CN112457331A

CN112457331A - Nitrogen-containing heterocyclic compound, and preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN112457331A
Application number: CN201910848960.6A
Authority: CN
Inventors: 王喆; 潜安然; 李德亮; 张基勇; 曾志宏
Original assignee: Shanghai Longwood Biopharmaceuticals Co Ltd
Current assignee: Shanghai Longwood Biopharmaceuticals Co Ltd
Priority date: 2019-09-09
Filing date: 2019-09-09
Publication date: 2021-03-09
Also published as: WO2021047556A1; CN114364685A

Abstract

The invention provides a nitrogen-containing heterocyclic compound, and a preparation method, a pharmaceutical composition and application thereof, and particularly provides a compound shown as a formula I below, or optical isomers thereofA body, hydrate, solvate, or pharmaceutically acceptable salt thereof; wherein, the definition of each group is described in the specification. The compounds of formula I are useful for treating diseases associated with the PD-1/PD-L1 signaling pathway.

Description

Nitrogen-containing heterocyclic compound, and preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of small molecule medicines, and particularly provides a small molecule compound which can be used for treating diseases related to a PD-1/PD-L1 signal pathway.

Background

The immune system plays a crucial role in controlling and curing many diseases, such as various cancers, diseases caused by viruses, and the like. Cancer cells often multiply rapidly by evading or suppressing the immune system in some way. One such way is to alter the expression of activating and inhibitory molecules on immune cells. Blocking the suppressive immune checkpoint, like PD-1, has proven to be a very effective method of suppressing cancer cells.

PD-1 is programmed cell death protein-1, also known as CD 279. It is expressed mainly in activated T cells and B cells and functions to inhibit the activation of cells, which is a normal homeostatic mechanism of the immune system, and PD-1 is a protective wall of our human body because excessive T/B cell activation causes autoimmune diseases. PD-1 is a type I transmembrane glycoprotein composed of 268 amino acids, and its structure mainly includes an outer immunoglobulin variable region, a hydrophobic transmembrane region, and an intracellular region. The intracellular region contains two phosphorylation sites, located in the immunoreceptor tyrosine inhibitory motif and immunoreceptor tyrosine switch motif, which also demonstrates that PD-1 is capable of back-regulating T cell receptor-mediated signaling. PD-1 has two ligands, PD-L1 and PD-L2, which differ in the manner of expression. PD-L1, which is up-regulated in many tumor cells, binds to PD-1 on T cells, inhibits T cell proliferation and activation, leaves T cells in an inactive state, and ultimately induces immune escape.

PD-1/PD-L1 exerts a reverse immunomodulatory effect. When PD-1 binds to PD-L1, tyrosine in the tyrosine-converting motif domain of the immune receptor of T cells can be phosphorylated, and the phosphorylated tyrosine can bind to phosphatase protein tyrosinase 2 and protein tyrosinase 1. This can block activation of extracellular signal-regulated kinase, and can block activation of phosphoinositide 3-kinase (PI3K) and serine-threonine protein kinase (Akt), thereby inhibiting T lymphocyte proliferation and secretion of related cytokines. While the PD-1/PD-L1 signal inhibits the activation and proliferation of T cells, the secretion of cytokines interleukin 2, interferon gamma and IL-10 can be realized. In addition, PD-1/PD-L1 signal has similar immune function to B cell, and when PD-1 binds to B cell antigen receptor, PD-1 cytoplasm region acts with tyrosinase containing protein tyrosinase 2 binding site, thereby preventing B cell activation.

PD-1/PD-L1-based immunotherapy is a new generation of immunotherapy that is of great interest. In recent years, a series of surprising research results prove that the PD-1/PD-L1 inhibitor has strong antitumor activity on various tumors. PD-1/PD-L1 antibody inhibitors that are currently marketed are Ninolumab from BMS, Lamboluzumab from Merck, and Atezolizumab from Roche. In addition to this, there are many studied PD-1/PD-L1 antibody inhibitors, including Cure Tech's Pidilizumab, GSK's AMP-224, and AstraZeneca's MEDI-4736.

Although tumor immunotherapy is considered as a new generation of revolution for targeted post-treatment cancer therapy. However, currently marketed and researched PD-1 single drug has its own defects, including injection administration, oral administration, instability in vivo, easy protease decomposition, easy immune cross reaction, difficult purification, high production cost, etc. Therefore, small molecule inhibitors of the PD-1/PD-L1 interaction are better candidates for tumor immunotherapy.

In view of the foregoing, there is a pressing need in the art to develop novel small molecule inhibitors of the PD-1/PD-L1 interaction.

Disclosure of Invention

The invention aims to provide a novel small molecule inhibitor of PD-1/PD-L1 interaction.

In a first aspect of the present invention, there is provided a compound represented by the following formula I, or an optical isomer, hydrate, solvate, or a pharmaceutically acceptable salt thereof:

wherein n, m, p and q are each independently selected from 0,1, 2,3 or 4;

L₁、L₂selected from the group consisting of: a bond, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-, -O-, substituted or unsubstituted-NH-, -S (O)₂-, substituted or unsubstituted-NHC (O) NH-, or,

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Is a group having the structure shown below:

wherein the content of the first and second substances,

Z¹selected from the group consisting of: o, S, NRf, N-O-Rf; wherein, said Rf is selected from the group consisting of: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted C₆-C₁₀Heteroaryl, cyano, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C₁-C₆Alkoxy, -C (═ O) -substituted or unsubstituted C₁-C₆Alkyl, -C (═ O) -substituted or unsubstituted C₃-C₁₀Cycloalkyl, -C (═ O) -substituted or unsubstituted C₂-C₆Alkenyl, -C (═ O) -substituted or unsubstituted C₂-C₆An alkynyl group;

Z²、Z³、Z⁴each independently selected from the group consisting of: n, CH₂、N-O、SO、SO₂C (═ O), NRa, CRa; wherein Ra is selected from the group consisting of: H. chloro, bromo, fluoro, iodo, cyano, halogen, hydroxy, nitro, NRf, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted C₆-C₁₀Heteroaryl, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C₁-C₆Alkoxy, -C (═ O) -substituted or unsubstituted C₁-C₆Alkyl, -C (═ O) -substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, -C (═ O) -substituted or unsubstituted C₂-C₆Alkenyl, -C (═ O) -substituted or unsubstituted C₂-C₆An alkynyl group;

Y¹、Y²、Y³each independently selected from the group consisting of: CH. CH (CH)₂、NH、NRa、N、N-O、CF、CRa、C(Ra)₂O, S, SO or SO₂；

Is a single bond or a double bond;

and is

Is an aromatic or non-aromatic moiety;

r is H, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₆-C₁₀Aryl, cyano, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C₁-C₆Alkoxy, -C (═ O) -substituted or unsubstituted C₁-C₆Alkyl, -C (═ O) -substituted or unsubstituted C₃-C₁₀Cycloalkyl, -C (═ O) -substituted or unsubstituted C₂-C₆Alkenyl, -C (═ O) -substituted or unsubstituted C₂-C₆Alkynyl, or- (L)_1a)_r-(L_2a)_s-(L_3a)_s-, in which,

each L_1aEach independently is a group selected from the group consisting of; chemical bond, substituted or unsubstituted C₁-C₇Alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-, -O-, substituted or unsubstituted-NH-, -S (O)₂-、

L_2aSelected from the group consisting of: substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted 5-12 membered heteroarylene having 1-3 heteroatoms, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 5-10 membered heterocyclylene having 1-3 heteroatoms;

L_3aselected from the group consisting of: H. substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxy, amino, carboxy, -CO-NH-SO₂-R_g、-NH-SO₂-R_g、-SO₂-NH-CO-R_g；

r is 1,2,3, 4, 5, 6;

s is 0,1, 2 respectively;

rd, Re are each independently selected from the group consisting of: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₆-C₁₀An aryl group;

selected from the group consisting of: substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclyl, substituted or unsubstituted 5-12 membered C5-C12 cyclyl, wherein the 5-12 membered heteroaryl and 5-12 membered heterocyclyl have 1-4 heteroatoms selected from B, P, N, O, S, wherein P, N, O as ring-forming atoms may be oxo and one or more ring-forming carbon atoms may be replaced by carbonyl; or the said

Is absent; or the said

Is equal to

Each independently a ring-forming divalent group selected from the group consisting of:

wherein, the bonding position of the ring can be N or C;

R₁、R₂、R₃and R₄Each independently selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., ═ O), ═ NRf, -CN, hydroxy, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted- (C1-C6 alkylene) -NH- (C1-C6 alkylene), or a pharmaceutically acceptable salt thereof,Carboxyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl having 1-3 heteroatoms, substituted or unsubstituted 5-12 membered heterocyclyl having 1-4 heteroatoms, substituted or unsubstituted

Substituted or unsubstituted

Wherein, Rb, Rc and R_zEach independently selected from the group consisting of: H. substituted or unsubstituted C₁-C₈An alkyl group; or said Rb and Rc taken together with the adjacent N atom form a substituted or unsubstituted 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O; or (L)_1a)_r-(L_2a)_s-(L_3a)_s-；

Unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen: including but not limited to-F, Cl, Br, -CH₂Cl、-CHCl₂、-CCl₃、-CH₂F、-CHF₂、-CF₃Oxo, -CN, hydroxy, amino, C1-C6 alkylamino, carboxy, -NHAc, a group selected from the group consisting of unsubstituted or substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C3-C8 cycloalkyl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, hydroxy, carboxy, cyano, C1-C6 alkoxy, C1-C6 alkylamino;

in the formulae above, any of the heteroatoms is selected from the group consisting of: B. p, N, S and O.

In another preferred embodiment, the compound has the structure shown in formula II below:

wherein n, m, p and q are each independently selected from 0,1, 2,3 or 4;

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Is a group having the structure shown below:

wherein the content of the first and second substances,

Z¹selected from the group consisting of: o, S, NRf, N-O-Rf; wherein, said Rf is selected from the group consisting of: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted C₆-C₁₀Heteroaryl, cyano, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C₁-C₆Alkoxy, -C (═ O) -substituted or unsubstitutedC of (A)₁-C₆Alkyl, -C (═ O) -substituted or unsubstituted C₃-C₁₀Cycloalkyl, -C (═ O) -substituted or unsubstituted C₂-C₆Alkenyl, -C (═ O) -substituted or unsubstituted C₂-C₆An alkynyl group;

Is a single bond or a double bond;

and is

Are aromatic or non-aromatic segments.

R₁、R₂、R₃And R₄Each independently selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., ═ O), ═ NRf, -CN, hydroxy, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted- (C1-C6 alkylene) -NH- (C1-C6 alkylene), carboxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl having 1-3 heteroatoms, substituted or unsubstituted 5-12 membered heterocyclic having 1-4 heteroatoms, substituted or unsubstituted

Substituted or unsubstituted

Or (L)_1a)_r-(L_2a)_s-(L_3a)_s-

In another preferred embodiment, the

Has a structure represented by the following formula:

wherein the content of the first and second substances,

X₆、X₇、X₈、X₉、X₁₀and X₁₁Each independently selected from the group consisting of: n, CR, respectively;

R₆selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., ═ O), ═ NRf, -CN, hydroxy, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted- (C1-C6 alkylene) -NH- (C1-C6 alkylene), carboxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-to 12-membered heteroaryl having 1 to 3 heteroatoms, substituted or unsubstituted having 1 to 4 heteroatoms5-12 membered heterocyclic group of hetero atom, substituted or unsubstituted

Substituted or unsubstituted

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；

R₈And R₉Each independently selected from the group consisting of: H. hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., ═ O), ═ NRf, -CN, hydroxy, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted- (C1-C6 alkylene) -NH- (C1-C6 alkylene), carboxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-to 12-membered heteroaryl having 1 to 3 heteroatoms, substituted or unsubstituted 5-to 12-membered heterocyclyl having 1 to 4 heteroatoms, substituted or unsubstituted

Substituted or unsubstituted

Or (L)_1a)_r-(L_2a)_s-(L_3a)_s-；

In another preferred embodiment, R is₆Is R₁(ii) a Or is

Wherein Rb and Rc are each independently selected from the group consisting of: H. substituted or unsubstituted C₁-C₈An alkyl group; or said Rb and Rc taken together with the adjacent N atom form a substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O.

In another preferred embodiment, the

Is an optionally substituted monovalent radical formed from a ring selected from the group consisting of:

4. the compound of claim 1, wherein the compound of formula I is selected from the group consisting of formulae Id-1, Id-2, and Id-3, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

wherein each group is as defined above.

In another preferred embodiment, the ring is

And/or

Having a substituent represented by formula IV below:

wherein each L is₄Independently selected from the group consisting of: substituted or unsubstituted C1-C4 alkylene, -S-, -O-, -NRa-, -S (O) -, -S (O)₂-; preferably a substituted or unsubstituted C1-C4 alkylene group, with the proviso that each L₄The co-formed structure is chemically stable;

selected from the group consisting of: substituted or unsubstituted C5-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl having 1-3 heteroatoms selected from B, P, N, S and O; preferably, said

Is a 3-8 membered nitrogen containing heterocyclic group;

each R is₅Each independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxy, amino, carboxy; wherein the substituents are selected from the group consisting of: halogen, hydroxy, carboxy, cyano, C1-C6 alkoxy.

In another preferred embodiment, the compound is selected from the following table;

in a second aspect of the invention, there is provided a process for the preparation of a compound of formula I as defined in claim 1, said process comprising a step selected from the group consisting of those depicted in schemes 1,2 or 3:

synthesis scheme 1

(e) Taking halide 1-1 and appropriate coupling reagent 1-2 (such as boric acid, boric acid ester, tin reagent or Grignard reagent) as basic raw materials, and obtaining an intermediate compound 1-3 through coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper;

(f) taking the intermediate 1-3 as a raw material, and reacting with carboxylic acid 1-4 under the action of a condensing agent (such as HATU, EDCI or HBTU) to obtain an amide intermediate 1-5;

(g) taking the intermediate 1-5 as a raw material, and removing a protecting group (Boc) under an acidic condition to obtain an intermediate 1-6;

(h) taking the intermediate 1-6 as a raw material, and carrying out nucleophilic substitution reaction with a halide under an alkaline condition, or carrying out reductive amination reaction with aldehyde or ketone under the action of a reducing agent to obtain a target compound I;

synthesis scheme 2:

(e) taking carboxylic ester 2-1 as a raw material, and carrying out an aminolysis reaction with amine 2-2 under the catalysis of Lewis acid to obtain an intermediate compound 2-3;

(f) taking the intermediate 2-3 and a proper coupling reagent 2-4 (such as boric acid, boric acid ester, a tin reagent or a Grignard reagent) as basic raw materials, and obtaining an intermediate compound 2-5 through a coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper;

(g) taking the intermediate 2-5 as a raw material, and removing a protecting group (Boc) under an acidic condition to obtain an intermediate 2-6;

(h) taking the intermediate 2-6 as a raw material, and carrying out nucleophilic substitution reaction with a halide under an alkaline condition, or carrying out reductive amination reaction with aldehyde or ketone under the action of a reducing agent to obtain a target compound I;

(b) carrying out reductive amination reaction in the synthesis scheme 3 to obtain a target compound I;

synthesis scheme 3:

the method 3 comprises the following steps:

(e) carrying out Suzuki coupling on the raw materials of the boron ester 3-1 and the halide 3-2 under the catalysis of palladium to obtain an intermediate compound 3-3;

(f) carboxylic acid 3-4 and a compound 3-5 are taken as raw materials, and a cyclization reaction is carried out under the action of a proper dehydrating agent to obtain an intermediate compound 3-3;

(g) taking aldehyde 3-6 as a raw material, and carrying out cyclization reaction under the action of a proper oxidant to obtain an intermediate 3-3;

(h) using the intermediate 3-3 and a proper coupling reagent 3-7 (such as boric acid, boric acid ester, a tin reagent or a Grignard reagent) as basic raw materials, and performing coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper to obtain a target compound I;

said Cy is

Is composed of

Y¹、Y²、Z¹、Z²、Z³R ofThe definition is the same as above.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) a pharmaceutically acceptable carrier.

In a fourth aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the present invention, for the preparation of a pharmaceutical composition for the prevention and/or treatment of a disease associated with an activity or an expression amount of PD-1/PD-L1.

In a fifth aspect of the invention, there is provided a PD-1/PD-L1 inhibitor, said inhibitor comprising a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment, the pharmaceutical composition is used for treating a disease selected from the group consisting of: cancer, infectious disease, autoimmune disease.

In another preferred embodiment, the cancer is selected from the group consisting of: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, 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, urologic tumors, hematologic tumors, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, head and neck cancer.

In another preferred embodiment, the cancer is selected from the group consisting of: acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), Chronic Myelogenous Leukemia (CML), Multiple Myeloma (MM), non-hodgkin's lymphoma (NHL), Mantle Cell Lymphoma (MCL), follicular lymphoma, Waldestrom Macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma or diffuse large B-cell lymphoma (DLBCL).

In another preferred embodiment, the infectious disease is selected from bacterial infection and viral infection.

In another preferred embodiment, the autoimmune disease is selected from organ-specific autoimmune disease, systemic autoimmune disease.

In another preferred embodiment, the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis.

In another preferred embodiment, the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia.

In another preferred embodiment, the pharmaceutical composition is also used for improving the T cell function of Chronic Hepatitis B (CHB) patients.

In another preferred embodiment, the inhibitor further comprises at least one therapeutic agent selected from the group consisting of: nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

In a sixth aspect of the present invention, there is provided a method for inhibiting the PD-1/PD-L1 interaction in vitro, comprising the steps of: contacting a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, with PD-L1 protein.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The inventor has extensively and intensively studied and found a PD-1/PD-L1 interaction inhibitor with excellent inhibitory effect. On this basis, the inventors have completed the present invention.

Definition of

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C₁-C₈Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C₂-C₆Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C₂-C₆Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "C₃-C₁₀Cycloalkyl "refers to cycloalkyl groups having 3 to 10 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.

As used herein, the term "C₁-C₈Alkylamino "is defined as being substituted by C₁-C₈The amino group substituted by the alkyl can be mono-substituted or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino and the like.

As used herein, the term "C₁-C₈Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxyAnd (c) a group, butoxy group, isobutoxy group, tert-butoxy group, and the like.

As used herein, the term "3-10 membered heterocycloalkyl 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 and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.

