Aromatic heterocyclic compounds having a tricyclic structure, and their preparation method and application

Abstract

Aromatic heterocyclic compounds having a tricyclic structure, and preparation methods and applications thereof, specifically, the compound represented by the following formula I, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof: The compound of formula I can be used to treat diseases associated with the PD-1 / PD-L1 signaling pathway.

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 in which cancer cells can evade or modulate 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 regulate 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 regulatory 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, regulates 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 regulates T lymphocyte proliferation and associated cytokine secretion 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 modulators have strong antitumor activity against various tumors. Currently available PD-1 / PD-L1 antibody inhibitors include Ninolumab from BMS, Lambrolizumab from Merck, and Atezolizumab from Roche. 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 or viral infection treatment. 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 according to formula I, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof: Formula I: [ka] wherein n, q, m, t, p, v and u are each independently selected from 0, 1, 2, 3, or 4, 5; 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; X7 is selected from the group consisting of N and CR; X8 and X9 are each independently selected from the group consisting of O, S, SO, SO2, C(R)2, and NR, where R is H, a C1-C6 alkyl group, chlorine, bromine, fluorine, iodine, a cyano group, a hydroxyl group, a nitro group, NR f , substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted C6-C 10 Heteroaryl 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 cycloalkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C2-C6 alkynyl groups, -C(=O)-substituted or unsubstituted C2-C6 alkenyl groups, -C(=O)-substituted or unsubstituted C2-C6 alkynyl groups, wherein the carbon atoms of X7, X8 and X9 can each independently be replaced by deuterium; M3, M4 and M5 are each independently selected from the group consisting of a chemical bond, CR, N, NR, O, S, SO and SO2; Each M6 is independently selected from the group consisting of CR, N and C; [ka] represents a single or double bond, [ka] each independently represents a substituted or unsubstituted C5-C 12 arylene group, or substituted or unsubstituted 5- to 12-membered (preferably 5- to 7-membered) heteroarylene group having 1 to 3 heteroatoms, substituted or unsubstituted 5- to 12-membered heterocyclylene group, and substituted or unsubstituted 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 3- to 12-membered (preferably 5- to 12-membered) heterocyclic groups, and substituted or unsubstituted C3-C 12 (Preferably, C5 to C 12 wherein the heterocyclic group has 1 to 3 heteroatoms; 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] , and substituted or unsubstituted [ka] is selected from the group consisting of G is none, H, a substituted or unsubstituted C1-C6 alkyl group, or [ka] where w is 0, 1, 2, 3, 4, 5, or 6; Each L4 is independently a substituted or unsubstituted C1-C4 alkylene group, -S-, -O-, NR f, -S(O)-, -S(O)2-, preferably a substituted or unsubstituted C1-C4 alkylene group, where the hydrogen on the carbon atom of the substituted or unsubstituted C1-C4 alkylene group may each independently be replaced by deuterium, with the prerequisite that the structure formed by each L4 is chemically stable; 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; R1, R2, R3, R4, R5, G and R each independently represent H, -CN, a trifluoromethyl group, -CHF2, -OCF3, -OCHF2, a sulfonylamino 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), =NR f , -CN, hydroxyl group, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amino 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), =NR f , -CN, hydroxyl group, NR d R e(e.g., amino group), substituted or unsubstituted C1-C6 amino group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl group, substituted or unsubstituted C6-C 10 Hydrogen on the carbon atom of an aryl group, a substituted or unsubstituted 5- to 12-membered heteroaryl group having 1 to 3 heteroatoms, and a substituted or unsubstituted 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms can each be independently replaced by deuterium, and a substituted or unsubstituted [ka] , substituted or unsubstituted [ka] , substituted or unsubstituted [ka] (Change the structure here), [ka] In the formula, Rb, Rc and R d 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, or Rb and Rc together with the adjacent N atom form a substituted or unsubstituted 4- to 10-membered ring, wherein Rb, Rc and R d Each hydrogen on the carbon atom 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, -C0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9, 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), =NR f , -CN, hydroxyl group, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amino 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] , and -(L 1a ) r -(L 2a ) s -(L 3a ) s - selected from the group consisting of 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 2ais a substituted or unsubstituted C6-C 12 selected 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 5- 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-R g , -NH-SO2-R g , -SO2-NH-CO-R g , -OR g , -N(R g )2, -CO2R g , -CON(R g )2, -CONHCOR g , N.R. g -CO-N(R g )2, -NR g -SO2-N(R g ) 2 selected from the group consisting of r is 1, 2, 3, 4, 5, or 6; s is 0, 1, or 2, R d , R e and R g 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, and substituted or unsubstituted C6-C 10 aryl groups or R d and R etogether form a substituted or unsubstituted 3- to 10-membered (preferably 5- to 10-membered) cycloalkyl group or a 3- 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 C6-C 10 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 selected from the group consisting of a cycloalkyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkenyl group, and a -C(=O)-substituted or unsubstituted C2-C6 alkynyl group; Unless otherwise specified, the above "substitution" includes halogen (including -F, Cl, Br), -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, oxo (=O), -CN, hydroxyl group, amino group, C1-C6 alkylamino group, carboxyl group, -NHAc, [ka] , a C1-C6 alkyl group, a C1-C6 alkoxy group, a 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 alkylamino group; In each of the above formulas, any of the heteroatoms are selected from the group consisting of B, P, N, S and O.

