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

Abstract

The present invention provides a nitrogen-containing heterocyclic compound, its preparation method, pharmaceutical composition and application. Specifically, the present invention provides a compound represented by the following formula I, or its optical isomer, hydrate, solvate, or its pharmaceutically acceptable salt; wherein the definitions of each group are 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. #imgabs0#

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

[0003] The immune system plays a crucial role in controlling and eradicating many diseases, such as various cancers and virus-induced diseases. However, cancer cells can often evade or suppress the immune system through some means, thus multiplying rapidly. One way is to alter the activation and inhibitory molecules expressed on immune cells. Blocking inhibitory immune checkpoints, such as PD-1, has proven to be a very effective method for inhibiting cancer cells.

[0004] 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 activation of T / B cells can cause autoimmune diseases, PD-1 is a protective wall of our body. PD-1 is a type I transmembrane glycoprotein composed of 268 amino acids, and its structure mainly includes an extracellular immunoglobulin variable region, a hydrophobic transmembrane region, and an intracellular region. The intracellular region contains two phosphorylation sites, which are located in the immunoreceptor tyrosine inhibitory motif and the immunoreceptor tyrosine switch motif, respectively, which also proves that PD-1 can reversely regulate the signal mediated by the T cell receptor. PD-1 has two ligands, PD-L1 and PD-L2, and they have different expression patterns. PD-L1 is upregulated in a variety of tumor cells. It binds to PD-1 on T cells, inhibits T cell proliferation and activation, renders T cells in an inactivated state, and ultimately induces immune escape.

[0005] PD-1 / PD-L1 plays a reverse immunomodulatory role. When PD-1 binds to PD-L1, it can cause tyrosine hyperphosphorylation in the tyrosine kinase domain of the immunoreceptor tyrosine switch motif of T cells. The phosphorylated tyrosine can bind to the phosphatase proteins tyrosine phosphatase 2 and protein tyrosine phosphatase 1. This can not only hinder the activation of extracellular signal-regulated kinase but 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 the PD-1 / PD-L1 signal inhibits T cell activation and proliferation, it can also cause the secretion of cytokines interleukin 2, interferon γ, and IL-10. In addition, the PD-1 / PD-L1 signal also has a similar immune function on B cells. When PD-1 binds to the B cell antigen receptor, the cytoplasmic region of PD-1 acts on the tyrosine kinase containing the binding site of protein tyrosine phosphatase 2, thereby hindering the activation of B cells.

[0006] 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, the marketed PD-1 / PD-L1 antibody inhibitors include Ninolumab from BMS, Lambrolizumab from Merck, and Atezolizumab from Roche. In addition, there are many PD-1 / PD-L1 antibody inhibitors under research, including Pidilizumab from Cure Tech, AMP-224 from GSK, and MEDI-4736 from AstraZeneca.

[0007] Although cancer immunotherapy is considered a new generation of revolution in cancer treatment after targeted therapy. However, the currently marketed and research PD-1 monoclonal drugs have their own defects, including only injectable administration, not oral administration, unstable in vivo, easily decomposed by proteases, prone to immune cross-reactions, difficult to purify, and high production costs. Therefore, small molecule inhibitors of PD-1 / PD-L1 interaction are a better choice for cancer immunotherapy.

[0008] In summary, there is an urgent need in the art to develop novel small molecule inhibitors of PD-1 / PD-L1 interaction. Summary of the Invention

[0009] The object of the present invention is to provide a novel small molecule inhibitor of PD-1 / PD-L1 interaction.

[0010] In the first aspect of the present invention, there is provided a compound represented by the following formula I, or its optical isomer, hydrate, solvate, or its pharmaceutically acceptable salt:

[0011]

[0012] Wherein, n, m, p, and q are each independently selected from 0, 1, 2, 3, or 4, 5;

[0013] L1, L2 are 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

[0014] is a group having the following structure:

[0015]

[0016] wherein,

[0017] Z 1 is selected from the group consisting of: O, S, NRf, N-O-Rf; wherein, said Rf is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C 10 heteroaryl, cyano, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C1-C6 alkoxy, -C(=O)-substituted or unsubstituted C1-C6 alkyl, -C(=O)-substituted or unsubstituted C3-C 10 cycloalkyl, -C(=O)-substituted or unsubstituted C2-C6 alkenyl, -C(=O)-substituted or unsubstituted C2-C6 alkynyl;

[0018] Z 2 、Z 3 、Z 4 each independently is selected from the group consisting of: N, CH2, N-O, SO, SO2, C(=O), NRa, CRa; wherein, said Ra is selected from the group consisting of: H, chlorine, bromine, fluorine, iodine, cyano, halogen, hydroxy, nitro, NRf, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C 10 heteroaryl, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C1-C6 alkoxy, -C(=O)-substituted or unsubstituted C1-C6 alkyl, -C(=O)-substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, -C(=O)-substituted or unsubstituted C2-C6 alkenyl, -C(=O)-substituted or unsubstituted C2-C6 alkynyl;

[0019] Y 1 、Y 2 、Y 3 each independently is selected from the group consisting of: CH, CH2, NH, NRa, N, N-O, CF, CRa, C(Ra)2, O, S, SO or SO2;

[0020] is a single bond or a double bond;

[0021] and is an aromatic or non-aromatic moiety;

[0022] R is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, cyano, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C1-C6 alkoxy, -C(=O)-substituted or unsubstituted C1-C6 alkyl, -C(=O)-substituted or unsubstituted C3-C 10 cycloalkyl, -C(=O)-substituted or unsubstituted C2-C6 alkenyl, -C(=O)-substituted or unsubstituted C2-C6 alkynyl, or -(L 1a ) r -(L 2a ) s -(L 3a ) s -, wherein,

[0023] each L 1a is independently a group selected from the group consisting of: a chemical bond, substituted or unsubstituted C1-C7 alkylene, substituted or unsubstituted C2-C4 alkenylene, substituted or unsubstituted C2-C4 alkynylene, -S-, -O-, substituted or unsubstituted -NH-, -S(O)-, -S(O)2-,

[0024] L 2a is selected from the group consisting of: substituted or unsubstituted C6-C12 arylene, substituted or unsubstituted 5-12 membered heteroarylene having 1-3 heteroatoms, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 5-10 membered heterocycloalkylene having 1-3 heteroatoms;

[0025] L 3a is selected from the group consisting of: H, substituted or unsubstituted C1-C10 alkyl, C1-C10 aryl, -CN, hydroxy, amino, carboxy, -CO-NH-SO2-R g , -NH-SO2-R g , -SO2-NH-CO-R g ;

[0026] r is 1, 2, 3, 4, 5, 6;

[0027] s are each 0, 1, 2;

[0028] Rd, Re are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 10 aryl;

[0029] selected from the group consisting of: substituted or unsubstituted 5- to 12-membered heteroaryl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5- to 12-membered heterocyclic group, substituted or unsubstituted 5- to 12-membered C5-C12 cycloalkyl group, wherein the 5- to 12-membered heteroaryl and 5- to 12-membered heterocyclic group have 1 to 4 heteroatoms selected from B, P, N, O, S, wherein P, N, O as ring-forming atoms can be oxo and one or more ring-forming carbon atoms can be replaced by carbonyl; or the is none; or the is equal to

[0030] each independently is 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;

[0031] R1, R2, R3 and R4 each independently are selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., =O), =NRf, -CN, hydroxy, NRdRe (such as amino), substituted or unsubstituted C1-C6 amino group, substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl having 1 to 3 heteroatoms, substituted or unsubstituted 5- to 12-membered heterocyclic group having 1 to 4 heteroatoms, substituted or unsubstituted substituted or unsubstituted wherein, Rb, Rc and R z each independently are selected from the group consisting of: H, substituted or unsubstituted C1-C8 alkyl; or Rb and Rc together with the adjacent N atom form a substituted or unsubstituted 5- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S and O; or -(L 1a ) r -(L 2a ) s -(L 3a ) s -;

[0032] Unless otherwise specified, the term "substituted" means substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the following group: halogen, including but not limited to -F, Cl, Br, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, oxo, -CN, hydroxyl, amino, C1-C6 alkylamino, carboxyl, -NHAc, a group selected from the following groups which is unsubstituted or substituted by one or more substituents selected from the following group: 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 heterocyclic group having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 alkylamino;

[0033] In the above formulas, any of the said heteroatoms is selected from the following group: B, P, N, S and O.

