Novel tricyclic aromatic heterocyclic compounds, their preparation methods, pharmaceutical compositions and applications

Abstract

The present invention provides novel tricyclic aromatic heterocyclic compounds, and their preparation methods, pharmaceutical compositions and applications. Specifically, the present invention provides a compound represented by the following formula I, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the definitions of each group are as described in the specification. The compound of formula I can be used for the treatment of diseases associated with the PD-1 / PD-L1 signaling pathway. JPEG2022547201000180.jpg41163

Description

[Technical field]

[0001] The present invention relates to the field of small molecule drugs, specifically, the present invention provides small molecule compounds that can be used to treat diseases associated with the PD-1 / PD-L1 signaling pathway. [Background technology]

[0002] The immune system plays an important role in controlling and treating many diseases, including various cancers, diseases caused by viruses, etc. However, there are many ways that cancer cells can evade or inhibit the immune system through several pathways to proliferate rapidly. Here, one way is to modify the activating and inhibitory molecules expressed on immune cells. Blocking regulatory immune checkpoints such as PD-1 proves to be a very effective way to inhibit cancer cells.

[0003] PD-1 is programmed cell death protein-1, also known as CD279. It is mainly expressed on activated T cells and B cells, and its function is to inhibit cell activation, which is a normal homeostatic mechanism of the immune system, and excessive T / B cell activation can cause autoimmune diseases, so PD-1 is the body's defense wall. PD-1 is a type I transmembrane glycoprotein consisting of 268 amino acids, and its structure mainly includes the outer immunoglobulin variable region, the hydrophobic transmembrane region and the intracellular region. The intracellular region contains an immunoreceptor tyrosine inhibitory motif and an immunoreceptor tyrosine switch motif, which also proves that PD-1 can inversely regulate signaling through the T cell receptor. PD-1 has two ligands, PD-L1 and PD-L2, and their expression is different. PD-L1 is upregulated in various tumor cells, binds to PD-1 on T cells, inhibits T cell proliferation and activation, puts T cells into an inactivated state, and ultimately induces immune evasion.

[0004] PD-1 / PD-L1 plays an inverse immunoregulatory role. After binding of PD-1 and PD-L1, it can cause tyrosine polyphosphorylation at the immunoreceptor tyrosine switch motif domain in T cells, and the phosphorylated tyrosine can bind to the phosphatases protein tyrosinase 2 and protein tyrosinase 1. This controls T lymphocyte proliferation and the secretion of related cytokines by blocking the activation of extracellular signal-regulated kinase and further blocking the activation of phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (Akt). PD-1 / PD-L1 signaling inhibits T cell activation and proliferation while simultaneously inducing the secretion of cytokines interleukin-2, interferon-gamma, and IL-10. In addition, PD-1 / PD-L1 signaling also has a similar immune function on B cells, and after PD-1 binds to the B cell antigen receptor, the cytoplasmic region of PD-1 blocks B cell activation by interacting with the protein tyrosinase, which contains a tyrosinase 2-binding site.

[0005] PD-1 / PD-L1-based immunotherapy is a new generation of immunotherapy that has attracted much attention. In recent years, a series of surprising research results have confirmed that PD-1 / PD-L1 inhibitors have strong antitumor activity against various tumors. Currently available PD-1 / PD-L1 antibody modulators include Ninolumab from BMS, Lambrolizumab from Merck, and Atezolizumab from R℃he. In addition, CuR e A number of PD-1 / PD-L1 antibody modulators are in development, including Tech's pidilizumab, GSK's AMP-224 and AstraZeneca's MEDI-4736.

[0006] Tumor immunotherapy is considered to be a new generation revolution in cancer treatment after targeted therapy. However, the currently marketed and researched PD-1 monoclonal antibodies have their own defects, including that they can only be administered by injection, cannot be taken orally, are minutely stable in the body, are easily degraded by proteases, are prone to immune cross-reaction, are difficult to purify, have high production costs, etc. Therefore, small molecule modulators of PD-1 / PD-L1 interaction are a better option for tumor immunotherapy. In summary, there is an urgent need in the art to develop novel small molecule modulators of the PD-1 / PD-L1 interaction. Summary of the Invention [Problem to be solved by the invention]

[0007] It is an object of the present invention to provide novel small molecule modulators of the PD-1 / PD-L1 interaction. [Means for solving the problem]

[0008] A first aspect of the present invention provides a compound as shown in formula I below, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof: [ka] where n is 0, 1, 2, 3, 4 or 5; m, p, q, t, v and u are each independently selected from 0, 1, 2, 3 and 4; X1, X2, X3, X4, X5 and X6 are each independently selected from the group consisting of N, O, S, SO, SO2, C(R)2, CHR and NR; Y1, Y2, Y3, Y4, Y5 and Y6 are each independently selected from the group consisting of N, CH and C;

[0009] wherein hydrogens (if present) on carbon atoms of X3, X4, X5, X7, X8, and X9 can each independently be replaced by deuterium; [ka] each independently represents a substituted or unsubstituted C6-C 10 an arylene group, or a substituted or unsubstituted 5- to 12-membered (preferably 5- to 7-membered) heteroarylene group having 1 to 3 heteroatoms; a substituted or unsubstituted 5- to 12-membered heterocyclylene group; a substituted or unsubstituted 5- to 12-membered C3-C 12 (Preferably C5-C 12 ) cycloalkylene groups; [ka] is a substituted or unsubstituted 5- to 12-membered heteroaryl group, a substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted 5-12 membered C3-C 12 (Preferably C5-C 12 ) cyclic groups, wherein the heterocyclic group has 1 to 3 heteroatoms;

[0010] L1 is a chemical bond, a substituted or unsubstituted C1-C4 alkylene group, a substituted or unsubstituted C2-C4 alkenylene group, a substituted or unsubstituted C2-C4 alkynylene group, -S-, -O-, a substituted or unsubstituted -NH-, -S(O)-, -S(O)2-, a substituted or unsubstituted -NHC(O)NH-, [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] is selected from the group consisting of [ka] represents a single or double bond,

[0011] R, R1, R2, R3, R4 and R5 each independently represent H, -CN, a trifluoromethyl group, -CHF2, -OCF3, -OCHF2, sulfonamide, a nitro group, a hydroxyl group, a halogen, -S-R8, -S(O)-R8, -S(O)2-R8, a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C3-C8 cycloalkyl groups, oxo (i.e., =O), =NRf, -CN, hydroxyl groups (herein, two substituents are reserved), NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amine group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl group, substituted or unsubstituted C6-C 10 aryl groups, substituted or unsubstituted 5-12 membered heteroaryl groups having 1-3 heteroatoms, and substituted or unsubstituted 3-12 membered heterocyclic groups having 1-4 heteroatoms, wherein 10 Alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C3-C8 cycloalkyl groups, oxo (i.e., =O), =NRf, hydroxyl groups, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amine group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl group, substituted or unsubstituted C6-C 10All hydrogen atoms on the carbon atoms of the aryl group, the substituted or unsubstituted 5- to 12-membered heteroaryl group having 1 to 3 heteroatoms, and the substituted or unsubstituted 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms can be independently removed by deuterium, and the substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] (Please change the structural formula here) Change, [ka] In the formula, Rb and Rc are each independently selected from the group consisting of H and a substituted or substituted C1-C8 alkyl group; or Rb and Rc, together with the adjacent N atom, form a substituted or unsubstituted 3- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; or Rb and Rc, together with the adjacent N atom, form a substituted or unsubstituted 4- to 10-membered ring, and the substituents include, but are not limited to, a hydroxyl group, a carboxyl group, a mercapto group, an amino group, F, and C; and d All hydrogens on the carbon atoms of can be independently replaced by deuterium or -(L 1a ) r -(L 2a ) s -(L 3a ) s -, -C 0-8 -O-R8, -C 0-8 -C(O)OR8, -C 0-8 -OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9,

[0012] R8 and R9 are each independently H, a hydroxyl group, or a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C3-C8 cycloalkyl groups, oxo (i.e., =O), =NRf, -CN, hydroxyl groups, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amine group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5- to 12-membered heteroaryl group having 1 to 3 heteroatoms, substituted or unsubstituted 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms, substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Or -(L 1a ) r -(L 2a ) s -(L 3a ) s - selected from the group consisting of

[0013] Each L 1a are each independently a group selected from the group consisting of a chemical bond, a substituted or unsubstituted C1-C7 alkylene group, a substituted or unsubstituted C2-C4 alkenylene group, a substituted or unsubstituted C2-C4 alkynylene group, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, or -S(O)2-; L 2a is a substituted or unsubstituted C6-C 12selected from the group consisting of an arylene group, a substituted or unsubstituted 5- to 12-membered heteroarylene group having 1 to 3 heteroatoms, a substituted or unsubstituted C3-C8 cycloalkylene group, and a substituted or unsubstituted 3- to 10-membered heterocyclylene group having 1 to 3 heteroatoms; L 3a is a substituted or unsubstituted C1-C 10 Alkyl groups, C1-C 10 Aryl group, -CN, hydroxyl group, amino group, carboxyl group, -CO-NH-SO2-Rg, -NH-SO2-Rg, -SO2-NH-CO-Rg, -ORg, -N(R g )2-CO2Rg, -CON(Rg)2, -CONHCORg, NRg-CO-N(Rg)2, -NRg-SO2-N(Rg)2;

[0014] r is 1, 2, 3, 4, 5, 6, s is 0, 1, and 2, respectively. R d , R e and Rg are each independently H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted C6-C 10 aryl groups or R d and R e together form a substituted or unsubstituted 4- to 10-membered (preferably 5- to 10-membered) heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; R f is H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, cyano groups, -C(=O)-NR d R e , -C(=O)-substituted or unsubstituted C1-C6 alkoxy group, -C(=O)-substituted or unsubstituted C1-C6 alkyl group, -C(=O)-substituted or unsubstituted C3-C 10a cycloalkyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkenyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkynyl group;

[0015] Unless otherwise specified, the above "substitution" includes halogen (including -F, -Cl, -Br, -I), -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, oxo (=O), -CN, hydroxyl group, amino group, C1-C6 alkylamine group, carboxyl group, -NHAc, [ka] C1-C6 alkyl groups, C1-C6 alkoxy groups, C6-C 10 Aryl groups, C3-C8 cycloalkyl groups, halogenated C6-C 10 It refers to being substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of an aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O, and a 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S, and O, wherein the substituents are selected from the group consisting of halogen, a hydroxyl group, a carboxyl group, an oxy group, a cyano group, a C1-C6 alkoxy group, and a C1-C6 alkylamine group; In each of the above formulas, any of the heteroatoms are selected from the group consisting of B, P, N, S and O.

[0016] In another preferred embodiment, when both A and L are absent, B is a substituted or unsubstituted C6-C 10 an aryl group, or a substituted or unsubstituted 5- to 12-membered (preferably 5- to 7-membered) heteroaryl group having 1 to 3 heteroatoms; a substituted or unsubstituted 5- to 12-membered heterocyclic group; a substituted or unsubstituted 5- to 12-membered C3-C 12 (Preferably C5-C 12 ) a group selected from the group consisting of cycloalkyl groups.