[0009] In another preferred embodiment, there is provided a compound according to formula I, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof: Formula I: [ka] wherein n, q, m, t, and p 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; X7 is selected from the group consisting of N and CR; X8 and X9 are each independently selected from the group consisting of O, S, SO, SO2, C(R)2, and NR, where R is H, a C1-C6 alkyl group, chlorine, bromine, fluorine, iodine, a cyano group, a hydroxyl group, a nitro group, NR f , substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted C6-C 10 Heteroaryl 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 selected from the group consisting of a cycloalkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkenyl group, a -C(=O)-substituted or unsubstituted C2-C6 alkynyl group; M3, M4 and M5 are each independently selected from the group consisting of a chemical bond, CR, N, NR, O, S, SO and SO2; Each M6 is independently selected from the group consisting of CR, N and C; [ka] represents a single or double bond, [ka] each independently represents a substituted or unsubstituted C5-C 12 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 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 C5-C 12 cycloalkyl groups, wherein the heterocyclic group has 1 to 3 heteroatoms; 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] , and substituted or unsubstituted [ka] is selected from the group consisting of G is [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 5-10 membered heterocyclic group having 1-3 heteroatoms selected from substituted or unsubstituted N, S and O; R1, R2, R3, R4, R5, G and R each independently represent H, -CN, a trifluoromethyl group, a sulfonylamino 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), =NR f , -CN, hydroxyl group, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amino 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] wherein Rb and Rc are each independently selected from the group consisting of H, 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, 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, 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), =NR f , -CN, hydroxyl group, NR d R e (e.g., amino group), substituted or unsubstituted C1-C6 amino 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] , and -(L 1a ) r -(L2a ) s -(L 3a ) s - selected from the group consisting of 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)-, and -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 Aryl group, -CN, hydroxyl group, amino group, carboxyl group, -CO-NH-SO2-R g , -NH-SO2-R g , and -SO2-NH-CO-R g is selected from the group consisting of r is 1, 2, 3, 4, 5, or 6; s is 0, 1, or 2, R d , R e and R g 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 Rd and R e taken together form a substituted or unsubstituted 5- to 10-membered cycloalkyl group or a 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-C 10 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; Unless otherwise specified, the term "substituted" refers to halogen (including, but not limited to, -F, Cl, Br), -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, oxo, -CN, hydroxyl group, amino group, C1-C6 alkylamino 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 alkylamino group; In each of the above formulas, any of the heteroatoms are selected from the group consisting of B, P, N, S and O. In another example, the [ka] is a benzene ring, and preferably, R3 is a methyl group, a C1-C6 alkyl or alkoxy group, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, halogen (including -F, Cl, Br), -CH2Cl, -CH2Br, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, -CN, a hydroxyl group, an amino group, or an alkyl group-substituted amino group.

[0010] In another example, the [ka] wherein the ring attachment point can be N or C (substituents on the ring are not shown).

[0011] In another example, the ring [ka] has the substituents shown in formula IV: Formula IV: [ka] where w is 0, 1, 2, 3, 4, 5, or 6; Each L4 is independently a substituted or unsubstituted C1-C4 alkylene group, -S-, -O-, NR f , -S(O)-, -S(O)2-, preferably a substituted or unsubstituted C1-C4 alkylene group, in which all hydrogens on the carbon atoms of the substituted or unsubstituted C1-C4 alkylene group are each independently replaced by deuterium, with the prerequisite that the structure formed by each L4 is chemically stable; [ka] is a substituted or unsubstituted C3-C 10cycloalkyl 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, or a substituted or unsubstituted 4- to 10-membered cyclic amide group, wherein all hydrogens on ring-forming carbon atoms of the substituted or unsubstituted 4- to 10-membered cyclic amide group of the 3- to 8-membered nitrogen-containing heterocyclic group can be independently replaced by deuterium; Each R7 is independently a substituted or unsubstituted C1-C6 alkyl group, -CN, a hydroxyl group, an amino group, a carboxyl group, -OR g , -N(R g )2, -CO-NH-SO2-R g , -NH-SO2-R g , -SO2-NH-CO-R g , -CO2R g , -CON(R g )2, CONHCOR g , N.R. g -CO-N(R g )2, -NR g -SO2-N(R g )2, and R f and R g is as defined above, where R f and R g may be replaced independently by deuterium, wherein the substituents are selected from the group consisting of halogen, hydroxyl, carboxyl, cyano, and C1-C6 alkoxy.

[0012] In another example, the compound of formula I has the structure shown in the following formula: [ka]

[0013] In another example, the compound of formula I has the structure shown in the following formula: [ka]

[0014] In another example, the [ka] is selected from the group consisting of: [ka]

[0015] In another preferred embodiment, 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 are taken together to form a substituted or unsubstituted 5- to 10-membered cycloalkyl group or a 5- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O, and in another preferred embodiment, the substituents described herein are a carboxyl group, a hydroxyl group, [ka] and R 10 represents a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C 10 A cycloalkyl group, preferably R10 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.

[0016] In another example, the compound is selected from the following table: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0017] A second aspect of the present invention provides a process for the preparation of a compound of formula I according to the first aspect of the present invention, said process comprising steps selected from those shown in synthesis schemes 1 or 2, Synthetic Scheme 1: [ka] (a) intermediate II-1 and II-2 are used as raw materials to undergo a Sonogashira coupling reaction catalyzed by a palladium catalyst to obtain intermediate II-3; (b) II-3 and III-1 are used as raw materials to carry out a coupling reaction (e.g., Suzuki, Buchwald, etc.) under palladium catalyst and ligand conditions to give intermediate I-1; Preferably, the process for preparing intermediate II-1 is as follows: [ka] Using II-4 as a raw material, a halogenation reaction is carried out under the catalytic action of Lewis acid to obtain intermediate II-1; Preferably, the process for preparing intermediate III-1 is as follows: [ka] (a) using the compound 4-bromoindanone as a raw material, under the action of a chiral auxiliary (e.g., R / S-CBS) and a reducing agent (e.g., borane) to form a chiral alcohol 1-2; (b) using III-1 (or III-5) and III-2 as raw materials, an affinity substitution reaction is carried out under basic conditions to obtain intermediate III-3 (or III-6); (c) using III-3 (or III-6) and bis(pinacolato)diboron as raw materials, a boronation reaction is carried out under palladium catalysis and ligand conditions to obtain intermediate III-1; (d), (e) compound 4-bromoindanone and R / ST-butylsulfonimide are used as raw materials to form a protected chiral amino group compound under the action of Lewis acid (e.g., ethyl tetratitanate) and reducing agent (e.g., lithium aluminum hydride, sodium borohydride, etc.), and the protecting group is removed under acidic conditions to obtain chiral amino group compound III-5; Synthetic Scheme 2: [ka] (a) Using compound II-4 as a raw material, reacting it 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 suitable dehydrating reagent (e.g., PPh3 / DDQ) conditions 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 the target product I-2; X1-X above 10 , R1-R 10 , t and m are as defined above.