[0034] In another preferred embodiment, the said Z 2 、Z 3 、Z 4 are each independently selected from the following group: trifluoromethyl, -CHF2, -OCF3, -OCHF2, sulfonamido.

[0035] In another preferred embodiment, the said L 3a is selected from the following group: -OR g 、-N(R g )2-CO2R g 、-CON(R g )2、-CONHCOR g 、NR g -CO-N(R g )2、-NR g -SO2-N(R g )2.

[0036] In another preferred embodiment, the said is a substituted or unsubstituted 6-10 membered ring group.

[0037] In another preferred embodiment, the term "substituted" includes that at least one hydrogen atom on the group is substituted by the following substituents: or a substituted or unsubstituted 3-4 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, and the substituents are selected from the following group: halogen, hydroxyl, carboxyl, cyano, C1-C6 alkoxy, C1-C6 alkylamino.

[0038] In another preferred embodiment, Rb and Rc together with the adjacent N atom form a substituted or unsubstituted 3- to 5-membered heterocyclic group having 1 to 3 heteroatoms selected from N, S, and O, or Rb and Rc together with the adjacent N atom form a substituted or unsubstituted 4- to 10-membered cyclic amide.

[0039] In another preferred embodiment, any one or more of R1, R2, R3, and R4 are substituted or unsubstituted or a 3- to 4-membered heterocyclic group.

[0040] In another preferred embodiment, the compound has the structure shown in Formula II below:

[0041]

[0042] wherein n, m, p, and q are each independently selected from 0, 1, 2, 3, or 4;

[0043] L1 and L2 are selected from the group consisting of: a chemical bond, a substituted or unsubstituted C1-C4 alkylene group, a substituted or unsubstituted C2-C4 alkenylene group, a substituted or unsubstituted C2-C4 alkynylene group, -S-, -O-, a substituted or unsubstituted -NH-, -S(O)-, -S(O)2-, a substituted or unsubstituted -NHC(O)NH-, substituted or unsubstituted substituted or unsubstituted substituted or unsubstituted

[0044] is a group having the following structure:

[0045]

[0046] wherein,

[0047] Z 1 is selected from the group consisting of: O, S, NRf, N-O-Rf; wherein Rf is selected from the group consisting of: H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C 10 aryl group, a substituted or unsubstituted C6-C 10 heteroaryl group, cyano group, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C1-C6 alkoxy group, -C(=O)-substituted or unsubstituted C1-C6 alkyl group, -C(=O)-substituted or unsubstituted C3-C 10 cycloalkyl group, -C(=O)-substituted or unsubstituted C2-C6 alkenyl group, -C(=O)-substituted or unsubstituted C2-C6 alkynyl group;

[0048] Z 2 、Z 3 、Z 4 are each independently selected from the group consisting of: N, CH2, N-O, SO, SO2, 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 C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C 10 heteroaryl, -C(=O)-NRdRe, -C(=O)-substituted or unsubstituted C1-C6 alkoxy, -C(=O)-substituted or unsubstituted C1-C6 alkyl, -C(=O)-substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, -C(=O)-substituted or unsubstituted C2-C6 alkenyl, -C(=O)-substituted or unsubstituted C2-C6 alkynyl;

[0049] Y 1 、Y 2 、Y 3 are each independently selected from the group consisting of: CH, CH2, NH, NRa, N, N-O, CF, CRa, C(Ra)2, O, S, SO or SO2;

[0050] is a single bond or a double bond;

[0051] and is an aromatic or non-aromatic moiety.

[0052] R1, R2, R3 and R4 are each independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e. =O), =NRf, -CN, hydroxyl, NRdRe (such as amino), substituted or unsubstituted C1-C6 amino, 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 heterocyclic group having 1-4 heteroatoms, substituted or unsubstituted substituted or unsubstituted or -(L 1a ) r -(L 2a ) s -(L 3a )s .

[0053] In another preferred embodiment, the hydrogen atoms on the carbon atoms of a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, oxo (i.e., =O), =NR f , hydroxy, NR d R e (such as amino), a substituted or unsubstituted C1-C6 amino group, a substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group having 1-3 heteroatoms, a substituted or unsubstituted 3-12 membered heterocyclic group having 1-4 heteroatoms can each independently be replaced by deuterium.

[0054] In another preferred embodiment, the has the structure shown in the following formula:

[0055]

[0056] Wherein,

[0057] X6, X7, X8, X9, X 10 and X 11 each independently selected from the group: N, CR;

[0058] R6 is selected from the group: H, halogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, oxo (i.e., =O), =NRf, -CN, hydroxy, NRdRe (such as amino), a substituted or unsubstituted C1-C6 amino group, a substituted or unsubstituted -(C1-C6 alkylene)-NH-(C1-C6 alkylene), carboxyl, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group having 1-3 heteroatoms, a substituted or unsubstituted 5-12 membered heterocyclic group having 1-4 heteroatoms,, substituted or unsubstituted substituted or unsubstituted or -(L 1a ) r -(L 2a ) s -(L 3a ) s -,-C 0-8 -O-R8,-C 0-8 -C(O)OR8,-C 0-8-OC(O)OR8, -C 0-8 -NR8R9, -C 0-8 -N(R8)C(O)R9, -C 0-8 -C(O)NR8R9;

[0059] R8 and R9 are each independently selected from the group consisting of: H, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, oxo (i.e., =O), =NRf, -CN, hydroxy, NRdRe (such as amino), substituted or unsubstituted C1-C6 amino, 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 heterocyclic group having 1-4 heteroatoms,, substituted or unsubstituted substituted or unsubstituted or -(L 1a ) r -(L 2a ) s -(L 3a ) s ;

[0060] In another preferred embodiment, said R6 is R1; or is wherein, Rb and Rc are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C8 alkyl; or Rb and Rc together with the adjacent N atom form a substituted or unsubstituted 3-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O.

[0061] In another preferred embodiment, said is a monovalent group formed by any substituted ring selected from the group consisting of: <00>

[0062]

[0063] In another preferred embodiment, the compound of formula I is selected from formula Id-1, Id-2 and Id-3, or its optical isomers, hydrates, solvates, or pharmaceutically acceptable salts thereof:

[0064]

[0065] wherein the definitions of each group are as described above.

[0066] In another preferred embodiment, the hydrogen atoms on the carbon atoms of Rf, R3, R2 and R1 can each independently be replaced by deuterium.