[0017] In another preferred embodiment, the compound of formula I has the structure shown in the following formula: [ka]

[0018] In another preferred embodiment, the present invention provides a compound according to formula I, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof: [ka] where n is 0, 1, 2 or 3; m, p, q, and t are each independently selected from 0, 1, 2, 3, or 4; X1, X2, X3, X4, X5 and X6 are each independently selected from the group consisting of N, O, S, SO, SO2, C(R)2 and NR; Y1, Y2, Y3, Y4, Y5 and Y6 are each independently selected from the group consisting of N, CH and C; [ka] each independently represents a substituted or unsubstituted C6-C 10 an arylene group, or a substituted or unsubstituted 5- to 12-membered (preferably 5- to 7-membered) heteroarylene group having 1 to 3 heteroatoms; a substituted or unsubstituted 5- to 12-membered heterocyclylene group; a substituted or unsubstituted 5- to 12-membered C5-C 12 cycloalkylene groups; [ka] is a substituted or unsubstituted 5- to 12-membered heteroaryl group, a substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted 5-12 membered C5-C 12 wherein the heterocyclic group has 1 to 3 heteroatoms;

[0019] L1 is a chemical bond, a substituted or unsubstituted C1-C4 alkylene group, a substituted or unsubstituted C2-C4 alkenylene group, a substituted or unsubstituted C2-C4 alkynylene group, -S-, -O-, a substituted or unsubstituted -NH-, -S(O)-, -S(O)2-, a substituted or unsubstituted -NHC(O)NH-, [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] is selected from the group consisting of

[0020] R, R1, R2, R3, R4 and R5 each independently represent H, -CN, a trifluoromethyl group, a sulfonamide group, a nitro group, a hydroxyl group, a halogen, -S-R8, -S(O)-R8, -S(O)2-R8, a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C3-C8 cycloalkyl groups, oxo (i.e., =O), =NRf, -CN, hydroxyl groups, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amine group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkyl group), carboxyl group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5- to 12-membered heteroaryl group having 1 to 3 heteroatoms, substituted or unsubstituted 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms, substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Or -(L 1a ) r -(L 2a ) s -(L 3a ) s -, -C 0-8 -O-R8, -C 0-8 -C(O)OR8, -C 0-8 -OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9;

[0021] R8 and R9 are each independently H, a hydroxyl group, or a substituted or unsubstituted C1-C 10 Alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C3-C8 cycloalkyl groups, oxo (i.e., =O), =NRf, -CN, hydroxyl groups, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amine group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5- to 12-membered heteroaryl group having 1 to 3 heteroatoms, substituted or unsubstituted 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms, substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Or -(L 1a ) r -(L 2a ) s -(L3a ) s - selected from the group consisting of

[0022] Each L 1a are each independently a group selected from the group consisting of a chemical bond, a substituted or unsubstituted C1-C7 alkylene group, a substituted or unsubstituted C2-C4 alkenylene group, a substituted or unsubstituted C2-C4 alkynylene group, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, or -S(O)2-; L 2a is a substituted or unsubstituted C6-C 12 selected from the group consisting of an arylene group, a substituted or unsubstituted 5-12 membered heteroarylene group having 1 to 3 heteroatoms, a substituted or unsubstituted C3-C8 cycloalkylene group, and a substituted or unsubstituted 5-10 membered heterocyclylene group having 1 to 3 heteroatoms; L 3a is a substituted or unsubstituted C1-C 10 Alkyl groups, C1-C 10 selected from the group consisting of an aryl group, -CN, a hydroxyl group, an amino group, a carboxyl group, -CO-NH-SO2-Rg, -NH-SO2-Rg, and -SO2-NH-CO-Rg;

[0023] r is 1, 2, 3, 4, 5, 6, s is 0, 1, and 2, respectively. R d , R e and Rg are each independently H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted C6-C 10 aryl groups or R d and R e taken together form a substituted or unsubstituted 5- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; R f is H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted C6-C10 Heteroaryl groups, cyano groups, -C(=O)-NR d R e , -C(=O)-substituted or unsubstituted C1-C6 alkoxy group, -C(=O)-substituted or unsubstituted C1-C6 alkyl group, -C(=O)-substituted or unsubstituted C3-C 10 a cycloalkyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkenyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkynyl group;

[0024] Unless otherwise specified, the term "substituted" refers to any of the following: halogen, including but not limited to -F, Cl, Br, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, oxo, -CN, hydroxyl group, amino group, C1-C6 alkylamine group, carboxyl group, -NHAc, C1-C6 alkyl group that is unsubstituted or substituted by one or more substituents, C1-C6 alkoxy group, C6-C 10 Aryl groups, C3-C8 cycloalkyl groups, halogenated C6-C 10 It refers to being substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of an aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O, and a 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S, and O, wherein the substituents are selected from the group consisting of halogen, a hydroxyl group, a carboxyl group, a cyano group, a C1-C6 alkoxy group, and a C1-C6 alkylamine group; In each of the above formulas, any of the heteroatoms are selected from the group consisting of B, P, N, S and O.

[0025] In another preferred embodiment, [ka] are each independently [ka] wherein the attachment point of said ring can be N or C (substituents on the ring are not shown). In another preferred example, R2 and R3 are each independently selected from the group consisting of a methyl group, -F, Cl, Br, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, -CN, a hydroxyl group, and an amino group.

[0026] In another preferred embodiment, [ka] The binding position of may be o, p or m position. In another preferred embodiment, [ka] At the bonding position, the H connected to the N or C is replaced by a bond. In another preferred embodiment, [ka] is the structure shown below. [ka]

[0027] In another preferred embodiment, [ka] has the structure shown in the formula: [ka] Where: X6, X7, X8, X9, X 10 and X 11 are each independently selected from the group consisting of N and CR; R6 is H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, oxo (i.e., =O), =NRf, -CN, a hydroxyl group, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amine group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5- to 12-membered heteroaryl group having 1 to 3 heteroatoms, substituted or unsubstituted 5- to 12-membered heterocyclic group having 1 to 4 heteroatoms, substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Substituted or unsubstituted [ka] Or -(L 1a ) r -(L 2a ) s -(L 3a ) s -, -C 0-8 -O-R8, -C 0-8 -C(O)OR8, -C 0-8 -OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9.

[0028] In another preferred embodiment, [ka] etc., where the attachment point of the ring can be N or C (substituents on the ring are not shown). In another preferred embodiment, R6 is R1 or [ka] wherein Rb and Rc are each independently selected from the group consisting of H and a substituted or unsubstituted C1-C8 alkyl group, or Rb and Rc, together with the adjacent N atom, form a substituted or unsubstituted 3- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O.

[0029] In another preferred embodiment, the ring [ka] has the substituents shown in formula IV: [ka] where w is 0, 1, 2, 3, 4, 5, or 6; each L4 is independently selected from the group consisting of a substituted or unsubstituted C1-C4 alkylene group, -S-, -O-, NRf, -S(O)-, -S(O)2-, preferably a substituted or unsubstituted C1-C4 alkylene group, in which all hydrogens on carbon atoms of the substituted or unsubstituted C1-C4 alkylene group can be independently replaced by deuterium, provided that the structure jointly formed by each L4 is chemically stable; [ka] is a substituted or unsubstituted C3-C 10 cycloalkyl groups, and substituted or unsubstituted 3- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from B, P, N, S and O. [ka] is a substituted or unsubstituted 3- to 8-membered nitrogen-containing heterocyclic group, or a substituted or unsubstituted 4- to 10-membered cyclic amide group, in which all hydrogens on ring-forming carbon atoms of the 3- to 8-membered nitrogen-containing heterocyclic group or the substituted or unsubstituted 4- to 10-membered cyclic amide group can each independently be replaced by deuterium; Each R7 is independently selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, -CN, a hydroxyl group, an amino group, a carboxyl group, -ORg, -N(Rg)2, -CO-NH-SO2-Rg, -NH-SO2-Rg, -SO2-NH-CO-Rg, -CO2Rg, -CON(Rg)2, CONHCORg, NRg-CO-N(Rg)2, -NRg-SO2-N(Rg)2, where Rf and Rg are as defined above, and where all hydrogens on the carbon atoms of Rf and Rg can each independently be replaced by deuterium, and where the substituents are selected from the group consisting of halogens, hydroxyl groups, carboxyl groups, cyano groups, and C1-C6 alkoxy groups.

[0030] In another preferred embodiment, at least one R4 is NR d R e wherein R d and R e are each independently H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, -C 0-8 -O-R8, -C 0-8 -C(O)OR8, -C 0-8 -OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9, substituted or unsubstituted C6-C 10 aryl groups or R d and R e taken together form a substituted or unsubstituted 3- to 10-membered cycloalkyl group, or a 3- to 10-membered heterocyclic group having 1 to 3 substituted or unsubstituted heteroatoms selected from N, S and O.

[0031] In another preferred embodiment, the substituents described herein are carboxyl groups, hydroxyl groups, [ka] and R 10 represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 A cycloalkyl group, preferably R 10 is a methyl group, an isopropyl group, a cyclopropyl group, and a 1-methylcyclopropyl group, where R d , R e and R 10 All hydrogens on the carbon atoms of can each independently be replaced by deuterium.

[0032] In another preferred embodiment, the ring [ka] has the substituents shown in formula IV: [ka] wherein each L4 is independently selected from the group consisting of a substituted or unsubstituted C1-C4 alkylene group, -S-, -O-, -NRa-, -NRf, -S(O)-, -S(O)2-, preferably a substituted or unsubstituted C1-C4 alkylene group, with the prerequisite that the structure jointly formed by each L4 is chemically stable; [ka] is a substituted or unsubstituted C5-C 10 cycloalkyl groups, and substituted or unsubstituted 3- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from B, P, N, S and O. [ka] is a 3- to 8-membered nitrogen-containing heterocyclic group, Each R7 is independently selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, -CN, a hydroxyl group, an amino group, a carboxyl group, -ORg, -N(Rg)2, -CO-NH-SO2-Rg, -NH-SO2-Rg, -SO2-NH-CO-Rg, -CO2Rg, -CON(Rg)2, CONHCORg, NRg-CO-N(Rg)2, -NRg-SO2-N(Rg)2, where the substituents are selected from the group consisting of halogens, hydroxyl groups, carboxyl groups, cyano groups, and C1-C6 alkoxy groups.

[0033] In another preferred embodiment, at least one R4 is NR d R e wherein R d and R e are each independently H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, -C 0-8 -O-R8, -C 0-8 -C(O)OR8, -C 0-8 -OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9, substituted or unsubstituted C6-C 10 aryl groups or R d and R e taken together form a substituted or unsubstituted 3- to 10-membered cycloalkyl group, or a 3- to 10-membered heterocyclic group having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of N, S, and O. In another preferred embodiment, the substituents described herein are carboxyl groups, hydroxyl groups, [ka] and R 10 represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10A cycloalkyl group, preferably R 10 is a methyl group, an isopropyl group, a cyclopropyl group, and a 1-methylcyclopropyl group, where R d , R e and R 10 All hydrogens on the carbon atoms of can each independently be replaced by deuterium.

[0034] In another preferred embodiment, the compound of formula I has the structure shown in the following formula: [ka] In another preferred embodiment, at least one of the R4 is NR d R e wherein R d and R e are each independently H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups, -C 0-8 -O-R8, -C 0-8 -C(O)OR8, -C 0-8 -OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9, substituted or unsubstituted C6-C 10 aryl groups or R d and R e together form a substituted or unsubstituted 5- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O, and preferably said substituent is a carboxyl group.

[0035] In another preferred embodiment, [ka] is a structure selected from the group consisting of: [ka]

[0036] In another preferred embodiment, the compound is selected from the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0037] A second aspect of the present invention provides a method for preparing a compound of formula I according to the first aspect of the present invention, said method comprising steps selected from those shown in synthetic schemes 1, 2 or 3, [ka] (a) intermediates II and III are used as raw materials to obtain the target product I-1 by Sonogashira coupling reaction catalyzed by palladium catalyst; Preferably, the process for preparing intermediate II-2 is as follows: [ka] (a) Using II-1 as a raw material, a halogenation reaction is carried out under the catalytic action of a Lewis acid to obtain intermediate II-2; Preferably, the process for preparing intermediate III is as follows: [ka] (a) Compounds III-1 and III-2 are used as raw materials to carry out a coupling reaction (e.g., Suzuki, Buchwald, etc.) under palladium catalyst and ligand conditions to obtain intermediate III-3; (b) using III-3 as starting material, removing the silicon-based protecting group using an appropriate reagent to give intermediate III; [ka] (a) Compound II-1 is used as a raw material and reacted with a nitrating agent (e.g., concentrated sulfuric acid / NaNO3, concentrated sulfuric acid / fuming nitric acid, etc.) to form intermediate IV-1; (b) Using IV-1 as a raw material, a reduction reaction is carried out under reducing conditions (Pd-C / H2, zinc powder / ammonium chloride, iron powder / acetic acid, etc.) to form intermediate IV-2; (c) Using IV-2 and IV-3 as starting materials, an affinity displacement reaction takes place under basic conditions to give an amide intermediate, which is then cyclized under a suitable dehydrating agent (e.g., PPh3 / DDQ) to give intermediate IV-4; (d) Using IV-4 and IV-5 as raw materials, a coupling reaction takes place under catalytic and ligand conditions to form intermediate I-2; [ka] (a) Using V-1 and V-2 as raw materials, a coupling reaction takes place under catalytic and ligand conditions to form intermediate V-3; (d) coupling reaction using IV-4 and a suitable boron source (e.g., B2PiN2) as starting materials under catalytic and ligand conditions to form intermediate V-4; (d) Using V-4 and IV-4 as raw materials, a coupling reaction takes place under catalytic and ligand conditions to form the target product I-3; X1~X above 12, R1 to R9, t, m and n are as defined above.

