Nitrogen-containing heterocyclic compounds, preparation methods, pharmaceutical compositions and applications thereof

Abstract

The present invention provides a nitrogen-containing heterocyclic compound, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the present invention provides a compound as shown in the following formula I, or an optical isomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; wherein the definition of each group is as described in the specification. The compound of formula I can be used to treat diseases related to the PD-1 / PD-L1 signaling pathway.

Description

Technical Field

[0001] The present invention relates to the field of small molecule drugs. Specifically, the present invention provides a small molecule compound that can be used to treat diseases related to the PD-1 / PD-L1 signaling pathway. Background of the Invention

[0002] The immune system plays a vital role in controlling and curing many diseases, such as various cancers and diseases caused by viruses. However, cancer cells can often evade or suppress the immune system in some ways, thereby multiplying rapidly. One of the ways is to change the activation and inhibition molecules expressed on immune cells. Blocking inhibitory immune checkpoints, such as PD-1, has proven to be a very effective way to inhibit cancer cells.

[0003] PD-1 is programmed cell death protein-1, also known as CD279. It is mainly expressed in activated T cells and B cells, and its function is to inhibit cell activation, which is a normal self-stabilizing mechanism of the immune system. Because excessive T / B cell activation can cause autoimmune diseases, PD-1 is a protective wall for our body. PD-1 is a type I transmembrane glycoprotein composed of 268 amino acids. Its structure mainly includes the outer immunoglobulin variable region, the hydrophobic transmembrane region, and the intracellular region. The intracellular region contains two phosphorylation sites, which are located in the immunoreceptor tyrosine inhibitory motif and the immunoreceptor tyrosine conversion motif, which also proves that PD-1 can reversely regulate T cell receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2, which are expressed differently. PD-L1 is upregulated in a variety of tumor cells. It binds to PD-1 on T cells, inhibits T cell proliferation and activation, and makes T cells inactive, ultimately inducing immune escape.

[0004] PD-1 / PD-L1 plays a reverse immunomodulatory role. When PD-1 binds to PD-L1, it can cause tyrosine polyphosphorylation in the tyrosine conversion motif domain of the T cell immune receptor, and the phosphorylated tyrosine can bind to the phosphatase protein tyrosinase 2 and protein tyrosinase 1. This can hinder the activation of extracellular signal-regulated kinases, and can also block the activation of phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (Akt), thereby inhibiting T lymphocyte proliferation and the secretion of related cytokines. While PD-1 / PD-L1 signals inhibit T cell activation and proliferation, they can also cause the secretion of cytokines interleukin 2, interferon γ, and IL-10. In addition, PD-1 / PD-L1 signals also have similar immune functions on B cells. When PD-1 binds to the B cell antigen receptor, the PD-1 cytoplasmic region interacts with tyrosinase containing the protein tyrosinase 2 binding site, thereby hindering the activation of B cells.

[0005] PD-1 / PD-L1-based immunotherapy is a new generation of immunotherapy that has attracted much attention. In recent years, a series of surprising research results have confirmed that PD-1 / PD-L1 inhibitors have strong anti-tumor activity against a variety of tumors. Currently available PD-1 / PD-L1 antibody inhibitors include BMS's Ninolumab, Merck's Lambrolizumab, and Roche's Atezolizumab. In addition, there are many PD-1 / PD-L1 antibody inhibitors under development, including Cure Tech's Pidilizumab, GSK's AMP-224, and AstraZeneca's MEDI-4736.

[0006] Although tumor immunotherapy is considered to be a new generation of revolution in cancer treatment after targeted therapy, the PD-1 monoclonal antibodies currently on the market and under development have their own defects, including only being injected and not orally administered, being unstable in the body, being easily decomposed by proteases, being prone to immune cross-reactions, being difficult to purify and having high production costs, etc. Therefore, small molecule inhibitors of PD-1 / PD-L1 interaction are a better choice for tumor immunotherapy.

[0007] In summary, there is an urgent need to develop novel small molecule inhibitors of PD-1 / PD-L1 interaction in this field. Summary of the invention

[0008] The purpose of the present invention is to provide a novel small molecule inhibitor of PD-1 / PD-L1 interaction.

[0009] The first aspect of the present invention provides a compound as shown in the following formula I, or an optical isomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

[0010]

[0011] wherein n, m, p and q are each independently selected from 0, 1, 2, 3 or 4;

[0012] L 1 , L 2 Selected from the following group: chemical 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)-, -S(O) 2 -, substituted or unsubstituted -NHC(O)NH-, Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted

[0013] A group having the following structure:

[0014]

[0015] in,

[0016] Z 1 is selected from the group consisting of O, S, NRf, and NO-Rf; wherein the Rf is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 6 -C 10 heteroaryl, cyano, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkoxy, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkyl, -C(=O)-substituted or unsubstituted C 3 -C 10 Cycloalkyl, -C(=O)-substituted or unsubstituted C 2 -C 6 alkenyl, -C(=O)-substituted or unsubstituted C 2 -C 6 Alkynyl;

[0017] Z 2 , Z 3 , Z 4 Each independently selected from the following group: N, CH 2 、NO、SO、SO 2 , C(=O), NRa, CRa; wherein Ra is selected from the group consisting of H, chlorine, bromine, fluorine, iodine, cyano, halogen, hydroxyl, nitro, NRf, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 6 -C 10 heteroaryl, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkoxy, -C(=O)-substituted or unsubstituted C1 -C 6 Alkyl, -C(=O)-substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, -C(=O)-substituted or unsubstituted C 2 -C 6 alkenyl, -C(=O)-substituted or unsubstituted C 2 -C 6 Alkynyl;

[0018] Y 1 , Y 2 , Y 3 Each independently selected from the group consisting of CH, CH 2 ,NH,NRa,N,NO,CF,CRa,C(Ra) 2 ,O,S,SO or SO 2 ;

[0019] is a single bond or a double bond;

[0020] and is an aromatic or non-aromatic fragment;

[0021] R is H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6 -C 10 Aryl, cyano, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkoxy, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkyl, -C(=O)-substituted or unsubstituted C 3 -C 10 Cycloalkyl, -C(=O)-substituted or unsubstituted C 2 -C 6 alkenyl, -C(=O)-substituted or unsubstituted C 2 -C 6 Alkynyl, or -(L 1a ) r -(L 2a ) s -(L 3a ) s -,in,

[0022] Each L 1aEach is independently a group selected from the group consisting of: a chemical bond, a substituted or unsubstituted C 1 -C 7 Alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, -S(O) 2 -、

[0023] L 2a Selected from the following group: 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;

[0024] L 3a Selected from the following group: H, substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxyl, amino, carboxyl, -CO-NH-SO 2 -R g 、-NH-SO 2 -R g 、-SO 2 -NH-CO-R g ;

[0025] r is 1, 2, 3, 4, 5, 6;

[0026] s is 0, 1, and 2 respectively;

[0027] Rd and Re are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl;

[0028] Selected from the following group: substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered C5-C12 cyclic group, wherein the 5-12 membered heteroaryl and 5-12 membered heterocyclic group have 1-4 heteroatoms selected from B, P, N, O, S, wherein P, N, O as ring atoms may be oxo-substituted and one or more ring carbon atoms may be replaced by carbonyl; or is none; or equal

[0029] Each is independently a divalent group formed by a ring selected from the group consisting of: Wherein, the bonding position of the ring can be N or C;

[0030] R 1 , R 2 , R 3 and R 4 Each is independently selected from the following group: 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, hydroxyl, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), 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 Among them, Rb, Rc and R z are independently selected from the following groups: H, substituted or unsubstituted C 1 -C 8 or said Rb and Rc together with the adjacent N atom constitute 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 -;

[0031] Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3, 4, etc.) substituents selected from the following groups: Halogen: including but not limited to -F, Cl, Br, -CH 2 Cl, -CHCl 2 , -CCl 3 、-CH 2 F, -CHF 2 , -CF 3, oxo, -CN, hydroxyl, amino, C1-C6 alkylamino, carboxyl, -NHAc, a group 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 group consisting of halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 alkylamino;

[0032] In the above formulae, any of the heteroatoms is selected from the group consisting of B, P, N, S and O.

[0033] In another preferred embodiment, the compound has a structure shown in the following formula II:

[0034]

[0035] wherein n, m, p and q are each independently selected from 0, 1, 2, 3 or 4;

[0036] L 1 , L 2 Selected from the following group: chemical 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)-, -S(O) 2 -, substituted or unsubstituted -NHC(O)NH-, Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted

[0037] A group having the following structure:

[0038]

[0039] in,

[0040] Z 1 is selected from the group consisting of O, S, NRf, and NO-Rf; wherein the Rf is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 6 -C10 heteroaryl, cyano, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkoxy, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkyl, -C(=O)-substituted or unsubstituted C 3 -C 10 Cycloalkyl, -C(=O)-substituted or unsubstituted C 2 -C 6 alkenyl, -C(=O)-substituted or unsubstituted C 2 -C 6 Alkynyl;

[0041] Z 2 , Z 3 , Z 4 Each independently selected from the following group: N, CH 2 、NO、SO、SO 2 , C(=O), NRa, CRa; wherein Ra is selected from the group consisting of H, chlorine, bromine, fluorine, iodine, cyano, halogen, hydroxyl, nitro, NRf, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 6 -C 10 heteroaryl, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkoxy, -C(=O)-substituted or unsubstituted C 1 -C 6 Alkyl, -C(=O)-substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, -C(=O)-substituted or unsubstituted C 2 -C 6 alkenyl, -C(=O)-substituted or unsubstituted C 2 -C 6 Alkynyl;

[0042] Y 1 , Y 2 , Y 3Each independently selected from the group consisting of CH, CH 2 ,NH,NRa,N,NO,CF,CRa,C(Ra) 2 ,O,S,SO or SO 2 ;

[0043] is a single bond or a double bond;

[0044] and It is an aromatic or non-aromatic fragment.

[0045] R 1 , R 2 , R 3 and R 4 Each is independently selected from the following group: 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, hydroxyl, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), 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 or -(L 1a ) r -(L 2a ) s -(L 3a ) s -

[0046] In another preferred embodiment, the It has the structure shown below:

[0047]

[0048] in,

[0049] X 6 , X 7 , X 8 , X 9 , X 10 and X 11 Each independently selected from the following group: N, CR;

[0050] R 6is selected from the following group: 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, hydroxyl, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), 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 or -(L 1a ) r -(L 2a ) s -(L 3a ) s -,-C 0-8 -OR 8 ,-C 0-8 -C(O)OR 8 ,-C 0-8 -OC(O)OR 8 ,-C 0-8 -NR 8 R 9 ,-C 0-8 -N(R 8 )C(O)R 9 ,-C 0-8 -C(O)NR 8 R 9 ;

[0051] R 8 and R 9 Each is independently selected from the following group: H, hydroxyl, 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, hydroxyl, NRdRe (e.g., amino), substituted or unsubstituted C1-C6 amine, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), 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 or -(L 1a ) r -(L2a ) s -(L 3a ) s -;

[0052] In another preferred embodiment, the R 6 For R 1 or wherein Rb and Rc are each independently selected from the following group: H, substituted or unsubstituted C 1 -C 8 or said Rb and Rc together with the adjacent N atom constitute a substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O.

[0053] In another preferred embodiment, the A monovalent group formed by an optionally substituted ring selected from the following group:

[0054]

[0055] 4. The compound according to claim 1, characterized in that the compound of formula I is selected from formula Id-1, Id-2 and Id-3, or optical isomers, hydrates, solvates, or pharmaceutically acceptable salts thereof:

[0056]

[0057] Wherein, the definitions of each group are as described above.

[0058] In another preferred embodiment, the ring and / or Having a substituent as shown in the following formula IV:

[0059]

[0060] Among them, each L 4 Independently selected from the following group: substituted or unsubstituted C1-C4 alkylene, -S-, -O-, -NRa-, -S(O)-, -S(O) 2 -; preferably substituted or unsubstituted C1-C4 alkylene, provided that each L 4 The structure formed together is chemically stable;

[0061] is selected from the following group: a substituted or unsubstituted C5-C10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from B, P, N, S and O; preferably, the is a 3-8 membered nitrogen-containing heterocyclic group;

[0062] Each R 5Each is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl; wherein the substituent is selected from the following group: halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy.

[0063] In another preferred embodiment, the compound is selected from the following Table 1;

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] The second aspect of the present invention provides a method for preparing the compound of formula I according to claim 1, wherein the method comprises steps selected from those shown in synthesis schemes 1, 2 or 3:

[0074] Synthesis Scheme 1

[0075]

[0076] (e) using halide 1-1 and a suitable coupling reagent 1-2 (such as boronic acid, boronic ester, tin reagent or Grignard reagent) as basic raw materials, and obtaining intermediate compound 1-3 through a palladium or copper catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling);

[0077] (f) intermediate 1-3 is used as a raw material, and reacts with carboxylic acid 1-4 in the presence of a condensing agent (such as HATU, EDCI or HBTU) to obtain amide intermediate 1-5;

[0078] (g) Using intermediate 1-5 as a raw material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 1-6;

[0079] (h) using intermediate 1-6 as a raw material, undergoing a nucleophilic substitution reaction with a halide under alkaline conditions, or undergoing a reductive amination reaction with an aldehyde or ketone under the action of a reducing agent to obtain the target compound I;

[0080] Synthesis Scheme 2:

[0081]

[0082] (e) using carboxylate 2-1 as a raw material, and carrying out an aminolysis reaction with amine 2-2 under Lewis acid catalysis to obtain an intermediate compound 2-3;

[0083] (f) using intermediate 2-3 and a suitable coupling reagent 2-4 (such as boronic acid, boronic ester, tin reagent or Grignard reagent) as basic raw materials, and obtaining intermediate compound 2-5 through a palladium or copper catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling);

[0084] (g) Using intermediate 2-5 as a starting material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 2-6;

[0085] (h) Using intermediate 2-6 as a raw material, a nucleophilic substitution reaction is carried out with a halide under alkaline conditions, or a reductive amination reaction is carried out with an aldehyde or ketone under the action of a reducing agent to obtain the target compound I;

[0086] (b) Reductive amination reaction was carried out in Synthesis Scheme 3 to obtain the target compound I;

[0087] Synthesis Scheme 3:

[0088]

[0089] Method 3 includes the following steps:

[0090] (e) Using boron ester 3-1 and halide 3-2 as raw materials, Suzuki coupling is carried out under palladium catalysis to obtain intermediate compound 3-3;

[0091] (f) Using carboxylic acid 3-4 and compound 3-5 as raw materials, a cyclization reaction occurs under the action of a suitable dehydrating agent to obtain an intermediate compound 3-3;

[0092] (g) Using aldehyde 3-6 as a raw material, a cyclization reaction occurs under the action of a suitable oxidant to obtain intermediate 3-3;

[0093] (h) using intermediate 3-3 and a suitable coupling reagent 3-7 (such as boronic acid, boronic ester, tin reagent or Grignard reagent) as basic raw materials, through a palladium or copper catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling) to obtain the target compound I;

[0094] The Cy is for Y 1 , Y 2 , Z 1, Z 2 , Z 3 , R is defined as above.

[0095] The third aspect of the present invention provides a pharmaceutical composition comprising (1) a compound as described in the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.

[0096] The fourth aspect of the present invention provides the use of the compound or its stereoisomer or tautomer as described in the first aspect of the present invention, or its pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition as described in the second aspect of the present invention, for preparing a pharmaceutical composition for preventing and / or treating diseases related to the activity or expression of PD-1 / PD-L1.