[0067] In another preferred example, the ring and / or has a substituent as shown in the following formula IV:

[0068]

[0069]

[0070] Wherein each of the L4s is independently selected from the group consisting of: substituted or unsubstituted C1-C4 alkylene, -S-, -O-, -NRa-, -S(O)-, -S(O)2-; preferably substituted or unsubstituted C1-C4 alkylene, provided that the structure formed by each L4 together is chemically stable;

[0071] Selected from the group consisting of: substituted or unsubstituted C5-C10 cycloalkyl, 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;

[0072] Each R5 is independently selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, -CN, hydroxy, amino, carboxy, -OR g , -N(R g )2, -CO-NH-SO2-R g , -NH-SO2-R g , -SO2-NH-CO-R g、 -CO2R g , -CON(R g )2, CONHCOR g , NR g -CO-N(R g )2, -NR g -SO2-N(R g )2; R f and R g are as defined above; wherein the substituents are selected from the group consisting of: halogen, hydroxy, carboxy, cyano, C1-C6 alkoxy.

[0073] In another preferred example, the hydrogen atoms on the carbon atoms of the substituted or unsubstituted C1-C4 alkylene can each be independently replaced by deuterium.

[0074] In another preferred example, the compounds are selected from the following table;

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] The second aspect of the present invention provides a method for preparing a compound of formula I as described in claim 1, said method comprising the steps selected from those shown in Synthesis Scheme 1, 2 or 3:

[0089] Synthesis Scheme 1

[0090]

[0091] (e) Using halide 1-1 and a suitable coupling reagent 1-2 (such as boric acid, borate, tin reagent or Grignard reagent) as basic raw materials, an intermediate compound 1-3 is obtained through a palladium- or copper-catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling);

[0092] (f) Using intermediate 1-3 as a raw material, it reacts with carboxylic acid 1-4 under the action of a condensing agent (such as HATU, EDCI or HBTU) to obtain amide intermediate 1-5;

[0093] (g) Using intermediate 1-5 as a raw material, the protecting group (Boc) is removed under acidic conditions to obtain intermediate 1-6;

[0094] (h) Using intermediate 1-6 as a raw material, it undergoes a nucleophilic substitution reaction with a halide under basic conditions, or a reductive amination reaction with an aldehyde or a ketone under the action of a reducing agent to obtain the target compound I;

[0095] Synthesis Scheme 2:

[0096]

[0097] (e) Using carboxylic acid ester 2-1 as the raw material, under the catalysis of Lewis acid, it undergoes aminolysis reaction with amine 2-2 to obtain intermediate compound 2-3;

[0098] (f) Using intermediate 2-3 and a suitable coupling reagent 2-4 (such as boric acid, borate, tin reagent or Grignard reagent) as the basic raw materials, through a palladium- or copper-catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling) to obtain intermediate compound 2-5;

[0099] (g) Using intermediate 2-5 as the raw material, the protecting group (Boc) is removed under acidic conditions to obtain intermediate 2-6;

[0100] (h) Using intermediate 2-6 as the raw material, it undergoes a nucleophilic substitution reaction with a halide under basic conditions, or a reductive amination reaction with an aldehyde or a ketone under the action of a reducing agent to obtain the target compound I;

[0101] (b) Perform reductive amination reaction according to Synthetic Scheme 3 to obtain the target compound I;

[0102] Synthetic Scheme 3:

[0103]

[0104] Method 3 includes the following steps:

[0105] (e) Using borate 3-1 and halide 3-2 as the raw materials, perform Suzuki coupling under the catalysis of palladium to obtain intermediate compound 3-3;

[0106] (f) Using carboxylic acid 3-4 and compound 3-5 as the raw materials, under the action of a suitable dehydrating agent, a cyclization reaction occurs to obtain intermediate compound 3-3;

[0107] (g) Using aldehyde 3-6 as the raw material, under the action of a suitable oxidizing agent, a cyclization reaction occurs to obtain intermediate 3-3;

[0108] (h) Using intermediate 3-3 and a suitable coupling reagent 3-7 (such as boric acid, borate, tin reagent or Grignard reagent) as the basic raw materials, through a palladium- or copper-catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling) to obtain the target compound I;

[0109] The defined Cy is is Y 1 、Y 2 、Z 1 、Z 2 、Z 3 、The definitions of R are the same as above.

[0110] In the third aspect of the present invention, there is provided a pharmaceutical composition comprising (1) a compound as described in the first aspect of the present invention, or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.

[0111] In the fourth aspect of the present invention, there is provided the use of a compound as described in the first aspect of the present invention, or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described in the second aspect of the present invention, for the preparation of a pharmaceutical composition for preventing and / or treating a disease related to the activity or expression level of PD-1 / PD-L1.

[0112] In the fifth aspect of the present invention, there is provided a PD-1 / PD-L1 inhibitor, which inhibitor comprises a compound as described in the first aspect of the present invention, or its stereoisomer or tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0113] In another preferred embodiment, the pharmaceutical composition is used for treating diseases selected from the group consisting of: cancer, infectious diseases, autoimmune diseases.

[0114] In another preferred embodiment, the cancer is selected from the group consisting of: pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular 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, hematological tumors, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, head and neck cancer.

[0115] In another preferred embodiment, the cancer is selected from the group consisting of: acute lymphoblastic 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 lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenström macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma or diffuse large B-cell lymphoma (DLBCL).

[0116] In another preferred embodiment, the infectious diseases are selected from bacterial infections and viral infections.

[0117] In another preferred embodiment, the autoimmune diseases are selected from organ-specific autoimmune diseases and systemic autoimmune diseases.

[0118] In another preferred example, 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.

[0119] In another preferred example, the systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, and autoimmune hemolytic anemia.

[0120] In another preferred example, the pharmaceutical composition is also used to improve the T cell function of patients with chronic hepatitis B (CHB).

[0121] In another preferred example, the inhibitor further includes at least one therapeutic agent selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

[0122] In a sixth aspect of the present invention, a method for inhibiting PD-1 / PD-L1 interaction in vitro is provided, which is characterized by including the step 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.

[0123] 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 in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed Description of the Invention

[0124] Through extensive and in-depth research, the present 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.

[0125] Definitions

[0126] As used herein, the term "alkyl" includes straight-chain or branched-chain alkyl groups. For example, C1-C8 alkyl represents a straight-chain or branched-chain alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0127] As used herein, the term "alkenyl" includes straight-chain or branched-chain alkenyl groups. For example, C2-C6 alkenyl refers to a straight-chain or branched-chain alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0128] As used herein, the term "alkynyl" includes straight-chain or branched alkynyl groups. For example, C2-C6 alkynyl refers to straight-chain or branched alkynyl groups having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or similar groups.

[0129] As used herein, the term "C3-C 10 cycloalkyl" refers to cycloalkyl groups having 3 to 10 carbon atoms. It can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be in bicyclic form, such as bridged or spiro form.

[0130] As used herein, the term "C1-C8 alkylamino" refers to an amino group substituted by a C1-C8 alkyl group, which can be mono-substituted or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, etc.

[0131] As used herein, the term "C1-C8 alkoxy" refers to straight-chain or branched alkoxy groups having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0132] As used herein, the term "3- to 10-membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S, and O" refers to saturated or partially saturated cyclic groups having 3 to 10 atoms and in which 1 to 3 atoms are heteroatoms selected from the group consisting of N, S, and O. It can be monocyclic or in bicyclic form, such as bridged or spiro form. Specific examples can be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl, etc.

[0133] As used herein, the term "C6-C 10 aryl" refers to aryl groups having 6 to 10 carbon atoms, such as phenyl or naphthyl and similar groups.

