yl)carbaldehyde

[0286]

[0287] (5-{[(1s)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-yl)(hydrogenated)formaldehyde 16f (0.77 g, 1.8 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (0.69 g, 2.7 mmol, 1.5 eq), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.13 g, 0.18 mmol, 0.1 eq), potassium acetate (0.35 g, 3.6 mmol, 2.0 eq) were added to a 50 mL single-mouth bottle, N2 was protected, and the temperature was raised to 100 ° C for 2 hours. The mixture was dried by rotation and purified by column (petroleum ether: ), to obtain 3-methoxy-5-{[(1s)-5-(tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-(trifluoromethyl)pyrazine-2-yl)carbaldehyde 16g (light yellow solid, 0.70g, 81.3%). LCMS m / z (ESI): 478.20 [M+1] + .

[0288] Step 7

[0289] 5-((S)-5-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde

[0290]

[0291] (3R)-1-[(8-[(3-bromo-2-chlorophenyl)amino]-1,7-naphthyridin-3-yl)methyl]pyrrolidin-3-ol (216.86 mg, 0.5 mmol, 1.0 eq), 3-methoxy-5-{[(1s)-5-(tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-6-(trifluoromethyl)pyrazin-2-yl)carbaldehyde 16g (357.96mg, 0.75mmol, 1.5eq) dichloro[1,1-di(phosphine di-tert-butyl)ferrocene]palladium(II) (32.59mg, 0.05mmol, 0.1eq), sodium carbonate (105.99mg, 1.0mmol, 2.0eq) were added to a 50mL single-mouth bottle, dissolved in 6mL tetrahydrofuran and 2mL water, N2 protected, heated to 60℃ for 1.5 hours. Spin dry, and purify by column (petroleum ether: ), to give 5-((S)-5-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-carboxaldehyde 16h (light yellow solid, 0.25 g, 71.0%). LCMS m / z (ESI): 704.20 [M+1] + .

[0292] Step 8

[0293] (R)-1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid

[0294]

[0295] 5-{[(1S)-5-(2-chloro-3-(3-{[(3R)-3-hydroxypyrrolidinone-1-yl]methyl}-1,7-naphthyridin-8-yl]amino]phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 16h (35.21 mg, 0.05 mmol, 1.0 eq) and (3R)-pyrrolidine-3-carboxylic acid (8.63 mg, 0.08 mmol, 1.5 eq) were dissolved in methanol solution (2 mL), and then reacted at room temperature for 30 minutes, cooled to 0°C, and sodium cyanoborohydride (6.2 8 mg, 0.10 mmol, 2.0 eq). The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were used to prepare (R)-1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)pyrrolidine-3-carboxylic acid (trifluoroacetate) 16 (white solid, 8.5 mg, 21.2%). LCMS m / z (ESI): 803.20 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.90 (s, 1H), 9.10-9.07 (m, 1H), 8.91 (d, J = 5.6Hz, 1H), 8 .26(s,1H),8.19(d,J=5.6Hz,1H),7.49(dd,J=13.6,7.6Hz,1H),7.34-6.85(m ,6H),5.46(s,1H),4.75(s,1H),4.24(s,1H),3.87-3.78(m,6H),3.54(s,1H) ,2.78-2.57(m,6H),2.52-2.35(m,3H),2.26-1.88(m,6H),1.72-1.57(m,2H).