[0097] In the fifth aspect of the present invention, a PD-1 / PD-L1 inhibitor is provided, which comprises the compound described in the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0098] In another preferred embodiment, the pharmaceutical composition is used to treat a disease selected from the following group: cancer, infectious diseases, and autoimmune diseases.

[0099] In another preferred embodiment, the cancer is selected from the following group: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, skin cancer, lung cancer, urinary system tumors, blood tumors, gliomas, digestive system tumors, reproductive system tumors, lymphomas, nervous system tumors, brain tumors, head and neck cancer.

[0100] In another preferred embodiment, the cancer is selected from the following group: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid 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).

[0101] In another preferred embodiment, the infectious disease is selected from bacterial infection and viral infection.

[0102] In another preferred embodiment, the autoimmune disease is selected from organ-specific autoimmune disease and systemic autoimmune disease.

[0103] In another preferred embodiment, the organ-specific autoimmune diseases include 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, and acute idiopathic polyneuritis.

[0104] In another preferred embodiment, the systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.

[0105] In another preferred embodiment, the pharmaceutical composition is also used to improve T cell function in patients with chronic hepatitis B (CHB).

[0106] In another preferred embodiment, the inhibitor further comprises at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

[0107] The sixth aspect of the present invention provides an in vitro method for inhibiting PD-1 / PD-L1 interaction, characterized in that it comprises the steps of: contacting the compound described in the first aspect of the present invention, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate with PD-L1 protein.

[0108] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0109] After extensive and in-depth research, the inventors have discovered a class of PD-1 / PD-L1 interaction inhibitors with excellent inhibitory effects. On this basis, the inventors have completed the present invention.

[0110] definition

[0111] As used herein, the term "alkyl" includes straight chain or branched chain alkyl. 1 -C 8 The alkyl group represents a straight chain or branched chain alkyl group having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.

[0112] As used herein, the term "alkenyl" includes straight chain or branched chain alkenyl.2 -C 6 The alkenyl group refers to 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.

[0113] As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. 2 -C 6 The alkynyl group refers to a straight chain or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0114] As used herein, the term “C 3 -C 10 The term "cycloalkyl" refers to a cycloalkyl group having 3 to 10 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be a bicyclic ring, such as a bridged ring or a spiro ring.

[0115] As used herein, the term “C 1 -C 8 "Alkylamino" refers to 1 -C 8 The amine group substituted by the alkyl group may be monosubstituted or disubstituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino and the like.

[0116] As used herein, the term “C 1 -C 8 The term "alkoxy" refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0117] 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, wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic or bicyclic form, such as a bridged ring or a spirocyclic form. Specific examples may include oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, etc.

[0118] As used herein, the term “C 6 -C 10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

[0119] 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, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic ring or a condensed ring. Specific examples may include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

[0120] Unless otherwise specified as "substituted or unsubstituted", the groups of the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C 1 -C 6 Alkyl-amino, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, halogenated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halogenated C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkoxy, allyl, benzyl, C 6 -C 12 Aryl, C 1 -C 6 Alkoxy-C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 Alkynyl-carbonyl, C 2 -C 6 Alkenyl-carbonyl, C 3 -C 6 Cycloalkyl-carbonyl, C 1 -C 6 Alkyl-sulfonyl, etc.

[0121] 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.

[0122] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0123] As used herein, the term "tautomer" means that structural isomers with different energies can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropic) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via reorganization of some bonding electrons.

[0124] As used herein, the term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0125] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

[0126] Active ingredients

[0127] As used herein, "compounds of the present 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.

[0128] Preferred compounds of the present invention include compounds 1-360 (including various R-configuration and / or S-configuration stereoisomers of each compound, and / or E- / Z-cis-trans isomers).

[0129] In another preferred embodiment, the pharmaceutically acceptable salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases that can provide physiologically acceptable cations, and ammonium salts.

[0130] 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, citric acid, maleic tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ion is selected from lithium ion, sodium ion, potassium ion; the alkaline earth metal ion is selected from calcium ion and magnesium ion; the organic base capable of providing physiologically acceptable cations is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[0131] All of these salts within the scope of the present invention can be prepared by conventional methods. In the preparation process of the compound of general formula I, its solvate and its salt, different crystallization conditions may result in polymorphism or co-crystal.

[0132] Preparation of compounds of formula I

[0133] In order to prepare the compound of general formula I of the present invention, according to the structure of general formula I, the compound of general formula I of the present invention can be obtained by the following method 1 or 2.

[0134] Method 1 includes the following steps:

[0135]

[0136] (a) using halide 1-1 and a suitable coupling reagent 1-2 (such as boronic acid, boronic ester, tin reagent or Grignard reagent) as basic raw materials, and obtaining intermediate compound 1-3 through a palladium or copper catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling);

[0137] (b) intermediate 1-3 is used as a raw material, and reacts with carboxylic acid 1-4 in the presence of a condensing agent (such as HATU, EDCI or HBTU) to obtain amide intermediate 1-5;

[0138] (c) Using intermediate 1-5 as a raw material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 1-6;

[0139] (d) using intermediate 1-6 as a raw material, undergoing a nucleophilic substitution reaction with a halide under alkaline conditions, or undergoing a reductive amination reaction with an aldehyde or ketone under the action of a reducing agent to obtain the target compound I;

[0140]

[0141] Method 2 includes the following steps:

[0142] (c) using carboxylate 2-1 as a raw material, and carrying out an aminolysis reaction with amine 2-2 under Lewis acid catalysis to obtain an intermediate compound 2-3;

[0143] (d) using intermediate 2-3 and a suitable coupling reagent 2-4 (such as boronic acid, boronic ester, tin reagent or Grignard reagent) as basic raw materials, a palladium or copper catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling) is performed to obtain intermediate compound 2-5;

[0144] (e) Using intermediate 2-5 as a raw material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 2-6;

[0145] (f) Using intermediate 2-6 as a raw material, a nucleophilic substitution reaction is carried out with a halide under alkaline conditions, or a reductive amination reaction is carried out with an aldehyde or ketone under the action of a reducing agent to obtain the target compound I;

[0146]

[0147] Method 3 includes the following steps:

[0148] (i) Carboxylate 3-1 is used as a raw material, and Buchwald-Hartwig coupling or Ullman coupling is carried out with amine 3-2 under palladium or copper catalysis to obtain intermediate compound 3-3;

[0149] (j) using intermediate 3-3 and a suitable coupling reagent 3-4 (such as boronic acid, boronic ester, tin reagent or Grignard reagent) as basic raw materials, and obtaining intermediate compound 3-5 by a palladium or copper catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling);

[0150] (k) Using intermediate 3-5 as a raw material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 3-6;

[0151] (1) Using intermediate 3-6 as a raw material, a nucleophilic substitution reaction is carried out with a halide under alkaline conditions, or a reductive amination reaction is carried out with an aldehyde or ketone under the action of a reducing agent to obtain the target compound I;

[0152] The Cy is for Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , R is defined as above.

[0153] In addition, the starting materials and intermediates in the above reactions are easily available, and each step of the reaction can be easily synthesized according to the reported literature or by conventional methods in organic synthesis for those skilled in the art. The compound described in general formula I may exist in the form of a solvate or an unsolvate, and different solvates may be obtained by crystallization using different solvents.

[0154] Pharmaceutical compositions and methods of administration

[0155] Since the compounds of the present invention have excellent inhibitory activity on PD-1 / PD-L1 interaction, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) PD-1 / PD-L1 interaction-related diseases (e.g., cancer, infectious diseases, autoimmune diseases).

[0156] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and 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. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0157] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0158] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration).

[0159] 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, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl 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 the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0160] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0161] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0162] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0163] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0164] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0165] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, other anticancer agents).

[0166] When administered in combination, the pharmaceutical composition also includes 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 can be used simultaneously, separately or sequentially with the compounds of the present invention to prevent and / or treat PD-1 / PD-L1 interaction-related diseases.

[0167] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0168] The main advantages of the present invention include:

[0169] (1) The compounds of the present invention have high inhibitory activity on PD-1 / PD-L1 interaction, have strong binding ability with PD-L1 protein, and have the ability to relieve PD-L1 from inhibiting IFNγ.

[0170] (2) The compounds of the present invention have better solubility and very low toxicity to normal cells, and thus can be applied to therapeutic subjects within a larger dosage range.

[0171] (3) Compared with the compounds of the prior art, the compounds of the present invention have better solubility and thus have good drugability. Compared with the existing compounds, the compounds of the present invention show good bioavailability in in vivo experiments. In addition, compared with the existing compounds, the compounds of the present invention are very easy to prepare into pharmaceutically acceptable salts, thus facilitating the further formation of preparations.

[0172] (4) In vivo efficacy studies have shown that the compounds of the present invention can significantly inhibit the growth of subcutaneous tumors, both in terms of tumor volume and weight, and can significantly increase the number of lymphocytes in the blood and spleen of mice.

[0173] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0174] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0175] General materials and test methods:

[0176] The instruments and raw materials involved in the embodiments are described as follows:

[0177] The hydrogen nuclear magnetic resonance spectrum was obtained by Bruker AV-400 (400 MHz) nuclear magnetic resonance spectra.

[0178] Chemical shifts were recorded using tetramethylsilane as an internal standard and expressed in ppm (CDC1 3 :δ7.26ppm). The recorded data information is as follows: chemical shift and its splitting and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad peak; m: multiplet).

[0179] Mass spectrometry data were analyzed by Finnigan LCQ Advantage LC / MS, and all reactions were performed under dry argon protection in anhydrous and oxygen-free conditions. Solid metal organic compounds were stored in an argon protection dry box.

[0180] Tetrahydrofuran and ether are obtained by distillation, in which sodium metal and benzophenone are added. Dichloromethane, pentane and hexane are treated with calcium hydride.

[0181] The special raw materials and intermediates involved in the present invention are provided by Tianjin Changsen Pharmaceutical Co., Ltd., and all other chemical reagents are purchased from reagent suppliers such as Shanghai Chemical Reagent Company, Aldrich, and Acros. If the intermediates or products required for the reaction during the synthesis are insufficient for the next test, the synthesis is repeated several times until a sufficient amount is obtained.

[0182] Unless otherwise specified, the raw materials and reagents involved in the present invention can be purchased commercially or customized.

[0183] The compounds of the present invention may contain one or more asymmetric centers, so the series of compounds may be in the form of racemates or single enantiomers. The compounds prepared by the present invention are heterocyclic compounds with a purity higher than 95%. The structure of each final product is characterized by MS and / or H NMR ( 1 The following examples illustrate the synthesis of various compounds and intermediates of the present invention.

[0184] Example 1 Synthesis of Compound LW1005-001

[0185]

[0186] Step 1-1:

[0187]

[0188] Compound 1 (51 g, Journal of Medicinal Chemistry, 2019, 62, 276-287) and 2-methyl-3-bromobenzoic acid (95.56 g) were added to PPA (500 g) in sequence, and the mixture was stirred mechanically at 140 ° C for 6 hours. After the reaction was complete, ice water was poured into the reaction bottle, and after dilution, it was poured out and slurried for 30 minutes and filtered. 500 ml of water was added to the filtered solid, and solid sodium hydroxide was added under mechanical stirring. The aqueous phase was adjusted to pH = 6-8 and filtered. The filter cake solid was dried at 55 ° C to obtain 80 g of off-white solid product. MS-APCI: 305 [M + H] + .

[0189] Step 1-2:

[0190]

[0191] 3 (2.0 g), DMAP (805 mg) was added to DMF (30 mL), the turbid solution was added with Boc2O, the solid dissolved, and the reaction was heated at 40 degrees overnight. TLC showed that a small amount of 1 remained. The reaction solution was spun dry with an oil pump. The solid was slurried with EA / HEP and filtered to obtain 1.6 g of a white solid product. MS-APCI: 405.2 [M+H] +

[0192] Steps 1-3:

[0193]

[0194] 4 (202 mg), 5 (230 mg, WO2018119286), Pd(dppf)Cl2 / DCM (19.5 mg) and Na 2 CO 3 (21.2 mg) was placed in a reaction bottle, vacuum degassed, and dioxane / H2O (5 mL / 1 mL) was injected into the syringe. After degassed again, the reaction was heated at 100 degrees for 4 hours. The reaction solution was poured into water, extracted with EA, dried, and the EA layer was spin-dried. It was slurried with EA / HEP (1:1) and filtered to obtain 100 mg of crude product. 50 mg was prepared, separated and purified to obtain 9.0 mg of LW1005-001 as a yellow solid. MS-APCI: 559.2 [M+H] +

[0195] 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),2.4 5(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).

[0196] Example 2 Synthesis of Compound LW1005-002

[0197]

[0198] Step 2-1:

[0199]

[0200] Compound 3 (10 g) was dissolved in DMF (150 ml), and 6 (14.3 g; Macromolecules, 2015, 48, 1688-1702) and Cs2CO3 (21.4 g) were added and reacted at room temperature overnight. TLC detected that the reaction was complete. Filtered, the filtrate was added with water and then extracted with EtOAc, the organic phase was spin-dried, and slurried with HEP:EtOAc = 10:1 to obtain 11 g of white solid 7. MS-APCI: 587.1 [M+H]+

[0201] 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).

[0202] Step 2-2:

[0203]

[0204] 7 (11 g) was dissolved in THF (110 mL) at room temperature, and 1NTA F / THF (20.7 mL) was added and reacted for 2 hours. TLC showed that the reaction of the raw material was complete. The reaction solution was dried and passed through a column (DCM: MeOH = 20: 1) to obtain 4.5 g of white solid product 8. MS-APCI: 349.1 [M+H] +

[0205] Step 2-3:

[0206]

[0207] 8 (350 mg), Bpin2 (304.8 mg), Pd (dppf) Cl2 (81.7 mg) and KOAc (196 mg) were placed in a reaction bottle at room temperature, vacuum degassed, and dioxane (5 mL) was injected into the syringe. After degassed again, the mixture was heated at 100 degrees for overnight reaction. TLC showed that the reaction was complete. After adding water to the reaction solution, EtOAc was extracted, and the organic phase was washed with saturated NaCl, dried, spin-dried, and passed through a column (DCM: MeOH = 20: 1) to obtain 350 mg of compound 9 as a gray solid. MS-APCI: 397.1 [M + H] +

[0208] Steps 2-4:

[0209]

[0210] 9 (350 mg), 10 (364 mg, WO2018119286), Pd(dppf)Cl2 / DCM (71.9 mg) and Na 2 CO 3 (186.6 mg) was placed in a reaction bottle, vacuum degassed, and dioxane / H2O (3.6 mL, 5:1) was injected into the syringe. After degassed again, the reaction was heated at 100 degrees for 4 hours. TLC showed that the raw material was completely reacted. After adding water to the reaction solution, EtOAc was extracted, and the organic phase was washed with saturated NaCl, dried, spin-dried, and passed through a column (DCM:MeOH=20:1) to obtain 45 mg of compound LW1005-002 as a yellow solid.