[0018] 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 carrier.

[0019] A fourth aspect of the present invention provides the use of 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, or a pharmaceutical composition according to the third aspect of the invention, for use in the preparation of a pharmaceutical composition for the prevention and / or treatment of a disease associated with the activity or expression level of PD-1 / PD-L1.

[0020] 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. 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] A sixth aspect of the invention provides a method of modulating PD-1 / PD-L1 interaction in vitro, 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. Effect of the Invention

[0025] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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-C12 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.

[0037] 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.

[0038] 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. 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.

[0039] 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.

[0040] 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).

[0041] 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.

[0042] 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, medularic 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, morpholin or tris(2-hydroxyethyl)amine.

[0043] 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 process of the compound of the present invention can be 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.

[0044] Pharmaceutical Compositions and Methods of Administration Because the compounds of the present invention have excellent inhibitory activity against PD-1 / PD-L1 interaction, the compounds of the present invention and various crystal forms thereof, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates thereof, as well as pharmaceutical compositions comprising 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).

[0045] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharma- ceutically acceptable excipient or carrier. 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.

[0046] "Pharmaceutically acceptable carrier" 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 carriers 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®), wetting agents (e.g., sodium lauryl sulfate, sodium lauryl sulfate, sodium glycerin ... sulfates), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0047] 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). Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as, 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 ...

[0048] 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.

[0049] 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 carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0051] 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.

[0052] 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.

[0053] The main advantages of the present invention are: (1) The compounds of the present invention have high inhibitory activity against PD-1 / PD-L1 interaction, have strong binding ability to PD-L1 protein, and have 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.

[0054] 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.

[0055] 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).

[0056] 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.

[0057] 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.

[0058] 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.

[0059] Example 1. Synthesis of Compound 001 [ka] [ka] Phase 1-1: Compound 1-1 (5.0 g, WO2012158550), 1-2 (4.4 g), Pd(OAc)2 (265 mg) and Cs2CO3 (15.4 g) are added to dioxane (100 mL) and reacted under N2 protection at 95°C for 2 hours. The reaction completion is detected by TLC spot plate. The reaction solution is filtered, the filtrate is spin-dried, and 4.8 g of pale yellow solid is obtained by column chromatography (EA:HEP=1:30). MS-APCI: 348 [M+H] + .

[0060] Phase 1-2: Compound 1-3 (4.8 g), 1-4 (2.5 g, dissolved in 1.5 mL of AcOH) are added to DCM, then 2.8 g of TEA is added, and stirred at room temperature for 1 hour, followed by NaBH(OAc)3 (4.4 g). After 30 minutes, the reaction is complete by TLC spot plate. The reaction solution is washed with saturated NaHCO3, extracted with DCM, the DCM is dried, spin-dried, and purified by column (MeOH:DCM=1:20) to obtain 5.1 g of product, a pale yellow oily viscous substance. MS-APCI: 419 [M+H] + .

[0061] Phases 1-3: Compound 1-5 (5.1 g), BpiN2 (3.4 g), Pd(dppf)Cl2.DCM (498 mg), and KOAc (2.4 g) are added to dioxane (100 mL) and reacted under N2 gas protection at 90 °C for 2.5 h. Completion of the reaction is detected by LC-MS. The reaction solution is filtered, washed with water, extracted with DCM, dried, spin-dried, and column (DCM:MeOH = 30:1) to obtain 5.2 g of product as a gray solid. MS-APCI: 467 [M + H] + . 1H NMR (400MHz, Chloroform-d)δ 7.85(d, J=8.1Hz, 1H), 7.75(d, J=7.3Hz, 1H), 7.50(d, J=7.5Hz, 1H), 7.21(t, J=7.4Hz, 1H), 6.45(dd, J=7.1, 4.5Hz, 1H), 6.37(d, J=8.0Hz, 1H), 4.5 8(s, 1H), 4.22(s, 2H), 4.01(s, 3H), 3.38-3.30(m, 2H), 3.15-3.07(m, 2H) , 2.62-2.53(m, 2H), 2.45-2.35(m, 2H), 2.27-2.17(m, 3H), 1.33(s, 12H).

[0062] Phases 1-4: Dissolve 1-7 (5 g) in 50 mL of DMF, add NIS (7.6 g, dissolved in 20 mL of DMF) dropwise at 0° C., complete the addition in 2 hours, and react at 0° C. for 1 hour. TLC detects the completion of the reaction of the raw material. Pour the reaction liquid into water, extract with EA, dry, and column to obtain 7.0 g of product as a pale yellow solid. MS-APCI: 275.2 [M+H] + .