[0038] A third aspect of the present invention provides a pharmaceutical composition comprising: (1) a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof; and (2) a pharma- ceutically acceptable vector. A fourth aspect of the present invention provides the use of a compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the third aspect of the present invention, for use in the preparation of a pharmaceutical composition for the prophylaxis and / or treatment of a disease associated with the activity or expression level of PD-1 / PD-L1 (such as HBV, HCV, solid tumors, hematological tumors, etc.). A fifth aspect of the invention provides a PD-1 / PD-L1 modulator, said modulator comprising a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0039] In another example, the pharmaceutical composition is used to treat a disease selected from the group consisting of cancer, an infectious disease, and an autoimmune disease. In another example, the cancer is selected from the group consisting of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, skin cancer, lung cancer, urological tumors, hematological tumors, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, and head and neck cancer. In another preferred embodiment, the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myelogenous leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma (DLBCL). In another example, the infection is selected from a bacterial infection, a viral infection.

[0040] In another example, the autoimmune disease is selected from an organ-specific autoimmune disease, a systemic autoimmune disease. In another example, the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritic syndrome, primary biliary cirrhosis, multiple cerebral sclerosis, and acute idiopathic polyneuropathy. In another example, the systemic autoimmune disease includes rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, penumbra, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia. In another example, the pharmaceutical composition is used to improve T cell function in patients with chronic hepatitis B (CHB). In another example, the inhibitor further comprises at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, or ipilimumab. A sixth aspect of the invention provides a method of modulating PD-1 / PD-L1 interaction in vivo, comprising contacting a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, with a PD-L1 protein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] After extensive and detailed research, the present inventors have discovered a class of PD-1 / PD-L1 interaction modulators with excellent regulatory effects, and based on this, the present inventors have completed the present invention. definition As used herein, the term "alkyl group" includes straight or branched chain alkyl groups. For example, a C1-C8 alkyl group refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, and the like. As used herein, the term "alkenyl group" includes straight-chain or branched-chain alkenyl groups. For example, a C2-C6 alkenyl group refers to a straight-chain or branched-chain alkenyl group having from 2 to 6 carbon atoms, such as a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, or a similar group. As used herein, the term "alkynyl group" includes straight-chain or branched-chain alkynyl groups. For example, a C2-C6 alkynyl group refers to a straight-chain or branched-chain alkynyl group having from 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or a similar group. As used herein, "C3-C 10 The term "cycloalkyl group" refers to a cycloalkyl group having from 3 to 10 carbon atoms. It may be monocyclic, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar group. It may be bicyclic, such as bridged or spiro.

[0042] As used herein, the term "C1-C8 alkylamino group" refers to an amine group substituted with a C1-C8 alkyl group, which may be mono- or di-substituted, such as a methylamine group, ethylamine group, propylamine group, isopropylamine group, butylamine group, isobutylamine group, t-butylamine group, dimethylamine group, diethylamine group, dipropylamine group, diisopropylamine group, dibutylamine group, diisobutylamine group, di-t-butylamine group. As used herein, the term "C1-C8 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a isobutoxy group, a t-butoxy group, and the like. As used herein, the term "3-10 membered heterocyclic alkyl group having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or bicyclic, for example, in a bridged or spiro form. Specific examples may include oxetane, azetidine, tetrahydro-2H-pyranyl group, piperidinyl group, tetrahydrofuranyl group, morpholinyl group and pyrrolidinyl group.

[0043] As used herein, "C6-C 10 The term "aryl group" refers to an aryl group having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group or the like. As used herein, the term "5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic or fused ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl groups, tetrazolyl, furyl, thienyl, isoxazolyl, thiazole, oxazolyl, etc. Unless the group described in the present invention is specifically stated to be "substituted or unsubstituted", all groups in the present invention are substituted or unsubstituted with halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6 alkyl-amino group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, halogenated C1-C6 alkyl group, halogenated C2-C6 alkenyl group, halogenated C2-C6 alkynyl group, halogenated C1-C6 alkoxy group, allyl group, benzyl group, C6-C 12 It may be substituted by a substituent selected from the group consisting of an aryl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkoxy-carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl-carbonyl group, a C2-C6 alkenyl-carbonyl group, a C3-C6 cycloalkyl-carbonyl group, a C1-C6 alkyl-sulfonyl group, and the like.

[0044] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" refers to substitution by an atom selected from F, Cl, Br, and I. Unless otherwise indicated, the structural formulae depicted in the present invention are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric (or conformational) isomers), e.g., R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Thus, all individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric (or conformational) isomers are within the scope of the present invention. Unless otherwise stated, the structural formulae depicted in this invention are intended to include all possible deuterated derivatives (ie, where one or more hydrogen atoms in the molecule are replaced by D). As used herein, the term "tautomer" refers to structural isomers that have different energies and can interconvert across a low energy barrier. For example, proton tautomers (i.e., protonated) include interconversions via migration of a proton, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversions via recombination of some of the bond electrons. As used herein, the term "solvate" refers to a complex in which a compound of the invention coordinates with solvent molecules to form a complex in a specific ratio. As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0045] Active ingredient As used herein, "compounds of the invention" refers to compounds according to Formula I, and further includes various crystalline forms, pharma- ceutically acceptable salts, hydrates or solvates of the compounds of Formula I. Preferred compounds of the present invention include compounds 1-360 (the various R- and / or S-configured stereoisomers, and / or E- / Z-cis-trans isomers of each compound). In another example, the pharma- ceutically acceptable salts include salts formed in combination with inorganic acids, organic acids, alkali metal ions, alkaline earth ions, or organic bases which provide a physiologically acceptable cation, as well as ammonium salts. In another example, the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, medullic acid, maleic acid, tartaric acid, fumaric acid, citric acid, or lactic acid, the alkali metal ion is selected from lithium ion, sodium ion, or potassium ion, the alkaline earth ion is selected from calcium ion or magnesium ion, and the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholino, or tris(2-hydroxyethyl)amine. All of these salts within the scope of the present invention can be prepared using conventional methods. In the preparation process of the compounds of formula I and their solvates and salts, polymorphism or co-crystallization may occur under different crystallization conditions. The starting materials and intermediates in the preparation method of the present invention are easily obtained, and the reaction of each step can be easily synthesized according to the reported literature or by conventional methods in organic synthesis for those skilled in the art.The compound shown in formula I can exist in solvated or nonsolvated form, and different solvates can be obtained by crystallization from different solvents.

[0046] Pharmaceutical Compositions and Methods of Administration Because the compounds of the present invention have excellent PD-1 / PD-L1 interaction modulating activity, the compounds of the present invention and their various crystal forms, pharma- ceutically acceptable inorganic salts or snow salts, hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as a main active ingredient, can be used for the prevention and / or treatment (stabilization, alleviation or cure) of PD-1 / PD-L1 interaction associated diseases (e.g., cancer, infectious diseases, autoimmune diseases). The pharmaceutical composition of the present invention contains the compound of the present invention and a pharma- ceutical acceptable excipient or vector within a safe and effective amount. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 10-200 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0047] "Pharmaceutically acceptable vector" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly decreasing the efficacy of the compounds of the present invention and among themselves. Some examples of pharma- ceutically acceptable vectors include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like. Water) etc. The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral and parenteral (intravenous, intramuscular or subcutaneous).

[0048] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as, for example, sodium citrate or dicalcium phosphate, or with other suitable carriers such as: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate. (e) a disintegrant such as paraffin (R e taR d The pharmaceutical composition is mixed with ingredients such as (i) an aqueous sorbent, (ii) an aqueous sorbent such as an aqueous sorbent, (iii) an aqueous sorbent such as an aqueous sorbent, (iv) an aqueous sorbent such as an aqueous sorbent, (v) an aqueous sorbent such as an aqueous sorbent, (vi) an aqueous sorbent such as an aqueous sorbent, (vii) an aqueous sorbent such as an aqueous sorbent, (viii) an aqueous sorbent such as an aqueous sorbent, (ix) an aqueous sorbent such as an aqueous sorbent, (x) an aqueous sorbent such as an aqueous sorbent, (xii) an aqueous sorbent, (xiii) an aqueous sorbent, (xiv) an aqueous sorbent, (xv) an aqueous sorbent, (xvi ...

[0049] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0050] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances. Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. The compounds of the present invention can be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, other anti-cancer agents). When administered in combination, the pharmaceutical composition further comprises one or more species (two, three, four or more species) of other pharma- ceutically acceptable compounds, which may be used simultaneously, separately or sequentially with the compounds of the present invention for use in the prevention and / or treatment of diseases associated with PD-1 / PD-L1 interaction. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dosage at the time of administration is a pharmacologic effective dosage, and for a human weighing 60 kg, the daily dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should further take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0051] The main advantages of the present invention are: (1) The compounds of the present invention have high regulatory activity on PD-1 / PD-L1 interaction, strong binding ability to PD-L1 protein, and the ability to alleviate IFNγPD-L1 inhibition. (2) The compounds of the present invention have better solubility and very low toxicity to normal cells, so that they can be applied to a wide range of doses for treatment of the target. (3) Compared with the compounds of the prior art, the compounds of the present invention have better solubility, and therefore have good drug discoverability; compared with the existing compounds, the compounds of the present invention show better bioavailability in in vivo experiments; in addition, compared with the existing compounds, the compounds of the present invention can be easily made into pharma- ceutically acceptable salts, which is further conducive to formulation into formulations. (4) In vivo pharmacodynamic studies show that the compounds of the present invention can significantly inhibit the growth of subcutaneous tumors in terms of tumor volume and weight, and significantly increase the number of each lymphocyte in the blood and spleen of mice. The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight percentages and parts by weight. Experimental materials and reagents used in the following examples are available from commercial channels unless otherwise stated.

[0052] Common materials and test methods: The equipment and materials referred to in the examples are as described below. 1 H NMR spectra were obtained using a Bruker AV-400 (400 MHz) NMR analyzer. Chemical shifts were recorded using tetramethylsilane as internal standard and are expressed in ppm (CDC13: δ 7.26 ppm). The recorded data information is: chemical shifts and their splittings and coupling constants (s: singlet, d: doublet, t: triplet, q: quartet, br: broad peak, m: multiplet). All mass spectral data, unless otherwise required, are analyzed using LC / MS on a Finnigan LCQ Advantage and all reactions are carried out under anhydrous and oxygen-free conditions under dry argon gas protection. Solid metal-organic compounds are stored in a dry box under argon gas protection. Tetrahydrofuran and the ethers are obtained by distillation with the addition of sodium metal and benzophenone. Dichloromethane, pentane and hexane are treated with calcium hydride. The special raw materials and intermediates mentioned in this invention are provided by customized processing such as Tianjin Changsen Pharmaceutical Co., Ltd., and all other chemical reagents are purchased from reagent suppliers such as Shanghai Chemical Reagent Company, Aldrich, Acros, etc. If the intermediates or products required for the reaction in the synthesis process are not enough for the next stage test, the synthesis is repeated several times until there are enough. Unless otherwise specified, the raw materials and reagents referred to in the present invention can be purchased commercially or through customized processing. The compounds of the present invention may contain one or more asymmetric centers, so that the series of compounds may be in racemic or single enantiomeric form. The compounds prepared in the present invention are heterocyclic compounds with a purity of more than 95%, and the structural characteristics of each final product are characterized by MS or / and hydrogen spectroscopy nuclear magnetic resonance (NMR) spectroscopy, respectively. 1 The synthesis of various compounds and intermediates of the present invention is described below through the examples.

[0053] Example 1. Synthesis of Compound 001 [ka] Dissolve 1.3g of 1-1 in 200mL of DCM-3M H2SO4 (1:1), add 0.71g of sodium nitrite to the reaction system under ice bath at 5℃, and react overnight at room temperature under nitrogen gas protection. TLC spot plate shows disappearance of 1-1, LCMS analysis shows the product is generated. Purify by column chromatography to obtain 600mg of product 1-2, MS-APCI: 208[M+H] + and 300mg of 1-3, MS-APCI: 208[M+H] + . get.

[0054] [ka] Dissolve 4.5g of compound 1-2 in 200mL of DCM (in a 500mL single-neck flask), add 6.3g of NIS, and protect with argon gas. Allow to react overnight at room temperature. Detect the completion of the reaction of 1-2 by TLC spot plate. Add 100ML of 2M HCl to the reaction solution, separate the liquid, and dry. Spin dry and purify by column (Hep-DCM 1:1, then DCM) to obtain 6g of pale yellow solid product. MS-APCI: 334 [M+H] + .