[0211] MS-APCI: 603.2[M+H] +

[0212] 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),7.7 7(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)

[0213] Example 3 Synthesis of Compound LW1005-003

[0214]

[0215] Step 3-1:

[0216]

[0217] 3 (1.38 g) was added to DMF (40 ml) at room temperature, and Cs 2 CO 3 (2.95 g) and compound 11 (1.45 g; Organic Letters, 2018, 20, 6938-6942), react at room temperature overnight. Add water to the reaction solution, stir, filter, and slurry the crude solid with EA / HEP (1:10) and filter to obtain 1.33 g of product. MS-APCI: 491.1 [M+H] +

[0218] Step 3-2:

[0219]

[0220] 12 (1.33 g) was added to 30 mL dioxane, and Pd (dppf) Cl2 (0.22 g), KOAc (0.53 g), and bis-pinacol borate (0.76 g) were added. The mixture was replaced with nitrogen and reacted at 100 °C for 3 h. Post-treatment: filtration with water, extraction with EA, column chromatography with HEP: EA = 3:1, and spin drying to obtain 1.14 g of the product. MS-APCI: 539.2 [M+H] +

[0221] Step 3-3:

[0222]

[0223] 13 (1.14 g) was added to 30 mL dioxane / 6 mL water, and Pd(dppf)Cl2·DCM (0.17 g), Na 2 CO 3 (0.45g) and 10 (875mg, WO2018119286), nitrogen replacement, reaction at 100°C for 4h. Post-treatment: add water to filter, extract with EA, pass through column with DCM / MeOH=20:1, spin dry, and obtain 0.9g of product. MS-APCI: 745.2[M+H] +

[0224] Step 3-4:

[0225]

[0226] 14 (100 mg) was dissolved in tetrahydrofuran (10 mL), 4N HCl / dioxane (2 mL) was added dropwise, and the mixture was reacted at RT. The reaction was complete by TLC detection, and part of the product was prepared and isolated to obtain 20 mg of the 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),5.5 1(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).

[0227] Example 4 Synthesis of Compound LW1005-004

[0228]

[0229] Step 4-1:

[0230]

[0231] 15 (1.0 g) was dissolved in DMF (10 mL), and imidazole (0.64 g) and TBSCl (1.1 g) were added. The reaction was allowed to react overnight at room temperature. The TLC plate showed that the reaction was complete. The reaction solution was washed with water, extracted with EA, and the EA layer was dried by spin drying and passed through a column to obtain 1.6 g of a light yellow oily product.

[0232] Step 4-2:

[0233]

[0234] LAH (0.33 g) was added to THF (15 mL), and compound 16 (1.6 g dissolved in 5 mL THF) was added dropwise at 0 degrees, and the mixture was reacted at 0 degrees for 1 hour. TLC showed that the reaction was complete. 0.33 mL of water, 0.33 mL of NaOH (10%), and 0.33 mL of water were added to the reaction solution at 0 degrees, and the mixture was filtered and the filtrate was dried to obtain 1.3 g of a light yellow oily product.

[0235] Step 4-3:

[0236]

[0237] 17 (0.5 g) and TEA (0.41 g) were dissolved in DCM (5 mL), and MsCl (0.35 g) was added dropwise at 0°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was washed with water, extracted with DCM, and dried to obtain 0.66 g of a light yellow oily product.

[0238] Step 4-4:

[0239]

[0240] 18(0.66g),3(0.48g),Cs 2 CO 3 (1.5 g) was added to DMF (20 mL) and reacted at room temperature overnight. The reaction solution was poured into water and solid precipitated. After filtration, the solid was spin-dried to obtain 0.5 g of compound 19 as a white solid. MS-APCI: 531.1 [M+H] +

[0241] Step 4-5:

[0242]

[0243] 19 (200 mg), 5 (142.6 mg, WO2018119286), Pd(dppf)Cl 2 / DCM (31 mg) and Na 2 CO 3 (80.6 mg) was placed in a reaction bottle, vacuum degassed, and dioxane / H 2 O (6 mL, 5:1), degassed again and heated at 100 degrees to react overnight. The reaction solution was washed with water and passed through a column (DCM: MeOH = 20:1) to obtain 120 mg of product 20. MS-APCI: 785.4 [M+H] +

[0244] Steps 4-6:

[0245]

[0246] 20 (120 mg) was dissolved in THF (3 mL), 4N HCl / dioxane (0.3 mL) was added, and the mixture was reacted at room temperature for 30 minutes. Solids were precipitated. Filtered. Solid preparation and separation gave 40 mg of yellow solid product. MS-APCI: 671.3 [M+H] +

[0247] 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),2.4 5(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).

[0248] Example 5 Synthesis of Compound LW1005-005

[0249]

[0250] Step 5-1:

[0251]

[0252] 7 (1 g), Bpin2 (605 mg), Pd(dppf)Cl 2 (180 mg) and KOAc (431.2 mg) were placed in a reaction bottle, vacuum degassed, and dioxane (15 mL) was injected into the syringe. After degassed again, the reaction was heated at 100 degrees for 2 h. TLC showed that the reaction was complete. After adding water to the reaction solution, EtOAc was extracted, and the organic phase was washed with saturated NaCl, dried, spin-dried, and passed through a column to obtain 900 mg of yellow solid 21. MS-APCI: 635 [M+H] +

[0253] Step 5-2:

[0254]

[0255] 21 (102 mg), 10 (82.4 mg, WO2018119286), Pd(dppf)Cl2 / DCM (16.3 mg) and Na2CO3 (42.4 mg) were placed in a reaction bottle at room temperature, vacuum degassed, and dioxane / H2O (5 mL / 1 mL) was injected into the syringe. After degassed again, the reaction was heated at 100 degrees overnight. TLC showed that the reaction was complete. The reaction solution was washed with water, extracted with EA, and passed through a column (DCM:MeOH=20:1) to obtain 80 mg of the product as a yellow solid. MS-APCI: 842 [M+H] +

[0256] Step 5-3:

[0257]

[0258] 22 (500 mg), BzCl (146.6 mg), TEA (211.5 mg) were added to DCM (5 mL) and reacted at room temperature overnight. TLC showed that the raw materials were completely reacted. The reaction solution was poured into water, extracted with DCM, dried, passed through a column (EA / HEP=1:1), and dried to obtain 350 mg of a yellow solid. MS-APCI: 945 [M+H] +

[0259] Step 5-4:

[0260]

[0261] 23 (350 mg) was dissolved in DCM (5 mL), TBAF (1 mL, 1 M in THF) was added, and the mixture was reacted at room temperature for 10 min. The reaction was completed after TLC detection. The reaction solution was washed with brine and passed through a column (DCM: MeOH = 20: 1) to obtain 200 mg of a yellow solid product. MS-APCI: 707.3 [M+H] +

[0262] Step 5-5:

[0263]

[0264] 24 (100 mg) was dissolved in DMF (2 mL), and Dess-martin (120 mg) was added at zero degrees, and the reaction was continued at zero degrees overnight. TLC showed that the remaining starting material was about 20%. The reaction solution was added with saturated NaHCO 3 Quench, extract with EA, spin dry the EA layer, and directly use the crude product for the next step. MS-APCI: 705.2[M+H] +

[0265] Step 5-6:

[0266]

[0267] 25 (50 mg), 26 (12.3 mg), and TEA (21.2 mg) were added to DMF (2 mL), reacted at room temperature for 1 hour, and NaBH 3 CN (6.9 mg), reacted at room temperature overnight. The reaction solution was washed with water, extracted with EA, dried, and the crude product was prepared and separated to obtain 10 mg of product 27 as a yellow solid. MS-APCI: 804.3 [M+H] +

[0268] Steps 5-7:

[0269]

[0270] 27 (10 mg) was dissolved in MeOH (2 mL), K2CO3 (3 mg) was added, and the mixture was reacted at room temperature for 1 hour. TLC showed that 27 was completely reacted. The reaction solution was dried by vortexing, dissolved in THF / MeOH / H2O (1:1:1), and LiOH. 2 O (1 mg), react at room temperature for 10 minutes. TLC detected that the reaction was complete. The reaction solution was prepared and separated to obtain 5.5 mg of a yellow solid product. MS-APCI: 686.3 [M+H] +

[0271] 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).

[0272] Example 6 Synthesis of Compound LW1005-006

[0273]

[0274] Step 6-1:

[0275]

[0276] 25 (50 mg), 28 (7.8 mg), and TEA (21.5 mg) were added to DMF (2 mL), reacted at room temperature for 1 hour, and NaBH 3 CN (6.7 mg), reacted at room temperature overnight. The reaction solution was washed with water, extracted with EA, dried, and the crude product was prepared and separated to obtain 10 mg of product 29 as a yellow solid. MS-APCI: 762.3 [M+H] +

[0277] Step 6-2:

[0278]

[0279] 29 (10 mg) was dissolved in MeOH (2 mL) and K 2 CO 3 (5.4 mg), reacted at room temperature for 1 hour, TLC showed that the raw material reacted completely. The reaction solution was prepared and separated to obtain 3 mg LW1005-006, yellow solid. MS-APCI: 658.3 [M+H] +

[0280] 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=6.1H z,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).

[0281] Example 7 Synthesis of Compound LW1005-007

[0282]

[0283] Step 7-1:

[0284]

[0285] 25 (90 mg), 30 (180 mg), TEA (254.5 mg) were added to DMF (2 mL), reacted at room temperature for 1 hour, and NaBH 3 CN (79 mg), reacted at room temperature overnight. The reaction solution was washed with water, extracted with EA, dried, and purified by TLC to obtain 40 mg of product 31 as a yellow solid. MS-APCI: 832.3 [M+H] +

[0286] Step 7-2:

[0287]

[0288] 31 (40 mg) was dissolved in MeOH (2 mL) and K 2 CO 3 (13.3 mg), react at room temperature for 1 hour, heat at 40 degrees for 10 minutes, TLC shows that 2 is completely reacted. The reaction solution is prepared and separated to obtain 8.2 mg of LW1005-007 as a yellow solid. MS-APCI: 714.3 [M+H] +

[0289] 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),3.34-3.2 7(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).

[0290] Example 8 Synthesis of Compound LW1005-008

[0291]

[0292] Step 8-1:

[0293]

[0294] Mix raw material 8 (19 g) and NIS (14.7 g), add MeCN (200 mL), and dropwise add 1 mL CF 3 COOH, stir in oil bath at 55°C for 2.5 hours. 10.5 g of white solid was obtained by filtration. MS-APCI: 475 [M+H] +

[0295] Step 8-2:

[0296]

[0297] The raw material 32 (10 g), Zn(CN) 2 (2.5g), Pd 2 (dba) 3 (900 mg), DPPf (1.2 g) were mixed in a 500 mL single-necked bottle, N 2 Replace 3 times, inject 200 mL of DMF, and stir at 85°C for 2 hours. After the reaction is completed, pour the reaction solution into water and filter to obtain 6.3 g of white solid. MS-APCI: 374 [M+H] +

[0298] Step 8-3:

[0299]

[0300] The raw material 33 (5.0 g) was dispersed in DCM (250 ml), and Dess-Martin (11.3 g) was added during stirring. The reaction was allowed to proceed at room temperature for 30 min. The reaction was complete on TLC plate. Saturated sodium bicarbonate solution (250 ml x 2) was then added in sequence and stirred. The aqueous phase was separated, and 10% sodium thiosulfate (250 ml x 2) was added to the organic phase and stirred. The mixture was allowed to stand, extracted, dried, and concentrated to obtain 4.0 g of an orange-yellow solid, which was directly used for the next step. MS-APCI: 372 [M+H] +

[0301] Step 8-4:

[0302]

[0303] The raw material 34 (4.0 g) and 35 (3.53 g) were dissolved in DCM (200 mL) and Et 3 N (2.4 g), after one hour of reaction, NaBH(OAc) was added 3(2.25g), react at room temperature for 1 hour, TLC shows the reaction is complete, add 200ml of water, stir, separate, extract, dry, concentrate and purify by column chromatography to obtain 3.5g of light yellow solid. MS-APCI: 541[M+H] +

[0304] Step 8-5:

[0305]

[0306] 36(1080mg),5(756mg, WO2018119286), Pd(dppf)Cl 2 / DCM (167.4 mg), Na 2 CO 3 (530 mg) was placed in a reaction bottle, N 2 Degassing protection, 15mL dioxane / 3mL water was injected into the reaction bottle, and the reaction was carried out at 90 degrees for 2 hours. TLC spot 36 showed that the reaction was complete. The reaction solution was washed with water, extracted with EA, dried, spin-dried, and passed through a column (DCM:MeOH=30:1) to obtain 1.0g of product as a yellow solid. MS-APCI:795.3[M+H] +

[0307] Step 8-6:

[0308]

[0309] Compound 37 (3.9 g) was dissolved in THF (50 mL), and TFA (10 mL) was added and stirred at room temperature overnight. TLC detected that the reaction was complete. The reaction solution was spun off THF, and the TFA was dried by oil pump to obtain a crude yellow solid. Further purification by column (DCM: MeOH = 10: 1) obtained 3.5 g of product. MS-APCI: 739.3 [M + H] +

[0310] 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,2 H),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,3 H),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).

[0311] Example 9 Synthesis of Compound LW1005-009

[0312]

[0313] Step 9-1:

[0314]

[0315] The raw material 5 (5.0 g, WO2018119286) was dissolved in DCM (100 mL), Et3N (3.2 g) was added, stirred evenly, BzCl (3.0 g) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was washed with saturated brine, extracted with DCM, dried, concentrated, and purified by column chromatography to obtain 3.7 g of a yellow solid. MS-APCI: 565.3 [M+H] +

[0316] Step 9-2:

[0317]

[0318] The starting material 38 (1.97 g), the starting material 33 (3.3 g), Pd(dppf)Cl2 / DCM (431 mg), Na 2 CO 3 (1.12g) was mixed, replaced with nitrogen, and Dioxane / H2O (4:1) (50mL) was added and reacted at 95°C for 3 hours. After the reaction was completed, it was washed with water, extracted with EA, dried, concentrated, and purified by column chromatography to obtain 2.7g of yellow solid. MS-APCI: 732.3 [M+H] + Step 9-3:

[0319]

[0320] 39 (200 mg) was dissolved in DCM (20 mL), and DMP (406 mg) was added at room temperature. The reaction was allowed to react at room temperature for 10 minutes. The reaction was complete according to TLC. The reaction solution was firstly treated with saturated NaHCO 3 Wash with 10% Na 2 S 2 O 3 Wash. Extract the aqueous phase with DCM. Combine the DCM layers, dry, spin dry, and use directly in the next step. MS-APCI: 730.3 [M + H] +

[0321] Step 9-4:

[0322]

[0323] To a solution of 40 (150 mg) in DCM (15 mL) were added 41 (52 mg) and TEA (103 mg), and the mixture was reacted at room temperature for 1 hour. Then, NaBH(OAc) was added. 3 (216.2 mg), react at room temperature overnight. TLC plate showed that the reaction was complete. The reaction solution was saturated with NaHCO 3 Wash, extract with DCM, dry, and pass through a column to obtain 100 mg of the product as a yellow solid. MS-APCI: 815.3 [M+H] + Step 9-5:

[0324]

[0325] Compound 6 (100 mg) was dissolved in 10 mL THF, and 2 d NaOMe (5 N in MeOH) was added dropwise at room temperature. The reaction was allowed to proceed for 5 minutes. Solids were precipitated. TLC showed that the reaction was complete. The reaction solution was adjusted to neutral with 4 N HCl / dioxane. The mixture was dried and separated to obtain 19 mg of the product as a yellow solid. MS-APCI: 711.3 [M+H] +

[0326] 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).