[0063] Phases 1-5: In a 100mL two-neck flask, 1-8 (3.0g) is dissolved in DMF (30mL), Zn(CN)2 (1.3g) and Pd(pph3)4 (2.5g) are added, and the mixture is reacted under N2 protection at 105℃ for 1 hour, and the reaction completion of the raw materials is detected by TLC spot plate. After cooling, the reaction solution is diluted with EA / HEP and filtered. The filtrate is washed with saturated NaCl and extracted with EA. Purify by column to obtain 1.5g of pure product as a yellow solid. MS-APCI: 174.0[M+H] + .

[0064] Phases 1-6: In a 25mL two-neck flask, 1-9 (400mg) was suspended in DCM (5mL), and NIS (520mg) was added at room temperature and reacted for 10 minutes, and the raw material disappeared on TLC spot plate. Work-up: Water was added to the reaction solution, and it was extracted with DCM. The DCM layer was washed with Na2S2O3, dried, and spin-dried to obtain 600mg of the product as a brown solid. MS-APCI: 300.2 [M+H] + .

[0065] Stages 1-7: In a 15 mL reaction tube, 1-10 (400 mg), 1-11 (337 mg, WO2018195321), Pd(PPh3)2Cl2 (232 mg), CuI (13 mg), and DIPEA (838 mg) are dissolved in DMAc (3 mL) and reacted under N2 protection at 85 °C for 2 h. The disappearance of 15 is detected by TLC. The reaction solution is washed with water and extracted with EA. The EA is dried, spin-dried, and purified by column to obtain 260 mg of the product as a pale yellow solid. MS-APCI: 366.2 [M+H] + .

[0066] Stages 1-8: In a 15 mL reaction tube, 1-16 (150 mg), 1-17 (135 mg), NaBH3CN (39 mg), TEA (83 mg) are added to THF (5 mL) and reacted at 70° C. overnight. The disappearance of 16 is detected by TLC. The reaction solution is spin-dried, water is added, and the mixture is extracted with EA. The EA is dried, spin-dried, and purified by column to obtain 120 mg of a pale yellow oily product. MS-APCI: 479.2 [M+H] + .

[0067] Stages 1-12: 1-18 (120 mg) was dissolved in THF / HO (4 mL, 1:1), LiOH (18 mg) was added, and the mixture was allowed to react at room temperature for 1 h. The disappearance of 18 was detected by TLC. The THF was spun off from the reaction solution, and the pH was adjusted to 4 by adding 2N HCl to precipitate a solid, which was then filtered and spin-dried to obtain 100 mg of the product as a white solid. MS-APCI: 465.2 [M+H] + .

[0068] Stages 1-9: Compound 1-19 (100 mg), 1-6 (110 mg), Pd(dppf)Cl2 (10 mg), and Na2CO3 (43 mg) are added to dioxane / H2O (2.5 mL, 4:1) and reacted under N2 gas protection at 90 °C for 2 h. Completion of the reaction is detected by TLC. The reaction solution is filtered, washed with water, extracted with EA, dried, spin-dried, and column (DCM:MeOH = 10:1) to obtain 80 mg of the product as a pale yellow solid. MS-APCI: 725.3 [M + H] + .

[0069] Example 2. Synthesis of Compound 002 [ka] Phase 2-1: Dissolve raw material 2-1 (51g) in 500ml of methanol, add 300ml of water, add sodium bicarbonate (28.9g), add methanol solution of NIS at about 0℃, and react overnight after addition. Work-up: 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 130g of gray solid.

[0070] Phase 2-2: In a 1000mL three-neck flask, add 1000mL of raw material 2-2 (63g), ZnCN2 (27g), and Pd(PPh3)4 (12.8g) and add 1000mL of DMF. Replace with N2 three times and stir at 90℃ for 3 hours. TLC spot plate shows a small amount of raw material remaining, and LCMS shows the reaction of raw material is complete.

[0071] Stage 2-3: Add acetic anhydride (75 mL), concentrated nitric acid (5 mL) to a 250 mL single-neck flask, add raw material 2-3 (5.0 g, 28.9 mmol) in batches, stir under water bath, after 20 min, precipitate forms, monitor reaction completion by TLC spot plate, filter the precipitate, suck dry, slurry, and pull dry to obtain 4 g of white solid.

[0072] Stages 2-4: Add THF (200 mL) to a 500 mL single-neck flask, add raw material 2-4 (5.0 g), TFA (0.2 mL), and Pt / C, replace with H2 three times, stir at room temperature, and react for 1 hour. TLC spot plate is used to monitor the completion of the reaction of raw materials, and Pt / C is filtered, and the filtrate is used directly in the next step.

[0073] Stages 2-5: To the above filtrate 2-5 (11 g) in THF solution, add 180 mmol of Et3N, and slowly add 2-6 (11.8 g, Organic Letters, 2019, 21, 5971-5976) in 15 ml of DCM solution. Allow to react at room temperature for 1 hour, and a lot of suspension will appear. Filter the solid and purify it by slurrying with ethyl acetate to obtain 15 g of gray-white solid.

[0074] Stages 2-4: At room temperature, PPh3 (9.7 g) is dissolved in toluene, DDQ (8.4 g) is slowly added, and the mixture is stirred uniformly. At this point, the system becomes suspended. Raw material 2-7 (8 g) is added, and the mixture is reacted at 110°C for 1 hour. The reaction is monitored by TLC spot plate. The product is mainly a transparent liquid, which is poured off, concentrated and dried, and slurried with EA to obtain 3.7 g of a white solid.

[0075] Stages 2-5: In a 15 mL reaction tube, 2-8 (1 g), methyl 3-acridine carboxylate (0.6 g), NaBH3CN (0.1 g), TEA (83 mg) are added to THF (5 mL) and reacted at 70°C for 5 hours. The disappearance of 1-6 is detected by TLC. The reaction solution is spin-dried, water is added, and the mixture is extracted with EA. The EA is dried, spin-dried, and purified by column to obtain 0.5 g of a yellow solid.