[0296] Embodiment 17

[0297] N-((5-((S)-5-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine

[0298]

[0299] Compound 5-{[(1S)-5-(2-chloro-3-(3-{[(3R)-3-hydroxypyrrolidinone-1-yl]methyl}-1,7-naphthyridin-8-yl]amino]phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 16h (35.21 mg, 0.05 mmol, 1.0 eq) and (2S)-2-(methylamino)propionic acid (8.63 mg, 0.08 mmol, 1.5 eq) were dissolved in methanol solution (2 mL), and then reacted at room temperature for 30 minutes, and then cooled to 0°C and cyanoborohydride was added. Sodium (6.28 mg, 0.10 mmol, 2.0 eq). The reaction mixture was reacted at 0°C for 4 hours, the reaction was monitored by LCMS, filtered and then subjected to Prep-HPLC (TFA) to prepare N-((5-((S)-5-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine (trifluoroacetate) 17 (white solid, 12.0 mg, 30.3%). LCMS m / z (ESI): 791.25 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.90 (s, 1H), 9.08 (d, J = 7.6Hz, 1H), 8.91 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 5.6Hz, 1H), 7.51 (dd, J = 13.6, 7.6Hz, 1H), 7.34-6.89 (m 7H),5.45(s,1H),4.76(s,1H),4.22(s,1H),3.83-3.63(m,7H),2.76-2.6 1(m,2H),2.48-2.32(m,4H),2.26(s,3H),2.12-1.65(m,6H),1.27(s,3H).

[0300] Embodiment 18

[0301] 1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)piperidine-4-carboxylic acid

[0302]

[0303] To a 25 mL single-necked reaction bottle, 5-{[(1S)-5-(2-chloro-3-(3-{[(3R)-3-hydroxypyrrolidinone-1-yl]methyl}-1,7-naphthyridin-8-yl]amino]phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 16h (30 mg, 0.04 mmol, 1.0 eq), piperidine-4-carboxylic acid (21 g, 0.16 mmol, 4 eq) and dichloromethane (1 mL) were added and stirred at room temperature for 1 hour. Under ice-water bath conditions, sodium cyanoborohydride (4 mg, 0.06 mmol, 1 .5eq), continue stirring and reacting for 15 minutes after addition, warm to room temperature and react for 2 hours, add dichloromethane (20mL) and water (5mL) and stir, the organic phase is spin-dried and separated and purified by prep-HPLC (TFA) to obtain 1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)piperidine-4-carboxylic acid (trifluoroacetate) 18 (white solid, 5.2mg, 13.1%). LCMS m / z(ESI): 817.2[M+1] + . 1 H NMR(400MHz,MeOD)δ9.06(d,J=2.0Hz,1H),8.78(d,J=8.4Hz,1H),8.49(s,1H),8.13(d,J=6.0Hz,1H),7.4 9(t,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),7.30-7.25(m,2H),7.10-7.00(m,2H),5.56(t,J=7.6Hz,1H),4. 77-4.69(m,2H),4.61-4.60(m,1H),4.33-4.31(m,2H),4.01(d,J=1.6Hz,3H),3.67-3.64(m,2H),3.54-3. 40(m,3H),3.18-3.10(m,2H),2.67-2.50(m,3H),2.34-2.23(m,3H),2.14-2.05(m,4H),1.95-1.79(m,4H).

[0304] Embodiment 19

[0305] N-((5-((S)-5-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine

[0306]

[0307] Compound 5-{[(1s)-5-(2-chloro-3-(3-{[(3r)-3-hydroxypyrrolidinone-1-yl]methyl}-1,7-naphthyridin-8-yl]amino]phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 16h (35.22 mg, 0.05 mmol, 1.0 eq) and (2s)-2-amino-3-hydroxy-2-methylpropionic acid (8.63 mg, 0.08 mmol, 1.5 eq) were dissolved in methanol solution (3 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and added with cyanoborohydride Sodium (6.28 mg, 0.10 mmol, 2.0 eq), the reaction mixture was reacted at 0 ° C for 4 hours, and the reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were then performed to obtain white solid N-((5-((S)-5-(2-chloro-3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-N-methyl-L-alanine (trifluoroacetate) 19 (white solid, 6.0 mg, 15.1%). LCMS m / z (ESI): 807.25 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.89(s,1H),9.09(d,J=7.6Hz,1H),8.91(s,1H),8.26(s,1H),8 .19(d,J=5.6Hz,1H),7.49(dd,J=13.6,7.6Hz,1H),7.34-6.66(M,1H),5.54-5.26(m ,2H),5.32(s,1H),4.78(s,1H),4.22(s,1H),3.86-3.79(m,6H),3.17(s,1H),2.83- 2.61(m,2H),2.48-2.32(m,4H),2.01-1.89(m,4H),1.72-1.58(m,2H),1.23(s,3H).