[0327] Example 10 Synthesis of Compound LW1005-010

[0328]

[0329] Step 10-1:

[0330]

[0331] Compound 43 (306 mg, FCH group), 44 (633.6 mg; Organic Process Research & Development, 2018, 22, 97-102.) and Na 2 S 2 O 5 (570 mg) was added to DMF (3 mL), and the reaction was carried out at 110 degrees under N2 protection overnight. The reaction was detected by LCMS. After the reaction was complete, the reaction solution was washed with water, extracted with EA, and passed through a column to obtain 360 mg of a light 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).

[0332] Step 10-2:

[0333]

[0334] 45 (260 mg) was added to HBr / AcOH (4 mL, 1:1) and reacted at 85°C for 1.5 h. The reaction was complete after TLC detection. The reaction solution was spin-dried and used directly in the next step. MS-APCI: 318 [M+H] + .

[0335] Step 10-3:

[0336]

[0337] 46 (344 mg), 6 (471 mg) and Cs 2 CO 3 (710 mg) was added to DMF (3 mL) and reacted at room temperature overnight. The reaction was detected by TLC. After the reaction was complete, the reaction solution was filtered, the filtrate was washed with water, extracted with EA, dried and then spin-dried to obtain a light yellow solid, which was slurried with EA / HEP (1:1) and filtered to obtain 400 mg of a white solid. MS-APCI: 600.2 [M+H] + .Step 10-4:

[0338]

[0339] 47 (340 mg), B 2 pin 2 (173 mg), Pd(dppf)Cl 2 / DCM (46.5 mg) and KOAc (111.7 mg) were placed in a reaction bottle, vacuum degassed, and dioxane (5 mL) was injected into the syringe. After degassed again, the mixture was heated at 100 degrees for 4 hours. TLC showed that a small amount of 6 remained. After adding water to the reaction solution, EtOAc was extracted, and the organic phase was washed with saturated NaCl, dried, spin-dried, and passed through a column to obtain 250 mg of a light yellow solid. MS-APCI: 648.2 [M+H] +

[0340] Step 10-5:

[0341]

[0342] 48 (150 mg), 10 (95.7 mg, WO2018119286), Pd(dppf)Cl2 / DCM (18.8 mg) and Na 2 CO 3 (48.8 mg) was placed in a reaction bottle, vacuum degassed, and dioxane / H 2 O (6mL, 5:1), degassed again and heated at 100 degrees for 3 hours. TLC showed that the raw material was completely reacted. The reaction solution was washed with water, extracted with EA, and passed through a column to obtain 150 mg of a yellow solid. MS-APCI: 854.2 [M+H] +

[0343] Step 10-6:

[0344]

[0345] 9 (150 mg) was dissolved in THF (2 ml) at room temperature, and TBAF / THF (0.2 mL, 1 M) was added. The mixture was reacted at room temperature for 2 hours. Solids precipitated from the reaction solution. The filter cake solid was dissolved with MeOH and passed through a cation exchange column to obtain 20.7 mg of a yellow solid. MS-APCI: 616.2 [M+H] +

[0346] 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),6.9 5(dd,J=7.5,1.3Hz,1H),6.68(d,J=7.3Hz,1H),4.85(t,J=5.4Hz,1H),4.7 3 (d, J = 4.5 Hz, 1H), 4.23 (s, 1H), 4.06 (t, J = 5.7 Hz, 2H), 3.82 (q, J = 13.7 Hz, 2H), 3.65 (q, J = 5.6 Hz, 2H), 3.57 (s, 3H), 2.75 (dd, J = 9.7, 6.1 Hz, 1H), 2.67 (q, J = 7.6 Hz, 1H), 2.39 (dd, J = 9.6, 3.7 Hz, 1H), 2.13 (s, 3H), 2.03 (dd, J = 13.3, 6.8 Hz, 1H), 1.88 (s, 3H), 1.66-1.49 (m, 1H). Example 11 Synthesis of Compound LW1005-011

[0347]

[0348] Step 11-1:

[0349]

[0350] Substrate 51 (200 mg, 1.858 mmol; CN108373476) and 2 (340 mg, 1.858 mmol) were added to a three-necked flask containing polyphosphoric acid (8 mL), and the reaction solution was heated and stirred in an oil bath at 140°C for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, sodium hydroxide aqueous solution (2M) was added to the reaction solution to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and column chromatographed to obtain 370 mg of a white solid with a yield of 76.3%. MS-APCI:305[M+H]+; 1H NMR (400MHz, DMSO-d6) δ9.38(d,J=1.0Hz,1H),8.60(d,J=5.4Hz,1H),8.28(dd,J=5.4,1.0H z,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).

[0351] Step 11-2:

[0352]

[0353] Substrate 53 (2.88 g, 9.44 mmol) and m-CPBA (3.83 g, 0.0188 mol) were dissolved in DCM (40 mL), stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was complete, the pH was adjusted to 6-7 with sodium hydroxide aqueous solution (2 M), extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate and column chromatographed to obtain 2.23 g of brown-yellow solid with a yield of 73.5%. MS-APCI: 321 [M+H] +

[0354] Step 11-3:

[0355]

[0356] Compound 4 (2.2 g, 6.94 mmol) was added to a single-mouth bottle containing acetic anhydride (30 mL, 0.38 mol), and then the reaction solution was heated and stirred at 140 ° C for 2 hours, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was cooled to 80 ° C, and then methanol (12 mL) and water (3.6 mL) were added to the reaction solution, and stirred at 80 ° C for 30 minutes. The reaction solution was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered, rinsed with ethyl acetate (10 mL x 3), and dried under reduced pressure to obtain 1.6 g of tea-white solid, with a yield of 71.8%. MS-APCI: 321 [M + H] + ; 1 H 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).

[0357] Step 11-4:

[0358]

[0359] Compound 55 (1.3 g, 4.05 mmol), 6 (2.94 g, 8.10 mmol) and cesium carbonate (2.6 g, 8.10 mmol) were added to a single-mouth bottle containing DMF (30 mL), and then the reaction solution was stirred at room temperature overnight, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and column chromatography to obtain 2.3 g of tea-white solid, with a yield of 94%. MS-APCI [M+H]+ ; 1 H 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,7 H),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).

[0360] Step 11-5:

[0361]

[0362] Compound 56 (500 mg, 0.83 mmol) and TBAF (650 mg, 2.5 mmol) were added to a single-mouth bottle containing THF (10 mL), and then the reaction solution was stirred at room temperature for 15 minutes, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and column chromatography to obtain 340 mg of tea-white solid, with a yield greater than 100% (containing TBAF). MS-APCI [M+H] + ; 1 H 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).

[0363] Step 11-6:

[0364]

[0365] Compound 57 (240 mg, 0.657 mmol), B 2 Pin 2 (333 mg, 1.31 mmol), potassium acetate (129 mg, 1.31 mmol) and Pd(dppf) 2 Cl 2.DCM (54 mg, 0.0657 mmol) was added to a single-mouth bottle containing 1,4-dioxane (10 mL), and the reaction solution was stirred at 100°C for 3 hours under nitrogen protection. The reaction was detected by TLC. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed to obtain 150 mg of tea-white solid with a yield of 55.3%. LC-MS: 413MS-APCI [M+H] + ; 1 HNMR (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).

[0366] Step 11-7:

[0367]

[0368] Compound 7 (150 mg, 0.364 mmol), 9 (150 mg, 0.364 mmol), sodium carbonate (265 mg, 0.91 mmol) and Pd(dppf)2Cl2.DCM (30 mg, 0.0364 mmol) were added to a single-mouth bottle containing 1,4-dioxane (10 mL) and water (2 mL), and nitrogen was used for protection. The reaction solution was then stirred at 100°C for 3 hours and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed. Then, 6 mg of a light green solid was prepared using a reverse phase column. 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).

[0369] Example 12 Synthesis of Compound LW1005-012

[0370]

[0371] Step 12-1:

[0372]

[0373] Compound 54 (1 g, 1.66 mmol) and NCS (221 mg, 1.66 mmol) were added to a single-mouth bottle containing DMF (15 mL), and then the reaction solution was stirred at 60°C for 45 minutes, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and column chromatography to obtain 600 mg of an oily substance with a yield of 56.6%. LC-MS: 637 [M+H] + ; 1 HNMR(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).

[0374] Step 12-2:

[0375]

[0376] Compound 57 (680 mg, 1066 mmol) and TBAF (128 mL, 1M THF solution) were added to a single-mouth bottle containing THF (10 mL), and the reaction solution was stirred at room temperature for 1 hour, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and column chromatography to obtain 230 mg of a tea-white solid with a yield of 54%. LC-MS: 399 [M+H] + ; 1 H 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).

[0377] Step 11-3:

[0378]

[0379] Compound 58 (230 mg, 0.575 mmol), B 2 Pin 2 (154 mg, 0.606 mmol), potassium acetate (141 mg, 1.43 mmol) and Pd(dppf) 2 Cl 2 .DCM (47 mg, 0.0575 mmol) was added to a single-mouth bottle containing 1,4-dioxane (10 mL), and the reaction solution was stirred at 110°C for 2 hours under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed to obtain 210 mg of brown-yellow oil, with a yield of 81.7%. LC-MS: 447 [M+H] + ;

[0380] Step 12-4:

[0381]

[0382] Compound 59 (210 mg, 0.47 mmol), 10 (194 mg, 0.47 mmol), sodium carbonate (125 mg, 1.18 mmol) and Pd(dppf)2Cl2.DCM (38 mg, 0.047 mmol) were added to a single-mouth bottle containing 1,4-dioxane (8 mL) and water (2 mL), and nitrogen was used for protection. The reaction solution was then stirred at 100°C for 3 hours and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed, and then LW1005-066 was prepared using a reverse phase column. LC-MS: 653 [M+H] + ; 1 H 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).

[0383] Example 13 Synthesis of Compound LW1005-013

[0384]

[0385] Step 13-1:

[0386]

[0387] Compound 7 (1.5 g, 2.55 mmol) and NCS (400 mg, 3.06 mmol) were added to a single-mouth bottle containing DMF (15 mL), and then the reaction solution was stirred at 60 ° C for 45 minutes, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, washed with ethyl acetate / water (1:1, 50 mL), filtered, and dried to obtain 1.2 g of white solid, with a yield of 75.7%. LC-MS: 621 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ8.13(s,1H),8.05(d,J=7.9Hz,1H),7.91(d,J=8.0Hz,1H),7.4 9–7.26(m,11H),4.26(d,J=5.3Hz,2H),3.95(t,J=4.5Hz,2H),2.80(s,3H),0.98(s,9H).

[0388] Step 13-2:

[0389]

[0390] Compound 60 (500 mg, 0.804 mmol), B2Pin2 (408 mg, 1.608 mmol), potassium acetate (197 mg, 2.01 mmol) and Pd(dppf)2Cl2.DCM (66 mg, 0.0804 mmol) were added to a single-mouth bottle containing 1,4-dioxane (20 mL), and nitrogen was protected. The reaction solution was then stirred at 110°C for 4 hours, and the reaction was detected by LC-MS. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed to obtain 518 mg of a white solid with a yield of 96.3%. LC-MS: 669.2 [M+H]+.

[0391] Step 13-3:

[0392]

[0393] Compound 61 (510 mg, 0.762 mmol), 10 (315 mg, 0.762 mmol), sodium carbonate (242 mg, 2.287 mmol) and Pd(dppf)2Cl2.DCM (62 mg, 0.0762 mmol) were added to a single-mouth bottle containing 1,4-dioxane (15 mL) and water (5 mL), and nitrogen was used for protection. The reaction solution was then stirred at 100°C for 3 hours, and the reaction was detected by LC-MS. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed to obtain 267 mg of a light yellow solid with a yield of 40%. LC-MS: 875 [M+H] + .

[0394] Step 13-4:

[0395]

[0396] Compound 62 (267 mg, 0.305 mmol) and TBAF (0.311 mL, 1 M THF solution, 0.311 mmol) were added to a single-mouth bottle containing THF (3 mL), and then the reaction solution was stirred at room temperature for 1 hour, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, mixed, and column chromatography was performed. The obtained solid was added with distilled water and methanol and freeze-dried to obtain a light yellow solid. LC-MS: 637 [M + H] +; 1 H 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=5.5H z,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).

[0397] Example 14 Synthesis of Compound LW1005-014

[0398]

[0399] Step 14-1:

[0400]

[0401] Compound 1 (1 g, 4.69 mmol) and triethylamine (0.66 mL, 4.69 mmol) were added to a single-mouth bottle containing acetonitrile (15 mL) and stirred at 0°C. Then, a solution of p-ABSA (1.15 g, 4.78 mmol) in acetonitrile (15 mL) was added dropwise to the reaction solution. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered, washed with ethyl acetate, and the organic layer was suspended and dried. After column chromatography, 1.03 g of a light yellow oil was obtained, with a yield of 91.8%. LC-MS: 140 [M-Boc+2H] + ; 1H NMR (400MHz, DMSO-d6) δ3.85 (t, J = 6.2 Hz, 2H), 2.66 (t, J = 6.2 Hz, 2H), 1.48 (s, 9H).

[0402] Step 14-2:

[0403]

[0404] Compound 64 (640 mg, 2.99 mmol) and Rh 2 (OAc) 4 (33mg, 0.075mmoL) was added to a single-mouth bottle containing 1,2-dichloroethane (5mL), and then the reaction solution was refluxed and stirred at 81°C. A solution of 2 (1g, 4.18mmol) in 1,2-dichloroethane (10mL) was added dropwise to the above reaction solution. After the addition was completed, the mixture was refluxed and stirred overnight. After the reaction was complete, the reaction solution was suspended to dryness, mixed, and column chromatography was performed to obtain 650mg of a white solid with a yield of 51.1%. LC-MS: 425[M+H] + ; 1 H 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).

[0405] Step 14-3:

[0406]

[0407] Triphenylphosphine (123 mg, 0.47 mmol), iodine (120 mg, 0.47 mmol) and triethylamine (0.13 mL, 0.94 mmol) were added to a single-mouth bottle containing DCM (10 mL) in sequence and stirred at room temperature for 10 minutes. Then, a DCM (5 mL) solution of 66 (100 mg, 0.235 mmol) was added dropwise to the above reaction solution. After the addition was completed, stirring was continued at room temperature for 2 hours, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, mixed with silica gel, and column chromatography was performed to obtain 37 mg of white solid with a yield of 38.8%. 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).

[0408] Step 14-4:

[0409]

[0410] Compound 67 (290 mg, 0.172 mmol) and TFA (0.16 mL, 2.136 mmol) were added to DCM (10 mL) in sequence, stirred at room temperature for 2 hours, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography to obtain 170 mg of a white solid with a yield of 78%. LC-MS: 307 [M+H] +; 1 H 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).

[0411] Step 14-5:

[0412]

[0413] Compound 68 (100 mg, 0.326 mmol), O-TBS-bromoethanol (0.14 mL, 0.651 mmol) and NaH (26 mg, 0.651 mmol) were added to DMF (5 mL) in sequence, and stirred at room temperature for 2 hours under nitrogen protection. The reaction was monitored by TLC. After the reaction was complete, the solvent was dried, and then extracted with ethyl acetate / water. The organic layer was dried over anhydrous sodium sulfate and column chromatography was performed to obtain 70 mg of a white solid with a yield of 46.1%. LC-MS: 465 [M+H] +;

[0414] Step 14-6:

[0415]

[0416] Compound 69 (70 mg, 0.15 mmol), 5 (104 mg, 0.23 mmol), sodium carbonate (40 mg, 3.015 mmol) and Pd(dppf)2Cl2.DCM (12 mg, 0.015 mmol) were added to a single-mouth bottle containing 1,4-dioxane (4 mL) and water (1 mL), and nitrogen was used for protection. The reaction solution was then stirred at 100°C for 3 hours, and the reaction was detected by LC-MS. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed to obtain 70 mg of a light yellow solid with a yield of 64.9%. LC-MS: 719 [M+H] + .