[0076] Stages 2-6: Bromine raw material 2-9 (1.7 g), 1-6 (1 g), Pd(dppf)Cl2 (0.12 g) and sodium carbonate (0.62 g) are placed in a 50 mL reaction flask, replaced with nitrogen gas three times, 1,4-dioxane (8 mL) and water (2 mL) are added, reacted at 90 ° C, monitored by TLC, worked up, quenched by adding ammonium chloride in an ice bath, extracted twice with MTBE, washed five times with saturated saline, passed through a column (HEP-DCM = 100, 50: 1, 10: 1, 5: 1), the product is washed off, concentrated, and 0.6 g of a yellow solid is obtained. MS-APCI: 740 [M + H] + .

[0077] Stages 2-7: Dissolve 2-10 (53 mg) in 5 mL of MeOH, add 2 mL of NaOH (2N), and react at 26° C. for 5 hours. Spin-dry the reaction solution at 40° C., add 50 mL of water to the remaining solid, adjust the pH to 7 with 2M HCl, filter the solid, wash with water, wash with THF, dry, and further purify to obtain 5 mg of a yellow solid. MS-APCI: 726 [M+H] + .

[0078] Example 3. Synthesis of Compound 003 [ka] Phase 3-1: Acetic anhydride (75 mL), concentrated nitric acid (5 mL) were added to a 250 mL single-neck flask, and raw material 14 (5.0 g, 28.9 mmol) was added in batches, stirred under water bath, after 20 min, a precipitate formed, and the reaction completion was monitored by TLC spot plate, the precipitate was filtered, sucked dry, slurried, and pulled dry to obtain 4.5 g of white solid, the yield is 71%.

[0079] Phase 3-2: In a 500 mL single-neck flask, add THF (200 mL), raw material 3-1 (5.0 g, 23 mmol), TFA (0.2 mL), and Pt / C, replace with 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 the Pt / C, and use the filtrate directly in the next step.

[0080] Stage 3-3: To a solution of the above filtrate 3-2 (10.0 g, 45.8 mmol) in THF, 180 mmol of EtN was added to obtain 2-6 (10.74 g, 46 mmol, OR g anic Letters, 2019, 21, 5971-5976) was dissolved in 15 ml of DCM and slowly added, and the mixture was allowed to react at room temperature for 1 hour. A large amount of suspension appeared, and the solid was filtered, slurried with ethyl acetate, and purified to obtain 18 g of an off-white solid.

[0081] Stage 3-4: At room temperature, PPh3 (9.7 g, 37 mmol) was dissolved in toluene, DDQ (8.4 g, 37 mmol) was slowly added and stirred uniformly, in this case the system was suspended, raw material 3-4 (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 mainly a transparent liquid, poured off, concentrated and dried, and slurried with EA to obtain 3.7 g of white solid.

[0082] Stages 3-5: Compounds 3-5 (1 g, 2.72 mmol) and 17 (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 steps 1-11. MS (APCI): 480 [M+H] + .

[0083] Stages 3-6: Compounds 3-6 (200 mg, 0.416 mmol) and 5 (233 mg, 0.5 mmol) were used as raw materials, and 0.21 g of a white solid was prepared according to the synthesis method of steps 1-12. MS (APCI): 740 [M+H] + .

[0084] Stages 3-7: Compound 3-7 (210 mg, 0.284 mmol) and LiOH (20 mg, 0.85 mmol) were added sequentially to a single-neck flask containing THF / MeOH / H2O (2:2:1, 5 mL), stirred at room temperature for 2 h, and the reaction was detected by TLC. After completion of the reaction, 50 mg of a white solid was prepared by reverse phase column. MS (APCI): 726 [M+H] + .

[0085] Example 4. Synthesis of Compound 004 [ka] Phase 4-1: Using compounds 3-2 (2 g, 0.106 mmol) and 4-1 (2.83 g, 0.011 mmol, WO2017059135) as raw materials, prepare 3 g of off-white solid according to the synthesis method of step 3-3. MS (APCI): 405 [M+H] + .

[0086] Phase 4-2: Compound 4-2 (2g) was used as the raw material, and 1.1g of an off-white solid was prepared according to the synthesis method of steps 3-4. MS (APCI): 387 [M+H] + .

[0087] Stage 4-3: Using compound 4-3 (1 g, 2.58 mmol) and compound 17 (0.85 g, 5.16 mmol) as raw materials, 0.9 g of off-white solid was prepared according to the synthesis method of steps 3-5. MS (APCI): 500 [M+H] + .

[0088] Stage 4-4: Compound 4-4 (0.2 g, 0.4 mmol) and compound 5 (0.22 g, 0.48 mmol) were used as raw materials, and 0.18 g of an off-white solid was prepared according to the synthesis method of steps 3-6. MS (APCI): 760 [M+H] + .

[0089] Stage 4-5: Compound 4-5 (0.2 g, 0.4 mmol) was used as the raw material, and 42 mg of a white solid was prepared according to the synthesis method of steps 3-7. MS (APCI): 746 [M+H] + .

[0090] Example 5. Synthesis of Compound 005 [ka] Phase 5-1: Compound 3 (1.5 g, 4.34 mmol), Palau' Chlor (1 g, 4.77 mmol) and TFA (0.35 mL, 4.77 mmol) are added sequentially to a single-neck flask containing CH3CN / DCM (2:1, 30 mL), stirred overnight at room temperature, and the reaction is detected by LC-MS. After completion of the reaction, it is filtered, rinsed twice with DCM, and then the filtrate is washed with saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.46 g of a white solid. MS-APCI: 188 [M-195+H] + (debris peak).