As used herein, the term "C₆-C₁₀Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C₁-C₆Alkyl-amino, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, halo C₁-C₆Alkyl, halo C₂-C₆Alkenyl, halo C₂-C₆Alkynyl, halo C₁-C₆Alkoxy, allyl, benzyl, C₆-C₁₂Aryl radical, C₁-C₆alkoxy-C₁-C₆Alkyl radical, C₁-C₆Alkoxy-carbonyl, phenoxycarbonyl, C₂-C₆Alkynyl-carbonyl, C₂-C₆Alkenyl-carbonyl, C₃-C₆Cycloalkyl-carbonyl, C₁-C₆Alkyl-sulfonyl, and the like.

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" means substituted with an atom selected from F, Cl, Br, and I.

Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.

As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules 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.

Active ingredient

As used herein, "compounds of the invention" refers to compounds of formula I, and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compounds of formula I.

Preferred compounds of the present invention include compounds 1-360 (including various classes of R configuration and/or S configuration stereoisomers of each compound, and/or E-/Z-cis-trans isomers).

In another preferred embodiment, the pharmaceutically acceptable salts include salts formed in combination with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions, or organic bases capable of providing physiologically acceptable cations, as well as ammonium salts.

In another preferred embodiment, 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, lycic acid, tartaric acid maleate, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.

All such salts within the scope of the present invention may be prepared by conventional methods. During the preparation of the compounds of formula I and solvates and salts thereof, different crystallization conditions may occur as polycrystals or co-crystals.

Preparation of Compounds of formula I

For the preparation of the compounds of the general formula I according to the invention, the compounds of the general formula I according to the invention can be obtained by the following process 1 or 2, depending on the structure of the general formula I.

The method 1 comprises the following steps:

(a) taking halide 1-1 and appropriate coupling reagent 1-2 (such as boric acid, boric acid ester, tin reagent or Grignard reagent) as basic raw materials, and obtaining an intermediate compound 1-3 through coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper;

(b) taking the intermediate 1-3 as a raw material, and reacting with carboxylic acid 1-4 under the action of a condensing agent (such as HATU, EDCI or HBTU) to obtain an amide intermediate 1-5;

(c) taking the intermediate 1-5 as a raw material, and removing a protecting group (Boc) under an acidic condition to obtain an intermediate 1-6;

(d) taking the intermediate 1-6 as a raw material, and carrying out nucleophilic substitution reaction with a halide under an alkaline condition, or carrying out reductive amination reaction with aldehyde or ketone under the action of a reducing agent to obtain a target compound I;

the method 2 comprises the following steps:

(c) taking carboxylic ester 2-1 as a raw material, and carrying out an aminolysis reaction with amine 2-2 under the catalysis of Lewis acid to obtain an intermediate compound 2-3;

(d) taking the intermediate 2-3 and a proper coupling reagent 2-4 (such as boric acid, boric acid ester, a tin reagent or a Grignard reagent) as basic raw materials, and obtaining an intermediate compound 2-5 through a coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper;

(e) taking the intermediate 2-5 as a raw material, and removing a protecting group (Boc) under an acidic condition to obtain an intermediate 2-6;

(f) taking the intermediate 2-6 as a raw material, and carrying out nucleophilic substitution reaction with a halide under an alkaline condition, or carrying out reductive amination reaction with aldehyde or ketone under the action of a reducing agent to obtain a target compound I;

the method 3 comprises the following steps:

(i) using carboxylic ester 3-1 as a raw material, and carrying out Buchwald-Hartwig coupling or Ullman coupling with amine 3-2 under the catalysis of palladium or copper to obtain an intermediate compound 3-3;

(j) taking the intermediate 3-3 and a proper coupling reagent 3-4 (such as boric acid, boric acid ester, a tin reagent or a Grignard reagent) as basic raw materials, and obtaining an intermediate compound 3-5 through a coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper;

(k) taking the intermediate 3-5 as a raw material, and removing a protecting group (Boc) under an acidic condition to obtain an intermediate 3-6;

(l) Taking the intermediate 3-6 as a raw material, and carrying out nucleophilic substitution reaction with a halide under an alkaline condition, or carrying out reductive amination reaction with aldehyde or ketone under the action of a reducing agent to obtain a target compound I;

said Cy is

Is composed of

Y¹、Y²、Z¹、Z²、Z³And R is as defined above.

In addition, the starting materials and intermediates in the above reactions are readily available, and the reactions in each step can be readily synthesized according to reported literature or by conventional methods in organic synthesis to those skilled in the art. The compounds of formula I may exist in the form of solvates or non-solvates, and crystallization using different solvents may give different solvates.

Pharmaceutical compositions and methods of administration

The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) diseases (e.g., cancer, infectious diseases, autoimmune diseases) associated with the PD-1/PD-L1 interaction, because the compound of the present invention has excellent inhibitory activity of the PD-1/PD-L1 interaction.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" is defined hereinIt is meant that the components of the composition can be admixed with the compounds of the invention and with each other without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, 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 sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise 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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., other anti-cancer agents).

When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately or sequentially with the compounds of the invention for the prevention and/or treatment of a disease associated with the PD-1/PD-L1 interaction.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention include:

(1) the compound has high inhibitory activity on the interaction of PD-1/PD-L1, has strong binding capacity with PD-L1 protein, and has the capacity of relieving the inhibition of IFN gamma by PD-L1.

(2) The compound of the invention has better solubility; the toxicity to normal cells is very low and can therefore be applied to the treated subject over a wide dose range.

(3) Compared with the prior art, the compound of the invention has better solubility and good drug forming property, and the compound of the invention has good bioavailability in vivo experiments, and in addition, compared with the prior art, the compound of the invention can be easily prepared into pharmaceutically acceptable salts, thereby being beneficial to further preparation.

(4) The in vivo efficacy research shows that the compound can obviously inhibit the growth of subcutaneous tumors no matter on the tumor volume or the tumor weight, and can obviously increase the number of lymphocytes in the blood and the spleen of a mouse.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

The test materials and reagents used in the following examples are commercially available without specific reference.

General materials and test methods:

the instruments and materials involved in the examples are described below:

the NMR spectrum was obtained by analysis with a Bruker AV-400(400MHz) NMR spectrometer.

Chemical shifts are reported in ppm units using tetramethylsilane as an internal standard (CDC 1)₃Delta 7.26 ppm). The data reported are the chemical shifts and their split and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad; m: multiplet).

Mass spectrometry data were analyzed using a liquid mass spectrometer from the Finnigen advanced LCQ company (Finnigan LCQ Advantage), all reactions operated under anhydrous and oxygen-free conditions under dry argon protection, except for other requirements. The solid organometallic compound was stored in an argon protected dry box.

The tetrahydrofuran and the diethyl ether are obtained by distillation, and metal sodium and benzophenone are added into the tetrahydrofuran and the diethyl ether during the distillation. Methylene chloride, pentane and hexane were treated with calcium hydride.

The special raw materials and intermediates involved in the present invention are provided by custom-made processing of Tianjin Changsen pharmaceutical Co., Ltd, and all other chemical reagents are purchased from reagent suppliers such as Shanghai chemical reagent company, Aldrich company (Aldrich), Acros company (Acros). If the intermediates or products needed by the reaction in the synthesis process are not enough for the next experiment, the synthesis is repeated for a plurality of times until the intermediates or products are enough.

The raw materials and reagents related to the invention can be obtained by commercial or customized processing and purchase except for special instructions.

The compounds of the invention may contain one or more asymmetric centres and so the series of compounds may be in racemic or single enantiomeric form. The compound prepared by the invention is a heterocyclic compound with the purity of higher than 95%, and the structure table of each final productCharacterized by MS or/and hydrogen nuclear magnetic resonance (¹H NMR) analysis. The synthesis of the various compounds and intermediates of the invention is illustrated by the examples below.

EXAMPLE 1 Synthesis of LW1005-001 Compound

Step 1-1:

compound 1(51g, Journal of Medicinal Chemistry,2019,62,276-287) and 2-methyl-3-bromobenzoic acid (95.56g) were successively added to PPA (500g) and reacted at 140 ℃ for 6 hours with mechanical stirring. After the reaction is completed, pouring ice water into the reaction bottle, pouring out after dilution, pulping for 30min, and filtering. Filtering to obtain solid, adding 500ml water, adding sodium hydroxide solid under mechanical stirring, adjusting pH to 6-8, and filtering. The solid filter cake is dried at 55 ℃ to obtain 80g of off-white solid product. MS-APCI:305[ M + H]⁺.

Step 1-2:

3(2.0g), DMAP (805mg) was added to DMF (30mL), the solution was cloudy, Boc2O was added, the solid was dissolved and the reaction was heated at 40 ℃ overnight. TLC showed 1 small amount remaining. The reaction solution was spin-dried with an oil pump. The solid was slurried with EA/HEP and filtered to give 1.6g of the product as a white solid. MS-APCI of 405.2[ M + H ]]⁺

Step 1-3:

4(202mg), 5(230mg, WO2018119286), Pd (dppf) Cl2/DCM (19.5mg) and Na were added at room temperature₂CO₃(21.2mg) was placed in the reactionThe flask was degassed under vacuum, and dioxane/H2O (5mL/1mL) was injected via syringe, and the reaction was heated at 100 ℃ for 4H after degassing again. Pouring the reaction solution into water, extracting with EA, drying, spin-drying the EA layer, pulping with EA/HEP (1:1), filtering to obtain 100mg crude product, and separating and purifying 50mg to obtain 9.0mg LW1005-001 as yellow solid. MS-APCI 559.2[ M + H ]]⁺

1H NMR(400MHz,DMSO-d6)δ11.85(d,J＝6.1Hz,1H),10.55-10.28(m,1H),9.08(s,1H),8.52(s,1H),8.16(s,1H),8.0-8.05(m,2H),7.51(q,J＝7.1,6.4Hz,2H),7.46–7.32(m,2H),7.25(d,J＝6.1Hz,1H),7.06(s,1H),6.87(d,J＝7.1Hz,1H),5.51(s,1H),4.68(d,J＝25.9Hz,2H),4.47(d,J＝27.3Hz,2H),2.45(s,3H),2.34-2.29(m,1H),2.06(s,3H),2.02-2.01(m,1H),1.90-1.86(m,1H),1.52-1.46(m,1H).

EXAMPLE 2 Synthesis of the Compound LW1005-002

Step 2-1:

compound 3(10g) was dissolved in DMF (150ml), and 6(14.3 g; Macromolecules, 2015, 48, 1688-1702) and Cs2CO3(21.4g) were added to react at room temperature overnight. The reaction was complete by TLC. Filtration, addition of water to the filtrate followed by extraction with EtOAc, spin drying of the organic phase and slurrying with HEP: EtOAc 10:1 afforded 11g of 7 as a white solid. MS-APCI:587.1[ M + H ] +

1H NMR(400MHz,Chloroform-d)δ8.05(dd,J＝7.9,1.3Hz,1H),7.75(dd,J＝8.0,1.3Hz,1H),7.54(dt,J＝6.7,1.5Hz,4H),7.49(d,J＝7.3Hz,1H),7.41–7.35(m,2H),7.34–7.27(m,4H),7.22(t,J＝7.9Hz,1H),6.58(d,J＝7.3Hz,1H),4.26(t,J＝4.7Hz,2H),4.05(dd,J＝5.5,4.1Hz,2H),2.92(s,3H),1.05(s,9H).

Step 2-2:

7(11g) was dissolved in THF (110mL) at room temperature, 1NTBAF/THF (20.7mL) was added and the reaction was allowed to proceed for 2 hours. TLC showed the starting material reaction was complete. The reaction was spun dry and chromatographed (DCM: MeOH ═ 20:1) to give 4.5g of product 8 as a white solid. MS-APCI 349.1[ M + H ]]⁺

Step 2-3:

8(350mg), Bpin2(304.8mg), Pd (dppf) Cl2(81.7mg) and KOAc (196mg) were placed in a reaction flask at room temperature, degassed under vacuum, and dioxane (5mL) was injected via a syringe, degassed again, and then heated at 100 ℃ for reaction overnight. TLC showed the reaction was complete. The reaction was extracted with water and EtOAc, the organic phase washed with saturated NaCl, dried, spun-dried and chromatographed (DCM: MeOH ═ 20:1) to give 350mg of compound 9 as a grey solid. MS-APCI 397.1[ M + H ]]⁺

Step 2-4:

9(350mg), 10(364mg, WO2018119286), Pd (dppf) Cl2/DCM (71.9mg) and Na at room temperature₂CO₃(186.6mg) was placed in a reaction flask, degassed under vacuum, and dioxane/H2O (3.6mL, 5:1) was injected via syringe, and the reaction was heated at 100 ℃ for 4 hours after degassing again. TLC showed the starting material reaction was complete. The reaction was extracted with water and EtOAc, and the organic phase was washed with saturated NaCl, dried, spun-dried and passed through a column (DCM: MeOH ═ 20:1) to give 45mg of the compound LW1005-002 as a yellow solid.

MS-APCI:603.2[M+H]⁺

1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.88(d,J＝2.0Hz,1H),8.47(d,J＝8.2Hz,1H),8.19(d,J＝1.6Hz,1H),8.13–8.00(m,2H),7.77(d,J＝7.3Hz,1H),7.51(t,J＝7.7Hz,1H),7.37(dd,J＝14.2,7.4Hz,2H),7.19(d,J＝5.8Hz,1H),6.92(dd,J＝7.2,4.3Hz,2H),4.90(t,J＝5.4Hz,1H),4.72(d,J＝4.5Hz,1H),4.23(s,1H),4.11(t,J＝5.4Hz,2H),3.82(q,J＝13.8Hz,2H),3.68(q,J＝5.5Hz,2H),2.80–2.72(m,1H),2.67(d,J＝8.0Hz,2H),2.43(s,3H),2.39–2.30(m,1H),2.10(s,3H),2.03(dd,J＝13.4,6.9Hz,1H),1.61–1.55(m,1H)

EXAMPLE 3 Synthesis of Compound LW1005-003

Step 3-1:

3(1.38g) was added to DMF (40ml) at room temperature, Cs was added₂CO₃(2.95g) and Compound 11(1.45 g; Organic Letters,2018,20,6938-6942) were reacted at room temperature overnight. Water is added into reaction liquid, stirring and filtering are carried out, and the crude solid is pulped by EA/HEP (1:10) and filtered to obtain 1.33g of product. MS-APCI 491.1[ M + H ]]⁺

Step 3-2:

12(1.33g) was added to 30ml of dioxane, and Pd (dppf) Cl2(0.22g), KOAc (0.53g), bis (pinacolato) borate (0.76g) were added to the mixture, and the mixture was reacted at 100 ℃ for 3 hours while purging with nitrogen. And (3) post-treatment: adding water, filtering, extracting with EA, passing through a column with HEP (high efficiency particulate) and EA being 3:1, and spin-drying to obtain 1.14g of the product. MS-APCI 539.2[ M + H ]]⁺

Step 3-3:

13(1.14g) was added to 30mL of dioxane/6mL of water, and Pd (dppf) Cl2.DCM (0.17g), Na₂CO₃(0.45g) and 10(875mg, WO2018119286), purged with nitrogen and reacted at 100 ℃ for 4 h. And (3) post-treatment: water was added for filtration, EA extracted, DCM/MeOH 20:1 column filtered, spin dried to give 0.9g of product. MS-APCI 745.2[ M + H ]]⁺

Step 3-4:

14(100mg) was dissolved in tetrahydrofuran (10mL) and 4N HCl/dioxane (2mL) was added dropwise, r, t. TLC detection reaction was complete, and some of them were preparative separated to yield 20mg of product as a yellow solid. MS-APCI 631.2[ M + H ]]⁺1H NMR(400MHz,DMSO-d6)δ10.56-10.31(m,1H),9.08(s,1H),8.52(s,1H),8.18(s,1H),8.06(dd,J＝7.9,1.4Hz,2H),7.86(d,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,1H),7.45–7.35(m,2H),7.25(d,J＝6.0Hz,1H),7.06(s,1H),6.94(d,J＝7.3Hz,1H),5.51(s,1H),4.77-4.62(m,2H),4.50-4.43(m,2H),4.06(t,J＝7.2Hz,2H),3.70-3.65(m,3H),3.42(t,J＝6.4Hz,2H),2.44(s,3H),2.34-2.30(m,1H),2.06(s,3H),2.02-1.96(m,1H),1.87-1.82(m,1H),1.72(p,J＝7.3Hz,2H),1.44(p,J＝6.6Hz,2H).

Example 4 Synthesis of Compound LW1005-004

Step 4-1:

15(1.0g) was dissolved in DMF (10mL), and imidazole (0.64g), TBSCl (1.1g) was added to the solution to react at room temperature overnight. TLC plate reaction was complete. The reaction solution was washed with water, EA extracted, and the EA layer was spin-dried and passed through a column to obtain 1.6g of a pale yellow oily product.

Step 4-2:

LAH (0.33g) was added to THF (15mL), compound 16(1.6g in 5mL THF) was added dropwise at 0 deg.C and reacted for 1 hour at 0 deg.C. TLC showed the reaction was complete. To the reaction mixture was added 0.33mL of water, 0.33mL of NaOH (10%), and 0.33mL of water at 0 deg.C, followed by filtration and spin-drying of the filtrate to give 1.3g of a pale yellow oily product.

Step 4-3:

17(0.5g) and TEA (0.41g) were dissolved in DCM (5mL), and MsCl (0.35g) was added dropwise at 0 ℃ to react at 0 ℃ for 1 hour. TLC showed the reaction was complete. The reaction was washed with water, extracted with DCM and spin dried to give 0.66g of a pale yellow oily product.

Step 4-4:

18(0.66g),3(0.48g),Cs₂CO₃(1.5g) was added to DMF (20mL) and reacted at room temperature overnight. The reaction solution was poured into water and a solid precipitated. Filtration and spin-drying of the solid gave 0.5g of compound 19 as a white solid. MS-APCI 531.1[ M + H ]]⁺

And 4-5:

19(200mg), 5(142.6mg, WO2018119286), Pd (dppf) Cl at room temperature₂/DCM (31mg) and Na₂CO₃(80.6mg) was placed in a reaction flask, vacuum degassed, and dioxane/H was injected via syringe₂O (6mL,5:1), degassed again and then heated at 100 ℃ for reaction overnight. The reaction was washed with water and chromatographed (DCM: MeOH ═ 20:1) to give 120mg of product 20.MS-APCI:785.4[ M + H ]]⁺

And 4-6:

20(120mg) was dissolved in THF (3mL), 4N HCl/dioxane (0.3mL) was added and the reaction was carried out at room temperature for 3After 0min, a solid precipitated. And (5) filtering. Preparation of the solid isolation gave 40mg of the product as a yellow solid. MS-APCI 671.3[ M + H ]]⁺

1H NMR(400MHz,DMSO-d6)δ10.61-10.46(m,1H),9.11(s,1H),8.55(s,1H),8.06(dd,J＝7.9,1.4Hz,2H),7.97(s,1H),7.79(d,J＝7.3Hz,1H),7.52(t,J＝7.7Hz,1H),7.44(t,J＝7.8Hz,1H),7.38(dd,J＝7.7,1.4Hz,1H),7.27(d,J＝6.3Hz,1H),7.12(s,1H),6.92(d,J＝7.3Hz,1H),4.71-4.66(m,2H),4.50-4.44(m,2H),3.90(d,J＝7.2Hz,2H),3.68-3.50(m,2H),3.17-3.11(m,1H),2.45(s,3H),2.37-3.19(m,1H),2.03-1.90(m,1H),1.82-1.75(m,3H),1.72-1.68(m,1H),1.57-1.51(m,2H),1.12-1.01(m,4H).