[0417] Step 14-7:

[0418]

[0419] Compound 70 (110 mg, 0.162 mmol) and TBAF (0.1 mL, 0.107 mmol) were added to a single-mouth bottle containing 1,4-dioane (2 mL) and protected by nitrogen. The reaction solution was then stirred at room temperature for 24 hours and the reaction was monitored by TLC. After the reaction was complete, the product was purified by reverse phase column and then freeze-dried to obtain 1.1 mg of a light yellow solid. LC-MS: 605 [M+H] +; 1 H 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,2 H),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),2.6 8(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).

[0420] Example 15 Synthesis of Compound LW1005-015

[0421]

[0422] Step 15-1:

[0423]

[0424] The raw material 5 (5.0 g, WO2018119286) was dissolved in DCM (100 mL), imidazole (3.2 g) was added, stirred evenly, TBDPSCl (5.9 g) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was washed with saturated brine, extracted with DCM, dried, concentrated, and purified by column chromatography to obtain 3.7 g of a yellow solid. MS-APCI: 699 [M+H] +

[0425] Step 15-2:

[0426]

[0427] The raw materials 71 (1.97 g), 33 (3.3 g), Pd(dppf)Cl2 / DCM (431 mg), and Na2CO3 (1.12 g) were mixed, replaced with nitrogen, and Dioxane / H2O (4:1) (50 mL) was added, and the mixture was reacted at 95°C for 3 hours. After the reaction was completed, the mixture was washed with water, extracted with EA, dried, concentrated, and purified by column chromatography to obtain 2.7 g of a yellow solid. MS-APCI: 866 [M+H] +

[0428] Step 15-3:

[0429]

[0430] Compound 72 (140 mg, 0.162 mmol) was added to a single-mouth bottle containing DCM (15 mL), and Dess-Martin Reagent (240 mg, 0.567 mmol) was added to a plastic test tube containing DMF (3 mL) and shaken once. Then the Dess-Martin Reagent / DMF solution was added dropwise to the compound 1 / DCM solution within 1-2 minutes, and the reaction solution was stirred at room temperature for 10 minutes. After the reaction was complete, saturated sodium bicarbonate (5 mL) and 10% sodium thiosulfate solution (5 mL) were added to the reaction solution, extracted with DCM, dried over anhydrous sodium sulfate, and partially evaporated to remove the solvent until the solvent was about 15 mL, and set aside. It was used directly in the next step without further purification. MS-APCI: 864[M+H]+

[0431] Step 15-4:

[0432]

[0433] 3-azetidine carboxylic acid (23 mg, 0.23 mmol) was dissolved in AcOH (0.25 mL), and then the solution was added dropwise to the DCM solution of the above compound 73, and then triethylamine (0.3 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (49 mg, 0.23 mmol) was then added to the reaction solution, and the reaction solution was stirred at room temperature overnight. Water was added to quench, extracted with DCM / water, and the organic layer was dried over anhydrous sodium sulfate. Column chromatography gave 78 mg of a light yellow solid, with a two-step yield of 50.7%. LC-MS: 949 [M + H] + .

[0434] Step 15-5:

[0435]

[0436] Compound 74 (78 mg, 0.082 mmol) and TBAF (1M in THF, 0.1 mL, 0.1 mmol) were added to a single-mouth bottle containing THF (2 mL), and the reaction solution was stirred at room temperature overnight. After the reaction was complete, the reaction solution was suspended to dryness, water (20 mL) was added and stirred, and the residue was filtered and filtered through a reverse phase column to obtain 17.4 mg of a light yellow solid. LC-MS: 711 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.08(s,1H),8.82(s,1H),8.52(s,1H),8.25–8.14(br,1H),8.10(d,J=7.9Hz,1 H),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),3.3 7–3.26(m,2H),2.44(s,3H),2.33(s,1H),2.06(s,3H),2.01(br,1H),1.87(s,1H).

[0437] Example 16 Synthesis of Compound LW1005-016

[0438]

[0439] Step 16-1:

[0440]

[0441] 73 (300 mg, 1.0 eq) was added to the reaction flask and dissolved in 20 mL DCM. A solution of 3-hydroxyacridine hydrochloride (109.9 mg, 2 eq) in DMSO (0.5 mL) was added to the above solution, and then Et3N (35.1 mg, 1.0 eq) was added dropwise and stirred at room temperature for 1 h. Sodium triacetoxyborohydride (147.2 mg, 2.0 eq) was added and stirred at room temperature overnight. The reaction was monitored by TLC. The reaction solution was washed with saturated sodium bicarbonate, dried, concentrated, and column chromatographed to obtain 200 mg of a yellow solid. MS-APCI: 921 [M+H] +

[0442] Step 16-2:

[0443]

[0444] 75 (150 mg 1.0 eq) was added to the reaction flask, dissolved in THF, and TBAF / THF solution (1M in THF, 2 mL) was added dropwise, and stirred at room temperature for 1 h. The reaction was monitored by TLC, concentrated, column chromatography, prepared, and ion exchange column to obtain 25.60 mg of bright yellow solid. MS-APCI: 683 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )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

[0445] (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).

[0446] Example 17 Synthesis of Compound LW1005-017

[0447]

[0448] Step 17-1:

[0449]

[0450] (R)-pyrrolidine-3-carboxylic acid (44 mg, 0.384 mmol) was dissolved in AcOH (0.25 mL), and then the solution was added dropwise to a DCM solution of compound 73 (150 mg), and then triethylamine (0.3 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (163 mg, 0.768 mmol) was then added to the reaction solution, and the reaction solution was stirred at room temperature overnight. Water was added to quench, and the mixture was extracted with DCM / water. The organic layer was dried over anhydrous sodium sulfate, and 75 mg of a light yellow solid was obtained by column chromatography, with a two-step yield of 40.6%. LC-MS: 963 [M+H] + .

[0451] Step 17-2:

[0452]

[0453] Compound 76 (75 mg, 0.078 mmol) and TBAF (1 M in THF, 0.1 mL, 0.1 mmol) were added to a single-mouth bottle containing THF (2 mL), and the reaction solution was stirred at room temperature overnight. After the reaction was complete, the reaction solution was suspended to dryness, added with water (20 mL), stirred, filtered, and passed through a reverse phase column to obtain 12.57 mg of a light yellow solid. LC-MS: 725 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )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),4.79–4.6 1(m,3H),4.53–4.39(m,3H),4.10–3.61(m,7H),3.44–3.38(m,2H),3.34–3.2 9(m,2H),2.44(s,3H),2.34(s,1H),2.07(s,3H),2.00(br,1H),1.86(s,1H).

[0454] Example 18 Synthesis of Compound LW1005-018

[0455]

[0456] Step 18-1:

[0457]

[0458] Add 8 (1.72g 1.0eq) and Et3N (1.00g 2.0eq) to a reaction bottle containing 30mL DCM and 1mL DMF, cool to 0°C, add BzCl / DCM solution dropwise, warm to room temperature, and stir overnight. Monitor by TLC, the reaction is complete, the reaction solution is washed with saturated sodium bicarbonate solution and saturated brine, dried, and concentrated. The obtained solid is slurried with EA:PE=1:10 (200mL) solution for 2h. Filter by suction, wash the filter cake with PE, and dry to obtain 1.39g of white solid. MS-APCI:453[M+H] + ;

[0459] 1 H 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).

[0460] Step 18-2:

[0461]

[0462] 77 (200 mg) was added to the reaction flask, N2 was used for protection, 5 mL of POCl3 was added, the temperature was raised to 85°C, and the mixture was stirred for 2 h. The excess POCl3 was dried and the temperature was lowered to -20°C. 20 mL of ammonia water was diluted to 50 mL with ice and added dropwise to the reaction flask. White smoke was emitted, and the mixture was heated to room temperature and stirred for 30 min. The mixture was extracted with ethyl acetate twice, and the organic phase was washed with brine, dried, concentrated, and subjected to column chromatography. 67.2 mg of a light yellow solid was obtained. MS-APCI: 452 [M+H] + ; 1 H 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).

[0463] Step 18-3:

[0464]

[0465] 78 (200mg 1.0eq), 5 (240mg 1.2eq), Na2CO3 (120mg 2.5eq) and Pd(dppf)2Cl2 (50mg 0.1eq) were added to the reaction flask, protected by N2, 1,4-dioxane / H2O (10ml / 2ml) was added to dissolve, the temperature was raised to 100℃, and stirred for 3h. LC-MS monitored the completion of the reaction, cooled, the reaction solution was washed with water, dried, concentrated, and column chromatographed. 14.06mg of yellow solid was obtained. MS-APCI: 602[M+H] + ; 1 H 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),7.1 1(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).

[0466] Example 19 Synthesis of Compound LW1005-019

[0467]

[0468] Step 19-1:

[0469]

[0470] 77 (1.0 g) was added to the reaction flask, N2 was used for protection, POCl3 (15 mL) was added, the temperature was raised to 100°C, stirred for 2 h, the excess POCl3 was dried, and the temperature was lowered to -20°C. 2 OH (50% aqueous solution) (1.46g 10eq) was added dropwise to the reaction bottle, white smoke was released, and the mixture was heated to room temperature and stirred for 30 minutes. TLC monitored the completion of the reaction, and DCM was extracted twice (poor solubility), and the organic phase was washed with brine, dried, and concentrated. 2g of yellow solid was obtained. MS-APCI: 468[M+H]+

[0471] Step 19-2:

[0472]

[0473] 79 (2.0 g 1.0 eq) and imidazole (1.45 g 10.0 eq) were added to the reaction flask, dispersed with DMF, and TBSCl was added. The mixture was stirred at RT for 1 h. The reaction was monitored by TLC, extracted with EA / water, and the organic phase was washed with brine, dried, concentrated, and column chromatographed to obtain 2.65 g of a golden solid. MS-APCI: 582 [M+H] +

[0474] Step 19-3:

[0475]

[0476] Disperse 80 (300 mg 1.0 eq) in methanol, add K2CO3 (200 mg 3.0 eq), and stir overnight at room temperature. TLC monitors the completion of the reaction, extracts the reaction solution with ethyl acetate / water, and extracts the aqueous phase twice. The organic phase is washed with brine, dried, concentrated, and column chromatographed to obtain 200 mg of a light yellow solid. MS-APCI: 478 [M+H] +

[0477] Step 19-4:

[0478]

[0479] 81 (177.5 mg 1.0 eq), 5 (256.2 mg 1.5 eq), K3PO4 (196.9 mg 2.5 eq), Pd(PPh3)4 (42.8 mg 0.1 eq) were added to the reaction flask in sequence, N2 was used for protection, 1,4-dioxane / H2O (10 ml / 2 ml) was added to dissolve, the temperature was raised to 100°C, and stirred for 3 h. The reaction was monitored by TLC, the temperature was lowered, the reaction solution was washed with water, dried, concentrated, and column chromatography was performed to obtain 187.6 mg of a golden yellow solid. MS-APCI: 732 [M+H] +

[0480] Step 19-5:

[0481]

[0482] 82 (72.5 mg) was added to the reaction flask, dissolved in 2 mL of methanol, and then a methanol solution of hydrogen chloride (4.567 mol / L 0.4 ml) was added dropwise, and stirred at room temperature for 30 min. The reaction was monitored by TLC, and the reaction solution was directly prepared to obtain 23.15 mg of a bright yellow solid. MS-APCI: 618 [M+H] + ; 1 H 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=11.0,6.6 Hz,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).

[0483] Example 20 Synthesis of Compound LW1005-020

[0484]

[0485] Step 20-1:

[0486]

[0487] Compound 79 (120 mg, 0.256 mmol), 83 (48 mg, 0.307 mmol) and NaH (32 mg, 0.768 mmol) were added to a single-mouth bottle containing DMF (6 mL), and then the reaction solution was stirred at room temperature for 3 hours, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was suspended to dryness, extracted with ethyl acetate / water, and the organic layer was dried over anhydrous sodium sulfate. 70 mg of light yellow solid was obtained by column chromatography. LC-MS: 582 [M+H] + .

[0488] Step 20-2:

[0489]

[0490] Compound 84 (70 mg, 0.12 mmol), 5 (70 mg), potassium phosphate (95 mg, 0.45 mmol) and Pd(PPh 3 ) 4 (17mg, 0.015mmol) was added to a single-mouth bottle containing 1,4-dioxane (4mL) and water (1mL), and the reaction solution was stirred at 100°C for 3 hours. The reaction was detected by LC-MS. After the reaction was complete, the reaction solution was cooled, filtered, mixed with silica gel, and column chromatography was performed to obtain 30mg of a light yellow solid, which was then prepared by reverse phase column to obtain 11.5mg of a light yellow solid. LC-MS: 734[M+H] + ; 1 H 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=5.2H z,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).

[0491] Example 21 Synthesis of Compound LW1005-021

[0492]

[0493] Step 21-1:

[0494]

[0495] Add raw material 77 (18 g) and NIS (10.7 g) to MeCN (230 mL) in sequence, add 5 ml of TFA dropwise, and stir at 55°C in an oil bath for 1.5 hours. After the reaction is complete by TLC, cool, filter, and dry to obtain 13.8 g of a yellow solid. MS-APCI: 579 [M+H] + .

[0496] Step 21-2:

[0497]

[0498] Compound 85 (1.0 g, 1.73 mmol) was added to POCl 3 (15 ml), react at 90 ° C for 1 hour, concentrate to dryness and set aside. 2 OMe / HCl (10 g) was dissolved in 6 mL of water, NaOH (4.79 g) was added and stirred for 10 minutes, filtered, the filtrate was cooled in an ice bath and poured into the residue after the reaction, stirred in an ice bath, solid appeared, filtered and dried to obtain 1 g of crude solid. MS-APCI: 608 [M+H] + .

[0499] Step 21-3:

[0500]

[0501] Compound 86 (3 g, 4.9 mmol) was dissolved in MeOH / THF (30 mL / 30 mL), and 5N sodium methoxide solution (2.5 mL, 12.3 mmol) was added, stirred at room temperature, and monitored by TLC. After the reaction was completed, water was added to quench, the solvent was dried, and a solid appeared. The solid was filtered and dried to obtain 2.7 g of a light yellow solid. MS-APCI: 504 [M+H] + .

[0502] Step 21-4:

[0503]

[0504] The raw material 87 (7.8 g, 15.5 mmol), Zn(CN) 2 (1.09g,9.28mmol),Xantphos-PdCl2(1.17g,1.55mmol),Cs 2 CO 3 (7.56 g, 23.2 mmol) were mixed in a 250 mL three-necked flask, N 2 Replace 3 times, inject 150 mL of DMF, stir at 90°C for 2 h, and the reaction is complete when detected by LCMS. Filter, concentrate the filtrate to dryness, and slurry the solid with (DCM / MeOH=100 mL / 2 mL) to obtain 4.5 g of light yellow solid. MS-APCI: 403 [M+H] + .