[0091] Phase 5-2: Compound 5-1 (1.4 g, 3.66 mmol), B2piN2 (1.02 g, 4 mmol), KOAc (718 mg, 7.32 mmol), Pd(dppf)2Cl2 (257 mg, 0.366 mmol) are added sequentially to a single-neck flask containing dioxane (30 mL), heated and stirred in an oil bath at 95 °C under nitrogen gas protection for 3 hours, and the reaction is detected by LC-MS. After the reaction is completed, it is filtered, spin-dried, the sample is mixed, and 800 mg of oil is obtained by column chromatography. MS-APCI: 188 [M-243 + H] + (Debris Peak).

[0092] Phase 5-3: Compound 5-2 (800 mg, 1.86 mmol), R-3-hydroxytetrahydropyrrole hydrochloride (460 mg, 3.72 mmol), DIPEA (0.3 mL, 1.86 mmol) and NaBH(OAc)3 (1.18 g, 5.59 mmol) are added sequentially to a single-neck flask containing DCM (30 mL), stirred at room temperature for 2 h, and the reaction is detected by TLC. After completion of the reaction, it is washed with saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain 670 mg of a white solid. MS-APCI: 501 [M+H] + .

[0093] Phase 5-4: Compounds 5-3 (200 mg, 0.4 mmol) and 4-4 (160 mg, 0.32 mmol) were used as raw materials, and 160 mg of a white solid was obtained according to the synthesis method of steps 1-12. MS-APCI: 794 [M+H] + .

[0094] Stage 5-5: Compound 5-4 (160 mg) was used as the raw material, and 21 mg of a white solid was obtained according to the synthesis method of steps 3-7. MS (APCI): 780 [M+H] + .

[0095] Example 6. Synthesis of Compound 006 [ka] Phase 6-1: Chiral column separation using raw material 4-4 (10 g) gives S-(4-4) (4.2 g). Then, S-(4-4) is used as raw material and the synthesis method of step 3-7 is followed to give 3 g of white solid. MS (APCI): 486 [M+H] + .

[0096] Phase 6-2: Using raw materials 6-1 (200 mg, 0.41 mmol) and 5-3 (247 mg, 0.49 mmol) as raw materials, 38 mg of a white solid was prepared according to the synthesis method of steps 1-12. MS (APCI): 780 [M+H] + .

[0097] Example 7. Synthesis of Compound 007 [ka] Phase 7-1: 6-1 (200.0 mg, 1.0 eq), cyclopropylsulfonamide (200.0 mg, 4.0 eq), DMAP (202.0 mg, 4.0 eq), EDCI (314.0 mg, 4.0 eq) are added to the reaction flask, dissolved in 6 mL of DCM, and stirred at RT for 4 h. The reaction of the raw material is monitored for completion by TLC. The reaction is quenched with 1 M HCl, washed with saturated saline, dried, concentrated, and purified by column chromatography to give 180 mg of a yellow solid. MS (APCI): 563 [M+H] + .

[0098] Phase 7-2: Using raw materials 7-1 (200 mg, 0.355 mmol) and 5-3 (213 mg, 0.43 mmol) as raw materials, 26 mg of a white solid was obtained according to the synthesis method of steps 1-12. MS (APCI): 857 [M+H] + .

[0099] Example 8. Synthesis of Compound 008 [ka] Phase 8-1: Using raw materials 3-6 (200 mg, 0.41 mmol) and 5-3 (247 mg, 0.49 mmol), 120 mg of white solid was obtained by column chromatography according to the synthesis method of steps 1-12.

[0100] Stages 3-7: Compound 8-1 (210 mg) and LiOH (18 mg) were added sequentially to a single-neck flask containing THF / MeOH / H2O (2:2:1, 5 mL), stirred at room temperature for 2 hours, and the reaction was detected by TLC. After completion of the reaction, 50 mg of a white solid was prepared by reverse phase column. MS (APCI): 760 [M+H] + .

[0101] The compounds in the following table are synthesized by applying the method for synthesizing compounds 001 to 008. [ka] [ka]

[0102] Example 120. Synthesis of Compound 120 [ka] Stage 120-1: Dissolve 2-1 (1.3 g) in 200 mL of DCM-3M H2SO4 (1:1), add 0.71 g of sodium nitrite to the reaction system under ice bath at 5°C, and react overnight at room temperature under nitrogen gas protection. TLC spot plate shows disappearance of 1-1, and LCMS analysis shows the product is produced. Purify by column chromatography to obtain 300 mg of product. MS-APCI: 208 [M+H] + .

[0103] Stage 120-2: Compound 120-1 (4 g) is dissolved in 200 mL of DCM (in a 500 mL single-neck flask), 6.3 g of NIS is added, and the mixture is protected with argon gas. The mixture is reacted at room temperature overnight. The reaction is completed by TLC spot plate. 100 mL of 2 M HCl is added to the reaction solution, and the liquid is separated and dried. Spin-dry and purify by column to obtain 5 g of product as a pale yellow solid. MS-APCI: 334 [M+H] + .

[0104] Stage 120-3: Using 120-2 (390 mg) and 1-11 (337 mg) as raw materials, follow the synthesis method of steps 1-7 to obtain 200 mg of product. MS-APCI: 400 [M+H] + .

[0105] Stage 120-4: Using 2-8 (200 mg) and methyl 3-acridinecarboxylate (86 mg) as raw materials, follow the synthesis method of step 2-5 to obtain 100 mg of product. MS-APCI: 499 [M+H] + .

[0106] Stage 120-5: Using raw materials 120-4 (100 mg) and 5-3 (110 mg) as raw materials, follow the synthesis method of steps 1-12 to obtain 102 mg of a white solid by column chromatography. MS (APCI): 793 [M+H] + .