[0134] As used herein, the term "5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, S, and O" refers to cyclic aromatic groups having 5 to 10 atoms and in which 1 to 3 atoms are heteroatoms selected from the group consisting of N, S, and O. It can be monocyclic or in fused-ring form. Specific examples can be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-triazolyl, tetrazolyl, furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, etc.

[0135] Unless otherwise specified, the groups in the present invention are "substituted or unsubstituted", and the groups of the present invention can be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0136] As used herein, "halogen" or "halo atom" refers to F, Cl, Br, and I. More preferably, the halogen or halo atom is selected from F, Cl, and Br. "Halogenated" means substituted by an atom selected from F, Cl, Br, and I.

[0137] 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, the R and S configurations containing asymmetric centers, the (Z) and (E) isomers of double bonds, etc. Therefore, the individual 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.

[0138] Unless otherwise specified, the structural formulas described in the present invention are intended to include all possible deuterated derivatives (i.e., one or more hydrogen atoms in the molecule are replaced by D).

[0139] As used herein, the term "tautomer" means that structural isomers with different energies can interconvert over a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion through proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion through some reorganization of bonding electrons.

[0140] As used herein, the term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio.

[0141] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0142] Active ingredient

[0143] As used herein, "the compounds of the present invention" refers to the compounds represented by Formula I, and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compounds of Formula I.

[0144] Preferred compounds of the present invention include Compounds 1-360 (including stereoisomers of various R-configurations and / or S-configurations of each compound, and / or cis-trans isomers of E- / Z-).

[0145] In another preferred embodiment, the pharmaceutical salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases capable of providing physiologically acceptable cations, as well as ammonium salts.

[0146] 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, wolfberry acid, maleic acid tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions, potassium ions; the alkaline earth metal ions are selected from calcium ions, magnesium ions; the organic bases capable of providing physiologically acceptable cations are selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[0147] All these salts within the scope of the present invention can be prepared by conventional methods. During the preparation of the compounds of General Formula I and their solvates and their salts, different crystallization conditions may result in polymorphs or co-crystals.

[0148] Preparation of Compounds of Formula I

[0149] To prepare the compounds of General Formula I described in the present invention, according to the structure of General Formula I, the compounds of General Formula I of the present invention can be obtained by the following Method 1 or 2.

[0150] Method 1 includes the following steps:

[0151]

[0152] (a) Using halide 1-1 and a suitable coupling reagent 1-2 (such as boric acid, borate ester, tin reagent or Grignard reagent) as basic raw materials, an intermediate compound 1-3 is obtained through a palladium- or copper-catalyzed coupling reaction (such as Suzuki, Stille or Kumada coupling);

[0153] (b) Using intermediate 1-3 as a raw material, reacting with carboxylic acid 1-4 under the action of a condensing agent (such as HATU, EDCI or HBTU) to obtain amide intermediate 1-5;

[0154] (c) Using intermediate 1-5 as a raw material, removing the protecting group (Boc) under acidic conditions to obtain intermediate 1-6;

[0155] (d) Using intermediate 1-6 as a raw material, under basic conditions, it undergoes a nucleophilic substitution reaction with a halide, or under the action of a reducing agent, it undergoes a reductive amination reaction with an aldehyde or a ketone to obtain the target compound I;

[0156]

[0157] Method 2 includes the following steps:

[0158] (c) Using carboxylic acid ester 2-1 as a raw material, under the catalysis of a Lewis acid, it undergoes an aminolysis reaction with amine 2-2 to obtain intermediate compound 2-3;

[0159] (d) Using intermediate 2-3 and a suitable coupling reagent 2-4 (such as boric acid, borate, 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 intermediate compound 2-5;

[0160] (e) Using intermediate 2-5 as a raw material, under acidic conditions, the protecting group (Boc) is removed to obtain intermediate 2-6;

[0161] (f) Using intermediate 2-6 as a raw material, under basic conditions, it undergoes a nucleophilic substitution reaction with a halide, or under the action of a reducing agent, it undergoes a reductive amination reaction with an aldehyde or a ketone to obtain the target compound I;

[0162]

[0163] Method 3 includes the following steps:

[0164] (i) Using carboxylic acid ester 3-1 as a raw material, under palladium or copper catalysis, it undergoes a Buchwald-Hartwig coupling or Ullman coupling with amine 3-2 to obtain intermediate compound 3-3;

[0165] (j) Using intermediate 3-3 and a suitable coupling reagent 3-4 (such as boric acid, borate, 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 intermediate compound 3-5;

[0166] (k) Using intermediate 3-5 as a raw material, under acidic conditions, the protecting group (Boc) is removed to obtain intermediate 3-6;

[0167] (l) Using intermediate 3-6 as a raw material, under basic conditions, it undergoes a nucleophilic substitution reaction with a halide, or under the action of a reducing agent, it undergoes a reductive amination reaction with an aldehyde or a ketone to obtain the target compound I;

[0168] The described Cy is is Y1 , Y 2 , Z 1 , Z 2 , Z 3 , The definition of R is the same as above.

[0169] 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 compounds described by General Formula I may exist in the form of solvates or non-solvates, and different solvates may be obtained by crystallization using different solvents.

[0170] Pharmaceutical Compositions and Administration Methods

[0171] Since the compounds of the present invention have excellent inhibitory activity against 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 for preventing and / or treating (stabilizing, alleviating or curing) diseases related to PD-1 / PD-L1 interaction (for example, cancers, infectious diseases, autoimmune diseases).

[0172] The pharmaceutical compositions of the present invention contain the compounds of the present invention within a safe and effective amount range and pharmaceutically acceptable excipients or carriers. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, it contains 10 - 200 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0173] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein 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 are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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 dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0174] There is no particular limitation on the administration route of the compounds or pharmaceutical compositions of the present invention. Representative administration routes include (but are not limited to): oral administration, parenteral (intravenous, intramuscular or subcutaneous).

[0175] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate dibasic, or is admixed with the following components: (a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0176] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric materials and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0177] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0178] In addition to these inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0179] In addition to the active compound, the suspension can contain suspending agents, e.g., ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of these substances.

[0180] Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0181] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as other anticancer agents).

[0182] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of these other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention for the prevention and / or treatment of diseases related to PD-1 / PD-L1 interaction.

[0183] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is a pharmaceutically effective dosage. For a human weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 20 - 500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0184] The main advantages of the present invention include:

[0185] (1) The compounds of the present invention have high inhibitory activity against PD-1 / PD-L1 interaction, have a strong binding ability with the PD-L1 protein, and have the ability to relieve the inhibition of IFNγ by PD-L1.

[0186] (2) The compounds of the present invention have better solubility; the toxicity to normal cells is very low, so they can be applied to the treatment subject within a relatively large dosage range.

[0187] (3) Compared with the compounds of the prior art, the compounds of the present invention have better solubility, so they have good drug-forming properties. 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 form pharmaceutically acceptable salts, which helps to further form preparations.

[0188] (4) In vivo pharmacodynamic studies have shown that the compounds of the present invention can significantly inhibit the growth of subcutaneous tumors in terms of both tumor volume and weight, and can significantly increase the number of various lymphocytes in the blood and spleen of mice.

[0189] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0190] The experimental materials and reagents used in the following embodiments can be obtained from commercial channels without special instructions.

[0191] General materials and test methods:

[0192] The instruments and raw materials involved in the embodiments are described as follows:

[0193] 1H NMR spectra were analyzed on a Bruker AV-400 (400 MHz) NMR spectrometer.