[0308] Embodiment 20

[0309] (3R,5R)-1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-

[0310] (Trifluoromethyl)pyrazin-2-yl)methyl)-5-methylpyrrolidin-3-ol

[0311]

[0312] Compound 5-{[(1S)-5-(2-chloro-3-(3-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-1,7-naphthyridin-8-yl]amino]phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-3-methoxy-6-(trifluoromethyl)pyrazine-2-carbaldehyde 16h (35.20 mg, 0.05 mmol, 1.0 eq) and (3R,5R)-5-methylpyrrolidin-3-ol (7.59 mg, 0.08 mmol, 1.5 eq) were dissolved in methanol solution (3 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (6.2 8mg, 0.10mmol, 2.0eq). The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were used to prepare (3R, 5R)-1-((5-((S)-5-(2-chloro-3-((3-((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)methyl)-5-methylpyrrolidin-3-ol (trifluoroacetate) 20 (white solid, 8.0mg, 20.1%). LCMS m / z (ESI): 788.80 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.91 (s, 2H), 9.84 (s, 1H), 9.08 (s, 1H), 8.02 (d, J = 5.6Hz, 1H), 8.57 ( s,1H),8.26(d,J=5.6Hz,1H),7.54-6.88(m,8H),5.50(s,1H),4.67(s,2H),4.40-4.20(m 4H),3.90-3.72(m,5H),3.35-3.12(m,4H),2.41-2.37(m,2H),2.10–1.39(m,9H),1.23(s,3H).

[0313] Embodiment 21

[0314] 4-((5-((1S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)amino)bicyclo[2.2.2]octane-1-carboxylic acid

[0315]

[0316] Synthesized by referring to the method of Example 8, 4-((5-((1S)-4-(2-chloro-3-((2-(difluoromethyl)-7-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)amino)bicyclo[2.2.2]octane-1-carboxylic acid 20 (light yellow solid, 3.0 mg, 9%) was obtained. LCMS m / z(ESI): 908.00[M+1] + . 1 H NMR (400MHz, MeOD) δ9.10 (s, 1H), 8.81 (s, 1H), 8.51 (s, 1H), 7.55 (t, J = 8.0Hz, 1H),7.33-7.31(m,2H),7.25-7.16(m,2H),6.86(t,J=54.4Hz,1H),5.86(s,1H) ,4.15(s,3H),3.96(s,3H),2.85-2.82(m,2H),2.63-2.61(m,1H),2.38-2.15( m,4H),2.10-1.90(m,14H),1.66-1.64(m,2H),1.46(s,3H),1.45-1.40(m,3H).

[0317] Embodiment 22

[0318] 3-Hydroxy-2-((5-((S)-4-(3-(((R)-1-hydroxypropan-2-yl)amino)methyl-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)amino)-2-methylpropanoic acid

[0319]

[0320] Synthesized by referring to the method of Example 15, 3-hydroxy-2-((5-((S)-4-(3-(((R)-1-hydroxypropane-2-yl)amino)methyl-1,7-naphthyridin-8-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazin-2-yl)amino)-2-methylpropanoic acid 22 (light yellow solid, 5.0 mg, 10%) was obtained. LCMS m / z (ESI): 761.33 [M+1] + . 1 H NMR (400MHz, MeOD) δ9.16 (s, 1H), 8.53 (s, 1H), 7.67-7.62 (m, 2H), 7.51 (t, J = 8. 0Hz,1H),7.32-7.26(m,5H),7.18-7.16(m,1H),5.91-5.87(m,1H),4.62(s,3H), 4.32(s,3H),4.08-3.93(m,6H),3.87-3.84(m,1H),3.73-3.69(m,1H),3.58-3.5 4(m,1H),2.88-2.63(m,4H),2.14-2.11(m,5H),1.60(s,3H),1.45-1.44(m,4H).