EXAMPLE 5 Synthesis of the Compound LW1005-005

Step 5-1:

7(1g), Bpin2(605mg), Pd (dppf) Cl was added at room temperature₂(180mg) and KOAc (431.2mg) were placed in a reaction flask, vacuum degassed, and dioxane (15mL) injected via syringe, and the reaction was heated at 100 ℃ for 2h after degassing again. TLC showed the reaction was complete. Adding water to the reaction solution, extracting with EtOAc, washing the organic phase with saturated NaCl, drying, spin-drying, and passing through a column to obtain 900mg of a yellow solid 21.MS-APCI:635[ M + H ]]⁺

Step 5-2:

21(102mg), 10(82.4mg, WO2018119286), Pd (dppf) Cl2/DCM (16.3mg) and Na2CO3(42.4mg) were placed in a reaction flask at room temperature, degassed under vacuum, and the syringe was filled with dioxane/H2O (5mL/1mL), and the reaction was heated to 100 ℃ overnight after degassing again. TLC showed the reaction was complete. The reaction was washed with water, extracted with EA and passed through a column (DCM: MeOH: 20:1) to give 80mg of the product as a yellow solidAnd (3) a solid. MS-APCI:842[ M + H]⁺

Step 5-3:

22(500mg), BzCl (146.6mg), TEA (211.5mg) were added to DCM (5mL) and reacted overnight at room temperature. TLC showed the starting material reaction was complete. The reaction was poured into water, extracted with DCM, dried and applied to a column (EA/HEP ═ 1:1) and spin dried to give 350mg of a yellow solid. MS-APCI:945[ M + H ]]⁺

Step 5-4:

23(350mg) was dissolved in DCM (5mL), TBAF (1mL,1M in THF) was added and the reaction was run for 10min at RT and was checked by TLC for completion. The reaction was washed with brine and then passed through a column (DCM: MeOH ═ 20:1) to give 200mg of the product as a yellow solid. MS-APCI 707.3[ M + H ]]⁺

Step 5-5:

24(100mg) was dissolved in DMF (2mL), Dess-martin (120mg) was added at zero degrees and the reaction was continued overnight at zero degrees. TLC showed approximately 20% starting material remaining. Adding saturated NaHCO into reaction liquid₃Quenching, EA extraction, spin-drying the EA layer, and directly feeding the crude product to the next step. MS-APCI 705.2[ M + H ]]⁺

And 5-6:

25(50mg),26(12.3mg), TEA (21.2mg) were added to DMF (2mL), reacted at room temperature for 1 hour, and NaBH was added₃CN (6.9mg), and reacted at room temperature overnight. Washing the reaction solution with water, extracting with EA, drying, and separating the crude product to obtain 10mg of product 27And a yellow solid. MS-APCI 804.3[ M + H ]]⁺

And 5-7:

27(10mg) was dissolved in MeOH (2mL), K2CO3(3mg) was added and the reaction was allowed to proceed at room temperature for 1 hour, and TLC indicated that 27 was complete. The reaction solution was spun dry, dissolved in THF/MeOH/H2O (1:1:1), and LiOH₂O (1mg) was reacted at room temperature for 10 minutes. The reaction was complete by TLC. The reaction solution was prepared and separated to obtain 5.5mg of a yellow solid product. MS-APCI 686.3[ M + H ]]⁺

1H NMR(400MHz,DMSO-d6)δ10.57-10.47(m,1H),9.80-9.68(m,1H),9.03(s,1H),8.48(s,1H),8.22-8.45(m,1H),8.08–8.01(m,2H),7.82(d,J＝7.5Hz,1H),7.50(t,J＝7.7Hz,1H),7.37(d,J＝7.4Hz,1H),7.21(d,J＝6.0Hz,1H),7.04(d,J＝7.4Hz,1H),7.03–6.92(m,2H),4.78–4.62(m,2H),4.53–4.34(m,2H),4.36–4.15(m,6H),3.32–3.24(m,2H),2.42(s,3H),2.34–2.24(m,2H),2.03(s,3H),2.00–1.91(m,1H),1.87–1.79(m,1H),1.49–1.40(m,1H),1.37–1.31(m,1H).

EXAMPLE 6 Synthesis of the Compound LW1005-006

Step 6-1:

25(50mg),28(7.8mg), TEA (21.5mg) were added to DMF (2mL) and reacted at room temperature for 1 hour, followed by addition of NaBH₃CN (6.7mg), and reacted at room temperature overnight. The reaction solution was washed with water, extracted with EA, dried, and the crude product was isolated to yield 10mg of product 29 as a yellow solid. MS-APCI 762.3[ M + H ]]⁺

Step 6-2:

29(10mg) in MeOH (2mL) and K added₂CO₃(5.4mg) was reacted at room temperature for 1 hour, and TLC showed completion of the reaction of the starting materials. Preparation and isolation of the reaction mixture yielded 3mg of LW1005-006 as a yellow solid. MS-APCI 658.3[ M + H ]]⁺

1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),10.63-9.66(m,1H),9.08(s,1H),8.53(s,1H),8.14(s,1H),8.06(d,J＝7.9Hz,1H),8.03(d,J＝6.2Hz,1H),7.85(d,J＝7.4Hz,1H),7.54(t,J＝7.7Hz,1H),7.42(dd,J＝9.9,7.4Hz,2H),7.24(d,J＝6.1Hz,1H),7.06(dd,J＝7.5,3.7Hz,2H),4.74-4.62(m,2H),4.58–4.43(m,2H),4.40-4.29(m,4H),3.99-3.85(m,3H),3.33-3.31(m,3H),2.45(s,3H),2.34-2.31(m,1H),2.05(s,3H),2.00-1.95(m,1H),1.89-1.81(m,1H),1.30-1.21(m,3H).

EXAMPLE 7 Synthesis of Compound LW1005-007

Step 7-1:

25(90mg),30(180mg), TEA (254.5mg) was added to DMF (2mL), reacted at room temperature for 1 hour, and NaBH was added₃CN (79mg), and reacted at room temperature overnight. The reaction was washed with water, extracted with EA, dried and purified by TLC plate to give 40mg of product 31 as a yellow solid. MS-APCI 832.3[ M + H ]]⁺

Step 7-2:

31(40mg) in MeOH (2mL) and K added₂CO₃(13.3mg) was reacted at room temperature for 1 hour, heated at 40 ℃ for 10 minutes, and TLC showed that the reaction was complete 2. Isolation of the reaction solution yielded 8.2mg of LW1005-007 as a yellow solid. MS-APCI 714.3[ M ]+H]⁺

1H NMR(400MHz,DMSO-d6)δ10.56–10.36(m,1H),9.24–9.17(m,1H),9.06(s,1H),8.51(s,1H),8.22(s,1H),8.08–8.04(m,2H),7.89(d,J＝7.4Hz,1H),7.53(t,J＝7.8Hz,1H),7.40(d,J＝6.9Hz,2H),7.24(d,J＝5.9Hz,1H),7.09(d,J＝7.2Hz,1H),6.97(s,1H),5.58–5.43(s,1H),4.73–4.62(m,2H),4.50-4.38(m,2H),3.75-3.64(m,4H),3.34-3.27(m,4H),3.15-2.94(m,5H),2.44(s,3H),2.15-2.10(m,2H),2.07(s,3H),2.04-1.94(m,1H),1.78-1.67(m,2H).

EXAMPLE 8 Synthesis of the Compound LW1005-008

Step 8-1:

raw materials 8(19g) and NIS (14.7g) were mixed, MeCN (200mL) was added, and 1mLCF was added dropwise₃COOH, stirred in an oil bath at 55 ℃ for 2.5 hours. Filtration afforded 10.5g of a white solid. MS-APCI:475[ M + H ]]⁺

Step 8-2:

mixing the raw materials 32(10g), Zn (CN)₂(2.5g),Pd₂(dba)₃(900mg), DPPf (1.2g) in a 500mL single-necked flask, N₂The mixture was displaced 3 times, and 200ml of DMF was injected and stirred at 85 ℃ for 2 hours. After completion of the reaction, the reaction solution was poured into water and filtered to obtain 6.3g of a white solid. MS-APCI 374[ M + H ]]⁺

Step 8-3:

starting material 33(5.0g) was dispersed in DCM (250ml) and stirred overIn the process, Dess-Martin (11.3g) is added, the reaction is carried out for 30min at room temperature, a TLC point plate is completely reacted, then saturated sodium bicarbonate solution (250ml x 2) is sequentially added and stirred, the water phase is separated, 10% sodium thiosulfate (250ml x 2) is added into the organic phase and stirred, the mixture is kept stand, extracted, dried and concentrated to obtain orange solid 4.0g, and the orange solid is directly put into the next step. MS-APCI:372[ M + H ]]⁺

Step 8-4:

starting material 34(4.0g),35(3.53g) was dissolved in DCM (200mL) and Et was added₃N (2.4g), one hour after reaction NaBH (OAc) was added₃(2.25g) and reacted at room temperature for 1 hour, TLC showed complete reaction, 200ml of water was added, stirred, separated, extracted, dried, concentrated and purified by column chromatography to give 3.5g of pale yellow solid. MS-APCI 541[ M + H ]]⁺

And 8-5:

36(1080mg),5(756mg，WO2018119286)，Pd(dppf)Cl₂/DCM(167.4mg),Na₂CO₃(530mg) in a reaction flask, N₂Degassing protection, injecting 15mL of dioxane/3mL of water into a reaction flask, and reacting for 2 hours at 90 ℃. TLC plate 36 was completely reacted. The reaction was washed with water, extracted with EA, dried, spun-dried, and passed through a column (DCM: MeOH ═ 30:1) to afford 1.0g of the product as a yellow solid. MS-APCI 795.3[ M + H ]]⁺

And 8-6:

compound 37(3.9g) was dissolved in THF (50mL) and added TFA (10mL) and stirred at room temperature overnight. The reaction was complete by TLC. The reaction was spun off THF and the TFA was pumped dry to afford the crude yellow solid. Further purification on column (DCM: MeOH ═ 10:1) afforded 3.5g of product. MS (Mass Spectrometry)-APCI:739.3[M+H]⁺

1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),9.06(s,1H),8.85(s,1H),8.51(s,1H),8.11–8.09(m,2H),7.57(t,J＝7.7Hz,1H),7.49–7.34(m,2H),7.24(d,J＝6.1Hz,1H),7.02(s,1H),4.77-4.64(m,2H),4.53-4.38(m,3H),3.72-3.64(m,2H),3.35-3.26(m,2H),3.20–2.91(m,4H),2.44(s,3H),2.16-2.10(m,2H),2.07(s,3H),2.01-1.95(m,1H),1.95-1.83(m,2H),1.80-1.66(m,2H).

EXAMPLE 9 Synthesis of the Compound LW1005-009

Step 9-1:

starting material 5(5.0g, WO2018119286) was dissolved in DCM (100mL), Et3N (3.2g) was added, stirring was carried out, BzCl (3.0g) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction is finished, washing with saturated salt water, DCM extracting, drying, concentrating and purifying by column chromatography to obtain 3.7g of a yellow solid MS-APCI (American Petroleum institute) -565.3 [ M + H ] (M + H)]⁺

Step 9-2:

starting material 38(1.97g), starting material 33(3.3g), Pd (dppf) Cl2/DCM (431mg), Na₂CO₃(1.12g) were mixed, purged with nitrogen, and then Dioxane/H2O (4:1) (50mL) was added to the mixture to conduct a reaction at 95 ℃ for 3 hours. After the reaction is finished, washing with water, extracting with EA, drying, concentrating, and purifying by column chromatography to obtain 2.7g of yellow solid. MS-APCI 732.3[ M + H ]]⁺Step 9-3:

39(200mg) was dissolved in DCM (20mL), DMP (406mg) was added at room temperature,the reaction was carried out at room temperature for 10 minutes. TLC spot plate reaction is complete. The reaction solution is firstly saturated NaHCO₃Washing with 10% Na₂S₂O₃And (6) washing. The aqueous phase was extracted with DCM. The DCM layers were combined, dried, spun dried and used directly in the next reaction. MS-APCI 730.3[ M + H ]]⁺

Step 9-4:

40(150mg) in DCM (15mL) was added 41(52mg), TEA (103mg), reacted at room temperature for 1 hour, and NaBH (OAc) was added₃(216.2mg) and reacted at room temperature overnight. TLC spot plate reaction is complete. Saturated NaHCO of reaction solution₃Washed, extracted with DCM, dried and passed through the column to give the product 100mg as a yellow solid. MS-APCI 815.3[ M + H ]]⁺Step 9-5:

compound 6(100mg) was dissolved in 10mL THF, and 2d NaOMe (5N in MeOH) was added dropwise at room temperature. The reaction was carried out for 5 minutes. Solid was precipitated. TLC point plate raw material reaction is complete. The reaction solution was neutralized with 4N HCl/dioxane. Isolation by spin-drying gave 19mg of product as a yellow solid. MS-APCI 711.3[ M + H ]]⁺

1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.87(s,1H),8.71(s,1H),8.47(d,J＝8.4Hz,1H),8.20(d,J＝1.7Hz,1H),8.08(dd,J＝6.7,4.1Hz,2H),7.54(t,J＝7.6Hz,1H),7.42(d,J＝7.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.19(d,J＝5.7Hz,1H),6.93(d,J＝7.6Hz,1H),4.75-4.70(m,1H),4.57-4.53(m,1H),4.26-4.21(m,1H),4.18-4.14(m,2H),3.82(q,J＝13.8Hz,2H),3.51-3.82(m,3H),2.77-2.72(m,3H),2.67-2.64(m,1H),2.60-2.53(m,3H),2.43(s,3H),2.39-2.36(m,1H),2.09(s,3H),2.02-1.98(m,1H),1.71-1.65(m,2H),1.60-1.55(m,1H).

Example 10 Synthesis of Compound LW1005-010

Step 10-1:

compound 43(306mg, FCH group),44(633.6 mg; Organic Process Research)&Development,2018,22,97-102.) and Na₂S₂O₅(570mg) was added to DMF (3mL) and the reaction was carried out overnight at 110 ℃ under protection of N2 and checked by LCMS. After the reaction was completed, the reaction solution was washed with water, EA extracted, and passed through a column to obtain 360mg of a pale yellow solid. MS-APCI:332[ M + H]⁺.1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝5.8Hz,1H),7.74(dd,J＝8.0,1.3Hz,1H),7.38(dd,J＝7.7,1.4Hz,1H),7.20(t,J＝7.8Hz,1H),7.02(d,J＝5.8Hz,1H),4.20(s,3H),3.61(s,3H),2.29(s,3H).

Step 10-2:

45(260mg) was added to HBr/AcOH (4mL,1:1), reacted at 85 ℃ for 1.5h and the reaction was complete by TLC. The reaction solution was spin-dried and used directly in the next reaction. MS-APCI:318[ M + H ]]⁺.

Step 10-3:

46(344mg),6(471mg) and Cs₂CO₃(710mg) was added to DMF (3mL) and reacted at room temperature overnight. The reaction was checked by TLC. After the reaction is completed, the reaction solution is filtered, the filtrate is washed with water, EA is extracted, drying and spin-drying are carried out, thus obtaining a light yellow solid, and EA/HEP (1:1) is used for pulping and filtering to obtain 400mg of a white solid. MS-APCI of 600.2[ M + H ]]⁺Step 10-4:

47(340mg), B at room temperature₂pin₂(173mg)，Pd(dppf)Cl₂the/DCM (46.5mg) and KOAc (111.7mg) were placed in a reaction flask, degassed under vacuum, and dioxane (5mL) was injected via syringe, and the reaction was heated at 100 ℃ for 4 hours after degassing again. TLC showed 6 small amount remaining. The reaction was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried, spun-dried and chromatographed to give 250mg of a pale yellow solid. MS-APCI 648.2[ M + H ]]⁺

Step 10-5:

48(150mg), 10(95.7mg, WO2018119286), Pd (dppf) Cl2/DCM (18.8mg) and Na were added at room temperature₂CO₃(48.8mg) was placed in a reaction flask, vacuum degassed, and the dioxane/H was injected via syringe₂O (6mL,5:1), degassed again and then heated at 100 ℃ for 3 hours. TLC showed the starting material reaction was complete. The reaction solution was washed with water, extracted with EA, and passed through a column to obtain 150mg of a yellow solid. MS-APCI 854.2[ M + H ]]⁺

Step 10-6:

9(150mg) was dissolved in THF (2mL) at room temperature, and TBAF/THF (0.2mL,1M) was added to react at room temperature for 2 hours. Solid precipitated from the reaction solution. Filtration and cake solids dissolved in MeOH and passed through a cation exchange column afforded 20.7mg of a yellow solid. MS-APCI 616.2[ M + H ]]⁺

¹H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.87(d,J＝2.0Hz,1H),8.46(dd,J＝8.2,1.3Hz,1H),8.19(d,J＝2.0Hz,1H),8.06(d,J＝5.8Hz,1H),7.51(d,J＝7.3Hz,1H),7.48–7.40(m,2H),7.39–7.30(m,2H),7.19(d,J＝5.8Hz,1H),6.95(dd,J＝7.5,1.3Hz,1H),6.68(d,J＝7.3Hz,1H),4.85(t,J＝5.4Hz,1H),4.73(d,J＝4.5Hz,1H),4.23(s,1H),4.06(t,J＝5.7Hz,2H),3.82(q,J＝13.7Hz,2H),3.65(q,J＝5.6Hz,2H),3.57(s,3H),2.75(dd,J＝9.7,6.1Hz,1H),2.67(q,J＝7.6Hz,1H) 2.39(dd, J ═ 9.6,3.7Hz,1H),2.13(s,3H),2.03(dd, J ═ 13.3,6.8Hz,1H),1.88(s,3H), 1.66-1.49 (m,1H), synthesis of example 11 compound LW1005-011

Step 11-1:

substrate 51(200mg,1.858 mmol; CN108373476), 2(340mg, 1.858mmol) was added to a three-necked flask containing polyphosphoric acid (8mL), and the reaction was stirred in an oil bath at 140 ℃ for 3 hours and checked by TLC. And after the reaction is completed, adding a sodium hydroxide aqueous solution (2M) into the reaction solution, adjusting the pH value to 6-7, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, and carrying out column chromatography. 370mg of a white solid was obtained in a yield of 76.3%. MS-APCI:305[ M + H ] +; 1H NMR (400MHz, DMSO-d6) δ 9.38(d, J ═ 1.0Hz,1H),8.60(d, J ═ 5.4Hz,1H),8.28(dd, J ═ 5.4,1.0Hz,1H),7.87(dd, J ═ 8.0,1.3Hz,1H),7.77(dd, J ═ 7.8,1.3Hz,1H),7.38(m,1H),2.63(s,3H).