[0107] Stage 120-6: Compound 120-5 (102 mg) and LiOH (20 mg) were added sequentially to a single-neck flask containing THF / MeOH / H2O (2:2:1, 5 mL), stirred at room temperature for 2 hours, and the reaction was detected by TLC. After completion of the reaction, 26 mg of a white solid was prepared by reverse phase column. MS (APCI): 779 [M+H] + .

[0108] Example 121. Synthesis of Compound 121 [ka] Stage 121-1: Using 3-12 (2 g) as raw material and following the synthesis method of step 3-1, 0.8 g of white solid is obtained. MS (APCI): 320 [M+H] + .

[0109] Stage 121-2: Using 121-1 (800 mg) and 1-11 (756 mg) as raw materials, 615 mg of product is obtained according to the synthesis method of steps 1-7. MS-APCI: 386 [M+H] + .

[0110] Stage 121-3: Using 121-2 (200 mg) and methyl 3-acridinecarboxylate (86 mg) as raw materials, and following the synthesis method of steps 2-5, 152 mg of product is obtained. MS-APCI: 485 [M+H] + .

[0111] Stage 121-4: Using 121-3 (100 mg) and 5-3 (108 mg) as raw materials, follow the synthesis method of steps 1-12 to obtain 96 mg of a white solid by column chromatography. MS (APCI): 779 [M+H] + .

[0112] Stage 121-5: Compound 121-4 (96 mg) and LiOH (15 mg) were added sequentially to a single-neck flask containing THF / MeOH / H2O (2:2:1, 5 mL), stirred at room temperature for 2 hours, and the reaction was detected by TLC. After completion of the reaction, 26 mg of a white solid was prepared by reverse phase column. MS (APCI): 765 [M+H] + .

[0113] 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 0.1 μl of HTR containing Light®-allophycocyanin (APC, PerkinElmer-AD0059H)-conjugated antibody f Add detector solution. After centrifugation, incubate the well plate at 25°C for 60 min. Read data on a PHERAstar FS plate reader (665nm / 620nm ratio). Final concentrations during the measurement are ~3nM PD1, 10nM PD-L1, 1nM Europium anti-human IgG and 20nM anti-His-allophycocyanin. Activity data are fitted using GraphPad Prism 5.0 software to obtain IC values ​​of inhibitors. 50 Derive the value.

[0114] IC of compounds exemplified in the Examples 50 The values ​​are as follows: IC 50 :+ is ≦10 nM, ++ is 10 nM to 100 nM, and +++ is >100 nM. PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTR) as described in Example A f) Data for the compounds of the examples obtained using binding assays are shown in Table 1 as IC values ​​for the compounds of the invention tested. 50 are all less than 10 nm, and several compounds (about 25%) are even less than 1 nM, with activity test data for several preferred compounds as provided in Table 1.

[0115] Table 1. [Table 1]

[0116] 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 according to formula I: Formula I: 【Chemistry 1】 【Chemistry 2】 teeth, 【Chemistry 3】 is selected from the group consisting of wherein n, m, and p are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5; X ７ is CR, X ８ and X ９ are each independently C(R) ２ where R is H; M ３ , M. ４ and M. ５ are each independently CR; M ６ is C, 【Chemistry 4】 represents a single or double bond, 【Chemistry 5】 is phenyl, 【Chemistry 6-1】 is either substituted or unsubstituted 【Chemistry 6-2】 is selected from the group consisting of L １ is -O-, G is, 【Chemistry 7】 where w is 0, 1, 2 or 3; each Rd' is independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, and substituted or unsubstituted C6-C10 aryl; Each of the above L ４ is independently a substituted or unsubstituted C １ -C ４ Alkylene group, or NR ｆ wherein substituted or unsubstituted C １ -C ４ Each hydrogen on a carbon atom of an alkylene group may be independently replaced by deuterium, provided that each L ４ is chemically stable, and Rf is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl; Rb and Rc are each independently H and substituted or unsubstituted C １ -C ８ or Rb and Rc, together with the adjacent N atom, constitute a substituted or unsubstituted 3- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; R １ , R ２ , R ３ , and R ５ are each independently H, —CN, a trifluoromethyl group, or —CHF ２ , -OCF ３ , -OCHF ２ , a sulfonylamino group, a nitro group, a hydroxyl group, a halogen, a substituted or unsubstituted C １ -C １０ Alkyl group, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C ３ -C ８ Cycloalkyl groups, -CN, hydroxyl groups, and substituted or unsubstituted C １ -C ６ selected from the group consisting of amino groups; R ４ is NR ｄ R ｅ is selected from R ｄ and R ｅ are each independently H, substituted or unsubstituted C １ -C ６ Alkyl groups, and substituted or unsubstituted C ３ -C １０ cycloalkyl groups or R ｄ and R ｅ forms, together with the adjacent N atom, a substituted or unsubstituted 3- to 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 , oxo, -CN, hydroxyl group, amino group, C １ -C ６ Alkylamino group, carboxyl group, -NHAc, 【Chemistry 8】 and unsubstituted or substituted by Rz, said substituted groups being selected from the group consisting of C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ８ It refers to being substituted by one or more substituents selected from the group consisting of a cycloalkyl group and a 5-10 membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O, and the Rz substituent is a halogen, a hydroxyl group, a carboxyl group, a cyano group, a C １ -C ６ Alkoxy group, C １ -C ６ alkylamino 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 9】 is a benzene ring; 2. The compound of claim 1, an optical isomer, a hydrate, a solvate, or a pharma- ceutically acceptable salt thereof.