[0321] Embodiment 23

[0322] 3-Hydroxy-2-((3-methoxy-5-((1S)-4-(2-methyl-3-((3-((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)amino)-2-methylpropanoic acid

[0323]

[0324] Compound 3-methoxy-5-((1S)-4-(2-methyl-3-(((5-oxypyrrolidin-2-yl)methyl)amino)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde (50.16 mg, 0.07 mmol, 1.0 eq, synthesis method reference Example 15) 23a, (2S)-2-amino-3-hydroxy-2-methylpropionic acid (12.86 mg, 0.11 mmol, 1.5 eq) were dissolved in methanol solution (3 mL), reacted at room temperature for 30 minutes, then cooled to 0°C and sodium cyanoborohydride (8.61 mg, 0.14 mmol, 2.0 eq) was added. The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were performed to obtain white solid 3-hydroxy-2-((3-methoxy-5-((1S)-4-(2-methyl-3-((3-((5-oxopyrrolidin-2-yl)methyl)amino)methyl)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazin-2-yl)amino)-2-methylpropanoic acid (trifluoroacetate) 23 (white solid, 6.0 mg, 10.4%). LCMS m / z (ESI): 800.34 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.43(s,1H)9.10(s,1H),9.04(s,1H),9.02(s,1H),8. 43(s,1H),8.28(s,1H),8.09(s,1H),7.62(s,1H),7.27-6.92(m,7H),5.92 -5.87(m,1H),4.47(s,2H),4.20(s,2H),3.88-3.77(m5H),3.21-3.13(m,3 H),2.70-2.51(m,2H),2.29–2.09(m,5H),1.83-1.81(m,1H),1.49(s,3H).

[0325] Embodiment 24

[0326] 5-((S)-4-(3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde

[0327]

[0328] Referring to the synthesis method of Example 1, 5-((S)-4-(3-((2-(difluoromethyl)-7-((R)-3-hydroxypyrrolidin-1-yl)methyl)pyridin[3,2-d]pyrimidin-4-yl)amino)-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxy-6-(trifluoromethyl)pyrazine-2-aminocarbaldehyde 24 (white solid, 1.5 mg, 11.2%) can be obtained. LCMSm / z(ESI): 820.10[M+1] + . 1 H NMR (400MHz, DMSO) δ10.35(d,J=12.4Hz,1H),8.95(d,J=1.6Hz,1H),8.17(s,1H),7.74-7.60(m,1H), 7.41-7.31(m,1H),7.28(t,J=7.6Hz,1H),7.23-7.15(m,1H),7.14–7.04(m,2H),7.03-6.94(m,1H),6 .72(t,J=54.4Hz,1H),5.80(s,1H),4.23(s,1H),3.96-3.76(m,6H),2.94–2.83(m,2H),2.82-2.66(m ,6H),2.64-2.56(m,3H),2.24-2.14(m,1H),2.10-1.96(m,5H),1.95-1.84(m,3H),1.66-1.54(m,1H).

[0329] Embodiment 25

[0330] (3S)-1-[(3-methoxy-5-{[(1S)-4-(2-methyl-3-[(3-({[(5-oxopyrrolidin-2-yl)methyl]amino}methyl)-1,7-naphthyridin-8-yl)amino]phenyl)-2,3-dihydro-1H-inden-1-yl]amino}-6-

[0331] (Trifluoromethyl)pyrazin-2-yl)methyl]pyrrolidine-3-carboxylic acid

[0332]