[0055] [ka] 945mg of compound 1-4, 636mg of compound 1-5, 25mg of CuI and 25mg of Pd(PPh3)2Cl2 are added to a 50mL three-neck flask, and 20mL of DMF and 1.2mL of DIPEA are added under argon gas protection, and the mixture is reacted at 55℃ for 3 hours. The disappearance of the raw material is detected by TLC spot plate. The reaction solution is added to 300mL of ice water, extracted twice with 300mL of ethyl acetate, washed once with 2M NaOH, dried and spin-dried. The product is purified by column (DCM-MeOH 10:1) to obtain 220mg of pale yellow solid. MS-APCI: 654[M+H] + .

[0056] [ka] 215mg of compound 1-6, 248mg of methyl azetidine-3-carboxylate hydrochloride, 125mg of Na(CN)BH3 were dissolved in 10mL of THF, and 167mg of triethylamine was added under argon gas protection and reacted at 70℃ for 24 hours. The reaction solution was added to 100mL of ice water, extracted twice with 100mL of EA, and dried. The mixture was purified by column (DCM-MeOH 100, 50:1, 10:1, 5:1) to obtain 53mg of pale yellow solid 1-7. MS-APCI: 753[M+H] + .

[0057] [ka] 53mg of raw material 1-7 is dissolved in 5mL of MeOH, 2mL of 2M NaOH is added, and the mixture is reacted at 26℃ for 5 hours. The reaction solution is spin-dried at 40℃, 50mL of water is added to the residual solid, and the PH value is adjusted to 7 with 2M HCl. The solid is filtered, washed with water, washed with THF, dried, and further refined and purified to obtain 5mg of a yellow solid. MS-APCI: 739[M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.34(s, 1H), 9.00(s, 1H), 8.46(s, 1H), 8.34(d, J=8.0Hz, 1H), 8.08(d, J=8.0Hz, 1H), 7.77(d, J=8.0Hz, 1H), 7.44(t, J=8.0Hz, 1H), 7.35-7.25(m, 3H), 7.19(d, J=8.0Hz, 1H), 6.91(d, J=8.0 Hz, 1H), 6.52(m, 1H), 4.75(brs, 1H), 4.20(brs, 1H), 3.84-3.74(m, 2H), 3.37-2.83(m, 3H), 2. 66-2.28(m, 2H), 2.21(s, 3H), 2.18-2.06(m, 1H), 2.06(s, 3H), 1.96-1.58(m, 5H), 1.43(m, 1H).

[0058] [ka] Take the amino group raw material 1-9 (30 g) and dissolve it in 400 mL of acetonitrile-water (Water) (1:1). Under nitrogen gas protection, the system becomes clear. Add p-toluenesulfonic acid hydrate (901 g) under an ice bath at an internal temperature of 0-5 ° C. Stir for 10 minutes, the system becomes pink and cloudy, and add NaNO2 aqueous solution (22 g, 45 mL) dropwise at an internal temperature of 0-5 ° C. React for 30 minutes, the system becomes clear, protect from light, add potassium iodide aqueous solution (67 g, 60 mL) dropwise at 0-5 ° C., and react while naturally warming to room temperature. Monitor with TLC. Work-up: Add saturated sodium sulfite to quench under an ice bath, extract with HEP, wash once with saturated saline, stir the sample, pass through the column: wash the product with HEP, concentrate, obtain 46.9 g of yellow-brown liquid, yield: 98.1%. MS-APCI: 296 [M+H] + .

[0059] [ka] Take iodine raw material 1-10 (1g), CuI (0.03g), Pd(Ph3P)2Cl2 (0.12g), add to 50mL reaction flask, replace with nitrogen gas three times, add anhydrous DMF (20mL), the system becomes reddish brown and transparent, add triethylamine (1.7g), the system becomes brown and transparent, replace with nitrogen gas three times, protect from light, add alkyne raw material 1-11 (0.52g), react at room temperature, monitor by TLC, work-up: add saturated ammonium chloride under ice bath to quench, extract twice with MTBE, wash five times with saturated saline, stir the sample, pass through column: wash the product with HEP, concentrate, obtain 1.03g of yellow-brown liquid, yield: 95%. MS-APCI: 309 [M+H] + .

[0060] [ka] Bromine raw material 1-12 (1.1 g), borate raw material 1-14 (1 g, WO2018119286), Pd(dppf)Cl2 (0.12 g) and sodium carbonate (0.62 g) were taken and added to a 50 mL reaction flask, purged with nitrogen gas three times, 1,4-dioxane (8 mL) and 2 mL of water were added, reacted at 90 ° C, followed by TLC, post-treatment: quenched by adding saturated ammonium chloride under ice bath, extracted twice with MTBE, washed five times with saturated saline, stirred the sample, passed through a column: (HEP-DCM 100, 50:1, 10:1, 5:1) The product was washed and concentrated to obtain 0.5 g of yellow solid, yield: 41%. MS-APCI: 563 [M + H] + .

[0061] [ka] Add the alkyne raw material 1-15 (1.1 g) to THF (15 mL), replace with nitrogen gas three times, add 1 mL of 1M TBAF, react at room temperature, monitor by TLC, work-up: spin-dry THF, add 5 mL of water, extract twice with ethyl acetate, wash twice with saturated saline, stir the sample, pass through a column: (DCM-MeOH 100, 50:1, 10:1, 5:1) wash the product, concentrate to obtain 1.0 g of yellow solid, yield: 83%. MS-APCI: 449 [M+H] + .

[0062] Example 2. Synthesis of Compound 002 [ka] Phase 2-1: 1-1 (1.1 g) and sodium bicarbonate (0.57 g) are added to a 100 mL three-neck flask, and methanol (25 mL) and water (5 mL) are added to dissolve, and cooled to 5°C under ice bath. NIS (1.52 g) is slowly added, and after the entire addition, the temperature is naturally raised and the reaction is allowed to proceed overnight. The reaction completion of the raw materials is detected by TLC. Methanol is spin-dried, and 1 M hydrochloric acid is added to adjust the pH to <3, and a large amount of white solid precipitates. Filter, add the filter cake solid to 0.5 M hydrochloric acid (100 ML) and stir for 30 minutes, filter again, and dissolve the obtained filter cake solid in EA, and obtain 0.7 g of pale yellow / white solid product by column chromatography. MS-APCI: 289 [M+H] + .

[0063] Phase 2-2: In a 100mL two-neck flask, dissolve 2-1 (1.5g) in DMF (20mL), add Zn(CN)2 (1.3g) and Pd(PPh3)4 (1.2g), react under N2 protection at 105℃ for 1 hour, and detect the completion of the reaction of the raw materials by TLC spot plate. After cooling, add EA / HEP to the reaction solution to dilute and filter. Wash the filtrate with saturated NaCl and extract with EA. Purify by column to obtain 0.9g of pure product as yellow solid. MS-APCI: 188[M+H] + . Stage 2-3: In a 25mL two-neck flask, 2-2 (1.5g) was suspended in DCM (20mL), and NIS (2.0g) was added at room temperature, and the mixture was reacted for 10 minutes. The disappearance of the raw material was detected by TLC spot plate. Saturated NaHCO3 was added to the reaction solution, the aqueous phase was adjusted to pH=2, and the mixture was extracted with DCM three times. The DCM layer was washed with 10% Na2S2O3, dried, and spin-dried to obtain 1.9g of a brown solid product. MS-APCI: 314 [M+H] + .

[0064] Stages 2-4: In a 15mL reaction tube, 2-3 (1.6g), 2-4 (1.3g, WO2018195321), Pd(PPh3)2Cl2 (350mg), CuI (50mg), DIPEA (3g, 6.5mmol) are dissolved in DMF (8ML) and reacted under N2 protection at 85℃ for 2 hours. TLC detects the disappearance of raw materials. After the reaction is complete, the reaction solution is extracted with water / DCM. It is dried and spun dry. The residue is slurried with EA / HEP (20ML, 1:1). The obtained solid is purified by column and eluted with pure DCM to obtain 800mg of yellow solid product. MS-APCI: 355[M+H] + . Stages 2-5: In a 15 mL reaction tube, 2-5 (150 mg), 1-7 (135 mg), NaBH3CN (39 mg), TEA (83 mg) were added to THF (5 mL) and reacted at 70°C for 5 hours. The disappearance of 1-6 was detected by TLC. The reaction solution was spin-dried, water was added, and the mixture was extracted with EA. The EA was dried, spin-dried, and purified by column to obtain pure product 1-8 (120 mg) as a yellow solid. MS-APCI: 454 [M+H] + .

[0065] Stages 2-6: Compound 2-6 (100 mg), 1-14 (100 mg, WO2018119286), Pd(dppf)Cl2 / DCM (16.7 mg), Na2CO3 (57.2 mg) are added to a reaction flask, degassed with N2 to protect it, and 3ML of dioxane / 0.6ML of water is poured into the reaction flask and reacted at 90°C for 1 hour. The reaction completion is detected by TLC spot plate. 2mL of water is added to the reaction solution, and it is extracted with EA. EA is dried, spin-dried, and purified by column to obtain 80mg of yellow solid product. MS-APCI: 733 [M+H] + . Stages 2-7: Dissolve 2-7 (80 mg) in 2 mL of THF, add 2 mL of water, heat LiOH (7.8 mg) and react at room temperature for 1 h. Detect the completion of the reaction by TLC. Spin dry the reaction solution at 40°C, add 2M HCl to adjust the PH value to 7, filter the solid, wash with water, dry, and further refine and purify to obtain 50 mg of yellow solid. MS-APCI: 719 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.30(s, 1H), 8.84(d, J=2.0Hz, 1H), 8.43(d, J=8.1Hz, 1H), 8.16(d, J=1.9Hz, 1H), 8.04(d, J=5.8Hz, 1H), 7.84(s, 1H), 7.81(dd, J=7. 9, 1.3Hz, 1H), 7.46(t, J=7.7Hz, 1H), 7.32(t, J=7.9Hz, 1H), 7.29(d, J=1.3Hz, 1H), 7.26(dd, J=7.6, 1.3Hz, 1H), 7.16(d, J=5.8Hz, 1H) , 6.90(d, J=7.5Hz, 1H), 4.69(s, 1H), 4.20(s, 1H), 3.88-3.71(m, 2H), 3.50-3.39(m, 11H), 3.19-2.79(m, 3H), 2.76-2.58(m, 2H), 2.4 0-2.28(m, 1H), 2.22(s, 3H), 2.08(s, 3H), 2.00(dq, J=14.1, 7.4Hz, 1H), 1.87(d, J=12.8Hz, 1H), 1.71(s, 1H), 1.57(t, J=13.0Hz, 2H).

[0066] Example 3. Synthesis of Compound 003 [ka] Phase 3-1: Compound 3-1 (40 g, 230.7 mmol), 3-2 (58.5 g, 230.7 mmol, WO2012031004), Pd(dppf)Cl2 / DCM (10.2 g, 0.05 eq), Na2CO3 (53 g, 2 eq) are added sequentially to dioxane / H2O (300 mL, 5:1), degassed three times, reacted under N2 protection at 80 °C for 1 h, TLC shows reaction completion. Filter reaction solution, spin dry filtrate. Add EA to dissolve, add 500 mL of saturated saline to EA. Separate liquid. Dry EA layer, spin dry. Slurry the resulting solid with EA / HEP (200 mL, 1:3) and filter to obtain 40 g of yellow solid.

[0067] Phase 3-2: Dissolve 3-3 (66 g, 249 mmol) in 500 mL of THF, cool to 0° C., and add sodium methoxide solution (50 mL, 5N in MeOH) dropwise. After addition is complete, react at 0° C. for 30 minutes. Add 4N HCl / MeOH dropwise to the reaction solution at 0° C. to pH=7. Spin off the THF. Dissolve the residue in 1 L of DCM, add 2 L of water to wash, and separate the liquid. Dry the DCM layer. Spin dry. Slurry the resulting solid in EA / HEP (200 mL, 1:3) and filter to give 60 g of a yellow solid. Phase 3-3: In a 3 L reaction flask, with mechanical stirring, add CuBr (45.4 g, 316.5 mmol) to HBr (500 mL) and cool to 0 °C. Then, suspend compound 3-4 (55 g, 211 mmol) in HBr (500 mL), cool to 0 °C, and add dropwise a solution of NaNO2 (17.5 g, 253 mmol) (dissolved in 50 mL water). Brown smoke is generated. After the addition is complete, stir for 30 minutes. Pour the HBr solution of compound 3-4 into the HBr solution of CuBr in one portion, the reaction is black and a large amount of bubbles are generated. After stirring for 1 hour, monitor the disappearance of SM1 and the generation of a product spot by TLC. Add 2 L of water to the reaction solution, add 2 L of EtOAc, stir, dissolve the solid, and separate the liquid. The EA layer is dried, spin-dried and purified by column (EA:DCM:HEP=1:1:4) to give 45 g of yellow solid product. Stage 3-4: Compound 3-5 (15 g) is suspended in HCl / MeOH (250 mL, 4N) (closed reaction flask) and reacted overnight with heating at 60° C. The reaction becomes clear. Completion of the reaction of 5 is detected by TLC. After cooling the reaction to room temperature, a yellow solid precipitates. The reaction is spin-dried, and the remaining solid is added with saturated sodium bicarbonate (300 mL) and extracted with EA (200 mL x 3). The EA layer is dried and spin-dried. The resulting solid is slurried in EA / HEP (240 mL, 1:5). Filter and spin-dry the filter cake solid to obtain 12 g of yellow solid product.