[0505] Step 21-5:

[0506]

[0507] Compound 88 (80 mg, 0.198 mmol), 5 (76 mg, 0.2 mmol), Pd(dppf)2Cl2 (17 mg,) and Na 2 CO 3 (53 mg, 0.5 mmol) was placed in a reaction flask, N 2 Degassing protection, 3mL dioxane / 0.6mL water was injected into the reaction bottle, reacted at 90 degrees for 2 hours, and the reaction was complete on the TLC plate. The reaction solution was washed with water, extracted with ethyl acetate, dried, spin-dried, and passed through a column to obtain 23mg of yellow solid. MS-APCI: 657[M+H] + ; 1 H 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),6.8 8(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).

[0508] Example 22 Synthesis of Compound LW1005-022

[0509]

[0510] Raw material 77 (1.0 g) was added to POCl 3 (10 mL), react at 100 ° C for 1 hour, concentrate to dryness, add methylamine aqueous solution to the residual liquid, stir under ice bath, green solid appears, filter and dry to obtain 960 mg solid. MS-APCI: 592 [M+H] + .

[0511] Step 22-2:

[0512]

[0513] The raw material 89 (960 mg) and K 2 CO3 (770 mg) was added to MeOH (20 mL) in sequence, stirred at 55°C, monitored by TLC, until the reaction was complete, filtered, and dried to obtain 900 mg of a green solid. MS-APCI: 488 [M+H] + .

[0514] Step 22-3:

[0515]

[0516] The raw material 90 (48 mg), ZnCN 2 (22mg),Pd 2 (dba) 3 (11 mg), dppf (15 mg) were mixed in a 50 mL single-necked bottle, N 2 After protection, 5 mL of DMF was added and stirred at 95°C for 16 hours. The reaction was completed by TLC. The reaction solution was filtered, the filtrate was washed with water, and extracted with EA. After column chromatography, 28 mg of green solid was obtained. MS-APCI: 387 [M+H] + .

[0517] Step 22-4:

[0518]

[0519] Compound 1 (100 mg, 0.156 mmol), 5 (71 mg, 0.187 mmol), Pd(dppf)2Cl2 (13 mg) and Na 2 CO 3 (51 mg, 0.48 mmol) was placed in a reaction flask, N 2 Degassing protection, 3mL dioxane / 0.6mL water was injected into the reaction bottle, reacted at 90 degrees for 2 hours, and the reaction was complete on TLC plate. The reaction solution was washed with water, extracted with EA, dried, spin-dried, passed through a column (DCM: MeOH = 10: 1), and purified by reverse phase column to obtain 25mg of 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),8.0 7(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,2 H),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).

[0520] Example 23 Synthesis of Compound LW1005-023

[0521]

[0522] Step 23-1:

[0523]

[0524] 92 (9.1 g, 1.0 eq; EP2848622) and Cs2CO3 (41.56 g, 3.0 eq) were added to the reaction flask, DMF was added to dissolve, 2-bromoethanol (6.03 mL, 2.0 eq) was added dropwise, and stirred at 50°C for 18 h. The reaction was completed by LC-MS monitoring. DMF was spin-dried, and 100 mL of water was added to slurry for 1 h. Filtered, the filter cake was washed with 50 mL of water and 100 mL of n-heptane. 9.0 g of brown solid was obtained. MS-APCI: 258 [M+H] +

[0525] Step 23-2:

[0526]

[0527] 93 (9.0 g, 1.0 eq), 94 (13.46 g, 1.3 eq; Chem, 2019, 5, 929-939), Cs2CO3 (22.73 g, 2.0 eq), Pd(PPh3)4 (2.02 g, 0.05 eq) were added to the reaction flask, N2 was protected, 1,4-dioxane / water was added to dissolve, and stirred at 100°C for 3 h. LC-MS monitoring showed that the reaction was complete. The reaction solution was washed with water, brine, dried, concentrated, and column chromatographed to obtain 10.1 g of solid. MS-APCI: 348 [M+H] +

[0528] Step 23-3:

[0529]

[0530] 95 (5.0 g, 1.0 eq) and Et3N (6 mL, 3.0 eq) were added to dichloromethane, and BzCl was added dropwise at RT. The mixture was stirred for 2 h at RT. The reaction was monitored by TLC to be complete. The reaction solution was washed with saturated sodium bicarbonate solution and saturated brine, dried, concentrated, and column chromatographed. 6.4 g of a light yellow to off-white solid was obtained. MS-APCI: 452 [M+H] +

[0531] Step 23-4:

[0532]

[0533] Dissolve 96 (11.0 g, 1.0 eq) in acetonitrile, add NIS, and dropwise add TFA at RT. After addition, stir at 55°C for 3 h. A large amount of solid precipitates. TLC monitors the reaction completion, and the mixture is filtered, the filter cake is washed with n-heptane, the filtrate is dried by rotary evaporation, extracted with EA / water, washed with 10% Na2S2O3 solution, dried, concentrated, and mixed with the filter cake for column chromatography. 13 g of off-white solid is obtained. MS-APCI: 578 [M+H] +

[0534] Step 23-5:

[0535]

[0536] Add 97 (1.0 g) to the reaction flask, add 5 mL POCl3, and stir at 90 degrees Celsius for 1.5 h. Spin dry and pump until foamy solid. Add 30% methylamine aqueous solution (20 mL, 100 eq), dissolve in DCM, and stir at rt for 15 min. TLC monitors the complete conversion of the raw material, separates the liquid, washes the organic phase with brine, dries, concentrates, and performs column chromatography to obtain 1.0 g of a brown solid. MS-APCI: 591 [M+H] +

[0537] Step 23-6:

[0538]

[0539] Disperse 98 (1.0 g 1.0 eq) in methanol / THF, add K2CO3 (700 mg 3.0 eq) solid, and stir at room temperature for 3 h. TLC shows that a large amount of raw materials remain, add K2CO3 (700 mg 3.0 eq), continue stirring at room temperature overnight, TLC shows that the raw materials are basically completely reacted. Spin dry, extract with DCM / water, wash the organic phase with brine, dry, concentrate, and column chromatography. Obtain 700 mg of brown solid. MS-APCI: 487 [M+H] +

[0540] Step 23-7:

[0541]

[0542] 99 (2.7g 1.0eq), Zn(CN)2 (299.4mg 0.46eq), Cs2CO3 (2.17g 1.2eq), Xantphos-PdCl2 (418mg 0.1eq) were added to the reaction bottle, N2 was protected, DMF was added to dissolve, and stirred at 90℃ for 2h. LC-MS monitoring showed that the reaction was complete, DMF was dried, DCM / water was extracted, the organic phase was washed with brine, dried, concentrated, and column chromatography was performed. 2.2g of brown solid was obtained. MS-APCI: 386[M+H] +

[0543] Step 23-8:

[0544]

[0545] 100 (300 mg 1.0 eq), 5 (352.5 mg 1.2 eq), Na2CO3 (164.6 mg 2.0 eq), Pd(dppf)2Cl2 (41 mg, 0.1 eq) were added to the reaction flask, N2 was used for protection, 1,4-dioxane / water was added to dissolve, and stirred at 90°C for 2 h. LC-MS monitoring showed that the reaction was complete. The reaction solution was extracted with DCM / water, the organic phase was washed with brine, dried, concentrated, and column chromatographed to obtain 40 mg of a light yellow solid. MS-APCI: 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).

[0546] Example 24 Synthesis of Compound LW1005-024

[0547]

[0548] Step 24-1:

[0549]

[0550] Compound 97 (1.5 g, 2.59 mmol) was added to POCl 3 (30 ml), react at 90 ° C for 2 hours, concentrate to dryness and set aside. 2 OMe / HCl (22 g) was dissolved in 10 mL of water, NaOH (10.36 g) was added and stirred for 10 minutes, filtered, the filtrate was cooled in an ice bath and poured into the residue after 1 reaction, stirred in an ice bath, solid appeared, filtered and dried to obtain 1.5 g of crude solid. MS-APCI: 607 [M+H] + .

[0551] Step 24-2:

[0552]

[0553] Compound 101 (300 mg, 0.49 mmol) was dissolved in MeOH / THF (30 mL / 30 mL), K2CO3 (28 mg, 0.98 mmol) was added, stirred at room temperature, and monitored by TLC. After the reaction was completed, the solvent was dried, and a solid appeared. The solid was filtered and dried to obtain 200 mg of a light yellow solid. MS-APCI: 503 [M+H] + .

[0554] Step 24-3:

[0555]

[0556] The raw material 102 (135 mg, 0.268 mmol), Zn(CN) 2 (16mg,0.137mmol),Xantphos-PdCl2(20mg,0.0268mmol),Cs 2 CO 3 (131 mg, 0.402 mmol) were mixed in a 50 mL three-necked flask, N 2 Replace 3 times, inject 10 mL of DMF, stir at 90°C for 2 h, and the reaction is complete when detected by LC-MS. Filter, concentrate the filtrate to dryness, mix the sample, and perform column chromatography to obtain 4.5 g of light yellow solid. MS-APCI: 402 [M+H] + .

[0557] Step 24-4:

[0558]

[0559] Compound 103 (100 mg, 0.249 mmol), 5 (100 mg, 0.261 mmol), Pd(dppf)2Cl2 (21 mg) and Na 2 CO 3 (79 mg, 0.746 mmol) was placed in a reaction flask, N 2 Degassing protection, 3mL dioxane / 0.6mL water was injected into the reaction bottle, reacted at 90 degrees for 2 hours, and the reaction was complete on TLC plate. The reaction solution was washed with water, extracted with EA, dried, spin-dried, and passed through a column (DCM:MeOH=10:1) to obtain 11mg of 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=7.4 Hz,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).

[0560] Example 25 Synthesis of Compound LW1005-025

[0561]

[0562] Step 25-1:

[0563]

[0564] Compound 103 (50 mg, 0.124 mmol) was dissolved in DCM (120 mL), and Dess-Martin Reagent (158 mg, 0.373 mmol) was added to the above solution at one time, and stirred at room temperature for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, 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 turn, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic layer was poured into a 250 mL single-mouth bottle. 4-Carboxylic acid piperidine methyl ester (0.05 mL, 0.373 mmol), acetic acid (1 drop) and sodium acetate borohydride (79 mg, 0.373 mmol) were added to the above solution in turn, and stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, water was added to quench the reaction, and then the reaction solution was washed with saturated sodium bicarbonate and saturated brine in turn, and the organic layer was dried over anhydrous sodium sulfate. Column chromatography gave 20 mg of a light yellow solid. MS-APCI: 527[M+H] + .

[0565] Step 25-2:

[0566]

[0567] The raw material 104 (230 mg, 0.436 mmol) was dissolved in 10 mL THF / H2O (2:1), and LiOH (21 mg, 0.872 mmol) was added. The reaction was allowed to react at room temperature for 2 hours, and the reaction was monitored by TLC. After the reaction was complete, TFA (0.08 mL, 1.135 mmol) was added to adjust the solution to neutrality, THF was dried, and water was added to stir and wash. Solids precipitated, filtered, and the solids were dried to obtain 200 mg of light yellow solids. MS-APCI: 513 [M+H] + .

[0568] Step 25-3:

[0569]

[0570] Compound 105 (200 mg), 5 (148 mg), Pd(dppf)2Cl2 (34 mg) and Na2CO3 (170 mg) were placed in a reaction bottle, degassed with N2, and 3 mL dioxane / 0.6 mL water was injected into the reaction bottle. The reaction was carried out at 90 degrees for 2 hours. The reaction was complete on the TLC plate. The reaction solution was washed with water, extracted with EA, dried, spin-dried, and passed through a column (DCM:MeOH=10:1) to obtain 22.2 mg 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,1 H),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).

[0571] Example 26 Synthesis of Compound LW1005-026

[0572]

[0573] Step 26-1:

[0574]

[0575] Compound 97 (1.3 g) was added to POCl 3 (15mL), heated to 90 degrees, reacted for 1 hour. TLC spot plate raw material reaction completed. The reaction solution was vortexed until about 5mL remained, and was added dropwise to ammonia water (100mL) with a pipette, and a yellow solid precipitated. Filtered, the solid was spin-dried to obtain 1.0g of product 3, black gray solid. MS-APCI: 578[M+H] + ;

[0576] Step 26-2:

[0577]

[0578] Compound 104 (1.0 g) was suspended in MeOH (15 mL) and K was added at room temperature. 2 CO 3(478 mg). After the suspension was stirred for 1 hour, the reaction was complete by LCMS. The reaction solution was spun dry. The remaining solid was dissolved in DMF. The DMF solution was poured into water and solid precipitated. After filtration and drying of the solid, 600 mg of gray solid was obtained. MS-APCI: 474 [M+H] + ;

[0579] Step 26-3:

[0580]

[0581] The raw material 107 (300 mg), Zn(CN) 2 (116mg),Xantphos-PdCl2(80mg),Cs 2 CO 3 (200 mg) were mixed in a 50 mL three-necked flask, N 2 Replace 3 times, inject 10 mL of DMF, stir at 90°C for 2 h, and the reaction is complete when detected by LC-MS. Filter, concentrate the filtrate to dryness, mix the sample, and perform column chromatography to obtain 160 mg of light yellow solid. MS-APCI: 402 [M+H] + .

[0582] Step 26-4:

[0583]

[0584] Compound 108 (35 mg), 5 (40 mg), Pd (dppf) 2 Cl 2 (12mg) and Na 2 CO 3 (22 mg) was placed in a reaction bottle, N 2 Degassing protection, 3mL dioxane / 0.6mL water was injected into the reaction bottle, reacted at 90 degrees for 2 hours, and the reaction was complete on TLC plate. The reaction solution was washed with water, extracted with EA, dried, spin-dried, and passed through a column (DCM:MeOH=10:1) to obtain 12mg of yellow solid. MS-APCI: 627[M+H] + ; 1HNMR(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),4.51-4.3 7(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).

[0585] Example 27 Synthesis of Compound LW1005-027

[0586]

[0587] Step 27-1:

[0588]

[0589] Take the raw material 109 (6.8g, 1.0eq; Organic Syntheses, 2007, 84, 262-271) and add it to DMAc (70ml). After dissolving, add potassium carbonate (9.12g, 2.0eq), add iodomethane (7g, 1.5eq) dropwise, and react at room temperature overnight; treatment: add water (50ml), ammonia water (20ml), add EA (100ml*3) to extract, pass through the column: ethyl acetate / n-heptane = 15 / 85 for elution, and obtain 6.05g of yellow solid (yield: 83.4%). LCMS: found 221 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )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).

[0590] Step 27-2:

[0591]

[0592] Take the raw material 110 (5g, 1.0eq) and add it to acetic acid (82g, 30eq), add 47% hydrobromic acid aqueous solution (55g, 30eq), dissolve it and heat it to 95℃ for 2 hours; treatment: concentrate to obtain 9g of light yellow solid (yield: quantitative), directly use it for the next step. LCMS: found 193[M+H] +

[0593] Step 27-3:

[0594]

[0595] Take the raw material 111 (4.36g, 1.0eq) and add it to methanol (90ml). If it is insoluble, add concentrated sulfuric acid (5g, 1.0eq) and reflux at 85℃ overnight. Treatment: Add 70ml of saturated sodium bicarbonate dropwise under ice bath, pH = 7-8, solid precipitates, filter, rinse the solid with water, and dry to obtain 4.43g of white solid (yield: 94.8%). LCMS found: 207[M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )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).