[0333] Compound 3-methoxy-5-((1S)-4-(2-methyl-3-(((5-oxopyrrolidin-2-yl)methyl)amino)-1,7-naphthyridin-8-yl)amino)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-6-(trifluoromethyl)pyrazine-2-aminocarboxaldehyde 23a (50.0 mg, 0.07 mmol, 1.0 eq) and (3S)-pyrrolidine-3-carboxylic acid (12.43 mg, 0.11 mmol, 1.5 eq) were dissolved in a methanol solution (3 mL), and then reacted at room temperature for 30 minutes, and then cooled to 0°C and sodium cyanoborohydride (8.61 mg, 0.14 mmol, 2.0 eq) was added. The reaction mixture was reacted at 0°C for 4 hours. The reaction was monitored by LCMS. Filtration and Prep-HPLC (TFA) were performed to obtain a white solid (3S)-1-[(3-methoxy-5-{[(1S)-4-(2-methyl-3-[(3-({[(5-oxopyrrolidin-2-yl)methyl]amino}methyl)-1,7-naphthyridin-8-yl)amino]phenyl)-2,3-dihydro-1H-inden-1-yl]amino}-6-(trifluoromethyl)pyrazin-2-yl)methyl]pyrrolidine-3-carboxylic acid (trifluoroacetate) 25 (white solid, 15.0 mg, 26.2%). LCMS m / z (ESI): 796.30 [M+1] + . 1 H NMR(400MHz,DMSO)δ10.20(s,1H),9.25(s,1H),9.04(s,1H),8.46(s,1H),8 .12-8.03(m,2H),7.62(s,1H),7.58–6.85(m,6H),5.89-5.86(m,1H),4.49(s ,2H),4.40(s,2H),3.89-3.86(m,4H),3.81-3.63(m,4H),3.42-3.11(m,5H), 2.74-2.68(m,2H),2.49-2.33(m,2H),2.31-1.92(m,7H),1.84-1.81(m,1H).

[0334] Example 26 Evaluation of the inhibitory effect of compounds on PD1 / PDL1 binding

[0335] Experimental method: The HTRF method was used to detect the inhibitory ability of small molecule compounds on the binding of PD-1 and PD-L1. 3+(HTRF donor) and PAb Anti-Tag2-XL665 (HTRF acceptor) detect the interaction between Tag2-Human PD-1 and Tag1-Human PD-L1 / B7-H1 Protein. When the donor antibody and the acceptor antibody are close due to the binding of PD-1 and PD-L1, the excitation of the donor antibody triggers the fluorescence resonance energy transfer to the acceptor antibody, which specifically emits light at 665nm. This specific signal is proportional to the degree of PD-1 / PD-L1 interaction. Therefore, compounds that block the PD-1 / PD-L1 interaction will result in a reduction in the HTRF signal.

[0336] The detailed procedures are as follows:

[0337] 1) Use DMSO to dilute the test compound 3-fold, with 10 concentrations, and the 11th concentration is a DMSO control without compound.

[0338] 2) The compound after gradient dilution was added into a 384 reaction plate (6008260, PerkinElmer) using ECHO, 100 nL / well, and each concentration gradient was repeated 2 times.

[0339] 3) Add 5 μL of PDL1 solution to the 384 reaction plate containing the compound and centrifuge at 1000 rpm for 1 min.

[0340] 4) Add 5 μL of PD1 solution, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 15 min.

[0341] 5) After incubation, add 10 μL of Anti-Tag1-Eu3+ and Anti-Tag2-XL665 mixture to each well and centrifuge at 1000 rpm for 1 min.

[0342] 6) Incubate at 25°C for 3 h.

[0343] 7) Use Envision multi-function plate reader to read the 665 / 615 nm ratio.

[0344] 8) The IC50 levels of the test compounds were calculated and analyzed using a four-parameter logistic regression model (4PL) of GraphPad Prism software.