[0068] Stages 3-5: Compound 3-6 (31 g, 86.7 mmol) is dissolved in anhydrous THF (300 mL), cooled to 0°C, LiBH4 (2.1 g, 95.4 mmol) is added in batches, and reacted at 0°C for 1 h. Completion of the reaction is detected by TLC. The reaction is filtered. The filter cake is washed with DCM. The filtrate is spin-dried. 300 mL of water is added to the obtained solid, and it is extracted with EA (200 mL x 3). The EA layer is dried, spin-dried, and the obtained solid is slurried in EA / HEP (240 mL, 1:5). Filtration and spin-drying of the filter cake solid gives 24 g of yellow solid product. Stages 3-6: Compound 3-7 (32 g, 97.5 mmol) is dissolved in dioxane (500 mL), MnO2 (51 g, 585.4 mmol) is added, and the mixture is degassed and protected with N2, and reacted at 95 °C for 5 hours. Completion of the reaction is detected by TLC. The reaction is filtered, and the filtrate is spin-dried. The resulting solid is slurried in EA / HEP (180 mL, 1:5). Filter and spin-dried the filter cake solid to obtain 24 g of yellow solid product. Stages 3-7: Compounds 3-8 (22g, 67.5mmol), R-3-hydroxypyrrolidine hydrochloride (16.6g, 135mmol), TEA (20.5g, 202.5mmol) were added to DCM (300ML) and reacted at room temperature for 1 hour, then NaBH(OAc)3 (21.5g, 101.25mmol) was added and reacted for another 1 hour. The reaction was detected by TLC. Work-up: Water (300ML) was added to the reaction solution, the liquid was separated, and the DCM layer was washed with saturated saline. The liquid was separated, the DCM was dried, spin-dried, and purified by column (DCM:MeOH=40:1) to obtain 15.3g of brown oily product.

[0069] Stages 3-8: Compound 3-9 (2.0 g, 5 mmol), BpiN2 (6.37 g, 25.1 mmol), Pd(PPh3)2Cl2 (352 mg, 0.5 mmol), and KOAc (984.6 mg, 10 mmol) were added to dioxane (40 mL), degassed three times, and reacted overnight under N2 protection at 90 °C. After completion of the reaction, the mixture was filtered. The filtrate was spin-dried. After dissolving with 30 mL of DCM, 50 g of silica gel was added and the sample was stirred. The mixture was purified by silica gel column, elution gradient: EA = 100% (500 mL), EA:MeOH = 40:1 (2050 mL). 900 mg of the product was obtained as a brown oil. Stages 3-9: Dissolve raw material 3-11 (51g, 0.34mol) in 500ml of methanol, add 300ml of water, add sodium bicarbonate (28.9g, 0.34mmol), add methanol solution of NIS at about 0℃, react overnight after completion. Workup: Concentrate to dryness, add 500ml of water, adjust PH to 3 with 3M hydrochloric acid, filter the solid, slurried with ethyl acetate / ethanol, filtered and dried to obtain 146g of gray solid. Stages 3-10: Raw materials 3-12 (61 g, 230 mmol), ZnCN2 (27 g, 230 mmol), Pd(PPh3)4 (12.8 g, 11 mmol) were mixed in a 1000 mL three-neck flask, 1000 mL of DMF was added, the mixture was purged with N2 three times, and the mixture was stirred at 90°C for 3 hours. TLC spot plate showed that a small amount of raw materials remained, and LCMS showed that the reaction of the raw materials was complete.

[0070] Stages 3-11: In a 25mL two-neck flask, 3-13 (15g) was suspended in DCM (20mL), and NIS (20g) was added at room temperature, and the mixture was reacted for 10 minutes. The disappearance of the raw material was detected by TLC spot plate. Saturated NaHCO3 was added to the reaction solution, and the aqueous phase was adjusted to pH=2, and the mixture was extracted with DCM three times. The DCM layer was washed with 10% Na2S2O3, dried, and spin-dried to obtain 19g of brown solid product. Stages 3-12: In a 15mL reaction tube, 3-14 (16g), 2-4 (1.3g, WO2018195321), Pd(PPh3)2Cl2 (3.5g), CuI (500mg), DIPEA (30g, 65mmol) are dissolved in DMF (100ML) and reacted under N2 protection at 85℃ for 2 hours. TLC detects the disappearance of raw materials. After the reaction is complete, the reaction solution is extracted with water / DCM. Dry and spin dry. The residue is slurried with EA / HEP (20ML, 1:1). The resulting solid is purified by column and eluted with pure DCM to obtain 8g of yellow solid. Stages 3-13: 3-15 (150 mg), 3-16 (135 mg), NaBH3CN (39 mg), TEA (83 mg) were added to a 15 mL reaction tube in THF (5 mL) and reacted at 70°C for 5 hours. The disappearance of 1-6 was detected by TLC. The reaction solution was spin-dried, water was added, and the mixture was extracted with EA. The EA was dried, spin-dried, and purified by column to obtain 100 mg of a yellow solid.

[0071] Stages 3-14: Using compounds 3-17 (200 mg) and 3-10 (180 mg) as raw materials, follow the synthesis method of steps 2-6 to obtain 120 mg of yellow solid product. Stages 3-15: Compound 3-18 (120 mg) was used as raw material and synthesis method of step 2-7 was followed to obtain 40 mg of yellow solid product. MS (APCI): 684. 1H NMR (400MHz, DMSO-d6)δ 8.32(s, 1H), 7.87(d, J=3.9Hz, 1H), 7.80(d, J=8.0Hz, 1H), 7.50(d, J=7.6Hz, 1H), 7.45(t, J=7.6Hz, 1H), 7.40(t, J=7 .7Hz, 1H), 7.31(s, 1H), 7.27(d, J=7.6Hz, 1H), 7.24(d, J=7.4Hz, 1H), 5.29(t, J=5.0Hz, 1H), 4.65(d, J=4.6Hz, 1H), 4. 29(d, J=7.0Hz, 1H), 4.15(s, 1H), 3.99(q, J=7.1Hz, 2H), 3.92(s, 3H), 3.71(d, J=4.3Hz, 2H), 2.79(t, J=6.8Hz, 1H), 2. 68-2.60(m, 4H), 2.40(dd, J=9.7, 4.0Hz, 1H), 2.30(q, J=1.9Hz, 2H), 2.21(s, 3H), 2.04(s, 3H), 1.96(d, J=7.0Hz, 2H).

[0072] Example 4. Synthesis of Compound 004 [ka] Phase 4-1: Add acetic anhydride (75ML), concentrated nitric acid (5ML) to a 250ML single-neck flask, add raw material 3-13 (5.0g, 28.9mmol) in batches, stir under water bath, after 20 minutes, precipitate is formed, monitor the reaction completion by TLC spot plate, filter off the precipitate, suck dry, slurry, and pull dry to obtain 4.5g of white solid. Phase 4-2: In a 500mL single-neck flask, add THF (200mL), raw material 4-1 (5.0g, 23mmol) and TFA (0.2mL), replace with Pt / C and H2 three times, stir at room temperature, and react for 1 hour. Monitor the completion of the reaction of the raw materials by TLC spot plate, filter off Pt / C, and use the filtrate directly in the next step.

[0073] Stage 4-3: Add 180 mmol of Et3N to the THF solution of the above filtrate 4-2 (10.0 g, 45.8 mmol), dissolve 3-6 (10.74 g, 46 mmol, Organic Letters, 2019, 21, 5971-5976) in 15 ml of DCM, slowly add it, react at room temperature for 1 hour, a large amount of turbidity appears, filter the solid, slurried and purified with ethyl acetate to obtain 18 g of gray-white solid. Stage 4-4: PPh3 (9.7 g, 37 mmol) was dissolved in toluene at room temperature, DDQ (8.4 g, 37 mmol) was slowly added and stirred uniformly, in this case the system became suspended, raw material 4-4 (7.1 g, 18.5 mmol) was added, and the reaction was carried out at 110°C for 1 hour, monitored by TLC spot plate, the product was poured out as a mainly transparent liquid, concentrated and dried, and slurried with EA to obtain 3.7 g of white solid. Stage 4-5: Compounds 4-5 (1 g, 2.72 mmol) and 3-16 (902 mg, 5.45 mmol) were used as raw materials, and 0.8 g of a white solid was prepared according to the synthesis method of step 3-13. Stages 4-6: Using compounds 4-6 (200 mg, 0.416 mmol) and 1-14 (230 mg, 0.5 mmol, WO2018119286) as raw materials, prepare 180 mg of a white solid according to the synthesis method of steps 2-6. Stages 4-7: Compound 4-7 (120 mg) was used as raw material and synthesis method of steps 2-7 was followed to obtain 38 mg of yellow solid product. MS (APCI): 720. 1H NMR (400MHz, DMSO-d6)δ 9.30(s, 1H), 8.83(d, J=2.0Hz, 1H), 8.45(d, J=8.2Hz, 1H), 8.15(d, J=1.9Hz, 1H), 8.12(d, J=7.9Hz, 1H), 8.04(d, J=5.8Hz, 1H), 7.98(d, J=9.9H) z, 1H), 7.52(t, J=7.7Hz, 1H), 7.41(d, J=7.5Hz, 1H), 7.33(t, J=7.9Hz, 1H), 7.15(d, J=5.8Hz, 1H), 6.89(d, J=7.5Hz, 1H), 4.38-4.26(m, 1H), 4. 24-4.14(m, 1H), 3.78(q, J=13.7Hz, 2H), 3.24-3.15(m, 2H), 3.08-2.99 (m, 2H), 2.93-2.76(m, 2H), 2.76-2.64(m, 2H), 2.63-2.54(m, 3H), 2.44( s, 3H), 2.35(dd, J=9.7, 3.6Hz, 1H), 2.25-2.16(m, 2H), 2.10-2.05(m, 3 H), 2.00(dt, J=13.5, 7.3Hz, 1H), 1.95-1.87(m, 2H), 1.59-1.50(m, 1H).

[0074] Example 5. Synthesis of Compound 005 [ka] Phase 5-1: Compounds 4-2 (10 g, 45.8 mmol) and 5-1 (11.6 g, 45.8 mmol, WO2017059135) are used as raw materials and the synthesis method of step 4-3 is followed to obtain 15 g of an off-white solid. Phase 5-2: Using compound 5-2 (2g) as raw material, prepare 1.1g of off-white solid according to the synthesis method of step 4-4. MS (APCI): 387 [M+H] + . Phase 5-3: Using compound 5-3 (1 g, 2.58 mmol) and compound 3-16 (0.85 g, 5.16 mmol) as raw materials, 0.9 g of off-white solid was prepared according to the synthesis method of step 3-13. MS (APCI): 500 [M+H] + .

[0075] Phase 5-4: Using compounds 5-4 (200 mg) and 5-5 (200 mg, WO2018119286) as raw materials, prepare 210 mg of a white solid according to the synthesis method of steps 2-6. Stage 5-5: Compound 5-6 (120 mg) was used as raw material and synthesis method of steps 2-7 was followed to obtain 51 mg of yellow solid product. MS (APCI): 760. 1 H NMR (400MHz, DMSO-d6)δ 9.89(s, 1H), 9.15(d, J=8.4Hz, 1H), 8.91(s, 1H), 8.28-8.15(m, 2H), 8.07(d, J=11.0Hz, 1H), 7.71(d, J=7 .2Hz, 2H), 7.60-7.49(m, 2H), 7.34(d, J=5.8Hz, 1H), 7.09(d, J=7.5Hz, 1H), 5.31(s, 1H), 4.73(s, 2H), 4. 35(dt, J=20.7, 5.9Hz, 2H), 4.20(s, 1H), 3.93(s, 1H), 3.89-3.72(m, 2H), 2.87(dd, J=17.0, 9.6Hz, 2H), 2 .75-2.55(m, 2H), 2.40-2.29(m, 2H), 2.16-1.85(m, 4H), 1.56(s, 2H), 1.22(s, 4H), 0.84(t, J=6.8Hz, 1H).