[0194] Chemical shifts were recorded using tetramethylsilane as an internal standard and are expressed in ppm (CDC13: δ 7.26 ppm). The data information recorded is as follows: chemical shifts and their splitting and coupling constants (s: singlet; d: doublet; t: triplet; q: quartet; br: broad peak; m: multiplet).

[0195] Mass spectrometry data, unless otherwise required, were analyzed using a liquid chromatography-mass spectrometry instrument from Finnigan LCQ Advantage. All reactions were carried out under anhydrous and anaerobic conditions protected by dry argon. Solid metal-organic compounds were stored in an argon-protected drying oven.

[0196] Tetrahydrofuran and diethyl ether were obtained by distillation, and sodium metal and benzophenone were added during distillation. Dichloromethane, pentane, and hexane were treated with calcium hydride.

[0197] The special raw materials and intermediates involved in the present invention were custom processed and provided by Tianjin Changshen Pharmaceutical Co., Ltd. and others. All other chemical reagents were purchased from reagent suppliers such as Shanghai Chemical Reagent Company, Aldrich, and Acros. If the intermediates or products required in the reaction during the synthesis were not sufficient for the next step of the experiment, the synthesis was repeated multiple times until a sufficient amount was obtained.

[0198] The raw materials and reagents involved in the present invention can be commercially available or obtained by custom processing and purchasing, unless otherwise specified.

[0199] The compounds in the present invention may contain one or more asymmetric centers, so this series of compounds can be in racemic or single enantiomer form. The compounds prepared in the present invention are heterocyclic compounds with a purity higher than 95%. The structural characterization of each final product is determined by MS or / and 1H NMR1 Determined by (1H NMR) analysis. The synthesis of various compounds and intermediates of the present invention will be described below by examples.

[0200] Synthesis of Compound LW1005-001 in Example 1

[0201]

[0202] Step 1-1:

[0203]

[0204] Compound 1 (51 g, Journal of Medicinal Chemistry, 2019, 62, 276-287) and 2-methyl-3-bromobenzoic acid (95.56 g) were successively added to PPA (500 g), and the reaction was mechanically stirred at 140 °C for 6 hours. After the reaction was complete, ice water was poured into the reaction flask, diluted, and then poured out for pulping for 30 min, and then filtered. The obtained solid was added to 500 ml of water, and sodium hydroxide solid was added under mechanical stirring to adjust the aqueous phase to pH = 6-8, and then filtered. The filter cake solid was dried at 55 °C to obtain 80 g of an off-white solid product. MS-APCI: 305 [M+H] + .

[0205] Step 1-2:

[0206]

[0207] 3 (2.0 g) and DMAP (805 mg) were added to DMF (30 mL), and the mixture was a turbid solution. Boc2O was added, and the solid dissolved. The reaction was heated at 40 °C overnight. TLC showed a small amount of 1 remaining. The reaction solution was rotary evaporated with an oil pump. The solid was pulped with EA / HEP and filtered to obtain 1.6 g of a white solid product. MS-APCI: 405.2 [M+H] +

[0208] Step 1-3:

[0209]

[0210] At room temperature, 4 (202 mg), 5 (230 mg, WO2018119286), Pd(dppf)Cl2 / DCM (19.5 mg) and Na2CO3 (21.2 mg) were placed in a reaction flask, degassed under vacuum, and dioxane / H2O (5 mL / 1 mL) was injected with a syringe. After degassing again, the reaction was heated at 100 °C for 4 h. The reaction solution was poured into water, extracted with EA, dried, and the EA layer was evaporated to dryness. Then it was slurried with EA / HEP (1:1), filtered to obtain 100 mg of crude product. 50 mg of the crude product was taken for preparative separation and purification to obtain 9.0 mg of LW1005-001, a yellow solid. MS-APCI: 559.2 [M+H] +

[0211] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (d, J = 6.1 Hz, 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, 6.4 Hz, 2H), 7.46–7.32 (m, 2H), 7.25 (d, J = 6.1 Hz, 1H), 7.06 (s, 1H), 6.87 (d, J = 7.1 Hz, 1H), 5.51 (s, 1H), 4.68 (d, J = 25.9 Hz, 2H), 4.47 (d, J = 27.3 Hz, 2H), 2.45 (s, 3H), 2.34 - 2.29 (m, 1H), 2.06 (s, 3H), 2.02 - 2.01 (m, 1H), 1.90 - 1.86 (m, 1H), 1.52 - 1.46 (m, 1H).

[0212] Synthesis of Compound LW1005-002 in Example 2

[0213]

[0214] Step 2-1:

[0215]

[0216] Compound 3 (10 g) was dissolved in DMF (150 ml), 6 (14.3 g; Macromolecules, 2015, 48, 1688 - 1702) and Cs2CO3 (21.4 g) were added, and the reaction was carried out at room temperature overnight. The reaction was monitored by TLC until completion. After filtration, water was added to the filtrate and it was extracted with EtOAc. The organic phase was evaporated to dryness and slurried with HEP:EtOAc = 10:1 to obtain 11 g of white solid 7. MS-APCI: 587.1 [M+H]+

[0217] 1H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.3 Hz, 1H), 7.75 (dd, J = 8.0, 1.3 Hz, 1H), 7.54 (dt, J = 6.7, 1.5 Hz, 4H), 7.49 (d, J = 7.3 Hz, 1H), 7.41–7.35 (m, 2H), 7.34–7.27 (m, 4H), 7.22 (t, J = 7.9 Hz, 1H), 6.58 (d, J = 7.3 Hz, 1H), 4.26 (t, J = 4.7 Hz, 2H), 4.05 (dd, J = 5.5, 4.1 Hz, 2H), 2.92 (s, 3H), 1.05 (s, 9H).

[0218] Step 2-2:

[0219]

[0220] Dissolve 7 (11 g) in THF (110 mL) at room temperature, add 1N TBAF / THF (20.7 mL), and react for 2 hours. TLC shows that the raw material has completely reacted. The reaction solution is concentrated by rotary evaporation and purified by column chromatography (DCM:MeOH = 20:1) to obtain 4.5 g of white solid product 8. MS-APCI: 349.1 [M+H] +

[0221] Step 2-3:

[0222]

[0223] Place 8 (350 mg), Bpin2 (304.8 mg), Pd(dppf)Cl2 (81.7 mg) and KOAc (196 mg) in a reaction flask at room temperature, degas under vacuum, inject dioxane (5 mL) with a syringe, degas again, and heat the reaction at 100 °C overnight. TLC shows that the reaction is complete. Add water to the reaction solution, extract with EtOAc, wash the organic phase with saturated NaCl, dry, concentrate by rotary evaporation, and purify by column chromatography (DCM:MeOH = 20:1) to obtain 350 mg of compound 9, a gray solid. MS-APCI: 397.1 [M+H] +

[0224] Step 2-4:

[0225]

[0226] At room temperature, 9 (350 mg), 10 (364 mg, WO2018119286), Pd(dppf)Cl2 / DCM (71.9 mg) and Na2CO3 (186.6 mg) were placed in a reaction flask, degassed under vacuum, and dioxane / H2O (3.6 mL, 5:1) was injected with a syringe. After degassing again, the reaction was heated at 100 °C for 4 hours. TLC showed that the raw materials had completely reacted. After adding water to the reaction solution, it was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried, concentrated by evaporation, and purified by column chromatography (DCM:MeOH = 20:1) to obtain 45 mg of compound LW1005-002, a yellow solid.