[0596] Step 27-4:

[0597]

[0598] Take raw material 112 (4.2 g, 1.0 eq) and add it to DMAc (50 ml). Under argon protection, add cesium carbonate (13.3 g, 2.0 eq) and silanol raw material 8 (9.62 g, 1.3 eq), and react at room temperature overnight; treatment: add water (100 ml), 1M hydrochloric acid (80 ml) to adjust the pH to 5-6; extract with EA 3 times, column: elute with 20% EA / n-heptane, and concentrate to obtain 4.5 g of white solid. Yield: 45.4%. LCMS found:489[M+H]+; 1H NMR (400MHz, DMSO-d6) δ7.54(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).

[0599] Step 27-5:

[0600]

[0601] Compound 113 (300 mg) and compound 114 (149 mg) were dissolved in 15 mL THF, nitrogen protection, ice-salt bath, 2.5 ml NaHMDS (2M) was added dropwise, and the mixture was kept warm for 20 min. The reaction was detected by LC-MS. After the reaction was complete, water was added to quench the mixture, EA was extracted, the organic phases were combined, washed with brine, dried, and spin-dried to obtain 160 mg of light yellow solid. LC-MS found: 699 [M + H] +

[0602] Step 27-6:

[0603]

[0604] Compound 115 (160 mg) was dissolved in 2 ml methanol, and 100 mg 10% Pd / C was added. After addition, hydrogen was replaced and the mixture was reacted at room temperature for 30 min. The reaction was detected by TLC. After the reaction was complete, diatomaceous earth was added for filtration, and the filtrate was taken and dried to obtain 140 mg of off-white solid crude product, which was directly used for the next step. LC-MS found: 669 [M + H] +

[0605] Step 27-7:

[0606]

[0607] Compound 113 (55 mg) and compound 116 (75 mg) were dissolved in 3.8 ml THF, protected by nitrogen, and placed in an ice-salt bath. 0.45 mL NaHMDS (2 M) was added dropwise. After the addition was completed, the mixture was kept warm for 1 h and the reaction was monitored by LC-MS.

[0608] After the reaction was complete, water was added to quench, EA was extracted, the organic phases were combined, washed with salt, dried, and spin-dried to obtain 53 mg of yellow solid. LC-MS found: 1125 [M+H] +

[0609] Step 27-8:

[0610]

[0611] Compound 117 (53 mg) was dissolved in 2.5 ml THF, and 2.5 ml triethylamine trihydrofluoride was added. After the addition was complete, the mixture was reacted at room temperature for 2 h, and the reaction was monitored by TLC. After the reaction was complete, THF was removed by vortexing at low temperature, and the residue was concentrated and used to prepare 6.1 mg of white solid using a reverse phase column. LC-MS found: 1125 [M+H] + ; 1 H 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).

[0612] Example 28 Synthesis of Compound LW1005-028

[0613]

[0614] Step 28-1:

[0615]

[0616] Add 118 (7.6 g, 51.0 mmol, 1.0 eq) to the reaction bottle in sequence, freshly distilled anhydrous THF, inert gas protection; dry ice-acetone cooled to -78 ° C; n-BuLi (30.5 mL, 76.5 mmol, 1.5 eq, 2.5 M) was added dropwise; stirred at low temperature for ~30 min; carbon dioxide dried with concentrated sulfuric acid and anhydrous calcium chloride was introduced into the reaction solution; reacted for 3 h, slowly heated to ~0 ° C; quenched with saturated ammonium chloride solution; added water and ethyl acetate; separated the organic phase; washed the aqueous phase once with ethyl acetate; adjusted the pH of the aqueous phase to ~2; a large amount of solid precipitated, filtered, and dried to obtain 9.4 g of solid, with a yield of 95.5%. LCMS found: 194 [M + H] + ; 1 HNMR (400 MHz, DMSO-d 6 )δ8.15(d,J=6.0Hz,1H),7.60(s,1H),7.39(dd,J=6.0,0.9Hz,1H),4.02(s,3H).

[0617] Step 28-2:

[0618]

[0619] Compound 119 (9.0 g, 46.6 mmol, 1.0 eq), ethanol (270 mL) and concentrated sulfuric acid (11.5 mL) were added to a reaction flask and heated to reflux; stirred overnight, ethanol was evaporated, the residue was cooled in an ice-water bath, water was added dropwise to precipitate solid; 7.4 g of solid was obtained by filtration and drying, with a yield of 76.7%. LCMS found: 208 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )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).

[0620] Step 28-3:

[0621]

[0622] 120 (7.0 g, 33.8 mmol, 1.0 eq), 70 mL DMAc, cesium carbonate (22.0 g, 67.5 mmol, 2.0 eq) and compound 5 (14.7 g, 40.5 mmol, 1.2 eq) were added to a reaction bottle and stirred at room temperature for 2 h. Water and ethyl acetate were added, and ethyl acetate was separated. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride, and dried to obtain compound 121, which was directly used in the next step without purification. LCMS: found 490 [M+H] +

[0623] Step 28-4:

[0624]

[0625] Add the crude compound 121, ethanol (70 mL) and water (18 mL) to the reaction flask, and add solid LiOH (1.22 g, 20.9 mmol, 1.5 eq). Stir at room temperature for 0.5 h, concentrate the ethanol, add water and ethyl acetate to the residue; separate the ethyl acetate; put the aqueous phase in an ice-water bath, adjust the pH to ~5, and a large amount of solid precipitates; filter and dry to obtain 10.3 g of solid, with a yield of 66.1% (two steps). LCMS found: 462 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )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).

[0626] Step 28-5:

[0627]

[0628] Substrate 123 (600 mg; WO2018119286), 124 (1 g), TsOH (365 mg) were added to isopropanol (10 mL) and stirred at 85 degrees overnight. TLC detected the disappearance of the raw material, the reaction solution was spin-dried, washed with water, extracted with EtOAc, and passed through a column to obtain 350 mg of a light yellow solid. LC-MS: 540 [M+H] +

[0629] Step 28-6:

[0630]

[0631] 125 (190 mg) was added to 4N HCl / dioxane (1 ml) at room temperature and stirred at room temperature for 30 minutes. TLC showed that the reaction of the raw material was complete, and the reaction solution was dried to obtain 190 mg of a gray crude solid, which was directly used in the next step. LC-MS: 440 [M+H] +

[0632] Step 28-7:

[0633]

[0634] 126 (150 mg), 122 (102 mg), and HATU (108 mg) were dissolved in DMF (1 ml) at room temperature, and then DIEA (85 mg) was added and the reaction was continued at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, 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 70 mg of a yellow solid. LC-MS: 883 [M+H] +

[0635] Step 28-8:

[0636]

[0637] 127 (70 mg) was dissolved in THF (0.5 ml) at room temperature, and 0.1 mL TBAF / THF (1 N) was added and stirred for 1 hour. The starting material disappeared after TLC detection, and the reaction solution was directly passed through the column. The crude compound was passed through a cation exchange resin column to obtain 7.4 mg of a yellow solid. LC-MS: 645 [M+H] +; 1H NMR (400MHz, DMSO-d6) δ10.10(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=7.4Hz,1H),4.89(t,J=5.4Hz,1H),4.72(d,J=4.5Hz,1H),4.23(s,1H),4.06(t,J=5.6Hz,2H),3.83(q,J=13.8Hz,2H),3.66( q,J=5.5Hz,2H),2.75(dd,J=9.6,6.0Hz,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).

[0638] Example 29 Synthesis of Compound LW1005-029

[0639]

[0640] Step 29-1:

[0641]

[0642] 126 (120 mg) and 113 (86.5 mg) were dissolved in THF (2 ml) under ice bath, and NaHMDS (0.7 mL) was added under N2 protection, and the reaction was continued in ice bath for 1 hour. TLC showed that the raw material was completely reacted, and saturated NH4Cl was added to quench the reaction, and EA was extracted and passed through a column to obtain LW1005-011-3 80 mg yellow solid. LC-MS: 896 [M+H] +

[0643] Step 29-2:

[0644]

[0645] Substrate 128 (90 mg) was added to a mixture of THF and TEA / 3HF (2 mL, 1:1) and reacted for 2 hours. The starting material disappeared after TLC detection. The reaction solution was adjusted to pH = 9 with saturated NaHCO3, extracted with EtOAc, and dried by spin drying. The separation was performed to obtain 12.4 mg 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).

[0646] Example 30 Synthesis of Compound LW1005-030

[0647]

[0648] Step 30-1:

[0649]

[0650] Compound 128 (1g, 1eq; WO2012154213), CuI (0.03g, 0.05eq), ditriphenylphosphine palladium chloride (0.12g, 0.05eq) were added to a 50ml reaction bottle, replaced with nitrogen three times, anhydrous DMF (20ml) was added, and the system was reddish brown and clear; triethylamine (1.7g, 5.0eq) was added, and the system was brown and clear, replaced with nitrogen three times, protected from light, and alkyne raw material 3 (0.52g, 1.1eq) was added, reacted at room temperature, and the reaction was detected by TLC. After the reaction was complete, the reaction solution was poured into an icy ammonium chloride aqueous solution, extracted with MTBE twice, and the organic layer was washed with saturated sodium chloride 5 times. 1.03g of oily substance was obtained by column chromatography. 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,1 H), 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).

[0651] Step 30-2:

[0652]

[0653] Potassium phosphate (13g, 2eq) and palladium acetate (0.75g, 0.03eq) were added to a 500ml reaction bottle, replaced with nitrogen three times, and a dioxane solution (75ml) of 130 (10.5g, 1.3eq; LabNetwork) was added, and a dioxane solution (75ml) of compound 129 (9.5g, 1eq) was added, and water (30ml) was added. The reaction was carried out at 100°C for 2 hours. The system was dark brown, and the reaction was completed by TCL tracking. After the reaction was complete, 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 liquid. LC-MS: 366[M+H] + ; 1 H 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).

[0654] Step 30-3:

[0655]

[0656] Add the raw material 131 (10.17 g, 1 eq) into THF (50 ml), the system is brown and clear, add TBAF (17.55 g, 2 eq) in THF solution (50 ml) dropwise, and react at room temperature for 30 minutes. After the reaction is complete, mix the sample directly and pass it through the column to obtain 6.62 g of 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).

[0657] Step 30-4:

[0658]

[0659] Compound 132 (4.6 g, 1 eq), 133 (6.57 g, 1.15 eq; WO2014063199), ditriphenylphosphine palladium chloride (0.64 g, 0.05 eq), CuI (0.15 g, 0.05 eq), DIPEA (11.83 g, 5 eq) were added to the reaction bottle, nitrogen was replaced 3 times, DMF was added, nitrogen was replaced, the system was red-brown and clear, and the reaction was carried out at 55°C for 3 hours. After the reaction was complete, 1000 ml of water was added under ice bath, EA was extracted 500*2 times, saturated brine was washed 2 times, and 6.7 g was obtained by column chromatography. LCMS found 435[M] + ; 1 H 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).

[0660] Step 30-5:

[0661]

[0662] Compound 134 (6.76 g, 1 eq) was added to methanol (250 ml) and isopropyl acetate (600 ml), and then zinc powder (10 g, 10 eq) and ammonium chloride (8.3 g, 10 eq) were added and stirred at room temperature for 1 hour. Filtered, the solid was rinsed with isopropyl acetate, the solid was slurried with EA, filtered, and the filtrate was concentrated and column chromatography was performed to obtain 1.6 g of solid. LCMS found 406:408=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).

[0663] Step 30-6:

[0664]

[0665] Compound 135 (500 mg, 1 eq), palladium acetate (30 mg, 0.1 eq), BINAP (100 mg, 0.2 eq), cesium carbonate (1000 mg, 2.5 eq) were added to a 50 ml reaction bottle, replaced with nitrogen three times, and a toluene solution (20 ml) of chlorine raw material 123 (700 mg) was added, replaced with nitrogen, and reacted overnight at 100 ° C in an external bath. After the reaction was complete, the mixture was filtered, rinsed with EA, and the filtrate was concentrated and passed through a column to obtain 800 mg of a yellow solid. LCMS found 633 [M+H] + ;

[0666] Step 30-7:

[0667]

[0668] Compound 136 (550 mg) was added to THF (5 ml) and methanol (4 ml), and sodium borohydride (100 mg) and lithium chloride (100 mg) were added under ice bath, and the reaction was carried out at room temperature overnight. After the reaction was completed, an aqueous solution of ammonium chloride was added under ice bath, and EA was extracted twice, concentrated, and passed through a column to obtain 450 mg of a yellow solid. LCMS found: 605 [M+H] +

[0669] Step 30-8:

[0670]

[0671] Compound 137 (420 mg) was added to DCM (8 ml), and active manganese dioxide (430 mg) was added, and the mixture was refluxed overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth, rinsed with DCM, and the filtrate was concentrated and passed through a column to obtain 320 mg of a yellow solid. LCMS found: 603 [M+H] +

[0672] Step 30-9:

[0673]

[0674] Compound 138 (290 mg) was added to DCM (9 ml), and then a solution of R-3-carboxypyrrolidine (114 mg) in AcOH (0.25 mL) and triethylamine (0.4 mL) were added. The mixture was reacted at room temperature for 1 hour, and sodium acetate borohydride (600 mg) was added. The mixture was stirred at room temperature overnight. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, the mixture was separated, and DCM was extracted once. The organic phase was dried over sodium sulfate and passed through a column to obtain 100 mg of a light yellow solid. LCMS found: 702 [M+H] + ; 1 H 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).

[0675] Example 31 Synthesis of Compound LW1005-031

[0676]

[0677] Step 31-1:

[0678]

[0679] Compound 135 (510 mg, 1 eq), 122 (500 mg, 1.05 eq), HATU (825 mg, 2 eq), DIEA (295 mg, 2.1 eq) were added to a reaction bottle, and DMF (25 ml) was added. The mixture was stirred overnight at room temperature after clarification. After treatment, water (30 ml) was added, EA was extracted twice, saturated brine was washed once, and a yellow solid of 1.37 g was obtained by column chromatography. LCMS found 849 [M + H] +

[0680] Step 31-2:

[0681]

[0682] Add raw material 139 (910 mg, 1 eq) to freshly distilled THF (10 ml), add lithium borohydride (100 mg, 5 eq) under ice bath, react at room temperature for 6 hours, and track by TLC; after the reaction is complete, add aqueous ammonium chloride solution under ice bath, extract 3 times with EA, wash once with saturated brine, concentrate, and pass through column to obtain 690 mg of yellow solid. LCMS found: 821 [M+H] +

[0683] Step 31-3:

[0684]

[0685] Compound 140 (490 mg, 1 eq) was added to DCM (45 ml), which was slightly turbid. DMP (380 mg, 1.5 eq) was added and reacted at room temperature for 40 minutes, followed by TLC. After the reaction was complete, saturated sodium sulfite was added and stirred for 5 minutes, saturated sodium bicarbonate was added and stirred for 5 minutes; DCM was extracted twice, and saturated brine was washed once. The sample was mixed and passed through a column to obtain 319 mg of a yellow solid. LCMS found: 819 [M+H] +

[0686] Step 31-4:

[0687]

[0688] Compound 141 (100 mg, 1 eq), R-3-carboxypyrrolidine (41 mg) in AcOH (0.25 mL) and triethylamine (0.4 mL) were added to DCM (5 mL) in sequence. After reacting at room temperature for 1 hour, sodium acetate borohydride (120 mg) was added. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TCL. After the reaction was safe, saturated ammonium chloride was added, the liquids were separated, and DCM was extracted twice. The sample was concentrated and passed through a column to obtain 130 mg of a white solid. LCMS found: 918 [M+H] +

[0689] Step 31-5:

[0690]

[0691] Compound 142 (140 mg) was dissolved in THF (4 mL), and 1 M TBAF / THF (0.2 mL) solution was added to the solution. The mixture was reacted at room temperature for 30 minutes and the reaction was monitored by TCL. After the reaction was complete, the sample was directly mixed and passed through a column to obtain 80 mg 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).