[0076] Example 6. Synthesis of Compound 006 [ka] Phase 6-1: Using compounds 4-5 (10 g, 0.0272 mol) and 6-1 (9.3 g, 0.0544 mol, WO2018136935) as raw materials, prepare 8 g of a white solid according to the synthesis method of steps 3-13. Phase 6-2: Compound 6-2 (8 g) is separated using a chiral column to give compound 6-3 (3.5 g). Phase 6-3: Compound 6-3 (3.5 g) is dissolved in TFA (10 mL) and then stirred at room temperature for 1 hour. The TFA spin-drying is followed by azeotroping with toluene once. Saturated sodium bicarbonate solution and concentrated hydrochloric acid are added to the residual liquid to adjust the pH to 2-3, and a large amount of solid appears, which is filtered and dried to obtain 2 g of light brown solid. Phase 6-3: Using compound 6-4 (200 mg, 0.416 mmol) and 1-14 (230 mg, 0.5 mmol, WO2018119286) as raw materials, 32 mg of a white solid is prepared according to the synthesis method of steps 2-6. MS (APCI): 720. 1 H NMR (400MHz, DMSO-d6)δ 9.32(s, 1H), 8.86(s, 1H), 8.47(d, J=8.2Hz, 1H), 8.18(s, 1H), 8.15(d, J=7.8Hz, 1H), 8.06(d, J=5.8Hz, 1H), 8.02(s, 1H), 7.55(s, 1H), 7.43(d , J=7.6Hz, 1H), 7.35(s, 1H), 7.18(d, J=5.8Hz, 1H), 6.92(d, J=7.5Hz, 1H), 4.32(d, J=5.8Hz, 1H), 4.22(tt, J=6.9, 3.4Hz, 1H), 3.81(q, J=13.7 Hz, 3H), 3.07(q, J=9.3, 8.0Hz, 3H), 2.89(s, 2H), 2.83(d, J=8.8Hz, 2H), 2.74(dd, J=10.0, 6.3Hz, 2H), 2.63(dq, J=15.1, 7.5Hz, 3H), 2.46(s, 3 H), 2.37(dd, J=9.7, 3.6Hz, 2H), 2.24(q, J=6.8Hz, 2H), 2.09(s, 3H), 2.01(dt, J=13.7, 6.8Hz, 2H), 1.92(d, J=7.8Hz, 2H), 1.57(d, J=3.7Hz, 2H)

[0077] Example 7. Synthesis of Compound 007 [ka] Phase 6-2: Compound 6-2 (8g) is separated using a chiral column to give compound 7-1 (4g). Phase 6-3: Compound 7-1 (4 g) is dissolved in TFA (10 mL) and then stirred at room temperature for 1 hour. TFA is spin-dried and azeotroped once with toluene. Saturated sodium bicarbonate solution and concentrated hydrochloric acid are added to the remaining liquid to adjust the pH to 2-3. A large amount of solid appears, which is filtered and dried to obtain 3.2 g of light brown solid. Phase 6-3: Using compound 7-2 (200 mg, 0.416 mmol) and 1-14 (230 mg, 0.5 mmol, WO2018119286) as raw materials, prepare 30 mg of a white solid according to the synthesis method of steps 2-6. MS (APCI): 720. 1 H NMR (400MHz, DMSO-d6)δ 9.32(s, 1H), 8.86(d, J=2.0Hz, 1H), 8.46(d, J=8.1Hz, 1H), 8.18(s, 1H), 8.15 (d, J=7.9Hz, 1H), 8.06(d, J=5.8Hz, 1H), 8.01(s, 1H), 7.55(t, J=7.7Hz, 1H), 7 .43(d, J=7.4Hz, 1H), 7.35(t, J=7.9Hz, 1H), 7.18(d, J=5.8Hz, 1H), 6.92(d, J= 7.5Hz, 1H), 4.36(t, J=6.0Hz, 1H), 4.21(dt, J=6.9, 3.4Hz, 1H), 3.81(q, J=13. 8Hz, 2H), 3.12-3.01(m, 3H), 2.89(p, J=7.5Hz, 2H), 2.79(s, 1H), 2.75(d, J=6. 1Hz, 1H), 2.72(dd, J=6.3, 3.4Hz, 1H), 2.62(dt, J=12.3, 7.5Hz, 4H), 2.46(s, 3 H), 2.37(dd, J=9.7, 3.6Hz, 1H), 2.22(t, J=7.2Hz, 2H), 2.08(s, 2H), 2.00(dd, J=11.0, 4.9Hz, 2H), 1.94(dd, J=8.9, 6.0Hz, 2H), 1.57(qd, J=8.2, 3.8Hz, 2H).

[0078] Example 8. Synthesis of Compound 008 [ka] Phase 8-1: Compounds 8-1 (1.9 g, 6.41 mmol, WO2016207226), 8-2 (1.1 g, 6.41 mmol, WO2018006795), sodium carbonate (1.36 g, 12.82 mmol) and tetrakistriphenylphosphine palladium (222 mg, 0.19 mmol) were added sequentially to a single-neck flask containing dioxane / HO (4:1, 25 ML), stirred under nitrogen gas protection in an oil bath at 80 °C for 3 h, and the reaction was detected by LC-MS. After about 10% of the raw material remained, the reaction was cooled, filtered, spin-dried, extracted with DCM / HO, dried with anhydrous sodium sulfate, and obtained by column chromatography (pure PE passed through the column) to obtain 650 mg of a pale yellow solid. ESI (APCI): 306 [M+H] + . Phase 8-2: Compound 8-3 (200 mg, 0.653 mmol), R-3-hydroxypyrrolidine hydrochloride (121 mg, 0.98 mmol) and triethylamine (0.09 mL, 0.653 mmol) were added sequentially to a single-neck flask containing DCM (10 mL) and stirred at room temperature for 2 hours. NaBH(OAc)3 (415 mg, 1.96 mmol) was then added to the reaction solution and stirred at room temperature overnight, and the reaction was detected by TLC. After the reaction was completed, it was quenched by adding water, washed with brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 200 mg of an oil. ESI(APCI): 377 [M+H] + . Phase 8-3: Compound 8-5 (1g, 2.72mmol), B2PiN2 (1.04g, 4.08mmol), KOAc (668mg, 6.81mmol), X-phos (258mg, 0.544mmol) and Pd(dppf)2Cl2 (221mg, 0.272mmol) are added sequentially to a single-neck flask containing DMAc (20ML), stirred under nitrogen gas protection in an oil bath at 90°C for 3.5 hours, and the reaction is detected by LC-MS. After the reaction is completed, the solvent is spin-dried, extracted with DCM / H2O, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain 1g of a yellow solid. ESI(APCI): 415[M+H] + . Stage 8-4: Compound 8-4 (200 mg, 0.53 mmol), 8-6 (240 mg, 0.58 mmol), sodium carbonate (168 mg, 1.59 mmol) and Pd(dppf)2Cl2 (44 mg) were added sequentially to a single-neck flask containing dioxane / H2O (4:1, 5 ML), stirred in an oil bath at 100 °C for 3 hours, and the reaction was monitored by LC-MS. After the reaction was completed, it was filtered, the solvent was spin-dried, extracted with DCM / H2O, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain 120 mg of an oil. ESI (APCI): 585 [M + H] + . Stage 8-5: Compound 8-7 (120 mg, 0.205 mmol), 3-16 (51 mg, 0.308 mmol), triethylamine (0.03 mL, 0.205 mmol) and NaBH3CN (126 mg, 0.616 mmol) were added sequentially to a single-neck flask containing THF (5 mL), stirred overnight in an oil bath at 70°C, and the reaction was monitored by LC-MS. After completion of the reaction, the mixture was quenched by adding water, the solvent was spin-dried, extracted with DCM / H2O, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain 70 mg of an oil. ESI (APCI): 698 [M+H] + . Stage 8-6: Compound 8-8 (70 mg, 0.1 mmol) and LiOH (5 mg, 0.2 mmol) were added sequentially to a single-neck flask containing THF / MeOH / H2O (2:1:1, 4 ML), stirred at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, TFA was added to adjust the pH to neutral, and 10 mg of a white solid was prepared by reverse phase column. ESI (APCI): 684 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.13(d, J=7.9Hz, 1H), 7.99(d, J=9.6Hz, 1H), 7.74(d, J=7.5Hz, 1H), 7.52(t, J=7.7Hz, 1H), 7.48-7.40(m, 2H), 7.36(t, J=7.5Hz, 1H), 7.18(d, J=7.7Hz, 1H), 7.14(d, J=7.4Hz, 1H), 4.68(br, 1H), 4.40-4.26(m, 1H), 4.22-4.1 5(m, 1H), 3.86(s, 3H), 3.67-3.48(m, 2H), 3.28-3.14(m, 2H), 3.09-2.98(m, 1H), 2.93-2.74(m, 4H), 2.74-2.51 (m, 3H), 2.44(s, 3H), 2.44-2.34(m, 3H), 2.25-2.17(m, 2H), 2.02(s, 3H), 2.00-1.85(m, 3H), 1.58-1.51(m, 1H).

[0079] Example 9. Synthesis of Compound 009 [ka] Phase 9-1: Compound 6-2 (1 g) is dissolved in TFA (5 mL) and then stirred at room temperature for 1 hour. TFA is spin-dried and azeotroped once with toluene. Saturated sodium bicarbonate solution and concentrated hydrochloric acid are added to the remaining liquid to adjust the pH to 2-3. A large amount of solid appears, which is filtered and dried to obtain 0.5 g of light brown solid. Phase 9-2: Compound 9-1 (0.5 g, 1.07 mmol), cyclopropylsulfonamide (260 mg, 2.14 mmol), DMAP (261 mg, 2.14 mmol) and EDCI (410 mg, 2.14 mmol) were added at once to a single-neck flask containing DCM (15 mL), stirred overnight at room temperature, and the reaction was detected by TLC. After completion of the reaction, it was washed with saturated saline and 0.5 M dilute hydrochloric acid, and then the organic layer was dried with anhydrous sodium sulfate, and 0.3 g of a pale yellow solid was obtained by column chromatography. Phase 9-3: Compounds 9-2 (200 mg) and 1-14 (240 mg) were used as raw materials, and 60 mg of a pale yellow solid was prepared according to the synthesis method of step 8-4. ESI (APCI): 823 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.30(s, 1H), 8.86(d, J=2.0Hz, 1H), 8.42(d, J=8.1Hz, 1H), 8.20(d, J=1.9Hz, 1H), 8.15-8.09(m, 1H), 8.04(t, J=6.0Hz, 2 H), 7.53(t, J=7.7Hz, 1H), 7.41(d, J=7.5Hz, 1H), 7.33(t, J=7.9Hz, 1H), 7.16(d, J=5.8Hz, 1H), 6.91(d, J=7.5Hz, 1H), 4. 42(d, J=6.3Hz, 1H), 4.23(tt, J=6.5, 3.1Hz, 1H), 4.01-3.84(m, 2H), 3.30-3.17(m, 3H), 3.06(dt, J=16.6, 6.8Hz, 2H), 2. 98-2.75(m, 5H), 2.74-2.54(m, 4H), 2.44(s, 3H), 2.31-2.19(m, 3H), 2.07(s, 3H), 2.05-1.85(m, 4H), 1.64-1.55(m, 1H).

[0080] Example 10. Synthesis of compound 010 (222) [ka] Phase 10-1: Add 004 (30 mg, 0.0471 mmol), NH4HCO3 (7 mg, 0.0834 mmol) and BOC2O (18 mg, 0.0834 mmol) in a single-neck flask containing THF / pyridine (6:1, 3.5 mL) in sequence, stir at room temperature for 1 h, and detect the reaction by LC-MS. After the reaction is complete, add TFA to adjust the pH to 7-8, then run a reverse phase column to prepare 10 mg of a pale yellow solid. ESI(APCI): 719 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.35(s, 1H), 8.97(s, 1H), 8.39(s, 1H), 8.32(d, J=8.2Hz, 1H), 8.16(d, J=7.9Hz, 1H), 8.08(d, J =5.7Hz, 1H), 7.58-7.47(m, 2H), 7.43(d, J=7.5Hz, 1H), 7.35(t, J=7.8Hz, 1H), 7.17(d, J=5.8Hz , 1H), 6.94(d, J=7.5Hz, 1H), 5.40-5.26(m, 1H), 4.57-4.32(m, 2H), 3.20-2.89(m, 7H), 2.46(s, 3H), 2.31-2.21(m, 1H), 2.19-2.08(m, 2H), 2.06(s, 3H), 2.01-1.89(m, 2H), 1.85-1.75(m, 1H).