[0227] MS-APCI: 603.2 [M+H] +

[0228] 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.13–8.00 (m, 2H), 7.77 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.37 (dd, J = 14.2, 7.4 Hz, 2H), 7.19 (d, J = 5.8 Hz, 1H), 6.92 (dd, J = 7.2, 4.3 Hz, 2H), 4.90 (t, J = 5.4 Hz, 1H), 4.72 (d, J = 4.5 Hz, 1H), 4.23 (s, 1H), 4.11 (t, J = 5.4 Hz, 2H), 3.82 (q, J = 13.8 Hz, 2H), 3.68 (q, J = 5.5 Hz, 2H), 2.80–2.72 (m, 1H), 2.67 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.39–2.30 (m, 1H), 2.10 (s, 3H), 2.03 (dd, J = 13.4, 6.9 Hz, 1H), 1.61–1.55 (m, 1H)

[0229] Synthesis of Compound LW1005-003 in Example 3

[0230]

[0231] Step 3-1:

[0232]

[0233] At room temperature, 3 (1.38 g) was added to DMF (40 ml), and Cs2CO3 (2.95 g) and compound 11 (1.45 g; Organic Letters, 2018, 20, 6938 - 6942) were added. The reaction was carried out overnight at room temperature. Water was added to the reaction solution, stirred, filtered, and the crude solid was slurried with EA / HEP (1:10), filtered, and 1.33 g of the product was obtained. MS - APCI: 491.1[M + H] +

[0234] Step 3 - 2:

[0235]

[0236] 12 (1.33 g) was added to 30 mL of dioxane, Pd(dppf)Cl2 (0.22 g), KOAc (0.53 g), and bis(pinacolato)diboron (0.76 g) were added. The reaction system was purged with nitrogen, and the reaction was carried out at 100 °C for 3 h. Post - treatment: Water was added and filtered, extracted with EA, column - chromatographed with HEP:EA = 3:1, and concentrated by rotary evaporation to obtain 1.14 g of the product. MS - APCI: 539.2[M + H] +

[0237] Step 3 - 3:

[0238]

[0239] 13 (1.14 g) was added to 30 mL of dioxane / 6 mL of water, Pd(dppf)Cl2DCM (0.17 g), Na2CO3 (0.45 g), and 10 (875 mg, WO2018119286) were added. The reaction system was purged with nitrogen, and the reaction was carried out at 100 °C for 4 h. Post - treatment: Water was added and filtered, extracted with EA, column - chromatographed with DCM / MeOH = 20:1, and concentrated by rotary evaporation to obtain 0.9 g of the product. MS - APCI: 745.2[M + H] +

[0240] Step 3 - 4:

[0241]

[0242] 14 (100 mg) was dissolved in tetrahydrofuran (10 mL), and 4N HCl / dioxane (2 mL) was added dropwise, and the reaction was carried out at r.t. The reaction was monitored by TLC until completion. Part of the product was prepared and separated to obtain 20 mg of the product, a yellow solid. MS - APCI: 631.2[M + H] +

[0243] 1H NMR (400 MHz, DMSO-d6) δ 10.56 - 10.31 (m, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.06 (dd, J = 7.9, 1.4 Hz, 2H), 7.86 (d, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.45–7.35 (m, 2H), 7.25 (d, J = 6.0 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.51 (s, 1H), 4.77 - 4.62 (m, 2H), 4.50 - 4.43 (m, 2H), 4.06 (t, J = 7.2 Hz, 2H), 3.70 - 3.65 (m, 3H), 3.42 (t, J = 6.4 Hz, 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 = 7.3 Hz, 2H), 1.44 (p, J = 6.6 Hz, 2H).

[0244] Synthesis of Compound LW1005 - 004 in Example 4

[0245]

[0246] Step 4 - 1:

[0247]

[0248] 15 (1.0 g) was dissolved in DMF (10 mL), imidazole (0.64 g) and TBSCl (1.1 g) were added, and the reaction was carried out overnight at room temperature. TLC showed that the reaction was complete. The reaction solution was washed with water, extracted with EA, the EA layer was dried by rotation, and purified by column chromatography to obtain 1.6 g of a pale yellow oily product.

[0249] Step 4 - 2:

[0250]

[0251] LAH (0.33 g) was added to THF (15 mL). At 0 °C, a solution of compound 16 (1.6 g dissolved in 5 mL THF) was added dropwise, and the reaction was carried out at 0 °C for 1 hour. TLC showed that the reaction was complete. At 0 °C, 0.33 mL of water, 0.33 mL of NaOH (10%), and 0.33 mL of water were added to the reaction solution, filtered, and the filtrate was dried by rotation to obtain 1.3 g of a pale yellow oily product.

[0252] Step 4 - 3:

[0253]

[0254] 17 (0.5 g), TEA (0.41 g) were dissolved in DCM (5 mL). At 0 °C, MsCl (0.35 g) was added dropwise, and the reaction was carried out at 0 °C for 1 hour. TLC showed that the reaction was complete. The reaction solution was washed with water, extracted with DCM, and concentrated by rotary evaporation to obtain 0.66 g of a pale yellow oily product.

[0255] Step 4-4:

[0256]

[0257] 18 (0.66 g), 3 (0.48 g), and Cs2CO3 (1.5 g) were added to DMF (20 mL), and the reaction was carried out at room temperature overnight. The reaction solution was poured into water, and a solid precipitated. It was filtered, and the solid was concentrated by rotary evaporation to obtain 0.5 g of compound 19, a white solid. MS-APCI: 531.1 [M+H] +

[0258] Step 4-5:

[0259]

[0260] At room temperature, 19 (200 mg), 5 (142.6 mg, WO2018119286), Pd(dppf)Cl2 / DCM (31 mg), and Na2CO3 (80.6 mg) were placed in a reaction flask, degassed under vacuum, and dioxane / H2O (6 mL, 5:1) was injected with a syringe. After degassing again, the reaction was heated at 100 °C overnight. The reaction solution was washed with water and purified by column chromatography (DCM:MeOH = 20:1) to obtain 120 mg of product 20. MS-APCI: 785.4 [M+H] +

[0261] Step 4-6:

[0262]

[0263] 20 (120 mg) was dissolved in THF (3 mL), 4N HCl / dioxane (0.3 mL) was added, and the reaction was carried out at room temperature for 30 minutes, and a solid precipitated. It was filtered. The solid was separated by preparative chromatography to obtain 40 mg of a yellow solid product. MS-APCI: 671.3 [M+H] +

[0264] 1H NMR (400 MHz, DMSO-d6) δ 10.61 - 10.46 (m, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 8.06 (dd, J = 7.9, 1.4 Hz, 2H), 7.97 (s, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 1.4 Hz, 1H), 7.27 (d, J = 6.3 Hz, 1H), 7.12 (s, 1H), 6.92 (d, J = 7.3 Hz, 1H), 4.71 - 4.66 (m, 2H), 4.50 - 4.44 (m, 2H), 3.90 (d, J = 7.2 Hz, 2H), 3.68 - 3.50 (m, 2H), 3.17 - 3.11 (m, 1H), 2.45 (s, 3H), 2.37 - 3.19 (m, 1H), 2.03 - 1.90 (m, 1H), 1.82 - 1.75 (m, 3H), 1.72 - 1.68 (m, 1H), 1.57 - 1.51 (m, 2H), 1.12 - 1.01 (m, 4H).