Step 11-2:

substrate 53(2.88g,9.44mmol) and m-CPBA (3.83g, 0.0188mol) were dissolved in DCM (40mL), stirred overnight at RT and the reaction checked by TLC. After the reaction is completed, adjusting the pH value to 6-7 by using a sodium hydroxide aqueous solution (2M), extracting by using DCM, drying an organic layer by using anhydrous sodium sulfate, and carrying out column chromatography to obtain a brown yellow solid 2.23g, wherein the yield is 73.5%. MS-APCI 321[ M + H ]]⁺

Step 11-3:

compound 4(2.2g, 6.94 m)mol) was added to a single-necked flask containing acetic anhydride (30mL,0.38mol), and then the reaction solution was heated at 140 ℃ with stirring for 2 hours, followed by TLC detection. After completion of the reaction, the reaction solution was cooled to 80 ℃ and then methanol (12mL) and water (3.6mL) were added to the reaction solution, and stirred at 80 ℃ for 30 minutes. The reaction was cooled to room temperature, a large amount of solid precipitated, the solid was filtered, rinsed with ethyl acetate (10mL x 3), and dried under reduced pressure to give 1.6g of a tea white solid with a yield of 71.8%. MS-APCI 321[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ11.80(s,1H),7.82(d,J＝7.6Hz,1H),7.70(d,J＝6.6Hz,1H),7.42(t,J＝6.4Hz,1H),7.33(t,J＝7.8Hz,1H),7.00(d,J＝6.9Hz,1H),2.61(s,3H).

Step 11-4:

compound 55(1.3g, 4.05mmol),6(2.94g, 8.10mmol) and cesium carbonate (2.6g, 8.10mmol) were added to a single vial of DMF (30mL) and the reaction was stirred at room temperature overnight and checked by TLC. After the reaction was completed, the reaction solution was suspended to dryness, extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain a tea white solid 2.3g, with a yield of 94%. MS-APCI [ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ7.84(d,J＝8.1Hz,1H),7.77(d,J＝7.2Hz,1H),7.72(d,J＝7.6Hz,1H),7.48–7.32(m,7H),7.28(t,J＝7.4Hz,4H),7.06(d,J＝7.1Hz,1H),4.25(t,J＝4.8Hz,2H),3.94(t,J＝4.9Hz,2H),2.62(s,3H).

Step 11-5:

compound 56(500mg, 0.83mmol) and TBAF (650mg, 2.5mmol) were added to a single-necked flask containing THF (10mL), and then the reaction was stirred at room temperature for 15 minutes and checked by TLC. After the reaction is completed, the reaction solution is suspended to be dry, extracted by ethyl acetate/water, dried by anhydrous sodium sulfate and subjected to column chromatography to obtain 340mg of tea white solid, and the yield is more than 100 percent (containing TBAF). MS-APCI [ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ7.82(d,J＝8.0Hz,1H),7.68(dd,J＝7.5,5.4Hz,2H),7.33(t,J＝7.9Hz,1H),7.02(d,J＝7.2Hz,1H),4.90(t,J＝5.5Hz,1H),4.10(t,J＝5.5Hz,2H),3.70(q,J＝5.5Hz,2H),2.60(s,3H).

Step 11-6:

mixing compound 57(240mg, 0.657mmol), B₂Pin₂(333mg, 1.31mmol), potassium acetate (129mg, 1.31mmol) and Pd (dppf)₂Cl₂DCM (54mg, 0.0657mmol) was added to a single vial charged with 1,4-dioxane (10mL) under nitrogen, and then the reaction was stirred at 100 ℃ for 3 hours and checked by TLC. After the reaction is completed, the reaction liquid is cooled, filtered, mixed with silica gel and subjected to column chromatography to obtain a tea white solid 150mg with the yield of 55.3%. LC-MS 413MS-APCI [ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ7.79(dd,J＝7.4,1.5Hz,1H),7.74(dd,J＝7.7,1.5Hz,1H),7.65(d,J＝7.2Hz,1H),7.37(t,J＝7.5Hz,1H),7.01(d,J＝7.2Hz,1H),4.90(s,1H),4.09(t,J＝5.5Hz,2H),3.70(d,J＝5.0Hz,2H),2.67(s,3H),1.34(s,12H).

Step 11-7:

compound 7(150mg, 0.364mmol), 9(150mg, 0.364mmol), sodium carbonate (265mg, 0.91mmol) and Pd (dppf)2Cl2.DCM (30mg, 0.0364mmol) were added to a single vial charged with 1,4-dioxane (10mL) and water (2mL) under nitrogen, and the reaction was stirred at 100 ℃ for 3 hours and checked by TLC. After the reaction was completed, the reaction solution was cooled, filtered, and subjected to silica gel mixing, column chromatography, and reverse phase column chromatography to obtain a pale new green solid 6 mg. MS-APCI [ M + H ]]⁺,1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.54(s,1H),8.14(d,J＝8.0Hz,1H),8.02(d,J＝6.0Hz,1H),7.74(d,J＝7.7Hz,1H),7.66(d,J＝7.1Hz,1H),7.48(t,J＝7.7Hz,1H),7.41(t,J＝7.8Hz,1H),7.34(d,J＝7.4Hz,1H),7.23(d,J＝6.0Hz,1H),7.06(d,J＝7.0Hz,1H),7.03(d,J＝7.2Hz,1H),4.67(br,2H),4.48(br,1H),4.09(t,J＝5.6Hz,2H),3.70(t,J＝5.6Hz,2H),2.41–2.25(m,4H),2.08(s,3H),2.03–1.95(m,1H),1.92–1.82(m,1H).

EXAMPLE 12 Synthesis of the Compound LW1005-012

Step 12-1:

compound 54(1g, 1.66mmol) and NCS (221mg, 1.66mmol) were added to a single-necked flask containing DMF (15mL), and the reaction was stirred at 60 ℃ for 45 minutes and checked by TLC. After the reaction was completed, the reaction solution was suspended to dryness, extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain 600mg of an oily substance with a yield of 56.6%. LC-MS:637[ M + H ]]⁺；¹H NMR(400MHz,Chloroform-d)δ7.72(dd,J＝8.1,1.3Hz,1H),7.64(dd,J＝7.8,1.3Hz,1H),7.57–7.52(m,4H),7.50(s,1H),7.40–7.27(m,6H),7.19(t,J＝7.9Hz,1H),4.23(dd,J＝5.4,3.9Hz,2H),4.07(dd,J＝5.5,3.9Hz,2H),2.72(s,3H),1.09(s,9H).

Step 12-2:

compound 57(680mg, 1066mmol) and TBAF (128mL, 1M THF solution) were added to a single vial of THF (10mL), and the reaction was stirred at room temperature for 1 hour and checked by TLC. After the reaction was completed, the reaction solution was suspended to dryness, extracted with ethyl acetate/water, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain a tea white solid 230mg with a yield of 54%. LC-MS 399[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.84(dd,J＝8.0,1.2Hz,1H),7.74(dd,J＝7.8,1.2Hz,1H),7.34(t,J＝7.9Hz,1H),4.93(t,J＝5.6Hz,1H),4.11(t,J＝5.4Hz,2H),3.70(q,J＝5.5Hz,2H),2.61(s,3H).

Step 11-3:

compound 58(230mg, 0.575mmol), B₂Pin₂(154mg, 0.606mmol), potassium acetate (141mg, 1.43mmol) and Pd (dppf)₂Cl₂DCM (47mg, 0.0575mmol) was added to a single vial charged with 1,4-dioxane (10mL) under nitrogen, and the reaction was stirred at 110 ℃ for 2h and checked by TLC. After the reaction is completed, the reaction solution is cooled, filtered, mixed with silica gel and subjected to column chromatography to obtain a brown yellow oily substance of 210mg with the yield of 81.7%. LC-MS:447[ M + H]⁺；

Step 12-4:

compound 59(210mg, 0.47mmol), 10(194mg, 0.47mmol), sodium carbonate (125mg, 1.18mmol) and Pd (dppf)2Cl2.DCM (38mg, 0.047mmol) were added to a single vial charged with 1,4-dioxane (8mL) and water (2mL) under nitrogen, and the reaction was stirred at 100 ℃ for 3 hours and checked by TLC. After the reaction is completed, cooling the reaction liquid, filtering, mixing a sample with silica gel, performing column chromatography, and then preparing LW1005-066 by using a reverse phase column. LC-MS:653[ M + H]⁺；¹H NMR(400MHz,DMSO-d6)δ10.66(s,1H),9.11(s,1H),8.54(s,1H),8.09(s,1H),8.01(d,J＝9.8Hz,2H),7.81(dd,J＝7.9,1.3Hz,1H),7.50(t,J＝7.7Hz,1H),7.43(t,J＝7.8Hz,1H),7.37(dd,J＝7.6,1.3Hz,1H),7.25(d,J＝6.2Hz,1H),7.17–7.04(m,1H),4.78–4.59(m,3H),4.57–4.39(m,2H),4.12(t,J＝5.6Hz,2H),3.70(t,J＝5.4Hz,2H),3.57(s,1H),3.14(s,1H),2.37–2.26(m,4H),2.07(s,3H),2.04–1.95(m,1H),1.93–1.81(m,1H).

EXAMPLE 13 Synthesis of the Compound LW1005-013

Step 13-1:

compound 7(1.5g, 2.55mmol) and NCS (400mg, 3.06mmol) were added to a single vial of DMF (15mL), and the reaction was stirred at 60 ℃ for 45 minutes and checked by TLC. After completion of the reaction, the reaction solution was suspended, stirred with ethyl acetate/water (1:1,50mL), filtered and dried to give 1.2g of a white solid with a yield of 75.7%. LC-MS 621[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.05(d,J＝7.9Hz,1H),7.91(d,J＝8.0Hz,1H),7.49–7.26(m,11H),4.26(d,J＝5.3Hz,2H),3.95(t,J＝4.5Hz,2H),2.80(s,3H),0.98(s,9H).

Step 13-2:

compound 60(500mg, 0.804mmol), B2Pin2(408mg, 1.608mmol), potassium acetate (197mg, 2.01mmol) and Pd (dppf)2Cl2.DCM (66mg, 0.0804mmol) were charged into a single vial containing 1,4-dioxane (20mL) under nitrogen, and the reaction was then stirred at 110 ℃ for 4 hours and monitored by LC-MS. After the reaction is completed, the reaction solution is cooled, filtered, mixed with silica gel and subjected to column chromatography to obtain a white solid of 518mg with the yield of 96.3%. LC-MS 669.2[ M + H ] +.

Step 13-3:

compound 61(510mg, 0.762mmol), 10(315mg, 0.762mmol), sodium carbonate (242mg, 2.287mmol) and Pd (dppf)2Cl2.DCM (62mg, 0.0762mmol) were added to a single vial charged with 1,4-dioxane (15mL) and water (5mL) under nitrogen, and the reaction was stirred at 100 ℃ for 3 hours and monitored by LC-MS. After the reaction is completed, the reaction solution is cooled, filtered, mixed with silica gel and subjected to column chromatography to obtain a light yellow solid 267mgThe yield thereof was found to be 40%. LC-MS 875[ M + H ]]⁺.

Step 13-4:

compound 62(267mg, 0.305mmol) and TBAF (0.311mL,1M THF solution,0.311mmol) were added to a single vial with THF (3mL), and the reaction was stirred at room temperature for 1 hour and checked by TLC. After the reaction is completed, suspending the reaction solution, mixing the sample, carrying out column chromatography, adding distilled water and methanol into the obtained solid, and freeze-drying to obtain a light yellow solid. LC-MS:637[ M + H ]]+；¹H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.87(d,J＝2.0Hz,1H),8.47(d,J＝8.1Hz,1H),8.19(s,1H),8.10–8.04(m,3H),7.53(t,J＝7.8Hz,1H),7.41(d,J＝7.5Hz,1H),7.36(t,J＝7.9Hz,1H),7.19(d,J＝5.7Hz,1H),6.92(d,J＝7.6Hz,1H),4.92(t,J＝5.5Hz,1H),4.72(s,1H),4.30–4.17(m,1H),4.12(t,J＝5.6Hz,2H),3.82(d,J＝10.8Hz,1H),3.68(q,J＝5.5Hz,2H),2.79–2.71(m,1H),2.70–2.61(m,1H),2.46–2.35(m,4H),2.10(s,3H),2.06–1.97(m,1H),1.67–1.51(m,1H).

EXAMPLE 14 Synthesis of Compound LW1005-014

Step 14-1:

compound 1(1g, 4.69mmol) and triethylamine (0.66mL, 4.69mmol) were added to a single-necked flask containing acetonitrile (15mL) and stirred at 0 ℃. Then, a solution of p-ABSA (1.15g, 4.78mmol) in acetonitrile (15mL) was added dropwise to the reaction mixture, and after the addition, the mixture was warmed to room temperature and stirred for 1 hour, followed by TLC detection. After the reaction is completed, the reaction solution is filtered, rinsed by ethyl acetate, the organic layer is suspended and stirred, and column chromatography is carried out to obtain 1.03g of light yellow oily matter with the yield of 91.8%. LC-MS 140[ M-Boc +2H]⁺；¹H NMR(400MHz,DMSO-d6)δ3.85(t,J＝6.2Hz,2H),2.66(t,J＝6.2Hz,2H),1.48(s,9H).

Step 14-2:

compound 64(640mg, 2.99mmol) and Rh₂(OAc)₄(33mg, 0.075mmoL) was put in a single-necked flask containing 1, 2-dichloroethane (5mL), the reaction mixture was stirred under reflux at 81 ℃ and a solution of 2(1g,4.18mmoL) in 1, 2-dichloroethane (10mL) was added dropwise to the reaction mixture, and after the addition, the mixture was stirred under reflux overnight. After the reaction is completed, the reaction solution is suspended to be dry, and is stirred and subjected to column chromatography to obtain 650mg of white solid with the yield of 51.1%. LC-MS:425[ M + H]⁺；¹H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.91(s,1H),7.67(d,J＝8.0Hz,1H),7.49–7.44(m,1H),7.21(t,J＝7.9Hz,1H),3.76(t,J＝6.4Hz,2H),2.64(t,J＝6.3Hz,2H),2.44(s,3H),1.46(s,9H).

Step 14-3:

triphenylphosphine (123mg, 0.47mmol), elemental iodine (120mg, 0.47mmol) and triethylamine (0.13mL,0.94mmol) were added sequentially to a single vial with DCM (10mL) and stirred at room temperature for 10 min. Then, 66(100mg, 0.235mmol) in DCM (5mL) was added dropwise to the above reaction solution, and after the addition was completed, stirring was continued at room temperature for 2 hours, and the reaction was checked by TLC. After the reaction is completed, the reaction solution is suspended to be dry, silica gel is stirred and subjected to column chromatography to obtain 37mg of white solid with the yield of 38.8 percent. LC-MS 307[ M-Boc +2H]⁺；¹H NMR(400MHz,DMSO-d6)δ7.90(d,J＝7.7Hz,1H),7.85(d,J＝7.9Hz,1H),7.35(t,J＝7.8Hz,1H),4.13(t,J＝6.4Hz,2H),3.21(t,J＝6.4Hz,2H),1.49(s,9H).

Step 14-4:

compound 67(290mg, 0.172mmol) and TFA (0.16mL,2.136mmol) were added sequentially to DCM (10mL), stirred at RT for 2h and the reaction monitored by TLC. After the reaction is completed, adding a saturated sodium bicarbonate solution to adjust the pH value to 7-8, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and carrying out column chromatography to obtain a white solid 170mg with a yield of 78%. LC-MS 307[ M + H ]]+；¹H NMR(400MHz,DMSO-d6)δ7.89(d,J＝7.8Hz,1H),7.82(d,J＝8.0Hz,1H),7.58(s,1H),7.33(s,1H),3.55(td,J＝7.2,2.6Hz,2H),3.11(t,J＝7.2Hz,2H).

Step 14-5:

compound 68(100mg, 0.326mmol), O-TBS-bromoethanol (0.14mL,0.651mmol) and NaH (26mg, 0.651mmol) were added sequentially to DMF (5mL) under nitrogen, stirred at room temperature for 2h and monitored by TLC. After the reaction was complete, the solvent was suspended, followed by ethyl acetate/water extraction, drying of the organic layer over anhydrous sodium sulfate, and column chromatography to give 70mg of a white solid with a yield of 46.1%. LC-MS 465[ M + H ] +;

step 14-6:

compound 69(70mg, 0.15mmol), 5(104mg, 0.23mmol), sodium carbonate (40mg, 3.015mmol) and Pd (dppf)2Cl2.DCM (12mg, 0.015mmol) were added to a single vial charged with 1,4-dioxane (4mL) and water (1mL) under nitrogen, and the reaction was then stirred at 100 ℃ for 3 hours and monitored by LC-MS. After the reaction is completed, the reaction solution is cooled, filtered, mixed with silica gel and subjected to column chromatography to obtain a light yellow solid 70mg with the yield of 64.9%. LC-MS 719[ M + H ]]⁺.

Step 14-7:

compound 70(110mg, 0.162 mmo)l) and TBAF (0.1mL,0.107mmol) were added to a single vial containing 1,4-dioane (2mL) under nitrogen, and the reaction was stirred at room temperature for 24h and checked by TLC. After the reaction was completed, purification was carried out by reverse phase column preparation, followed by freeze-drying to obtain 1.1mg of a pale yellow solid. LC-MS of 605[ M + H]+；¹H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.88(d,J＝2.1Hz,1H),8.46(d,J＝8.1Hz,1H),8.20(s,1H),8.07(d,J＝5.8Hz,1H),7.93(dd,J＝7.8,1.4Hz,1H),7.47(t,J＝7.7Hz,1H),7.39–7.28(m,2H),7.19(d,J＝5.8Hz,1H),6.91(d,J＝7.4Hz,1H),4.73(d,J＝5.6Hz,2H),4.24(s,1H),3.89–3.73(m,4H),3.57(q,J＝5.8Hz,2H),3.49(t,J＝6.5Hz,2H),3.18(t,J＝7.2Hz,2H),2.80–2.72(m,1H),2.68(dd,J＝3.9,2.0Hz,1H),2.44–2.38(m,1H),2.36(s,3H),2.34–2.32(m,1H),2.08(s,3H),2.05–1.95(m,1H),1.66–1.52(m,1H).