[0081] Example 11. Synthesis of Compound 011 [ka] Phase 11-1: Compound 5-3 (5g, 12.9mmol), ST-butylsulfinamide (4.69g, 38.7mmol) and ethyl tetratitanate (11.77g, 51.60mmol) are added in toluene (50ML) in sequence, and stirred overnight at 70°C under nitrogen gas protection, and the reaction is detected by TLC. After the reaction is completed, it is cooled to room temperature and used directly in the next step. Phase 11-2: The above reaction solution is cooled to -70℃, then THF (20ML) and NaBH4 (3.9g, 103.2mmol) are added, and the mixture is stirred for 1 hour while keeping warm. Then the mixture is slowly warmed to room temperature and stirred for 1 hour, and the reaction is detected by TLC. After the reaction is completed, a saturated aqueous solution of ammonium chloride is added. Then, the mixture is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 5g of a black-gray solid. Phase 11-3: Compound 11-2 (1 g, 2.03 mmol) is dissolved in DCM (5 mL) and stirred under ice bath. Hydrogen chloride in dioxane (3 M, 1 mL) is then added to the solution, and after completion, the mixture is warmed to room temperature and stirred for 1 hour, and the reaction is detected by TLC. After completion of the reaction, it is filtered, the solid is washed with ethyl acetate, and dried to obtain 788 mg of a dark gray solid. Phase 11-4: Compound 11-3 (300 mg, 0.77 mmol), potassium carbonate (213 mg) are added to DMF (5 mL), then methyl 3-bromopropionate (129 mg) is added to the reaction solution, and then methyl 3-bromopropionate (129 mg) is added every hour for a total of three times, and the reaction is detected by LC-MS until the product does not increase. Extract with DCM and water, dry with anhydrous sodium sulfate, and obtain a mixture of 100 mg of product and raw material by column chromatography. Stage 11-5: The above mixture is dissolved in THF (30 mL), then BOC2O (413 mg) is added. Under nitrogen gas protection, the temperature is raised to 60° C. and stirring is performed. The reaction is monitored by TLC, and the BOC of the raw material and the product of the previous step can be separated by TLC. Then, it is extracted with DCM / H2O and dried over anhydrous sodium sulfate to obtain 20 mg of the target product as a grey solid. Stage 11-6: Compounds 11-5 (20 mg, 0.035 mmol) and 5-5 (15 mg) were used as raw materials, and 20 mg of a pale yellow solid was prepared according to the synthesis method of step 8-4. Stage 11-7: In a 15 mL Schlenk tube, add 11-6 (93 mg), DCM (2 mL), add HCl-dioxane (0.4 mL) dropwise, and react under N2 protection at room temperature with stirring for 1 h (yellow turbidity). LC-MS detects the completion of the reaction. Directly pull with an oil pump and dry to obtain 83 mg of a yellow solid. Stage 11-8: Compound 11-7 (83 mg) was used as the raw material, and 34 mg of a pale yellow solid was prepared according to the synthesis method of step 8-6. ESI (APCI): 734 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.88(s, 1H), 9.12-9.00(m, 2H), 8.53(s, 1H), 8.39(s, 1H), 8.31-8.19(m, 2H) , 7.73(q, J=7.0, 6.4Hz, 2H), 7.56(t, J=8.0Hz, 1H), 7.38(d, J=5.8Hz, 1H), 7.1 1(d, J=7.7Hz, 1H), 5.00(s, 1H), 4.61(s, 1H), 4.43(d, J=27.4Hz, 1H), 3.30-3. 14(m, 2H), 2.71-2.58(m, 3H), 2.39(dd, J=9.4, 4.3Hz, 0H), 2.07-1.75(m, 2H).

[0082] Example 12. Synthesis of Compound 012 [ka] Phase 12-1: Compound 11-3 (1 g, 2.35 mmol) is dissolved in THF (30 mL), then potassium carbonate (975 mg, 7.06 mmol) and ethyl bromoacetate (393 mg, 2.35 mmol) are added, and the mixture is stirred overnight under heating at 60° C., and the reaction is detected by LC-MS. After the reaction is complete, it is extracted with DCM / H2O, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 600 mg of a gray-brown solid. Phase 12-2: Compounds 12-1 (200 mg) and 5-5 (280 mg) were used as raw materials to prepare 52 mg of a pale yellow solid according to the synthesis method of step 8-4. Phase 12-3: Compound 11-7 (52 mg) was used as the raw material, and 21 mg of a pale yellow solid was prepared according to the synthesis method of step 8-6. ESI (APCI): 720 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.89(s, 1H), 9.12-8.98(m, 2H), 8.54(d, J=2.0Hz, 1H), 8.41(s, 1H), 8.29-8.1 7(m, 2H), 7.79-7.68(m, 2H), 7.56(t, J=8.0Hz, 1H), 7.38(d, J=5.8Hz, 1H), 7.12 (dd, J=7.6, 1.5Hz, 1H), 5.01(dd, J=8.1, 3.5Hz, 1H), 4.62(s, 1H), 3.96(d, J=6. 2Hz, 2H), 3.29(s, 2H), 2.69-2.52(m, 1H), 2.47(s, 2H), 1.90(d, J=55.7Hz, 2H).

[0083] Example 13. Synthesis of Compound 013 [ka] Phase 13-1: Add 12-1 (150 mg, 0.3159 mmol), MeI (54 mg, 0.3791 mmol), K2CO3 (87 mg, 0.6318 mmol), and THF (30 mL) to a 100 mL round-bottom flask, react overnight under N2 protection at room temperature with stirring (dark yellow transparent), and detect the reaction by LC-MS. After the reaction is complete, spin-dry the THF, extract with DCM (20 mL*2), and obtain 76 mg of a gray solid by column chromatography. Phase 13-2: Compounds 13-1 (50 mg) and 5-5 (52 mg) were used as raw materials to prepare 70 mg of a pale yellow solid according to the synthesis method of step 8-4. Phase 13-3: Compound 13-2 (62 mg) was used as the raw material, and 20.5 mg of a pale yellow solid was prepared according to the synthesis method of step 8-6. ESI (APCI): 734 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.89(s, 1H), 9.19-8.92(m, 2H), 8.54(s, 1H), 8.37(s, 1H), 8.33-8.12(m, 2H), 7. 88-7.63(m, 2H), 7.56(t, J=8.0Hz, 1H), 7.38(d, J=5.9Hz, 1H), 7.13(dd, J=7.6, 1. 5Hz, 1H), 5.47(s, 2H), 5.12(s, 1H), 4.64(d, J=17.9Hz, 2H), 4.43(d, J=26.4Hz, 1 H), 3.28(s, 2H), 3.25-3.15(m, 2H), 2.68(s, 2H), 2.08-1.90(m, 2H), 1.83(s, 2H).

[0084] Example 14. Synthesis of Compound 014 [ka] Phase 14-1: Compound 14-1 (5 g, 0.0231 mol, WO2019148036), vinyl boronate pinacol (7.7 ML, 0.0463 mmol), potassium phosphate (14.7 g, 0.0693 mol), Pd(OAc)2 (0.52 g, 0.0023 mol) and SPhos (1.89 g, 0.0046 mol) were added sequentially to a single-neck flask containing 1,4-dioxane / H2O (4:1, 50 ML), and the mixture was stirred overnight in an oil bath at 85 °C under nitrogen gas protection, and the reaction was detected by TLC. After the raw materials disappeared, the reaction solution was spin-dried and 2.4 g of a pale yellow solid was obtained by column chromatography. Phase 14-2: Compound 14-2 (1.4 g, 9 mmol) was suspended in triethyl orthoformate (20 ML) and refluxed in an oil bath at 145° C. for 6 hours, and the reaction was detected by TLC. After the raw material disappeared, the reaction solution was cooled, and n-heptane was added, stirred and washed for 10 minutes, filtered, and the above operation was repeated twice, filtered, and dried to obtain 1.35 g of a pale yellow solid. Phase 14-3: Compound 14-3 (1.25 g, 7.22 mmol) and DIPEA (1.4 g, 10.83 mmol) are added to toluene (75 mL), heated to 100 °C and stirred, then phosphorus oxychloride (1.1 g, 7.22 mmol) is added, the reaction solution is stirred in an oil bath at 100 °C for 1.5 hours, and the reaction is detected by TLC. After the raw material disappears, the reaction solution is slowly poured into ice cubes (50 g) and stirred for 20 minutes, filtered, the liquid is separated, washed twice with brine, the organic layer is dried over anhydrous sodium sulfate, and spin-dried to obtain 820 mg of a gray-green solid. Phase 14-4: Compound 14-4 (820 mg, 4.44 mmol), 3-bromo-2-methylaniline (908 mg, 4.88 mmol) and TsOH.H2O (844 mg, 4.44 mmol) are added to isopropanol (20 mL), heated to 85 °C and stirred overnight to completion, and the reaction is detected by TLC. After the raw material disappears, the solvent is spin-dried, extracted with DCM / H2O, the organic layer is combined, the organic layer is washed with saturated sodium bicarbonate solution, the organic layer is dried with anhydrous sodium sulfate, and 600 mg of a yellow solid is obtained by column chromatography. Phase 14-5: Compound 14-5 (600mg, 1.76mmol), NMO (412mg, 3.52mmol), K2OSO4.2H2O (65mg, 0.176mmol) and NaIO4 (2.63g, 12.31mmol) are dissolved in THF / H2O (10ML / 5ML) and stirred at room temperature for 3 hours, and the reaction is detected by TLC. After the raw materials disappear, it is filtered and the solid is washed with ethyl acetate. The filtrate is taken and washed with 10% sodium thiosulfate and brine, dried over anhydrous sodium sulfate, and concentrated to obtain 600mg of pale yellow oil, which is used directly in the next step reaction. Phase 14-6: Compound 14-6 (600 mg, 1.75 mmol), (R)-3-hydroxypyrrole hydrochloride (949 mg) and DIPEA (678 mg, 5.24 mmol) are dissolved in DCM (20 mL) and stirred at room temperature for 1 hour. Then NaBH(OAc)3 (741 mg, 3.5 mmol) is added to the above reaction solution and stirred at room temperature overnight. After the raw material disappears, the reaction is quenched by dropping saturated sodium bicarbonate solution, extracted with ethyl acetate / water, the organic layers are combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 350 mg of a pale yellow solid. Stage 14-7: Compound 14-7 (350 mg) is used as raw material and the synthesis method of step 8-3 is followed to obtain 300 mg of a pale yellow solid. Phase 14-8: Compound 14-8 (200 mg) and 7-2 (180 mg) were used as raw materials, and 300 mg of a pale yellow solid was obtained according to the synthesis method of step 8-4. MS (APCI): 721 [M+H] + .

[0085] Example 15. Synthesis of Compound 015 [ka] Phase 15-1: Compound 15-1 (200 mg) is used as raw material and the synthesis method of step 8-3 is followed to obtain 150 mg of a pale yellow solid. Phase 15-2: Using compound 15-1 (100 mg, WO2019191707) and 7-2 (120 mg) as raw materials, prepare 21 mg of a pale yellow solid according to the synthesis method of step 8-4. MS (APCI): 736 [M+H] + .

[0086] Example 16. Synthesis of Compound 016 [ka] Phase 16-1: Compound 16-1 (200 mg) is used as raw material and the synthesis method of step 8-3 is followed to obtain 100 mg of a pale yellow solid. Phase 16-2: Using compounds 16-1 (50 mg, WO2019191707) and 7-2 (56 mg) as raw materials, prepare 25 mg of a pale yellow solid according to the synthesis method of step 8-4. MS (APCI): 771 [M+H] + .

[0087] According to the synthesis method of compounds 001 to 016, the compounds in the following table are synthesized using the corresponding raw materials and reagents. [Table A-1] [Table A-2] [Table A-3]

[0088] Example 280. Synthesis of Compound 280 [ka] Stage 280-1: Compound 1-3 (2.4 g) was used as raw material and synthesis method of step 1-2 was followed to obtain 3.1 g of pale yellow solid. MS-APCI: 334 [M+H] + . Stage 280-2: Compound 280-1 (500 mg) was used as the raw material, and 200 mg of a pale yellow solid was obtained according to the synthesis method of steps 1-3. MS-APCI: 654 [M+H] + . Stage 280-3: Compound 280-2 (200 mg) was used as the raw material, and the synthesis method of steps 1-4 was followed to obtain 60 mg of a pale yellow solid. MS-APCI: 753 [M+H] + . Stage 280-4: Compound 280-3 (60 mg) was used as the raw material, and the synthesis method of steps 1-5 was followed to obtain 16 mg of a pale yellow solid. MS-APCI: 654 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.34(s, 1H), 9.00(s, 1H), 8.46(s, 1H), 8.34(d, J=8.0Hz, 1H), 8.08(d, J=8.0Hz, 1H), 7.77(d, J=8.0Hz, 1H), 7.44(t, J=8.0Hz, 1H), 7.35-7.25(m, 3H), 7.19(d, J=8.0Hz, 1H) , 6.91(d, J=8.0Hz, 1H), 6.52(m, 1H), 4.49-4.39(m, 3H), 3.37-2.83(m, 3H), 2.66-2.28 (m, 2H), 2.21(s, 3H), 2.18-2.06(m, 1H), 2.06(s, 3H), 1.96-1.58(m, 5H), 1.43(m, 1H).