[0692] Example 32 Synthesis of Compound LW1005-032

[0693]

[0694] Step 32-1:

[0695]

[0696] Compound 143 (5.6 g, 300 mmol), K2CO3 (5.5 g, 40 mmol) and 123 (5.2 g, 20 mmol) were added to a single-mouth bottle containing DMF (100 mL) in sequence, and then stirred overnight in an oil bath at 120 degrees. The reaction was monitored by TLC. After the reaction was complete, the organic solvent was suspended and washed with water, filtered, the solid was dried, mixed, and column chromatography was performed to obtain 3.1 g of brown solid. LCMS found: 414 [M+H] +

[0697] Step 32-2:

[0698]

[0699] The raw material 144 (1 g, 2.4 mmol), bis-pinacol borate (711 mg, 2.8 mmol), PdCl2(dppf)DCM (195 mg, 0.24 mmol), and KOAc (470 mg, 4.8 mmol) were mixed in a 25 mL single-mouth bottle, replaced with N2 three times, injected with 10 mL of dioxide, stirred at 95°C for 16 hours, washed with water, extracted, concentrated, and purified by column to obtain 850 mg of solid. LCMS found: 462 [M+H] +

[0700] Step 32-3:

[0701]

[0702] The raw material 145 (248 mg, 0.54 mmol), the raw material 33 (100 mg, 0.27 mmol), PdCl2(dppf)2DCM (22 mg, 0.027 mmol), and Na2CO3 (57 mg, 0.54 mmol) were mixed, replaced with nitrogen, and Dioxane / H2O (8 mL) was added. The mixture was reacted at 95°C for 3 hours, and washed with water to obtain 47 mg of a white solid. LCMS found: 629 [M+H] + ; 1 H 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).

[0703] Example 33 Synthesis of Compound LW1005-033

[0704]

[0705] Step 33-1:

[0706]

[0707] Compound 146 (1.0 g) was dissolved in DCM (30 mL), and 147 (1.16 g) and TEA (1.32 g) were added. After reacting at room temperature for 1 hour, NaBH(OAc)3 (3.31 g) was added in batches. After reacting for 1 hour, the reaction was complete on TLC. The reaction solution was washed with water, extracted with DCM, dried by spin drying, and filtered to obtain 1.0 g of a yellow solid product. LCMS found: 306 [M+H] +

[0708] Step 33-2:

[0709]

[0710] Compound 148 (1.0 g), 149 (0.92 g) and TsOH (0.75 g) were added to isopropanol (30 mL) and reacted at 85 degrees overnight. TLC showed that the reaction was complete. Water was added to the reaction solution, isopropanol was removed by evaporation, and impurities were extracted with EA. NaHCO3 aqueous solution was added to the aqueous phase to adjust pH to 7, solid precipitated, extracted with DCM, the solid dissolved, and the DCM was evaporation to obtain 1.24 g of yellow solid. LCMS found: 455 [M+H] +

[0711] Step 33-3:

[0712]

[0713] Compound 33 (1 g), bis-pinacol borate (815 mg), PdCl2 (dppf) DCM (180 mg), and KOAc (420 mg) were mixed in a 25 mL single-mouth bottle, replaced with N2 three times, injected with 10 mL of dioxide, stirred at 95°C for 16 hours, washed with water, extracted, concentrated, and purified by column to obtain 900 mg of solid. LCMS found: 422 [M+H] +

[0714] Step 33-3:

[0715]

[0716] 150 (119 mg), 151 (100 mg), Pd(dppf)Cl2 / DCM (19.4 mg) and Na2CO3 (50 mg) were placed in a reaction bottle at room temperature, vacuum degassed, and dioxane / H2O (6 mL, 5:1) was injected into the syringe. After degassed again, the reaction was heated at 100 degrees for 4 hours. TLC monitored the complete reaction of the raw materials. The reaction solution was washed with water and passed through a column (DCM:MeOH=20:1) to obtain 50 mg of crude product. The crude product was prepared and separated to obtain 20 mg of product 5 as a yellow solid. LCMS found: 670 [M+H] +

[0717] Step 33-4:

[0718]

[0719] Compound 152 (10 mg) was dissolved in THF / H2O (1.3 mL, 1:0.3), and LiOH / H2O (1.3 mg) was added. The mixture was reacted at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was prepared and separated to obtain 5 mg of a yellow solid product. LCMS found: 656 [M+H] +; 1 H 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).

[0720] Example 34 Synthesis of Compound LW1005-034

[0721]

[0722] Step 34-1:

[0723]

[0724] Compound 43 (8 g) was dissolved in acetic acid (100 mL), cooled in an ice bath, and compound 2,2,2-trichloroacetimidic acid methyl ester (16 mL) was added dropwise. After the addition was completed, the mixture was kept at room temperature overnight and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into ice water, extracted with EA, washed with saturated brine, dried, and spin-dried to obtain 10.5 g of white solid. LCMS found: 280 [M+H] +

[0725] Step 34-2:

[0726]

[0727] Compound 153 (10.4 g) was dissolved in ethanol / water (110 mL; 10:1), sodium carbonate (5.9 g) was added, and the temperature was raised to 75°C for 24 h; the reaction was detected by TLC. After the reaction was complete, the solvent was suspended and the sample was directly mixed and passed through the column to obtain 4.8 g of white solid. LCMS found: 236 [M+H] +

[0728] Step 34-3:

[0729]

[0730] Take the raw material 154 (4.5g, 1eq) and add it to 40% hydrobromic acid aqueous solution (45ml) and acetic acid (50ml), and react for 15 minutes at 86℃. LC-MS is used to detect the reaction. After the reaction is complete, the mixture is dried by oil pump at 40℃ to obtain 3.16g of red-brown solid. LCMS found 222[M+H]+

[0731] Step 34-4:

[0732]

[0733] Take the raw material 155 (3g, 1eq) and add it to DMAc (100ml), clear it, add the bromine raw material (10g, 2eq), add cesium carbonate (14g, 3eq), react at room temperature for 1 hour, and detect the reaction by LC-MS. After the reaction is complete, add ice water, add EA (100mL) to extract once, mix the organic phase and pass it through the column to obtain 2.2g of white solid. LCMS found: 504[M+H]+ Step 34-5:

[0734]

[0735] Take the raw material 126 (200 mg, 2 eq) and add it to freshly distilled THF (5 mL), cool it to about -15 ° C, protect it with argon, drop it with a 2M NaHMDS solution (1 mL, 4 eq), react for 5 minutes, then drop it with a THF (3 mL) solution of the raw material 156 (100 mg, 1 eq), naturally heat it and react for 2 hours, and monitor the reaction by TLC. After the reaction is complete, directly mix the sample and pass it through the column to obtain 104 mg of a light yellow solid. LCMS found: 897 [M + H] +

[0736] Step 34-6:

[0737]

[0738] The raw material 157 (50 mg) was dissolved in THF (1 mL), and then 1M TBAF / THF (0.1 mL) was added to the solution, and the mixture was reacted at room temperature for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, ethyl acetate / water was added for extraction, and a reverse phase column was used to prepare a yellow solid of 11 mg. 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),3.6 5(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),.

[0739] Table 2 According to the synthetic route of LW1005-002, the following compounds were synthesized using the corresponding raw materials

[0740]

[0741]

[0742] Table 3 According to the synthetic route of LW1005-032, the following compounds were synthesized using the corresponding raw materials

[0743]

[0744] Table 4 According to the synthetic route of LW1005-016, the following compounds were synthesized using the corresponding raw materials

[0745]

[0746] Table 5 According to the synthetic route of LW1005-013, the following compounds were synthesized using the corresponding raw materials

[0747]

[0748]

[0749] Table 6 According to the synthetic route of LW1005-026, the following compounds were synthesized using the corresponding raw materials

[0750]

[0751]

[0752]

[0753] Table 7 According to the synthetic route of LW1005-024, the following compounds were synthesized using the corresponding raw materials

[0754]

[0755]

[0756]

[0757] Table 8 According to the synthetic route of LW1005-025, the following compounds were synthesized using the corresponding raw materials

[0758]

[0759]

[0760] Table 9 According to the synthetic route of LW1005-008, the following compounds were synthesized using the corresponding raw materials

[0761]

[0762]

[0763] Biological Testing

[0764] Example A: PD-1 / PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) Binding Assay

[0765] The assay was performed in a standard black 384-well polystyrene plate in a final volume of 20 μL. The inhibitor was first serially diluted in DMSO and added to the wells before the other reaction components were added. The final concentration of DMSO in the assay was 1%. The assay was performed in PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA at 25°C. Recombinant human PD-L1 protein (19-238) with a His tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with an Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in assay buffer and 0.1 μl of the solution was extracted and added to the wells. The plate was centrifuged and the proteins were preincubated with the inhibitors for 40 minutes. After incubation, 0.1 μl of HTRF detection buffer containing europium-blocked anti-human IgG (PerkinElmer-AD0212) Fc-specific and anti-His -Allophycocyanin (APC, PerkinElmer-AD0059H) conjugated antibodies. After centrifugation, the wells were incubated at 25 ° C for 60 minutes. The data were read in a PHERAstar FS plate reader (665nm / 620nm ratio). The final concentrations in the assay were ~3nM 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 obtain the IC50 values ​​of the inhibitors.

[0766] The IC50 values ​​of the compounds illustrated in the examples are expressed in the following manner: IC50: + = ≤ 100 nM; ++ = 100 to 1000 nM; +++ = > 1000 nM

[0767] Data for Example compounds obtained using the PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay described in Example A are provided in Table 10.

[0768]

[0769]

[0770]

[0771] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound as shown in the following formula I, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof: in, n, m, p and q are each independently selected from 0, 1, 2, 3 or 4; L1 is selected from the group consisting of a chemical bond, -O-, substituted or unsubstituted -NH-, substituted or unsubstituted L2 is a chemical bond; A group having the following structure: in, Z 1 Selected from the group consisting of O, S, NRf, NO-Rf; Z 2 CRa; Z 3 CRa; wherein Ra is selected from the group consisting of H, chlorine, bromine, fluorine, iodine, cyano, halogen, hydroxyl, nitro, NRf, substituted or unsubstituted C1-C6 alkyl; Z 4 Selected from the group consisting of CH2, C(=O); The Rf is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl; Y 1 O; Y 2 Selected from the group consisting of: CH, N; is a single bond or a double bond; and It is an aromatic fragment; R is H, substituted or unsubstituted C1-C6 alkyl, or -(L 1a ) r -(L 2a ) s -L 3a ,in, Each L 1a Each is independently a group selected from the following group: a chemical bond, a substituted or unsubstituted C1-C7 alkylene group; L 2a Selected from the following group: substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 5-10 membered heterocyclylene having 1-3 heteroatoms; the heterocyclyl is a nitrogen heterocyclyl; L 3a Selected from the group consisting of H, hydroxyl, amino, carboxyl; r is 1, 2, 3, 4, 5, 6; s is 0, 1, and 2 respectively; The It has the structure shown below: in, X6 and X9 are N; X7, X8 and X 10 Each independently represents CH; X 11 N or CH; R6 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkyl); Each is independently a divalent group formed by a ring selected from the group consisting of: Wherein, the bonding position of the ring can be N or C; R2 and R3 are each independently selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkyl; the "substituted" means substituted by one or more substituents selected from the following group: halogen, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3; oxo, -CN, hydroxyl, amino; R1 is selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkyl; the "substituted" means substituted by one or more substituents selected from the following group: halogen, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, oxo, -CN, hydroxyl, amino, C1-C6 alkylamino, carboxyl, -NHAc, or a group selected from the following group which is unsubstituted or substituted by one or more substituents of Group A: C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O; R4 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkyl; Unless otherwise specified, the term "substituted" refers to being substituted by one or more substituents selected from the group consisting of halogen, oxo, -CN, hydroxy, amino, C1-C6 alkylamino, carboxyl, -NHAc, or a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy which is unsubstituted or substituted by one or more substituents of Group A; The substituents in group A are selected from the following groups: halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 alkylamino; In the above formulae, any of the heteroatoms is selected from the group consisting of N, S and O; And the compound is not a structure selected from the following group:

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that The compound has a structure shown in the following formula II: wherein n, m, p and q are each independently selected from 0, 1, 2, 3 or 4; L1 is selected from the group consisting of a chemical bond, -O-, substituted or unsubstituted -NH-, substituted or unsubstituted L2 is a chemical bond; A group having the following structure: in, Z 1 Selected from the group consisting of O, S, NRf, NO-Rf; Z 2 CRa; Z 3 is CRa; wherein said Ra is selected from the group consisting of H, chlorine, bromine, fluorine, iodine, cyano, halogen, hydroxyl, nitro, NRf, substituted or unsubstituted C1-C6 alkyl; The Rf is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl; is a single bond or a double bond; and It is an aromatic fragment; R1, R2, R3 and R4 are each independently selected from the group consisting of H, halogen, and substituted or unsubstituted C1-C6 alkyl.

3. The compound according to claim 1, characterized in that The It has the structure shown below: in, X6, X9 are N; X7, X8, X 10 and X 11 Each independently is CH; R6 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkyl).

4. The compound according to claim 1, characterized in that The compound of formula I is selected from formula Id-1, Id-2 and Id-3, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Wherein, each group is defined as in any of the preceding claims.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The ring and / or Having a substituent as shown in the following formula IV: Wherein, each L4 is independently selected from the following group: substituted or unsubstituted C1-C4 alkylene, -NRa-; Selected from the following group: 5-8 membered nitrogen-containing heterocyclic group; m and n are each independently 1, 2, 3 or 4; Each R5 is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxyl, amino, carboxyl; wherein the substituent is selected from the following group: halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy.

6. A compound selected from the group consisting of:

7. A method for preparing the compound of formula I as claimed in claim 1, characterized in that: The method comprises steps selected from those shown in Synthesis Schemes 1, 2 or 3: Synthesis Scheme 3: Method 3 includes the following steps: (a) Boron ester 3-1 and halide 3-2 are used as raw materials and Suzuki coupling is carried out under palladium catalysis to obtain intermediate compound 3-3; (b) using carboxylic acid 3-4 and compound 3-5 as raw materials, a cyclization reaction occurs under the action of a suitable dehydrating agent to obtain an intermediate compound 3-3; (c) Using aldehyde 3-6 as a raw material, a cyclization reaction occurs under the action of a suitable oxidant to obtain intermediate 3-3; (d) Using intermediate 3-3 and a suitable coupling reagent 3-7 as basic raw materials, a palladium or copper-catalyzed coupling reaction is performed to obtain the target compound I; The Cy is for Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , R is as defined in any of the above claims.

8. A pharmaceutical composition, characterized in that The method comprises: (1) the compound according to claim 1, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

9. The use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, characterized in that: Used for preparing a pharmaceutical composition for preventing and / or treating diseases related to the activity or expression of PD-1 / PD-L1.

10. A PD-1 / PD-L1 inhibitor, characterized in that The inhibitor comprises the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. A method for non-diagnostic and non-therapeutic inhibition of PD-1 / PD-L1 interaction in vitro, characterized in that: The method comprises the steps of contacting the compound according to claim 1 or a pharmaceutically acceptable salt thereof with a PD-L1 protein.

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