[0265] Synthesis of Compound LW1005 - 005 in Example 5

[0266]

[0267] Step 5 - 1:

[0268]

[0269] At room temperature, 7 (1 g), Bpin2 (605 mg), Pd(dppf)Cl2 (180 mg) and KOAc (431.2 mg) were placed in a reaction flask, degassed under vacuum, dioxane (15 mL) was injected with a syringe, and after degassing again, the reaction was heated at 100 °C for 2 h. TLC showed that the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with saturated NaCl, dried, concentrated by rotary evaporation, and purified by column chromatography to obtain 900 mg of a yellow solid 21. MS - APCI: 635 [M + H] +

[0270] Step 5 - 2:

[0271]

[0272] At room temperature, 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 flask, degassed under vacuum, and dioxane / H2O (5 mL / 1 mL) was injected with a syringe. After degassing again, the reaction was heated at 100 °C overnight. TLC showed that the reaction was complete. The reaction mixture was washed with water, extracted with EA, and purified by column chromatography (DCM:MeOH = 20:1) to obtain 80 mg of the product as a yellow solid. MS-APCI: 842 [M+H] +

[0273] Step 5-3:

[0274]

[0275] 22 (500 mg), BzCl (146.6 mg), and TEA (211.5 mg) were added to DCM (5 mL), and the reaction was carried out at room temperature overnight. TLC showed that the raw materials had completely reacted. The reaction mixture was poured into water, extracted with DCM, dried, purified by column chromatography (EA / HEP = 1:1), and concentrated by rotary evaporation to obtain 350 mg of a yellow solid. MS-APCI: 945 [M+H] +

[0276] Step 5-4:

[0277]

[0278] 23 (350 mg) was dissolved in DCM (5 mL), TBAF (1 mL, 1 M in THF) was added, and the reaction was carried out at room temperature for 10 min. TLC detected that the reaction was complete. The reaction mixture was washed with halogenated water and purified by column chromatography (DCM:MeOH = 20:1) to obtain 200 mg of the product as a yellow solid. MS-APCI: 707.3 [M+H] +

[0279] Step 5-5:

[0280]

[0281] 24 (100 mg) was dissolved in DMF (2 mL), Dess-Martin (120 mg) was added at 0 °C, and the reaction was continued at 0 °C overnight. TLC showed that about 20% of the raw materials remained. The reaction mixture was quenched with saturated NaHCO3, extracted with EA, the EA layer was concentrated by rotary evaporation, and the crude product was directly used in the next step. MS-APCI: 705.2 [M+H] +

[0282] Step 5-6:

[0283]

[0284] 25 (50 mg), 26 (12.3 mg), and TEA (21.2 mg) were added to DMF (2 mL), and the reaction was carried out at room temperature for 1 hour. Then, NaBH3CN (6.9 mg) was added, and the reaction was continued overnight at room temperature. The reaction mixture was washed with water, extracted with EA, dried, and separated by preparative separation to obtain 10 mg of product 27 as a yellow solid. MS-APCI: 804.3 [M+H] +

[0285] Steps 5-7:

[0286]

[0287] 27 (10 mg) was dissolved in MeOH (2 mL), K2CO3 (3 mg) was added, and the reaction was carried out at room temperature for 1 hour. TLC showed that the reaction of 27 was complete. The reaction mixture was concentrated under reduced pressure, dissolved in THF / MeOH / H2O (1:1:1), LiOH.H2O (1 mg) was added, and the reaction was carried out at room temperature for 10 minutes. TLC was used to detect the completion of the reaction. The reaction mixture was separated by preparative separation to obtain 5.5 mg of a yellow solid product. MS-APCI: 686.3 [M+H] +

[0288] 1H NMR (400 MHz, DMSO-d6) δ 10.57-10.47 (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 = 7.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 7.04 (d, J = 7.4 Hz, 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).

[0289] Synthesis of Compound LW1005-006 in Example 6

[0290]

[0291] Step 6-1:

[0292]

[0293] 25 (50 mg), 28 (7.8 mg), and TEA (21.5 mg) were added to DMF (2 mL), and the reaction was carried out at room temperature for 1 hour. Then, NaBH3CN (6.7 mg) was added, and the reaction was carried out overnight at room temperature. The reaction mixture was washed with water, extracted with EA, dried, and separated by preparative separation of the crude product to obtain 10 mg of product 29, a yellow solid. MS-APCI: 762.3 [M+H] +

[0294] Step 6-2:

[0295]

[0296] 29 (10 mg) was dissolved in MeOH (2 mL), K2CO3 (5.4 mg) was added, and the reaction was carried out at room temperature for 1 hour. TLC showed that the raw material had completely reacted. The reaction mixture was separated by preparative separation to obtain 3 mg of LW1005-006, a yellow solid. MS-APCI: 658.3 [M+H] +

[0297] 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 10.63 - 9.66 (m, 1H), 9.08 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 6.2 Hz, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.42 (dd, J = 9.9, 7.4 Hz, 2H), 7.24 (d, J = 6.1 Hz, 1H), 7.06 (dd, J = 7.5, 3.7 Hz, 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).

[0298] Synthesis of Compound LW1005-007 in Example 7

[0299]

[0300] Step 7-1:

[0301]

[0302] 25 (90 mg), 30 (180 mg), and TEA (254.5 mg) were added to DMF (2 mL), and the reaction was carried out at room temperature for 1 hour. Then, NaBH3CN (79 mg) was added, and the reaction was continued overnight at room temperature. The reaction mixture was washed with water, extracted with EA, dried, and purified by TLC on a large plate to obtain 40 mg of product 31 as a yellow solid. MS-APCI: 832.3 [M+H] +

[0303] Step 7-2:

[0304]

[0305] 31 (40 mg) was dissolved in MeOH (2 mL), K2CO3 (13.3 mg) was added, and the reaction was carried out at room temperature for 1 hour and then heated at 40 °C for 10 minutes. TLC showed that the reaction was complete. The reaction mixture was separated by preparative TLC to obtain 8.2 mg of LW1005-007 as a yellow solid. MS-APCI: 714.3 [M+H] +

[0306] 1H NMR (400 MHz, DMSO-d6) δ 10.56–10.36 (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 = 7.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 6.9 Hz, 2H), 7.24 (d, J = 5.9 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.97 (s, 1H), 5.58–5.43 (s, 1H), 4.73–4.62 (m, 2H), 4.50 - 4.38 (m, 2H), 3.75 - 3.64 (m, 4H), 3.34 - 3.27 (m, 4H), 3.15 - 2.94 (m, 5H), 2.44 (s, 3H), 2.15 - 2.10 (m, 2H), 2.07 (s, 3H), 2.04 - 1.94 (m, 1H), 1.78 - 1.67 (m, 2H).