Example 15 Synthesis of Compound LW1005-015

Step 15-1:

raw material 5(5.0g, WO2018119286) was dissolved in DCM (100mL), imidazole (3.2g) was added, stirring was uniform, TBDPSCl (5.9g) was added, and reaction was carried out at room temperature for 3 hours. After the reaction is finished, washing with saturated salt water, DCM extracting, drying, concentrating and purifying by column chromatography to obtain yellow solid 3.7g

Step 15-2:

the raw materials 71(1.97g), 33(3.3g), Pd (dppf) Cl2/DCM (431mg) and Na2CO3(1.12g) were mixed, purged with nitrogen, and Dioxane/H2O (4:1) (50mL) was added to conduct a reaction at 95 ℃ for 3 hours. After the reaction is finished, washing with water, extracting with EA, drying, concentrating, and purifying by column chromatography to obtain 2.7g of yellow solid. MS-APCI:866[ M + H ] +

Step 15-3:

compound 72(140mg, 0.162mmol) was added to a single vial containing DCM (15mL) and Dess-Martin Reagent (240mg, 0.567mmol) was added to a plastic tube containing DMF (3mL) with shaking once. Then, the Dess-Martin Reagent/DMF solution is dripped into the compound 1/DCM solution within 1-2 minutes, and the reaction solution is stirred for 10 minutes at room temperature. After completion of the reaction, saturated sodium bicarbonate (5mL) and 10% sodium thiosulfate solution (5mL) were added to the reaction solution, extracted with DCM, dried over anhydrous sodium sulfate, and evaporated to remove a portion of the solvent until about 15mL of the solvent remained. The reaction mixture was used in the next reaction without further purification. MS-APCI:864[ M + H ] +

Step 15-4:

3-azetidinecarboxylic acid (23mg, 0.23mmol) was dissolved in AcOH (0.25mL), and the solution was added dropwise to a solution of compound 73 above in DCM, followed by triethylamine (0.3mL), and the reaction was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (49mg, 0.23mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. Quenching with water, extracting with DCM/water, drying organic layer with anhydrous sodium sulfate, and performing column chromatography to obtain light yellow solid 78mg with two-step yield of 50.7%. LC-MS 949[ M + H ]]⁺。

Step 15-5:

compound 74(78mg, 0.082mmol), TBAF (1M in THF,0.1mL, 0.1mmol) was added to a single vial with THF (2mL), and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was suspended and water (20mL) was added) Stirring, filtering to obtain residue, and subjecting to reverse phase column to obtain 17.4mg of light yellow solid. LC-MS:711[ M + H]⁺；¹H NMR(400MHz,DMSO-d⁶)δ9.08(s,1H),8.82(s,1H),8.52(s,1H),8.25–8.14(br,1H),8.10(d,J＝7.9Hz,1H),8.05(s,1H),7.57(t,J＝7.8Hz,1H),7.48–7.38(m,2H),7.25(s,1H),7.05(s,1H),4.79–4.61(m,2H),4.53–4.41(m,1H),4.40–4.19(m,5H),3.71–3.51(m,5H),3.37–3.26(m,2H),2.44(s,3H),2.33(s,1H),2.06(s,3H),2.01(br,1H),1.87(s,1H).

Example 16 Synthesis of Compound LW1005-016

Step 16-1:

73(300mg, 1.0eq) was added to the reaction flask and 20mL of DCM was dissolved. To the above solution was added a solution of 3-hydroxyacridine hydrochloride (109.9mg, 2eq) in DMSO (0.5mL), followed by dropwise addition of Et3N (35.1mg, 1.0eq) and stirring at room temperature for 1 h. Sodium triacetoxyborohydride (147.2mg, 2.0eq) was added and stirred at room temperature overnight. TLC to monitor the reaction, the reaction liquid is washed by saturated sodium bicarbonate, dried, concentrated and chromatographed to obtain yellow solid 200 mg. MS-APCI of 921[ M + H]⁺

Step 16-2:

75(150mg, 1.0eq) was added to the flask, dissolved in THF, and a TBAF/THF solution (1M in THF, 2mL) was added dropwise and stirred at room temperature for 1 h. TLC to monitor the reaction, concentration, column chromatography, preparation, ion exchange column to obtain 25.60mg of bright yellow solid. MS-APCI 683[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ9.34(s,1H),8.88(d,J＝2.0Hz,1H),8.73(s,1H),8.47(d,J＝7.7Hz,1H),8.20(s,1H),8.07(d,J＝6.7Hz,2H),7.54(t,J＝7.9Hz,1H),7.43(d,J＝7.5Hz,1H),7.36(t,J＝7.9Hz,1H),7.19(d,J＝5.8Hz,1H),6.93(d,J＝7.5Hz,1H),4.28–4.17(m,1H),4.09–3.98

(m,2H),3.90–3.74(m,1H),3.61–3.50(m,2H),2.78–2.71(m,7H),2.42(s,3H),2.41–2.29(m,2H),2.09(s,3H),2.08–1.95(m,1H),1.65–1.51(m,1H).

EXAMPLE 17 Synthesis of the Compound LW1005-017

Step 17-1:

(R) -pyrrolidine-3-carboxylic acid (44mg, 0.384mmol) was dissolved in AcOH (0.25mL), and the solution was added dropwise to a solution of compound 73(150mg) in DCM, followed by triethylamine (0.3mL) and the reaction stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (163mg, 0.768mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. Quenching with water, extracting with DCM/water, drying organic layer with anhydrous sodium sulfate, and performing column chromatography to obtain light yellow solid 75mg with two-step yield of 40.6%. LC-MS 963[ M + H ]]⁺。

Step 17-2:

compound 76(75mg, 0.078mmol), TBAF (1M in THF,0.1mL, 0.1mmol) was added to a single vial of THF (2mL), and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was suspended, and water (20mL) was added thereto, followed by stirring, filtration and reverse phase column chromatography to obtain 12.57mg of a pale yellow solid. LC-MS:725[ M + H]⁺；¹H NMR(400MHz,DMSO-d⁶)δ9.06(s,1H),8.86(s,1H),8.52(s,1H),8.22(br,1H),8.13–8.04(m,2H),7.57(t,J＝7.7Hz,1H),7.47–7.37(m,2H),7.24(s,1H),7.03(s,1H),4.79–4.61(m,3H),4.53–4.39(m,3H),4.10–3.61(m,7H),3.44–3.38(m,2H),3.34–3.29(m,2H),2.44(s,3H),2.34(s,1H),2.07(s,3H),2.00(br,1H),1.86(s,1H).

EXAMPLE 18 Synthesis of Compounds LW1005-018

Step 18-1:

8(1.72g of 1.0eq) and Et3N (1.00g of 2.0eq) were added to a reaction flask containing 30mL of DCM and 1mL of DMF, the temperature was lowered to 0 ℃ and BzCl/DCM solution was added dropwise, after the addition was complete, the temperature was raised to room temperature and the mixture was stirred overnight. TLC detection, reaction completion, reaction liquid washed with saturated sodium bicarbonate solution and saturated brine, dried and concentrated. The solid obtained was purified with EA: the PE solution was beaten for 2h at 1:10(200 Ml). And (4) carrying out suction filtration, washing a filter cake by using PE, and drying to obtain 1.39g of white solid. MS-APCI of 453[ M + H ]]⁺；

¹H NMR(400MHz,DMSO-d6)δ8.04–7.91(m,4H),7.87(dt,J＝8.1,1.7Hz,2H),7.71–7.62(m,1H),7.52(t,J＝7.7Hz,2H),7.36(td,J＝7.9,3.6Hz,2H),6.95(d,J＝7.3Hz,1H),4.60(t,J＝5.7,4.1Hz,2H),4.48(t,J＝5.0Hz,2H),2.78(s,3H).

Step 18-2:

adding 77(200mg) into a reaction flask, protecting with N2, adding 5ml of OCl3, heating to 85 ℃, stirring for 2h, spin-drying excess POCl3, and cooling to-20 ℃. 20mL of ammonia water was diluted to 50mL with ice, added dropwise to the reaction flask, and then warmed to room temperature with white smoke and stirred for 30 min. Extracting with ethyl acetate for 2 times, washing organic phase with brine, drying, concentrating, and performing column chromatography. 67.2mg of a pale yellow solid was obtained. MS-APCI:452[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.14(s,2H),8.20(s,1H),8.06–7.89(m,4H),7.72–7.63(m,1H),7.54(t,J＝7.7Hz,2H),7.40(t,J＝7.9Hz,1H),4.75(t,2H),4.66(t,J＝4.8Hz,2H),2.81(s,3H).

Step 18-3:

78(200mg 1.0eq), 5(240mg 1.2eq), Na2CO3(120mg 2.5eq) and Pd (dppf)2Cl2(50mg 0.1eq) were charged into a reaction flask, protected with N2, dissolved by adding 1,4-dioxane/H2O (10ml/2ml), heated to 100 ℃ and stirred for 3H. Monitoring the reaction by LC-MS, cooling, washing the reaction solution with water, drying, concentrating, and performing column chromatography. 14.06mg of a yellow solid was obtained. MS-APCI of 602[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.87(d,J＝2.0Hz,1H),8.46(d,J＝8.2Hz,1H),8.34(s,1H),8.20(d,J＝1.9Hz,1H),8.10–8.03(m,2H),7.82(d,J＝7.4Hz,1H),7.54(t,J＝7.7Hz,1H),7.46–7.32(m,2H),7.20(d,J＝5.8Hz,1H),7.11(d,J＝7.1Hz,1H),6.92(d,J＝7.3Hz,1H),4.31(t,2H),4.23(s,1H),3.82(d,J＝10.9Hz,2H),3.76(t,2H),2.79–2.61(m,3H),2.45(s,4H),2.38(dd,J＝9.8,3.6Hz,2H),2.09(s,3H),2.02(dt,J＝14.3,7.2Hz,2H),1.62–1.54(m,1H).

Example 19 Synthesis of Compound LW1005-019

Step 19-1:

77(1.0g) was added to a reaction flask, protected by N2, POCl3(15mL) was added, the temperature was raised to 100 deg.C, stirred for 2h, excess POCl3 was spin dried, and the temperature was lowered to-20 deg.C. NH (NH)₂OH (50% aqueous solution) (1.46g, 10eq) was added dropwise to the flask, with white smoke evolved, and the mixture was warmed to room temperature and stirred for 30 min. TLC monitored the reaction was complete, DCM extracted 2 times (poor solubility), the organic phase was washed with brine, dried and concentrated. To get yellow2g of a colored solid. MS-APCI 468[ M + H [ ]]⁺

Step 19-2:

79(2.0g, 1.0eq) and imidazole (1.45g, 10.0eq) were added to a reaction flask, DMF was added to disperse, TBSCl was added, and stirring was carried out at RT for 1 h. TLC monitoring reaction is finished, EA/water extraction is carried out, organic phase is washed by brine, dried, concentrated and column chromatography is carried out, and golden yellow solid 2.65g is obtained. MS-APCI of 582[ M + H]⁺

Step 19-3:

80(300mg, 1.0eq) was dispersed in methanol, K2CO3(200mg, 3.0eq) was added, and the mixture was stirred at room temperature overnight. TLC monitoring reaction, reaction liquid ethyl acetate/water extraction, water phase back extraction for 2 times, organic phase washing with brine, drying and concentrating, column chromatography to obtain light yellow solid 200 mg. MS-APCI:478[ M + H ]]⁺

Step 19-4:

81(177.5mg 1.0eq), 5(256.2mg 1.5eq), K3PO4(196.9mg 2.5eq) and Pd (PPh3)4(42.8mg 0.1eq) were added to a reaction flask in sequence, protected with N2, dissolved by adding 1,4-dioxane/H2O (10ml/2ml), heated to 100 ℃ and stirred for 3H. TLC monitoring reaction end, cooling, reaction liquid washing, drying, concentrating, column chromatography, golden yellow solid 187.6 mg. MS-APCI:732[ M + H ]]⁺

Step 19-5:

82(72.5mg) was added to the reaction flask, and dissolved in 2mL of methanol,hydrogen chloride methanol solution (4.567mol/L0.4ml) was added dropwise thereto, and the mixture was stirred at room temperature for 30 min. TLC monitored the reaction was complete and the reaction was run straight to yield 23.15mg of a bright yellow solid. MS-APCI 618[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.33(s,1H),9.03(s,1H),8.87(d,J＝2.0Hz,1H),8.47(d,J＝8.2Hz,1H),8.22–8.16(m,2H),8.07(d,J＝5.8Hz,1H),7.97–7.90(m,1H),7.45(t,J＝7.7Hz,1H),7.39–7.27(m,3H),7.21(dd,J＝11.0,6.6Hz,2H),6.91(d,J＝7.4Hz,1H),6.12(d,J＝7.4Hz,1H),4.85(s,1H),4.74(s,1H),4.22(s,1H),3.89–3.78(m,4H),3.68(d,J＝5.3Hz,2H),2.75(dd,J＝9.6,6.2Hz,2H),2.37(s,3H),2.09(s,3H),2.02(dt,J＝14.5,7.1Hz,2H).

EXAMPLE 20 Synthesis of the Compounds LW1005-020

Step 20-1:

compound 79(120mg, 0.256mmol),83(48mg, 0.307mmol) and NaH (32mg,0.768mmol) were added to a single vial with DMF (6mL), and the reaction was stirred at room temperature for 3 hours and checked by TLC. After the reaction was completed, the reaction solution was suspended to dryness, extracted with ethyl acetate/water, and the organic layer was dried over anhydrous sodium sulfate and subjected to column chromatography to obtain 70mg of a pale yellow solid. LC-MS of 582[ M + H]⁺。

Step 20-2:

compound 84(70mg, 0.12mmol), 5(70mg), potassium phosphate (95mg, 0.45mmol) and Pd (PPh)₃)₄(17mg, 0.015mmol) was added to a single-neck flask containing 1,4-dioxane (4mL) and water (1mL) under nitrogen, the reaction was stirred at 100 ℃ for 3 hours and the reaction was monitored by LC-MS. After the reaction is completed, cooling the reaction liquid, filtering, and stirring with silica gelAnd performing column chromatography to obtain a light yellow solid 30mg, and then performing reverse phase column chromatography to obtain a light yellow solid 11.5 mg. LC-MS 734[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.15(s,1H),8.97(d,J＝2.0Hz,1H),8.91(d,J＝2.0Hz,1H),8.58(s,1H),8.39(d,J＝2.1Hz,1H),8.01(dd,J＝7.9,1.4Hz,1H),7.97–7.89(m,2H),7.54–7.42(m,2H),7.41–7.32(m,2H),7.31–7.27(m,1H),7.21–7.14(m,1H),6.38(d,J＝7.3Hz,1H),5.06(s,2H),4.79–4.61(m,2H),4.56–4.40(m,1H),3.93(t,J＝5.4Hz,1H),3.65(t,J＝5.2Hz,1H),3.57(s,1H),3.43(s,0H),3.33(s,1H),3.15(s,1H),2.38(s,3H),2.35–2.29(m,1H)2.03(s,3H),1.93–1.83(m,1H).

EXAMPLE 21 Synthesis of the Compound LW1005-021

Step 21-1:

the starting materials 77(18g) and NIS (10.7g) were added sequentially to MeCN (230mL), 5mL of dropwise TFA was added dropwise, and the mixture was stirred in an oil bath at 55 ℃ for 1.5 hours. After the TLC detection reaction, cooling, filtering and drying are carried out to obtain 13.8g of yellow solid. MS-APCI 579[ M + H ]]⁺.

Step 21-2:

compound 85(1.0g,1.73mmol) was added to POCl₃(15ml), reacted at 90 ℃ for 1 hour, and concentrated to dryness for further use. Reacting NH₂OMe/HCl (10g) was dissolved in 6mL of water, NaOH (4.79g) was added, stirred for 10 minutes, filtered, the filtrate was cooled in an ice bath and poured into the reacted residue, stirred in an ice bath to give a solid, which was filtered off and dried to give crude 1g of solid. MS-APCI of 608[ M + H ]]⁺.

Step 21-3:

compound 86(3g,4.9mmol) was dissolved in MeOH/THF (30mL/30mL), 5N sodium methoxide solution (2.5mL,12.3mmol) was added, stirred at room temperature, and monitored by TLC spot plate. After the reaction, water was added to quench, the solvent was dried, a solid appeared, filtered, and the solid was dried to obtain 2.7g of a pale yellow solid. MS-APCI 504[ M + H ]]⁺.

Step 21-4:

starting material 87(7.8g,15.5mmol), Zn (CN)₂(1.09g,9.28mmol),Xantphos-PdCl2(1.17g,1.55mmol)，Cs₂CO₃(7.56g,23.2mmol) in a 250mL three-necked flask, N₂The replacement is carried out for 3 times, 150mLDMF is injected, the mixture is stirred for 2 hours at the temperature of 90 ℃, and the reaction is detected to be finished by LCMS. Filtration, concentration of the filtrate to dryness and slurrying of the solid with DCM/MeOH ═ 100mL/2mL gave 4.5g of a pale yellow solid. MS-APCI:403[ M + H ]]⁺.

Step 21-5:

with compound 88(80mg,0.198mmol), 5(76mg,0.2mmol), Pd (dppf)2Cl2(17mg, v) and Na₂CO₃(53mg,0.5mmol) in a reaction flask, N₂Degassing protection, injecting 3mL of dioxane/0.6mL of water into a reaction flask, reacting at 90 ℃ for 2 hours, and completely reacting on a TLC point plate. The reaction solution was washed with water, extracted with ethyl acetate, dried, spun-dried, and passed through a column to give 23mg of a yellow solid. MS-APCI 657[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.84(d,J＝1.9Hz,1H),8.43(d,J＝8.2Hz,1H),8.21(s,1H),8.16(s,1H),8.04(d,J＝5.8Hz,1H),7.91(d,J＝7.8Hz,1H),7.46(t,J＝7.7Hz,1H),7.32(dd,J＝11.5,7.6Hz,2H),7.16(d,J＝5.8Hz,1H),6.88(d,J＝7.5Hz,1H),4.94(s,1H),4.70(s,1H),4.19(s,1H),3.96(t,J＝5.1Hz,2H),3.86–3.66(m,7H),2.72(dd,J＝9.7,6.1Hz,1H),2.63(q,J＝7.6Hz,1H),2.37–2.29(m,4H),2.06(s,3H),1.99(dd,J＝13.7,7.0Hz,1H),1.59–1.50(m,1H).