[0089] Example 281. Synthesis of Compound 280 [ka] Stage 281-1: Compounds 3-12 (5 g) were used as raw materials, and 3 g of a pale yellow solid was obtained according to the synthesis method of step 4-1. MS-APCI: 320 [M+H] + . Stage 281-2: Compound 280-1 (1g) was used as the raw material, and 400mg of a pale yellow solid was obtained according to the synthesis method of steps 1-3. MS-APCI: 640 [M+H] + . Stage 281-3: Compound 280-2 (400 mg) was used as the raw material, and the synthesis method of steps 1-4 was followed to obtain 10 mg of a pale yellow solid. MS-APCI: 739 [M+H] + . Stage 281-4: Compound 280-3 (100 mg) was used as the raw material, and 36 mg of a pale yellow solid was obtained according to the synthesis method of steps 1-5. MS-APCI: 725 [M+H]

[0090] Biological testing Example A: PD-1 / PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) Binding Assay The assay is carried out in a standard black 384-well polystyrene plate in a final volume of 20 μL. The inhibitors are first serially diluted in DMSO and added to the wells of the plate, followed by the addition of other reaction components. The final concentration of DMSO in the assay is 1%. The assay is carried out in PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA at 25°C. Recombinant human PD-L1 protein (19-238) with a His-tagged C-terminus is purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with an Fc-tagged C-terminus is also purchased from AcroBiosystems (PD1-H5257). After diluting the PD-L1 and PD-1 proteins with the assay buffer, 0.1 μl of the solution is extracted and added to the plate wells. The plate is centrifuged, and the proteins are pre-incubated with the inhibitors for 40 minutes. After incubation, europium-labeled anti-human IgG (PerkinElmer-AD0212) Fc-specific and anti-His SuR were used. e Add 0.1 μl of HTRf detection solution containing LightR-allophycocyanin (APC, PerkinElmer-AD0059H) conjugated antibody. After centrifugation, incubate the well plate at 25 °C for 60 min. Read data on a PHERAstar FS plate reader (665 nm / 620 nm ratio). Final concentrations during the measurement are ~3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG and 20 nM anti-His-allophycocyanin. Use GraphPad Prism 5.0 software to fit the activity data and calculate the IC of inhibitors. 50 Derive the value. IC of compounds exemplified in the Examples 50 The values ​​are as follows: IC50: + is ≦10 nM, ++ is 10 nM to 100 nM, +++ is >100 nM. Data for the example compounds obtained using the PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay described in Example A show that most of the compounds of the invention tested have an IC50 of less than 10 nM, with some compounds (about 25%) even less than 1 nM, and activity test data for some preferred compounds are provided in Table 1. [Table 1-1] [Table 1-2] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound as represented by formula I below, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Where: 【Chemistry 2】 teeth 【Chemistry 3】 is selected from the group consisting of n is 0, 1, 2, 3, or 4; m and p are each independently selected from 0, 1, 2, 3, and 4; 【Chemistry 4】 and 【Chemistry 5】 are each independently 【Chemistry 6】 or 【Chemistry 7】 and 【Chemistry 8】 teeth 【Chemistry 9】 and 【Chemistry 10】 teeth 【Chemistry 11】 or 【Chemistry 12】 teeth 【Chemistry 13】 where X ７ , X ８ , and X １０ are each independently CR; X ６ is N, and X ９ and X １１ are each independently selected from the group consisting of N, CR, and each R is H, —CN, trifluoromethyl, —CHF ２ , -OCF ３ , -OCHF ２ , sulfonamide, nitro, hydroxyl, halogen, substituted or unsubstituted C １ -C １０ independently selected from the group consisting of alkyl, R ６ is N.R. ｄ R ｅ , substituted or unsubstituted C １ -C ６ Amino, substituted or unsubstituted -(C １ -C ６ alkylene)-NH-(C １ -C ６ alkyl), and 【Chemistry 14】 is selected from the group consisting of L １ is selected from a chemical bond, a substituted or unsubstituted —NH—, R １ , R ２ , R ３ , and R ５ are each independently H, —CN, trifluoromethyl, or —CHF ２ , -OCF ３ , -OCHF ２ , sulfonamide, nitro, hydroxyl, halogen, substituted or unsubstituted C １ -C １０ Alkyl, substituted or unsubstituted C ２ -C ６ Alkenyl, substituted or unsubstituted C １ -C ６ Alkoxy, substituted or unsubstituted C ３ -C ８ Cycloalkyl, -CN, hydroxyl, C １ -C ６ selected from the group consisting of amino, carboxy; R １ ' and R ４ are each independently NR ｄ R ｅ , substituted or unsubstituted C1-C6 amine, substituted or unsubstituted -(C １ -C ６ alkylene)-NH-(C1-C6 alkyl), substituted or unsubstituted 【Chemistry 15】 is selected from the group consisting of Rb and Rc are each independently H, substituted or substituted C １ -C ８ alkyl groups, or Rb and Rc together with the adjacent N atom form a substituted or unsubstituted 3- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; R ｄ , and R ｅ are each independently H, substituted or unsubstituted C １ -C ６ alkyl groups or R ｄ and R ｅ taken together form a substituted or unsubstituted 4-10 membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; Unless otherwise specified, the term "substituted" includes halogen, -CH ２ Cl, -CHCl ２ , -CCl ３ , -CH ２ F, -CHF ２ , -CF ３ , =O, -CN, hydroxyl group, amine, C １ -C ６ Alkylamine group, carboxyl group, -NHAc, 【Chemistry 16】 C unsubstituted or substituted by one or more substituents １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ６ -C １０ Aryl group, C ３ -C ８ Cycloalkyl groups, halogenated C ６ -C １０ aryl group, a 5- to 10-membered heteroaryl group having 1 to 3 heteroatoms selected from N, S, and O, and a 5- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S, and O, wherein the substituents are halogen, a hydroxyl group, a carboxyl group, a cyano group, a C １ -C ６ Alkoxy group, C １ -C ６ alkylamine groups; A compound of formula I, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof, characterized in that in each of the above formulas, any of the heteroatoms is selected from the group consisting of B, P, N, S, and O.

2. The above 【Chemistry 17】 has the structure shown in the formula: 【Chemistry 18】 Each radical is as defined in claim 1. The compound of claim 1.

3. The above 【Chemistry 19】 teeth, 【Chemistry 20】 wherein the ring attachment point can be N or C.

2. The compound of claim 1, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof.

4. The ring 【Chemistry 21】 has the substituents shown in formula IV below: 【Chemical 22】 where w is 1, 2, or 3; Each of the above L ４ is independently a substituted or unsubstituted C １ -C ４ alkylene groups, NRf, wherein substituted or unsubstituted C １ -C ４ The hydrogens on the carbon atoms of the alkylene group can be optionally and independently replaced by deuterium, and each L ４ The prerequisite is that the structure formed jointly by is chemically stable. 【Chemistry 23】 is a substituted or unsubstituted C ３ -C １０ cycloalkyl groups, substituted or unsubstituted 3- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from B, P, N, S and O; Each R ７ each independently represents a substituted or unsubstituted C １ -C ６ Alkyl group, -CN, hydroxyl group, amino group, carboxyl group, -ORg, -N(Rg) ２ Rf and Rg are each independently H or a substituted or unsubstituted C1-C6 alkyl, where all hydrogens on the carbon atoms of Rf and Rg can each independently be replaced by deuterium, and where the substituents are selected from the group consisting of halogens, hydroxyl groups, carboxyl groups, cyano groups, C １ -C ６ alkoxy groups.

2. The compound of claim 1, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof.

5. w is 1, L ４ is C １ -C ４ is alkylene, 【Chemistry 24】 is a substituted or unsubstituted 3- to 8-membered nitrogen-containing heterocyclyl, or a substituted or unsubstituted 4- to 10-membered cyclic amide, wherein hydrogens on ring-forming carbon atoms of the 3- to 8-membered nitrogen-containing heterocyclyl or the substituted or unsubstituted 4- to 10-membered cyclic amide may each be independently replaced by deuterium.

6. (L 4 )w is -CH 2 -NH-CH 2 - and 【Chemistry 25】 is a 3-8 membered nitrogen-containing heterocyclyl, or a substituted or unsubstituted 4-10 membered cyclic amide, wherein hydrogens on ring-forming carbon atoms of the 3-8 membered nitrogen-containing heterocyclyl, substituted or unsubstituted 4-10 membered cyclic amide may be optionally and independently replaced with deuterium.

7. The above 【Chemistry 26】 is characterized in that it has a structure selected from the group consisting of: The compound of claim 1. 【Chemical 27】

8. A compound selected from the group consisting of: an optical isomer, a hydrate, a solvate, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】

9. A process for preparing a compound of formula I according to claim 1, comprising the steps of: The method includes steps selected from those shown in Synthetic Schemes 1, 2, or 3, 【Chemical 54】 (a) Using intermediates II and III as raw materials, Sonogashira coupling reaction catalyzed by palladium catalyst gives target product I-1; 【Chemistry 55】 (a) using compound II-1 as a raw material, reacting it with a nitrating agent to form intermediate IV-1; (b) using IV-1 as a raw material, a reduction reaction takes place under reducing conditions to form intermediate IV-2; (c) Using IV-2 and IV-3 as starting materials, affinity displacement reaction takes place under basic conditions to give an amide intermediate, which is then cyclized under a suitable dehydrating reagent to give intermediate IV-4; (d) using IV-4 and IV-5 as raw materials, a coupling reaction takes place under catalytic and ligand conditions to form intermediate I-2; 【Chemistry 56】 (a) Using V-1 and V-2 as raw materials, a coupling reaction takes place under catalytic and ligand conditions to form intermediate V-3; (b) coupling reaction using V-3 and a suitable boron source as starting materials under catalytic and ligand conditions to form intermediate V-4; (d) Using V-4 and IV-4 as starting materials, a coupling reaction takes place under catalytic and ligand conditions to form the target product I-3; 2. A process for the preparation of a compound of formula I according to claim 1, characterized in that in each of the above formulas, each group is as defined above.

10. The method according to claim 9, wherein the method for preparing intermediate II-2 is as follows: 【Chemistry 57】 (a) halogenating II-1 under Lewis acid catalysis to obtain intermediate II-2;

11. The method according to claim 9, wherein the method for preparing intermediate III is as follows: 【Chemistry 58】 (a) Compounds III-1 and III-2 are subjected to a coupling reaction under palladium catalyst and ligand conditions to obtain intermediate III-3; (b) removing the silicon-based protecting group from starting III-3 using a suitable reagent to obtain intermediate III;

12. 1. A pharmaceutical composition comprising: The pharmaceutical composition comprises (1) the compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and (2) a pharma- ceutically acceptable vector, wherein the pharma- ceutically acceptable vector is selected from cellulose and its derivatives, gelatin, talc, solid lubricants, calcium sulfate, vegetable oils, polyols, emulsifiers, wetting agents, colorants, flavoring agents, stabilizers, antioxidants, preservatives, and pyrogen-free water.

13. The pharmaceutical composition according to claim 12, for preventing and / or treating a disease associated with the activity or expression level of PD-1 / PD-L1.

14. The pharmaceutical composition is characterized in that it is used for treating a disease selected from the group consisting of cancer, infectious diseases, and autoimmune diseases. The pharmaceutical composition of claim 13.

15. The cancer is selected from the group consisting of pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, skin cancer, lung cancer, urological tumors, hematological tumors, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, head and neck cancer.

15. The pharmaceutical composition of claim 14.

16. The infectious disease is selected from bacterial infection and viral infection.

15. The pharmaceutical composition of claim 14.

17. The autoimmune disease is characterized in that it is selected from organ-specific autoimmune diseases and systemic autoimmune diseases.

15. The pharmaceutical composition of claim 14.

18. The pharmaceutical composition is characterized in that it contains at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

15. The pharmaceutical composition of claim 14.

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