3. R ３ is methyl, C １ -C ６ Alkyl or alkoxy; C ３ -C ６ Cycloalkyl, -F, Cl, Br, -CH ２ Cl, -CH ２ Br, -CHCl ２ , -CCl ３ , -CH ２ F, -CHF ２ , -CF ３ , -CN, hydroxyl, amino or alkyl substituted amino.

4. The above 【Chemistry 10】 teeth, 【Chemistry 11-1】 and 【Chemistry 11-2】 wherein the ring is bonded to an N or C atom; The compound of claim 1.

5. The ring 【Chemistry 12】 has the substituents shown in formula IV: Formula IV: 【Chemistry 13】 where w is 0, 1, 2, or 3; Each of the above L ４ is independently a substituted or unsubstituted C １ -C ４ Alkylene group, and NR ｆ , wherein substituted or unsubstituted C １ -C ４ Each hydrogen on a carbon atom of an alkylene group may be independently optionally replaced by deuterium, provided that each L ４ The structure formed by is chemically stable. 【Chemistry 14】 is selected from the group consisting of substituted or unsubstituted 3- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from N, S, and O; Each R ７ each independently represents a substituted or unsubstituted C １ -C ６ is selected from the group consisting of an alkyl group, -CN, a hydroxyl group, an amino group, and a carboxyl group; R ｆ is as defined above, where R ｆ may be optionally and independently replaced by deuterium, where the replacement is selected from the group consisting of halogen, hydroxyl, carboxyl, cyano, C １ -C ６ substituted by a group selected from the group consisting of alkoxy groups, 2. The compound of claim 1, or an optical isomer, hydrate, solvate, or pharma- ceutically acceptable salt thereof.

6. w is 1, L ４ is C １ -C ４ is alkylene, 【Chemistry 15】 is a 3- to 8-membered nitrogen-containing heterocyclic group, or a substituted or unsubstituted 4- to 10-membered cyclic amide group, wherein all hydrogens on ring-forming carbon atoms of the substituted or unsubstituted 4- to 10-membered cyclic amide group of the 3- to 8-membered nitrogen-containing heterocyclic group may be independently replaced by deuterium.

7. (L ４ ) w is -CH ２ -NH-CH ２ - and 【Chemistry 16】 is a 3- to 8-membered nitrogen-containing heterocyclic group, or a substituted or unsubstituted 4- to 10-membered cyclic amide group, wherein all hydrogens on ring-forming carbon atoms of the substituted or unsubstituted 4- to 10-membered cyclic amide group of the 3- to 8-membered nitrogen-containing heterocyclic group may be independently replaced by deuterium. 【Request 8】 【Chemical 17】 teeth, 【Chemistry 18】 2. The compound of claim 1 selected from the group consisting of:

9. R ４ is N.R. ｄ R ｅ wherein R ｄ and R ｅ are each independently H, substituted or unsubstituted C １ -C ６ Alkyl group, substituted or unsubstituted C ３ -C １０ cycloalkyl groups, or R ｄ and R ｅ together form a substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, where substitution is selected from carboxyl, hydroxyl, 【Chemistry 19】 R ｄ , and R ｅ 2. The compound of claim 1, wherein hydrogen on a carbon atom of is optionally and independently replaced with deuterium.

10. A compound selected from the following table: 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 【Chemistry 28】

11. A process for preparing a compound of formula I according to claim 1, comprising the steps of: The compound of formula I is represented by formula I-1 and formula I-2, and the method comprises steps selected from those depicted in synthetic schemes 1 or 2: Synthetic Scheme 1: 【Chemical 29】 (a) intermediate II-1 and II-2 are used as raw materials to obtain intermediate II-3 by Sonogashira coupling reaction catalyzed by palladium catalyst; (b) Using II-3 and III as raw materials, a coupling reaction takes place under palladium catalyst and ligand conditions to obtain intermediate I-1; Synthetic Scheme 2: 【Chemistry 30】 (a) using compound II-4 as raw material and 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 under basic conditions gives amide intermediates, which are then cyclized under suitable dehydrating reagent conditions to give intermediates IV-4; (d) using IV-4 and III-4 as starting materials, a coupling reaction takes place under catalytic and ligand conditions to form the target product I-2; 2. A process for the preparation of a compound of formula I according to claim 1, characterized in that each of the above groups is as defined above.

12. The method for preparing intermediate II-1 is as follows: 【Chemistry 31】 The method according to claim 11, wherein II-4 is subjected to a halogenation reaction catalyzed by a Lewis acid to obtain intermediate II-1.

13. The method for producing intermediate III-4 is as follows: 【Chemistry 32】 (a) using the compound 4-bromoindanone as a raw material, reacting it under the action of a chiral auxiliary and a reducing agent to form a chiral alcohol III-1; (b) using III-1 and III-2 as starting materials, an affinity displacement reaction is carried out under basic conditions to obtain intermediate III-3; (c) using III-3 and bis(pinacolato)diboron as raw materials, a boronation reaction is carried out in the presence of a palladium catalyst and a ligand to obtain intermediate III-4; The method of claim 11, wherein

14. 1. A pharmaceutical composition comprising: (1) a compound according to any one of claims 1 to 10, and (2) a pharma- ceutically acceptable carrier; The pharmaceutical composition, characterized in that the pharma- ceutically acceptable carrier is selected from the group consisting of 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.

15. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 14, The use as described above, characterized in that it is used for the preparation of a pharmaceutical composition for preventing and / or treating a disease associated with the activity or expression level of PD-1 / PD-L1.

16. 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.

16. The use according to claim 15.

17. 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; 17. The use according to claim 16.

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

17. The use according to claim 16.

19. The autoimmune disease is selected from an organ-specific autoimmune disease and a systemic autoimmune disease.

17. The use according to claim 16.

20. The pharmaceutical composition further comprises at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, and ipilimumab; 16. The use according to claim 15.

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