EXAMPLE 22 Synthesis of Compound LW1005-022

Charge 77(1.0g) to POCl₃(10mL) at 100 ℃ for 1 hour, concentrating to dryness, adding methylamine water solution to the residue, stirring in ice bath to obtain green solid, filtering, and drying to obtain 960mg of solid. MS-APCI 592[ M + H ]]⁺.

Step 22-2:

starting materials 89(960mg) and K₂CO₃(770mg) MeOH (20mL) was added in turn, stirred at 55 deg.C, monitored by TLC until the reaction was complete, filtered and dried to give 900mg of a green solid. MS-APCI:488[ M + H ]]⁺.

Step 22-3:

mixing the raw materials 90(48mg), ZnCN₂(22mg),Pd₂(dba)₃(11mg), dppf (15mg) was mixed in a 50mL single-necked flask, N₂Protecting, adding 5ml DMF, stirring at 95 ℃ for 16 hours, and detecting by TLC to finish the reaction. And filtering the reaction solution, washing the filtrate with water, and extracting with EA. Column chromatography gave 28mg of a green solid. MS-APCI 387[ M + H ]]⁺.

Step 22-4:

compound 1(100mg,0.156mmol), 5(71mg,0.187mmol), Pd (dppf)2Cl2(13mg) andNa₂CO₃(51mg,0.48mmol) in a reaction flask, N₂Degassing protection, injecting 3mL of dioxane/0.6mL of water into a reaction flask, reacting at 90 ℃ for 2 hours, and completely reacting on a TLC point plate. The reaction was washed with water, extracted with EA, dried, spun-dried, and purified on a reverse phase column (DCM: MeOH ═ 10:1) to give 25mg of a yellow solid. MS-APCI 641[ M + H ]]⁺；¹H NMR(400MHz,Chloroform-d)δ9.10(s,1H),8.79(s,1H),8.59(d,J＝8.3Hz,1H),8.13(d,J＝5.9Hz,1H),8.07(d,J＝7.7Hz,1H),7.97(s,1H),7.61(s,1H),7.43–7.31(m,2H),6.98(d,J＝5.9Hz,1H),6.90(d,J＝7.6Hz,1H),4.39(s,1H),4.24(s,2H),3.95(s,2H),3.85(s,2H),3.65(s,3H),2.98–2.89(m,1H),2.77–2.72(m,2H),2.68–2.62(m,2H),2.47(s,3H),2.44–2.38(m,1H),2.26–2.19(m,1H)2.18(s,3H),1.54–1.45(m,1H).

Example 23 Synthesis of Compounds LW1005-023

Step 23-1:

92(9.1g,1.0 eq; EP2848622) and Cs2CO3(41.56g,3.0eq) were added to a reaction flask, DMF was added to dissolve, 2-bromoethanol (6.03mL,2.0eq) was added dropwise, and stirring was carried out at 50 ℃ for 18 h. And (5) monitoring by LC-MS, and finishing the reaction. DMF was spin-dried and slurried with 100mL of water for 1 h. Suction filtration was carried out and the filter cake was washed with 50mL of water and 100mL of n-heptane. 9.0g of a coffee-colored solid was obtained. MS-APCI of 258[ M + H ]]⁺

Step 23-2:

93(9.0g,1.0eq), 94(13.46g,1.3 eq; Chem,2019,5, 929-. And (5) monitoring by LC-MS, and finishing the reaction. Reaction ofWashing with water, washing with brine, drying, concentrating, and performing column chromatography to obtain solid 10.1 g. MS-APCI 348[ M + H ]]⁺

Step 23-3:

95(5.0g,1.0eq) and Et3N (6mL,3.0eq) were added to dichloromethane, BzCl was added dropwise at RT, and stirring was carried out for 2h at RT. TLC monitored the reaction completion. The reaction solution is washed by saturated sodium bicarbonate solution and saturated brine, dried, concentrated and subjected to column chromatography. 6.4g of a pale yellow to off-white solid was obtained. MS-APCI:452[ M + H ]]⁺

Step 23-4:

96(11.0g,1.0eq) was dissolved in acetonitrile, NIS was added, TFA was added dropwise at RT and after addition, stirring was carried out at 55 ℃ for 3 hours, whereupon a large amount of solid precipitated. TLC monitoring reaction completion, suction filtration, filter cake washing with n-heptane, filtrate spin drying, EA/water extraction, 10% Na2S2O3 solution washing, drying, concentration, and filter cake mixing column chromatography. 13g of an off-white solid was obtained. MS-APCI:578[ M + H ]]⁺

Step 23-5:

97(1.0g) was added to the reaction flask, 5mL of POCl3 was added, and the mixture was stirred at 90 ℃ for 1.5 h. Spin-drying, and pumping to form foam solid. 30% methylamine in water (20mL, 100eq) was added and DCM dissolved and stirred at rt for 15 min. TLC monitors the complete conversion of the raw material, liquid separation, organic phase brine washing, drying, concentration and column chromatography to obtain 1.0g of coffee solid. MS-APCI:591[ M + H ]]⁺

Step 23-6:

98(1.0g 1.0eq) was dispersed in methanol/THF, K2CO3(700mg 3.0eq) was added as a solid and stirred at room temperature for 3 h. TLC showed a large amount of starting material remaining, supplemented with K2CO3(700mg 3.0eq), and stirring was continued overnight at room temperature, with TLC showing essentially complete reaction of starting material. Spin-dry, extract with DCM/water, wash the organic phase with brine, dry, concentrate, and column chromatographe. 700mg of a coffee-colored solid was obtained. MS-APCI:487[ M + H ]]⁺

Step 23-7:

99(2.7g 1.0eq), Zn (CN)2(299.4mg 0.46eq), Cs2CO3(2.17g 1.2eq), Xantphos-PdCl2(418mg 0.1eq) were charged into a reaction flask, protected with N2, dissolved in DMF and stirred at 90 ℃ for 2 h. Monitoring by LC-MS, reaction completion, spin-drying DMF, DCM/water extraction, washing organic phase with brine, drying, concentrating, and column chromatography. 2.2g of a coffee-colored solid was obtained. MS-APCI of 386[ M + H ]]⁺

Step 23-8:

100(300mg 1.0eq), 5(352.5mg 1.2eq), Na2CO3(164.6mg 2.0eq), Pd (dppf)2Cl2(41mg,0.1eq) were charged into a reaction flask, protected with N2, dissolved in 1, 4-dioxane/water and stirred at 90 ℃ for 2 h. And (5) monitoring by LC-MS, and finishing the reaction. Extracting the reaction solution with DCM/water, washing the organic phase with brine, drying, concentrating, and performing column chromatography to obtain a light yellow solid of 40 mg. MS-APCI of 640[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ8.87–8.81(m,1H),8.43(d,J＝7.1Hz,1H),8.23–8.13(m,3H),8.07–8.00(m,1H),7.71–7.64(m,1H),7.54–7.48(m,1H),7.41(d,J＝9.0Hz,1H),7.31(s,1H),7.24–7.12(m,2H),6.88(s,1H),4.20(s,1H),4.04(d,J＝5.2Hz,2H),3.79(q,J＝13.5Hz,3H),3.34–3.30(m,3H),2.72(s,1H),2.63(s,2H),2.41–2.32(m,1H),2.20–2.14(m,3H),2.10–2.04(m,3H),1.99(s,1H).

EXAMPLE 24 Synthesis of the Compound LW1005-024

Step 24-1:

compound 97(1.5g,2.59mmol) was added to POCl₃(30ml), react for 2 hours at 90 ℃, and concentrate to dryness for later use. Reacting NH₂OMe/HCl (22g) was dissolved in 10mL of water, NaOH (10.36g) was added, stirred for 10 minutes, filtered, the filtrate was cooled in an ice bath and poured into the residue after reaction 1, stirred in an ice bath to give a solid, which was filtered off and dried to give crude 1.5g of solid. MS-APCI 607[ M + H ]]⁺.

Step 24-2:

compound 101(300mg,0.49mmol) was dissolved in MeOH/THF (30mL/30mL), K2CO3(28mg,0.98mmol) was added, stirred at room temperature, and monitored by TLC spot plate. After the reaction was completed, the solvent was spin-dried, and a solid appeared, which was filtered and dried to obtain 200mg of a pale yellow solid. MS-APCI 503[ M + H ]]⁺.

Step 24-3:

starting material 102(135mg,0.268mmol), Zn (CN)₂(16mg,0.137mmol),Xantphos-PdCl2(20mg,0.0268mmol)，Cs₂CO₃(131mg,0.402mmol) in a 50mL three-necked flask, N₂And (3) replacing for 3 times, injecting 10mLDMF, stirring for 2 hours at 90 ℃, and finishing LC-MS detection reaction. Filtering, concentrating the filtrate to dryness, mixing the sample, and performing column chromatography to obtain 4.5g of light yellow solid. MS-APCI 402[ M + H ]]⁺.

Step 24-4:

compound 103(100mg,0.249mmol), 5(100mg,0.261mmol), Pd (dppf)2Cl2(21mg) and Na₂CO₃(79mg,0.746mmol) in a reaction flask, N₂Degassing protection, injecting 3mL of dioxane/0.6mL of water into a reaction flask, reacting at 90 ℃ for 2 hours, and completely reacting on a TLC point plate. The reaction was washed with water, extracted with EA, dried, spun-dried, and passed through a column (DCM: MeOH ═ 10:1) to afford 11mg of a yellow solid. MS-APCI:656[ M + H]⁺；¹H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.84(d,J＝1.9Hz,1H),8.44(d,J＝8.1Hz,1H),8.16(s,1H),8.08(s,1H),8.04(d,J＝5.8Hz,1H),7.66(d,J＝7.8Hz,1H),7.39(t,J＝7.7Hz,1H),7.36(s,1H),7.31(t,J＝7.9Hz,1H),7.20(d,J＝7.5Hz,1H),7.16(d,J＝5.8Hz,1H),6.88(d,J＝7.4Hz,1H),4.92(s,1H),4.69(s,1H),4.20(s,1H),3.92(t,J＝5.2Hz,2H),3.78(d,J＝16.2Hz,5H),3.69(t,J＝4.3Hz,2H),2.72(dd,J＝9.6,6.1Hz,1H),2.63(q,J＝7.6Hz,1H),2.36(dd,J＝9.7,3.7Hz,1H),2.15(s,3H),2.07(s,3H),2.00(dq,J＝13.9,7.3Hz,1H),1.60–1.50(m,1H).

Example 25 Synthesis of the Compound LW1005-025

Step 25-1:

compound 103(50mg, 0.124mmol) was dissolved in DCM (120mL) and Dess-Martin Reagent (158mg, 0.373mmol) was added to the above solution all at once, stirred at room temperature for 30min and the reaction monitored by TLC. After the reaction was completed, water was added to quench the reaction, and then the reaction solution was washed with saturated sodium bicarbonate, 10% sodium thiosulfate solution and saturated brine in this order, the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic layer was poured into250mL single-necked bottles. To the above solution were added piperidine methyl 4-carboxylate (0.05mL, 0.373mmol), acetic acid (1 drop) and sodium borohydride acetate (79mg, 0.373mmol) in that order, stirred at room temperature for 2 hours and monitored by TLC for reaction. After the reaction is completed, water is added to quench the reaction, then the reaction solution is washed by saturated sodium bicarbonate and saturated saline solution in sequence, an organic layer is dried by anhydrous sodium sulfate, and column chromatography is carried out to obtain 20mg of light yellow solid. MS-APCI 527[ M + H ]]⁺.

Step 25-2:

starting material 104(230mg,0.436mmol) was dissolved in 10mL THF/H2O (2:1), LiOH (21mg, 0.872mmol) was added and the reaction was allowed to react at room temperature for 2 hours and monitored by TLC. After completion of the reaction, TFA (0.08mL,1.135mmol) was added to adjust the solution to neutral, THF was spun off, water was added and the solid precipitated, filtered and dried to 200mg of a pale yellow solid. MS-APCI 513[ M + H ]]⁺.

Step 25-3:

compound 105(200mg), 5(148mg), Pd (dppf)2Cl2(34mg) and Na2CO3(170mg) were placed in a reaction flask, degassed with N2, 3mL of dioxane/0.6mL of water was poured into the flask, the reaction was carried out at 90 ℃ for 2 hours, and the TLC spot plate reaction was complete. The reaction was washed with water, extracted with EA, dried, spun-dried, and passed through a column (DCM: MeOH ═ 10:1) to give 22.2mg of a yellow solid. MS-APCI:767[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.84(d,J＝1.8Hz,1H),8.43(d,J＝8.1Hz,1H),8.16(s,1H),8.12(s,1H),8.04(d,J＝5.8Hz,1H),7.66(d,J＝7.8Hz,1H),7.39(t,J＝7.7Hz,1H),7.35(s,1H),7.31(t,J＝7.8Hz,1H),7.19(d,J＝7.6Hz,1H),7.16(d,J＝5.8Hz,1H),6.88(d,J＝7.5Hz,1H),4.71(s,1H),4.20(s,1H),3.93(t,J＝6.2Hz,2H),3.87–3.74(m,6H),2.82(d,J＝11.0Hz,2H),2.73(dd,J＝9.7,6.1Hz,1H),2.62(dt,J＝17.7,6.9Hz,3H),2.38(dd,J＝9.7,3.5Hz,1H),2.24–2.12(m,4H),2.11–2.02(s,5H),2.01–1.94(m,1H),1.80–1.64(m,2H),1.62–1.39(m,3H).

Example 26 Synthesis of Compounds LW1005-026

Step 26-1:

compound 97(1.3g) was added to POCl₃(15mL), the mixture was heated to 90 ℃ and reacted for 1 hour. TLC point plate raw material is reacted completely. The reaction mixture was poured into a remaining 5mL portion, and the mixture was added dropwise to aqueous ammonia (100mL) through a pipette to precipitate a yellow solid. Filtration and spin-drying of the solid gave 1.0g of product 3 as a dark grey solid. MS-APCI:578[ M + H ]]⁺；

Step 26-2:

compound 104(1.0g) was suspended in MeOH (15mL) and K was added at room temperature₂CO₃(478 mg). After stirring the suspension for 1 hour, LCMS checked reaction completion. And (4) spin-drying the reaction solution. The remaining solid was dissolved in DMF. The DMF solution was poured into water and a solid precipitated. Filtration and drying of the solid gave 600mg of a grey solid. MS-APCI:474[ M + H]⁺；

Step 26-3:

starting material 107(300mg), Zn (CN)₂(116mg),Xantphos-PdCl2(80mg)，Cs₂CO₃(200mg) in a 50mL three-necked flask, N₂And (3) replacing for 3 times, injecting 10mLDMF, stirring for 2 hours at 90 ℃, and finishing LC-MS detection reaction. Filtering, concentrating the filtrate, mixing, and performing column chromatography to obtain 160mg light yellowA colored solid. MS-APCI 402[ M + H ]]⁺.

Step 26-4:

mixing Compound 108(35mg), 5(40mg), Pd (dppf)₂Cl₂(12mg) and Na₂CO₃(22mg) in a reaction flask, N₂Degassing protection, injecting 3mL of dioxane/0.6mL of water into a reaction flask, reacting at 90 ℃ for 2 hours, and completely reacting on a TLC point plate. The reaction was washed with water, extracted with EA, dried, spun-dried, and passed through a column (DCM: MeOH ═ 10:1) to give 12mg of a yellow solid. MS-APCI 627[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ10.57-10.1(m,2H),9.74-9.53(m,2H),9.05(s,1H),9.01(s,1H),8.51(s,1H),8.24(s,1H),8.15(dd,J＝7.8,1.4Hz,1H),8.08(s,1H),7.61(t,J＝7.7Hz,1H),7.50(dd,J＝7.6,1.5Hz,1H),7.41(t,J＝7.8Hz,1H),7.23(d,J＝5.8Hz,1H),7.02(d,J＝7.4Hz,1H),5.50(s,1H),5.18(s,1H),4.75-4.58(m,2H),4.51-4.37(m,3H),3.83-3.77(m,3H),3.35-3.25(m,3H),2.43(s,3H),2.07(s,3H),2.03-1.98(m,1H),1.91-1.81(m,2H).

EXAMPLE 27 Synthesis of the Compound LW1005-027

Step 27-1:

taking raw material 109(6.8g, 1.0 eq; Organic Syntheses,2007,84,262-271) and adding into DMAc (70ml), after dissolving, adding potassium carbonate (9.12g, 2.0eq), dropwise adding methyl iodide (7g, 1.5eq) and reacting at room temperature overnight; and (3) treatment: water (50ml), ammonia (20ml), EA (100ml x 3) was added for extraction, column: elution with ethyl acetate/n-heptane 15/85 gave 6.05g of a yellow solid (yield: 83.4%). LCMS found 221[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)δ7.94(d,J＝6.1Hz,1H),7.39(d,J＝0.9Hz,1H),7.26(s,1H),6.97–6.83(m,1H),4.11(s,3H),4.04(s,3H),3.91(s,3H).

Step 27-2:

adding raw material 110(5g, 1.0eq) into acetic acid (82g, 30eq), adding 47% aqueous solution of hydrobromic acid (55g, 30eq), dissolving, heating to 95 deg.C, and reacting for 2 hr; and (3) treatment: concentration to give 9g (yield: quantitative) of pale yellow solid, which was directly fed to the next step. LCMS found 193[ M + H ]]⁺

Step 27-3:

adding 111(4.36g, 1.0eq) of raw material into 90ml of methanol for insolubilization, adding 5g of concentrated sulfuric acid (1.0 eq), and carrying out reflux reaction at 85 ℃ in an external bath overnight; and (3) treatment: under ice bath, 70ml of saturated sodium bicarbonate is added dropwise, the pH value is 7-8, a solid is precipitated, the solid is filtered, rinsed with water and dried to obtain 4.43g of a white solid (yield: 94.8%). LCMS found 207[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ11.02(s,1H),7.24(s,1H),7.20(t,J＝6.5Hz,1H),6.58(d,J＝7.4Hz,1H),3.93(s,3H),3.81(s,3H).

Step 27-4:

adding a raw material 112(4.2g, 1.0eq) into DMAc (50ml), under the protection of argon, adding cesium carbonate (13.3g, 2.0eq), adding a silanol raw material 8(9.62g, 1.3eq), and reacting at room temperature overnight; and (3) treatment: adding water (100ml) and 1M hydrochloric acid (80ml) to adjust the pH value to 5-6; EA extraction 3 times, column chromatography: 20% EA/n-heptane rinse, concentrate to give 4.5g of white solid, yield: 45.4 percent. LCMS found 489[ M + H ] +; 1H NMR (400MHz, DMSO-d6) δ 7.54(d, J ═ 7.5Hz,1H),7.45(d, J ═ 7.3Hz,4H),7.39(t, J ═ 7.5Hz,2H), 7.32-7.23 (m,5H),6.66(d, J ═ 7.5Hz,1H),4.13(t, J ═ 5.0Hz,2H),3.95(s,3H),3.86(t, J ═ 5.0Hz,2H),3.83(s,3H),0.93(s,9H).