[0345] Example 27 Cytological NFAT reporter gene experiment

[0346] Test method:

[0347] This experiment used Jurkat cells overexpressing PD-1 and luciferase reporter genes and CHO-K1 cells overexpressing PD-L1 to establish an experimental system for evaluating the binding of PD-1 and PD-L1 at the cellular level, which was used to evaluate the inhibitory effect of small molecule compounds or antibodies on the binding of PD-1 and PD-L1. This experiment used Bio-Glo reagent to detect and quantify the fluorescent product, thereby reflecting the inhibitory effect of different compounds.

[0348] The detailed procedures are as follows:

[0349] Day 1:

[0350] 1) Resuscitate PD-L1 aAPC / CHO-K1 cells. Place the cells in the cryopreserved tube in a centrifuge tube containing culture medium (F-12 + 10% FBS), centrifuge and discard the supernatant. Then resuspend the cells in culture medium (F-12 + 10% FBS) and count them, dilute the cells to 2.65*10 5 / mL.

[0351] 2) Add cells to a 384-well plate, 25 μL per well.

[0352] 3) Place the 384-well plate in a 37°C cell culture incubator containing 5% CO2 for 16-20 hours.

[0353] the next day:

[0354] 1) Compound dilution in DMSO: The test compound was diluted with DMSO to 3 mM. 3 mM was used as the first concentration, and 3-fold gradient dilutions were performed with DMSO, for a total of 10 concentration gradients.

[0355] 2) Take 2 μL of the above-mentioned gradient diluted samples and add them to a V-bottom dilution plate (Nunc, #249944) containing 18 μL of culture medium (RPMI-1640 culture medium + 1% FBS), and mix thoroughly.

[0356] 3) Take 2 μL of the sample diluted in 2) and add it to a V-bottom dilution plate (Nunc, #249944) containing 98 μL of culture medium (RPMI-1640 culture medium + 1% FBS), and mix thoroughly.

[0357] 4) The positive antibody Atezolizumab (10.11 mg / mL) was diluted to 4 μg / mL, i.e., 27.58 nM, with culture medium (RPMI-1640 culture medium + 1% FBS). 27.58 nM was used as the first concentration, and a 2.5-fold gradient dilution was performed with culture medium (RPMI-1640 culture medium + 1% FBS), for a total of ten concentration gradients.

[0358] 5) Take out the 384-well plate and remove the culture medium in the culture plate.

[0359] 6) Add 10 μL of the diluted compound to a 384-well plate and then culture in a cell culture incubator at 37° C. and 5% CO 2 for two hours.

[0360] 7) Resuscitate PD-1 cells, place the cells in the cryopreserved tube in a centrifuge tube containing culture medium (RPMI-1640 culture medium + 1% FBS), centrifuge and discard the supernatant. Then resuspend the cells in culture medium (RPMI-1640 culture medium + 1% FBS) and count them, dilute the cells to 8.75*10 5 / mL.

[0361] 8) Add cells to a 384-well plate, 10 μL per well.

[0362] 9) Place the 384-well plate in a 37°C cell culture incubator containing 5% CO2 for 17 hours.

[0363] 10) After 17 hours, add 20 μL Bio-Glo reagent to each well, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 5-30 minutes.

[0364] 11) Read the RLU value (relative luminescence unit) using the Envision multi-function plate reader. HTRF binding activity and cell test results: see Table 1

[0365] Table 1: Biological test results

[0366]

[0367]

[0368] NT means not tested.

[0369] From the biological activity data of the compounds in the specific examples, it can be seen that the series of compounds of the present invention have a strong inhibitory effect on the protein interaction of PD-1 / PD-L1 in both protein level and cell level experiments.

[0370] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the following specific structure: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases related to the inhibition of PD-1, PD-L1 and / or PD-1 / PDL1 interaction, characterized in that: The disease is cancer, and the cancer is selected from the group consisting of melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, head or neck cancer, rectal cancer, stomach cancer, testicular cancer, uterine cancer, cervical cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, thyroid cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, bladder cancer, primary central nervous system lymphoma, pituitary adenoma and Kaposi's sarcoma.

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