Step 27-5:

dissolving compound 113(300mg) and compound 114(149mg) in 15mL of THF under nitrogen protection, adding 2.5mL of NaHMDS (2M) dropwise in a salt bath, and reacting for 20min under heat preservation after dropwise addition; and detecting the reaction by LC-MS. After the reaction is completed, water is added for quenching, EA extraction is carried out, organic phases are combined, brine is used for washing, drying is carried out, and 160mg of light yellow solid is obtained after rotary dry mixing and column chromatography. LC-MS found:699[ M + H ] +

Step 27-6:

compound 115(160mg) was dissolved in 2ml of methanol, 100mg of 10% Pd/C was added, and after the addition, hydrogen substitution was performed, reaction was performed at room temperature for 30min, and the reaction was checked by TLC. After the reaction is completed, adding diatomite and filtering, taking filtrate and spin-drying to obtain 140mg of gray solid crude product, and directly putting the crude product into the next step. LC-MS found:669[ M + H ] +

Step 27-7:

dissolving compound 113(55mg) and compound 116(75mg) in 3.8mL THF, nitrogen protection, and ice salt bath, adding 0.45mL NaHMDS (2M) dropwise, after adding dropwise, keeping the temperature for 1h, and detecting the reaction by LC-MS.

After the reaction is completed, water is added for quenching, EA extraction is carried out, organic phases are combined, salt washing and drying are carried out, and 53mg of yellow solid is obtained after rotary dry mixing and column chromatography. LC-MS found 1125[ M + H ]]⁺

Step 27-8:

compound 117(53mg) was dissolved in 2.5ml of THF, 2.5ml of triethylamine trihydrofluoride salt was added, and after the addition was completed, the reaction was carried out at room temperature for 2 hours, and the reaction was checked by TLC. After completion of the reaction, THF was removed by rotary evaporation at low temperature, and the resulting residue was concentrated to give 6.1mg of a white solid by means of a reverse phase column. LC-MS found 1125[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.85(s,1H),7.55(s,1H),7.43(d,J＝7.5Hz,1H),7.39(d,J＝7.9Hz,1H),7.30(t,J＝7.8Hz,1H),7.02(d,J＝7.4Hz,1H),6.62(d,J＝7.5Hz,1H),4.00(t,J＝5.7Hz,2H),3.95(s,3H),3.62(t,J＝5.6Hz,2H),1.96(s,4H),1.24(s,1H).

Example 28 Synthesis of Compound LW1005-028

Step 28-1:

118(7.6g,51.0mmol,1.0eq) is added into a reaction bottle in turn, anhydrous THF is steamed, and inert gas is used for protection; cooling the dry ice-acetone to-78 ℃; n-BuLi (30.5mL,76.5mmol,1.5eq,2.5M) was added dropwise; stirring for 30min at low temperature; introducing carbon dioxide dried by concentrated sulfuric acid and anhydrous calcium chloride into the reaction solution; reacting for 3 hours, and slowly heating to 0 ℃ below zero; adding saturated solution of ammonium chloride for quenching; adding water and ethyl acetate; separating out an organic phase; the aqueous phase was washed once with ethyl acetate; adjusting the pH value of the water phase to 2; a large amount of solid was precipitated, filtered and dried to obtain 9.4g of solid with a yield of 95.5%. LCMS found:194[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ8.15(d,J＝6.0Hz,1H),7.60(s,1H),7.39(dd,J＝6.0,0.9Hz,1H),4.02(s,3H).

Step 28-2:

compound 119(9.0g, 46.6mmol, 1.0eq), ethanol (270mL) and concentrated sulfuric acid (11.5mL) were added to a reaction flask and heated to reflux; stirring overnight, evaporating ethanol, cooling the residue with ice water bath, and adding water dropwise to precipitate solid; filtration and drying gave 7.4g of solid in 76.7% yield. LCMS found 208[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ11.68(s,1H),7.61(d,J＝2.3Hz,1H),7.50(d,J＝7.5Hz,1H),6.73(d,J＝7.4Hz,1H),4.33(q,J＝7.1Hz,2H),1.31(td,J＝7.1,2.9Hz,3H).

Step 28-3:

120(7.0g, 33.8mmol, 1.0eq), 70mL DMAc, cesium carbonate (22.0g,67.5mmol,2.0eq) and compound 5(14.7g, 40.5mmol, 1.2eq) were added to a reaction flask, stirred at room temperature for 2h, water and ethyl acetate were added, ethyl acetate was separated, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, and spin-dried to give compound 121, which was directly fed to the next step without purification. LCMS: found 490[ M + H [ ]]⁺

Step 28-4:

crude compound 121 from the previous step, ethanol (70mL) and water (18mL) were added to the reaction flask and LiOH solid (1.22g, 20.9mmol, 1.5eq) was added. Stirring at room temperature for 0.5h, concentrating ethanol, and adding water and ethyl acetate to the residue; separating out ethyl acetate; water phase ice water bath, adjusting pH to 5, and separating out a large amount of solid; filtration and drying gave 10.3g of solid in 66.1% yield (two steps). LCMS found:462[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ7.82(d,J＝7.5Hz,1H),7.54(d,J＝0.9Hz,1H),7.48–7.34(m,7H),7.29(t,J＝7.3Hz,4H),6.80(dd,J＝7.5,0.9Hz,1H),4.19(t,J＝4.9Hz,2H),3.88(t,J＝4.9Hz,2H),0.92(s,9H).

Step 28-5:

substrate 123(600 mg; WO2018119286),124(1g), TsOH (365mg) was added to isopropanol (10mL) and stirred at 85 ℃ overnight. TLC detection of the disappearance of starting material, spin drying of the reaction, water washing, EtOAc extraction, column chromatography to yield 350mg of a pale yellow solid. LC-MS 540[ M + H ]]⁺

Step 28-6:

125(190mg) was added to 4N HCl/dioxane (1ml) at room temperature, and stirred at room temperature for 30 minutes. TLC detection raw material reaction is complete, reaction liquid is spin-dried, and 190mg of gray crude solid is obtained and is directly used for the next reaction. LC-MS 440[ M + H]⁺

Step 28-7:

126(150mg), 122(102mg), and HATU (108mg) were dissolved in DMF (1ml) at room temperature, followed by addition of DIEA (85mg), and the reaction was continued at room temperature overnight. The reaction was checked by TLC. After completion of the reaction, the reaction solution was washed with water, extracted with EtOAc, and the organic phase was washed with saturated NaCl, dried, spin-dried, and passed through a column to obtain 70mg of a yellow solid. LC-MS 883[ M + H ] +

Step 28-8:

127(70mg) was dissolved in THF (0.5mL) at room temperature, and 0.1mL of TBAF/THF (1N) was added thereto and stirred for 1 hour. TLC detection raw material disappeared, the reaction liquid was directly passed through the column, and the crude compound obtained was passed through the cation exchange resin column to obtain 7.4mg of a yellow solid. LC-MS 645[ M + H ] +; 1H NMR (400MHz, DMSO-d6) δ 10.10(s,1H),9.31(s,1H),8.87(d, J ═ 2.0Hz,1H),8.43(d, J ═ 8.2Hz,1H),8.19(s,1H),8.06(d, J ═ 5.7Hz,1H),7.78(s,1H),7.73(d, J ═ 7.5Hz,1H),7.42(d, J ═ 7.9Hz,1H),7.33(t, J ═ 7.5Hz,2H),7.18(d, J ═ 5.8Hz,1H),7.09(d, J ═ 7.4Hz,1H),6.88(d, J ═ 7.5Hz,1H),6.79(d, J ═ 4H, 7.79, 4H), 3.3.7.7, 3H, 3, 6.0Hz,1H),2.67(d, J ═ 7.0Hz,1H), 2.44-2.37 (m,1H),2.09(s,3H),1.99(m,4H),1.59(m,1H),1.24(s,2H).

EXAMPLE 29 Synthesis of the Compound LW1005-029

Step 29-1:

126(120mg), 113(86.5mg), was dissolved in THF (2mL) under ice-bath, NaHMDS (0.7mL) was added under protection of N2, and the reaction was continued for 1 hour in ice-bath. TLC shows that the raw material reaction is complete, saturated NH4Cl is added to quench the reaction, EA extraction is carried out, and the obtained product passes through a column to obtain LW1005-011 and 380mg of yellow solid. LC-MS 896[ M + H ]]⁺

Step 29-2:

substrate 128(90mg) was added to a mixture of THF and TEA/3HF (2mL,1:1) and reacted for 2 hours. TLC detected the starting material disappeared, the reaction was adjusted to pH 9 with saturated NaHCO3, extracted with EtOAc, spun dried and isolated to afford 12.4mg of a yellow solid. LC-MS 658[ M + H ]]⁺；1H NMR(400MHz,DMSO-d6)δ10.98(d,J＝94.5Hz,1H),9.88(s,1H),9.09(s,1H),8.52(s,1H),8.18(d,J＝8.3Hz,1H),8.05(d,J＝5.9Hz,1H),7.56(s,1H),7.38(ddd,J＝30.9,13.6,7.3Hz,4H),7.26–7.17(m,1H),7.08(t,J＝6.5Hz,1H),6.97(d,J＝7.6Hz,1H),6.62(d,J＝7.4Hz,1H),4.67(s,2H),4.47(s,1H),4.01(s,2H),3.95(s,3H),3.71–3.60(m,4H),2.93(m,1H),2.34-2.32(s,1H),2.07(s,3H),2.00(s,3H),1.95-1.85(m,1H),1.21-1.15(m,3H).

Example 30 Synthesis of Compound LW1005-030

Step 30-1:

adding compound 128(1g,1 eq; WO2012154213), CuI (0.03g,0.05eq), palladium (0.12g,0.05eq) bis (triphenylphosphine) chloride into a 50ml reaction flask, replacing with nitrogen for 3 times, adding anhydrous DMF (20ml), and leaving the system to be reddish brown and clear; triethylamine (1.7g,5.0eq) was added, the system was clear brown yellow, nitrogen was substituted 3 times, and light was avoided, and alkyne starting material 3(0.52g,1.1eq) was added, reacted at room temperature, and the reaction was checked by TLC. After the reaction was completed, the reaction solution was poured into an aqueous solution of ice-cold ammonium chloride, extraction was performed 2 times with MTBE, the organic layer was washed 5 times with saturated sodium chloride, and column chromatography was performed to obtain 1.03g of an oily substance. LC-MS 309[ M + H ]]⁺；¹H NMR(400MHz,Chloroform-d)δ7.49(dd,J＝8.0,1.4Hz,1H),7.40(dd,J＝7.7,1.3Hz,1H),6.97(t,J＝7.8Hz,1H),2.57(s,3H),1.06(t,J＝7.9Hz,9H),0.70(q,J＝7.8Hz,6H).

Step 30-2:

potassium phosphate (13g,2eq), palladium acetate (0.75g,0.03eq) were charged in a 500ml reaction flask, nitrogen gas was substituted 3 times, 130(10.5g,1.3 eq; LabNetwork) dioxane solution (75ml) was added, compound 129(9.5g,1eq) dioxane solution (75ml) was added, water (30ml) was added, the reaction was carried out for 2 hours in an external bath at 100 ℃ and the system was blackish brown, and TCL tracing reaction was completed. After the reaction was completed, water was added to quench, MTBE was extracted, the organic layer was washed with saturated brine, concentrated, and column chromatography was performed to obtain 9.8g of a liquid. LC-MS 366[ M + H]⁺；¹H NMR(400MHz,Chloroform-d)δ7.86(dd,J＝7.8,1.7Hz,1H),7.55(dd,J＝7.7,1.4Hz,1H),7.40–7.32(m,2H),7.23(t,J＝7.7Hz,1H),7.06(dd,J＝7.6,1.4Hz,1H),2.22(s,3H),2.19(s,3H),1.09(t,J＝7.9Hz,9H),0.72(q,J＝7.9Hz,6H).

Step 30-3:

the starting material 131(10.17g,1eq) was added to THF (50ml) to clear the system brown-yellow, and TBAF (17.55g,2eq) in THF (50ml) was added dropwise and reacted at room temperature for 30 minutes. After the reaction was complete, the column was directly packed with a sample to obtain 6.62g of a solid. LC-MS:252[ M + H ]]⁺；¹H NMR(400MHz,Chloroform-d)δ7.54(dd,J＝7.8,1.4Hz,1H),7.40–7.32(m,2H),7.22(t,J＝7.6Hz,1H),7.08(dd,J＝7.7,1.4Hz,1H),3.32(s,1H),2.19(s,3H),2.16(s,3H).

Step 30-4:

compound 132(4.6g,1eq), 133(6.57g,1.15 eq; WO2014063199), palladium bistriphenylphosphine chloride (0.64g,0.05eq), CuI (0.15g,0.05eq), DIPEA (11.83g,5eq) were charged into a reaction flask, and the mixture was replaced with nitrogen for 3 times, DMF was added, and the mixture was replaced with nitrogen, and the system was clear in reddish brown color, and then reacted at 55 ℃ for 3 hours in an external bath. After the reaction was completed, 1000ml of water was added in ice bath, 500 × 2 times of EA extraction was performed, 2 times of saturated brine washing was performed, and column chromatography was performed to obtain 6.7 g. LCMS found 435[ M ]]⁺；¹H NMR(400MHz,Chloroform-d)δ8.26(d,J＝1.5Hz,1H),8.05(d,J＝1.5Hz,1H),7.91–7.83(m,2H),7.46–7.36(m,3H),7.19(dd,J＝7.5,1.4Hz,1H),7.00(s,1H),3.96(s,3H),2.26(s,3H),2.24(s,3H).

Step 30-5:

compound 134(6.76g,1eq) was added to methanol (250ml) and isopropyl acetate (600ml) followed by zinc dust (10ml)g,10eq), ammonium chloride (8.3g,10eq), stirred at room temperature for 1 hour. Filtering, rinsing the solid with isopropyl acetate, adding EA into the solid, pulping, filtering, concentrating the filtrate, and performing column chromatography to obtain 1.6g of solid. LCMS found406:408 ═ 3:1[ M + H]⁺；¹H NMR(400MHz,DMSO-d6)δ8.27(d,J＝1.5Hz,1H),7.92(d,J＝1.5Hz,1H),7.85–7.69(m,1H),7.41(d,J＝7.2Hz,2H),7.26–7.12(m,1H),6.96(t,J＝7.7Hz,1H),6.68(d,J＝7.9Hz,1H),6.34(d,J＝7.4Hz,1H),4.92(s,2H),3.89(s,3H),2.19(s,3H),1.77(s,3H).

Step 30-6:

compound 135(500mg,1eq), palladium acetate (30mg, 0.1eq), BINAP (100mg,0.2eq), and cesium carbonate (1000mg,2.5eq) were charged in a 50ml reaction flask, and replaced with nitrogen 3 times, and a toluene solution (20ml) of chlorine starting material 123(700mg) was added, replaced with nitrogen, and reacted overnight at 100 ℃ in an external bath. After the reaction was complete, filtration and EA rinse were carried out and the filtrate was concentrated through the column to give 800mg of a yellow solid. LCMS found 633[ M + H ]]⁺；

Step 30-7:

compound 136(550mg) was added to THF (5ml) and methanol (4ml), and sodium borohydride (100mg), lithium chloride (100mg) were added under ice-bath to react at room temperature overnight. After the reaction is completed, ammonium chloride aqueous solution is added under ice bath, EA is extracted for 2 times, and the mixture is concentrated and is subjected to column chromatography to obtain 450mg of yellow solid. LCMS found 605[ M + H ]]⁺

Step 30-8:

compound 137(420mg) was added to DCM (8ml), and activated manganese dioxide (430mg) was added to conduct a reaction under reflux overnight. After the reaction was complete, celite was added, the mixture was filtered, DCM was rinsed, the filtrate was concentrated, and the residue was filtered through a column to give 320mg of a yellow solid. LCMS found 603[ M + H ] +

Step 30-9:

compound 138(290mg) was added to DCM (9mL), followed by addition of a solution of R-3-carboxypyrrolidine (114mg) in AcOH (0.25mL) and triethylamine (0.4mL), reaction at room temperature for 1 hour, addition of sodium borohydride acetate (600mg), and stirring at room temperature overnight. After the reaction is completed, adding saturated ammonium chloride to quench the reaction, separating liquid, extracting once by DCM, drying by organic phase sodium sulfate, and passing through a column to obtain 100mg of light yellow solid. LCMS found 702[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ12.90(s,1H),10.57(s,1H),10.13(s,1H),9.05(s,1H),8.50(s,1H),8.23(s,1H),8.07(d,J＝6.0Hz,1H),7.84(d,J＝1.5Hz,1H),7.83(s,1H),7.67(d,J＝1.5Hz,1H),7.49(t,J＝7.7Hz,1H),7.43(s,1H),7.38(t,J＝7.8Hz,1H),7.31(d,J＝7.5Hz,1H),7.22(d,J＝5.9Hz,1H),7.01(d,J＝7.4Hz,1H),5.49(s,1H),4.61～4.65(m,2H),4.41～4.55(m,2H),2.27(s,3H),2.08(s,3H),1.29(d,J＝46.4Hz,1H).

Synthesis of the Compounds LW1005-031 of example 31

Step 31-1:

compound 135(510mg,1eq), 122(500mg,1.05eq), HATU (825mg,2eq), DIEA (295mg,2.1eq) was added to a reaction flask, DMF (25ml) was added, clear, stirred at room temperature overnight; and (3) post-treatment: water (30ml) was added, EA was extracted 2 times, and the mixture was washed with saturated brine 1 time, and then the mixture was subjected to column chromatography to give 1.37g of a yellow solid. LCMS found849[ M + H ] +

Step 31-2:

adding 139(910mg,1eq) of raw material into freshly distilled THF (10ml), adding lithium borohydride (100mg,5eq) under ice bath, reacting at room temperature for 6 hours, and tracking by TLC; after the reaction was completed, an aqueous solution of ammonium chloride was added in an ice bath, EA was extracted 3 times, washed with saturated saline 1 time, concentrated, and passed through a column to obtain 690mg of a yellow solid. LCMS found:821[ M + H ]]⁺

Step 31-3:

compound 140(490mg,1eq) was added to DCM (45ml) and was slightly cloudy, DMP (380mg,1.5eq) was added and the reaction was run for 40 min at RT followed by TLC. After the reaction is completed, adding saturated sodium sulfite, stirring for 5 minutes, adding saturated sodium bicarbonate, and stirring for 5 minutes; DCM was extracted 2 times, washed 1 time with saturated brine, and the column was packed with a sample to give 319mg of a yellow solid. LCMS found 819[ M + H ]]⁺

Step 31-4:

after adding compound 141(100mg,1eq), a solution of R-3-carboxypyrrolidine (41mg) in AcOH (0.25mL) and triethylamine (0.4mL) in this order to DCM (5mL) and reacting at room temperature for 1 hour, sodium borohydride acetate (120mg) was added and reacted at room temperature overnight, and the reaction was checked by TCL. After the reaction is safe, saturated ammonium chloride is added, liquid separation is carried out, DCM is carried out for 2 times, and the mixture is mixed with a sample and concentrated to pass through a column to obtain 130mg of white solid. LCMS found 918[ M + H ]]⁺

Step 31-5:

compound 142(140mg) was dissolved in THF (4mL), a 1M solution of TBAF/THF (0.2mL) was added to the solution, the reaction was carried out at room temperature for 30 minutes, and the reaction was checked by TCL. Reaction ofAfter completion, the sample was directly applied to the column to give 80mg of a yellow solid. LCMS found 680[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.84(d,J＝7.9Hz,1H),7.78(s,1H),7.74(d,J＝7.5Hz,1H),7.62(s,1H),7.49(t,J＝7.7Hz,1H),7.46–7.39(m,2H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝7.5Hz,1H),7.11(d,J＝7.5Hz,1H),6.79(d,J＝7.4Hz,1H),4.89(s,1H),4.40(s,1H),4.06(t,J＝5.7Hz,2H),3.66(d,J＝5.4Hz,2H),2.23(s,3H),1.97(s,3H).

EXAMPLE 32 Synthesis of the Compound LW1005-032

Step 32-1:

compound 143(5.6g, 300mmol), K2CO3(5.5g, 40mmol) and 123(5.2g, 20mmol) were added sequentially to a single vial of DMF (100mL) and then stirred in an oil bath at 120 ℃ overnight and the reaction checked by TLC. After the reaction is completed, the organic solvent is suspended, stirred and washed by adding water, filtered, dried, mixed with a sample and subjected to column chromatography to obtain 3.1g of brown solid. LCMS found 414[ M + H ]]⁺

Step 32-2:

raw material 144(1g,2.4mmol), bis-pinacolato borate (711mg,2.8mmol), PdCl2(dppf) DCM (195mg,0.24mmol), KOAc (470mg, 4.8mmol) were mixed in a 25mL single vial, displaced 3 times with N2, injected with 10mL of Dioxide, stirred at 95 ℃ for 16 hours, washed with water, extracted, concentrated, purified over column to give 850mg of a solid. LCMS found:462[ M + H ]]⁺

Step 32-3:

raw material 145(248mg,0.54mmol), raw material 33(100mg,0.27mmol), PdCl2(dppf)2DCM (22mg,0.027mmol), Na2CO3(57mg,0.54mmol) were mixed, nitrogen was replaced, Dioxane/H2O (8mL) was added, the reaction was carried out at 95 ℃ for 3 hours, and water washing was carried out to obtain 47mg of a white solid. LCMS found 629[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ9.19(d,J＝2.4Hz,1H),8.72(s,1H),8.65–8.58(m,1H),8.16–8.06(m,2H),7.63(d,J＝5.7Hz,1H),7.56(t,J＝7.8Hz,1H),7.50–7.38(m,2H),7.27(d,J＝8.0Hz,1H),7.14(d,J＝7.4Hz,1H),5.60–5.44(m,1H),4.79–4.64(m,2H),4.47(dd,J＝31.1,4.5Hz,2H),4.16(t,J＝5.4Hz,2H),3.70(d,J＝5.2Hz,2H),3.32(s,2H),3.21–3.10(m,1H),2.44(s,3H),2.35–2.29(m,1H),2.05–1.97(m,1H),1.93–1.84(m,1H),1.82(s,3H).

EXAMPLE 33 Synthesis of Compound LW1005-033

Step 33-1:

compound 146(1.0g) was dissolved in DCM (30mL), 147(1.16g), TEA (1.32g) were added, and after 1 hour of reaction at RT NaBH (OAc)3(3.31g) was added in portions. The reaction was 1 hour and the TLC spot plate reaction was complete. The reaction solution was washed with water, extracted with DCM, spin-dried and passed through a column to give 1.0g of a yellow solid product. LCMS found 306[ M + H ]]⁺

Step 33-2:

compound 148(1.0g), 149(0.92g) and TsOH (0.75g) were added to isopropanol (30mL) and reacted at 85 ℃ overnight. TLC showed the reaction was complete. Adding water into the reaction solution, removing isopropanol by rotation, and extracting impurities by EA. Adding NaHCO3 aqueous solution into water phase, adjusting pH to 7, precipitating solid,extraction with DCM, dissolution of the solid and spin-drying of DCM gave 1.24g of a yellow solid. LCMS found:455[ M + H [ ]]⁺

Step 33-3:

compound 33(1g), bis-pinacolato borate (815mg), PdCl2(dppf), DCM (180mg), and KOAc (420mg) were mixed in a 25mL single-necked flask, and N2 was substituted 3 times, 10mL of Dioxide was injected, and the mixture was stirred at 95 ℃ for 16 hours, washed with water, extracted, concentrated, and purified by column chromatography to obtain 900mg of a solid. LCMS found 422[ M + H ]]⁺

Step 33-3:

150(119mg), 151(100mg), Pd (dppf) Cl2/DCM (19.4mg) and Na2CO3(50mg) were placed in a reaction flask at room temperature, degassed under vacuum, and the reaction was heated at 100 ℃ for 4 hours after syringe injection of dioxane/H2O (6mL,5:1) and degassing again. TLC monitored the starting material reaction was complete. The reaction was washed with water and passed through a column (DCM: MeOH ═ 20:1) to give 50mg of crude product, which was isolated as 20mg of product 5 as a yellow solid. LCMS found 670[ M + H ]]⁺

Step 33-4:

compound 152(10mg) was dissolved in THF/H2O (1.3mL,1:0.3), and LiOH/H2O (1.3mg) was added to the solution to react at room temperature for 1 hour, after which TLC starting material was completely reacted. The reaction solution was prepared and separated to obtain 5mg of a yellow solid product. LCMS found:656[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.07(s,1H),8.73(s,1H),8.50(s,1H),8.15(s,1H),8.09(d,J＝7.7Hz,1H),8.03(s,1H),7.56(t,J＝7.8Hz,18H),7.42(dd,J＝7.9,4.9Hz,2H),7.29–7.19(m,2H),7.08(s,1H),5.33(t,J＝4.8Hz,1H),4.68(s,2H),4.16(s,2H),3.69(t,J＝5.3Hz,2H),3.19–3.00(m,2H),2.44(s,3H),2.28–2.15(m,2H),2.05(s,3H),2.03–1.91(m,2H),1.49-1.43(m,1H).

Example 34 Synthesis of Compound LW1005-034

Step 34-1:

compound 43(8g) was dissolved in acetic acid (100mL), cooled in an ice bath, and compound 2,2, 2-trichloroacetimidate methyl ester (16mL) was added dropwise thereto, followed by TLC detection overnight at room temperature. After the reaction was completed, the reaction mixture was poured into ice water, extracted with EA, washed with saturated brine, dried, and applied to a column to obtain 10.5g of a white solid. LCMS found 280[ M + H ]]⁺

Step 34-2:

dissolving compound 153(10.4g) in ethanol/water (110 mL; 10:1), adding sodium carbonate (5.9g), heating to 75 ℃ and reacting for 24 h; the reaction was checked by TLC. After the reaction was complete, the solvent was suspended and directly stirred and passed through the column to give 4.8g of a white solid. LCMS found 236[ M + H ] +

Step 34-3:

the starting material 154(4.5g,1eq) was added to 40% aqueous hydrobromic acid (45ml) and acetic acid (50ml) and reacted for 15 minutes in an external bath at 86 ℃ with detection by LC-MS. After the reaction is completed, the mixture is subjected to external bath at 40 ℃, and then is subjected to oil pump drying to obtain 3.16g of reddish brown solid. LCMS found 222[ M + H ] +

Step 34-4:

raw material 155(3g,1eq) was added to DMAc (100ml), and the mixture was clarified, bromine raw material (10g,2eq) and cesium carbonate (14g,3eq) were added to react at room temperature for 1 hour, and the reaction was checked by LC-MS. After the reaction was completed, ice water was added, EA (100mL) was added and extracted once, and the organic phase was sampled and passed through a column to obtain 2.2g of a white solid. LCMS found: 504[ M + H ] + step 34-5:

adding a raw material 126(200mg,2eq) into freshly distilled THF (5mL), cooling to about-15 ℃, under the protection of argon, dropwise adding a 2M NaHMDS solution (1mL,4eq) for reaction for 5 minutes, dropwise adding a raw material 156(100mg,1eq) THF (3mL), naturally heating for reaction for 2 hours, and detecting the reaction by TLC. After the reaction is completed, the mixture is directly stirred and passed through a column to obtain 104mg of light yellow solid. LCMS found:897[ M + H ] +

Step 34-6:

the starting material 157(50mg) was dissolved in THF (1mL), and 1M TBAF/THF (0.1mL) was added to the solution, followed by reaction at room temperature for 30 minutes and detection by TLC. After the reaction was completed, ethyl acetate/water was added for extraction, and a reversed phase column was used to prepare 11mg of a yellow solid. LCMS found 659.2[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.32(s,1H),8.88(s,1H),8.43(d,J＝8.1Hz,1H),8.20(s,1H),8.15(s,1H),8.07(d,J＝5.7Hz,1H),7.67–7.54(m,2H),7.41–7.27(m,2H),7.18(d,J＝5.8Hz,1H),7.07(d,J＝7.6Hz,1H),6.89(d,J＝7.5Hz,1H),6.73(d,J＝7.4Hz,1H),4.86(s,1H),4.74(s,1H),4.23(s,1H),4.07(d,J＝7.8Hz,5H),3.84(q,J＝13.7Hz,2H),3.65(s,2H),2.77(t,J＝7.9Hz,1H),2.69(d,J＝8.1Hz,1H),2.41(d,J＝10.0Hz,1H),2.10(s,3H),2.04(s,4H),1.59(s,1H),.

TABLE 2 Synthesis of the following Compounds from the corresponding starting materials according to the synthetic route LW1005-002

TABLE 3 Synthesis of the following Compounds from the corresponding starting materials according to the synthetic route LW1005-032

TABLE 4 Synthesis of the following Table Compounds from the corresponding starting materials according to the synthetic route LW1005-016

TABLE 5 Synthesis of the following Compounds from the corresponding starting materials according to the synthetic route LW1005-013

TABLE 6 Synthesis of the following Table Compounds from the corresponding starting materials according to the synthetic route LW1005-026

TABLE 7 Synthesis of the following Table Compounds from the corresponding starting materials according to the synthetic route LW1005-024

TABLE 8 Synthesis of the following Compounds from the corresponding starting materials according to the synthetic route LW1005-025

TABLE 8 Synthesis of the following Table Compounds from the corresponding starting materials according to the synthetic route LW1005-008

Biological assay

Example A: PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay

The assay was performed in standard black 384 well polystyrene plates with a final volume of 20. mu.L. Firstly, the methodInhibitors were serially diluted in DMSO and added to the plate wells, followed by the addition of the other reaction components. The final concentration of DMSO in the assay was 1%. The assay was performed in PBS buffer (pH7.4) containing 0.05% Tween-20 and 0.1% BSA at 25 ℃. Recombinant human PD-L1 protein (19-238) with a His tag at the C-terminus was purchased from Acro biosystems (PD 1-H5229). Recombinant human PD-1 protein (25-167) with an Fc marker at the C-terminus was also purchased from Acrobiosystems (PD 1-H5257). PD-L1 and PD-1 protein were diluted in assay buffer and 0.1. mu.l of the solution was extracted and added to the plate well. The plates were centrifuged and the proteins were preincubated with inhibitors for 40 minutes. After incubation, 0.1. mu.l of HTRF detection buffer containing europium-blocked labeled anti-human IgG (Perkinelmer-AD0212) Fc specific and anti-His

Allophycocyanin (APC, Perkinelmer-AD0059H) conjugated antibody. After centrifugation, the plates were incubated at 25 ℃ for 60 minutes. The data were read (665nm/620nm ratio) in a PHERAStar FS plate reader. The final concentrations in the assay were-3 nM PD1, 10nM PD-L1, 1nM europium anti-human IgG and 20nM anti-His-allophycocyanin. The activity data were fitted using GraphPad Prism 5.0 software to give IC50 values for the inhibitors.

The compound IC50 values illustrated in the examples are represented in the following manner: IC 50: 100nM or less; 100-1000 nM; 1000nM +++, 2

Data for the example compounds obtained using the PD-1/PD-L1 Homogeneous Time Resolved Fluorescence (HTRF) binding assay described in example a are provided in table 1.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound of formula I, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

wherein n, m, p and q are each independently selected from 0,1, 2,3 or 4;

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Is a group having the structure shown below:

wherein the content of the first and second substances,

Is a single bond or a double bond;

and is

Is an aromatic or non-aromatic moiety;

L_3aselected from the group consisting of: H.substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxy, amino, carboxy, -CO-NH-SO₂-R_g、-NH-SO₂-R_g、-SO₂-NH-CO-R_g；

r is 1,2,3, 4, 5, 6;

s is 0,1, 2 respectively;

Is absent; or the said

Is equal to

wherein, the bonding position of the ring can be N or C;

R₁、R₂、R₃and R₄Each independently selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., ═ O), ═ NRf, -CN, hydroxy, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted- (C1-C6 alkylene) -NH- (C1-C6 alkylene), carboxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-to 12-membered heteroaryl having 1 to 3 heteroatoms, substituted or unsubstituted 5-to 12-membered heterocyclyl having 1 to 4 heteroatoms, substituted or unsubstituted

Substituted or unsubstituted

Unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen: including but not limited to-F, Cl, Br, -CH₂Cl、-CHCl₂、-CCl₃、-CH₂F、-CHF₂、-CF₃Oxo, -CN, hydroxy, amino, C1-C6 alkylamino, carboxy,-NHAc, a group selected from the group consisting of unsubstituted or substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C3-C8 cycloalkyl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, hydroxy, carboxy, cyano, C1-C6 alkoxy, C1-C6 alkylamino;

2. The compound of claim 1, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, having the structure of formula II:

wherein n, m, p and q are each independently selected from 0,1, 2,3 or 4;

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Is a group having the structure shown below:

wherein the content of the first and second substances,

Z²、Z³、Z⁴each independently selected from the group consisting of: n, CH₂、N-O、SO、SO₂C (═ O), NRa, CRa; wherein Ra is selected from the group consisting of: H. chloro, bromo, fluoro, iodo, cyano, halogen, hydroxy, nitro, NRf, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted C₆-C₁₀Heteroaryl, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C₁-C₆Alkoxy, -C (═ O) -substituted or unsubstituted C₁-C₆Alkyl, -C (O) -substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₂-C₆Alkynyl, -C (═ O) -substituted or unsubstituted C₂-C₆Alkenyl, -C (═ O) -substituted or unsubstituted C₂-C₆An alkynyl group;

Is a single bond or a double bond;

and is

Are aromatic or non-aromatic segments.

Substituted or unsubstituted

Or (L)_1a)_r-(L_2a)_s-(L_3a)_s-。

3. The compound of claim 1, wherein said compound is

Has a structure represented by the following formula:

wherein the content of the first and second substances,

R₆selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., ═ O), ═ NRf, -CN, hydroxy, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted- (C1-C6 alkylene) -NH- (C1-C6 alkylene), carboxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-to 12-membered heteroaryl having 1 to 3 heteroatoms, substituted or unsubstituted 5-to 12-membered heterocyclyl having 1 to 4 heteroatoms, substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Or (L)_1a)_r-(L_2a)_s-(L_3a)_s-。

wherein each group is as defined above.

5. The compound of claim 1, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein said ring is

And/or

Having a substituent represented by formula IV below:

Is a 3-8 membered nitrogen containing heterocyclic group;

Preferably, the compounds are selected from the following table;

6. a process for the preparation of a compound of formula I according to claim 1, comprising a step selected from the group consisting of schemes 1,2 and 3:

synthesis scheme 1

synthesis scheme 2:

(a) taking carboxylic ester 2-1 as a raw material, and carrying out an aminolysis reaction with amine 2-2 under the catalysis of Lewis acid to obtain an intermediate compound 2-3;

(b) taking the intermediate 2-3 and a proper coupling reagent 2-4 (such as boric acid, boric acid ester, a tin reagent or a Grignard reagent) as basic raw materials, and obtaining an intermediate compound 2-5 through a coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper;

(c) taking the intermediate 2-5 as a raw material, and removing a protecting group (Boc) under an acidic condition to obtain an intermediate 2-6;

(d) taking the intermediate 2-6 as a raw material, and carrying out nucleophilic substitution reaction with a halide under an alkaline condition, or carrying out reductive amination reaction with aldehyde or ketone under the action of a reducing agent to obtain a target compound I;

(a) carrying out reductive amination reaction in the synthesis scheme 3 to obtain a target compound I;

synthesis scheme 3:

the method 3 comprises the following steps:

(a) carrying out Suzuki coupling on the raw materials of the boron ester 3-1 and the halide 3-2 under the catalysis of palladium to obtain an intermediate compound 3-3;

(b) carboxylic acid 3-4 and a compound 3-5 are taken as raw materials, and a cyclization reaction is carried out under the action of a proper dehydrating agent to obtain an intermediate compound 3-3;

(c) taking aldehyde 3-6 as a raw material, and carrying out cyclization reaction under the action of a proper oxidant to obtain an intermediate 3-3;

(d) using the intermediate 3-3 and a proper coupling reagent 3-7 (such as boric acid, boric acid ester, a tin reagent or a Grignard reagent) as basic raw materials, and performing coupling reaction (such as Suzuki, Stille or Kumada coupling) catalyzed by palladium or copper to obtain a target compound I;

said Cy is

Is composed of

Y¹、Y²、Z¹、Z²、Z³And R is as defined above.

7. A pharmaceutical composition comprising (1) a compound of claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; (2) a pharmaceutically acceptable carrier.

8. Use of a compound according to claim 1 or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 7, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of diseases associated with the activity or expression of PD-1/PD-L1.

9. A PD-1/PD-L1 inhibitor, wherein said inhibitor comprises a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. A method of inhibiting the PD-1/PD-L1 interaction in vitro comprising the steps of: contacting a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, with PD-L1 protein.