[0307] Synthesis of Compound LW1005-008 in Example 8

[0308]

[0309] Step 8-1:

[0310]

[0311] Mix the raw material 8 (19 g) and NIS (14.7 g), add MeCN (200 mL), dropwise add 1 mL of CF3COOH, and stir in an oil bath at 55 °C for 2.5 hours. Filter to obtain 10.5 g of white solid. MS-APCI: 475 [M+H] +

[0312] Step 8-2:

[0313]

[0314] Mix the raw material 32 (10 g), Zn(CN)2 (2.5 g), Pd2(dba)3 (900 mg), and DPPf (1.2 g) in a 500 mL single-necked flask, displace with N2 three 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, filter to obtain 6.3 g of white solid. MS-APCI: 374 [M+H] +

[0315] Step 8-3:

[0316]

[0317] Disperse the raw material 33 (5.0 g) in DCM (250 ml), add Dess-Martin (11.3 g) during stirring, react at room temperature for 30 min, monitor the reaction by TLC until it is complete, then successively add saturated sodium bicarbonate solution (250 ml x 2) and stir, separate the aqueous phase, add 10% sodium thiosulfate (250 ml x 2) to the organic phase and stir, let stand, extract, dry, concentrate to obtain 4.0 g of orange solid, and directly use it for the next step. MS-APCI: 372 [M+H] +

[0318] Step 8-4:

[0319]

[0320] Dissolve the raw materials 34 (4.0 g) and 35 (3.53 g) in DCM (200 mL), add Et3N (2.4 g), after reacting for one hour, add NaBH(OAc)3 (2.25 g), react at room temperature for 1 hour, monitor the reaction by TLC until it is complete, add 200 ml of water, stir, separate the layers, extract, dry, and purify by column chromatography to obtain 3.5 g of light yellow solid. MS-APCI: 541 [M+H] +

[0321] Step 8-5:

[0322]

[0323] 36 (1080 mg), 5 (756 mg, WO2018119286), Pd(dppf)Cl2 / DCM (167.4 mg), and Na2CO3 (530 mg) were placed in a reaction flask, degassed and protected with N2. 15 mL of dioxane / 3 mL of water were injected into the reaction flask, and the reaction was carried out at 90 °C for 2 hours. TLC showed that the reaction of 36 was complete. The reaction solution was washed with water, extracted with EA, dried, concentrated by evaporation, and purified by column chromatography (DCM:MeOH = 30:1) to obtain 1.0 g of the product, a yellow solid. MS-APCI: 795.3 [M+H] +

[0324] Step 8-^{6}:

[0325]

[0326] Compound 37 (3.9 g) was dissolved in THF (50 mL), and TFA (10 mL) was added. The mixture was stirred overnight at room temperature. TLC showed that the reaction was complete. The THF in the reaction solution was removed by evaporation, and the TFA was removed by pumping to obtain a crude yellow solid. Further purification by column chromatography (DCM:MeOH = 10:1) gave 3.5 g of the product. MS-APCI: 739.3 [M+H] +

[0327] 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.06 (s, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 8.11–8.09 (m, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.49–7.34 (m, 2H), 7.24 (d, J = 6.1 Hz, 1H), 7.02 (s, 1H), 4.77-4.64 (m, 2H), 4.53-4.38 (m, 3H), 3.72-3.64 (m, 2H), 3.35-3.26 (m, 2H), 3.20–2.91 (m, 4H), 2.44 (s, 3H), 2.16-2.10 (m, 2H), 2.07 (s, 3H), 2.01-1.95 (m, 1H), 1.95-1.83 (m, 2H), 1.80-1.66 (m, 2H).

[0328] Synthesis of Compound LW1005-009 in Example 9

[0329]

[0330] Step 9-^{1}:

[0331]

[0332] Dissolve raw material 5 (5.0 g, WO2018119286) in DCM (100 mL), add Et3N (3.2 g), stir evenly, add BzCl (3.0 g), and react at room temperature for 3 hours. After the reaction is completed, wash with saturated brine, extract with DCM, dry, concentrate, and purify by column chromatography to obtain 3.7 g of yellow solid. MS-APCI: 565.3 [M+H] +

[0333] Step 9-2:

[0334]

[0335] Mix raw material 38 (1.97 g), raw material 33 (3.3 g), Pd(dppf)Cl2 / DCM (431 mg), and Na2CO3 (1.12 g), displace with nitrogen, add Dioxane / H2O (4:1) (50 mL), and react at 95 °C for 3 hours. After the reaction is completed, wash with water, extract with EA, dry, concentrate, and purify by column chromatography to obtain 2.7 g of yellow solid. MS-APCI: 732.3 [M+H] +

[0336] Step 9-3:

[0337]

[0338] Dissolve 39 (200 mg) in DCM (20 mL), add DMP (406 mg) at room temperature, and react at room temperature for 10 minutes. Check the completion of the reaction by TLC plate. First, wash the reaction solution with saturated NaHCO3, and then wash it with 10% Na2S2O3. Extract the aqueous phase with DCM. Combine the DCM layers, dry, and evaporate to dryness, and directly use it for the next reaction. MS-APCI: 730.3 [M+H] +

[0339] Step 9-4:

[0340]

[0341] Add 41 (52 mg) and TEA (103 mg) to a DCM (15 mL) solution of 40 (150 mg), react at room temperature for 1 hour, add NaBH(OAc)3 (216.2 mg), and react at room temperature overnight. Check the completion of the reaction by TLC plate. Wash the reaction solution with saturated NaHCO3, extract with DCM, dry, and column chromatograph to obtain 100 mg of the product, a yellow solid. MS-APCI: 815.3 [M+H] +

[0342] Step 9-5:

[0343]

[0344] Compound 6 (100 mg) was dissolved in 10 mL of THF, and 2 d of NaOMe (5 N in MeOH) was added dropwise at room temperature. The reaction was carried out for 5 minutes. A solid precipitated. TLC showed that the raw material had completely reacted. The reaction solution was adjusted to neutral with 4 N HCl / dioxane. It was rotary evaporated and prepared for separation to obtain 19 mg of the product, a yellow solid. MS-APCI: 711.3 [M+H] +

[0345] 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.87 (s, 1H), 8.71 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 6.7, 4.1 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 5.7 Hz, 1H), 6.93 (d, J = 7.6 Hz, 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 = 13.8 Hz, 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).

[0346] Synthesis of Compound LW1005-010 in Example 10

[0347]

[0348] Step 10-1:

[0349]

[0350] Compound 43 (306 mg, FCH group), 44 (633.6 mg; Organic Process Research & Development, 2018, 22, 97 - 102.), and Na2S2O5 (570 mg) were added to DMF (3 mL), and the reaction was carried out at 110 °C overnight under N2 protection. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was washed with water, extracted with EA, and purified by column chromatography to obtain 360 mg of a pale yellow solid. MS - APCI: 332 [M + H] + . 1 1H NMR (400 MHz, Chloroform - d) δ 8.04 (d, J = 5.8 Hz, 1H), 7.74 (dd, J = 8.0, 1.3 Hz, 1H), 7.38 (dd, J = 7.7, 1.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 5.8 Hz, 1H), 4.20 (s, 3H), 3.61 (s, 3H), 2.29 (s, 3H).

[0351] Step 10 - 2:

[0352]

[0353] 45 (260 mg) was added to HBr / AcOH (4 mL, 1:1), and the reaction was carried out at 85 °C for 1.5 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated in vacuo and directly used for the next step. MS - APCI: 318 [M + H] + .

[0354] Step 10 - 3:

[0355]

[0356] 46 (344 mg), 6 (471 mg), and Cs2CO3 (710 mg) were added to DMF (3 mL), and the reaction was carried out at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered, and the filtrate was washed with water, extracted with EA, dried, and concentrated in vacuo. The resulting pale yellow solid was triturated with EA / HEP (1:1), filtered, and 400 mg of a white solid was obtained. MS - APCI: 600.2 [M + H] + .

[0357] Step 10 - 4:

[0358]

[0359] At room temperature, 47 (340 mg), B2pin2 (173 mg), Pd(dppf)Cl2 / DCM (46.5 mg) and KOAc (111.7 mg) were placed in a reaction flask, degassed under vacuum, dioxane (5 mL) was injected with a syringe, and after degassing again, the reaction was heated at 100 °C for 4 hours. TLC showed a small amount of 6 remaining. After adding water to the reaction solution, it was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried, concentrated by evaporation, and purified by column chromatography to obtain 250 mg of a pale yellow solid. MS-APCI: 648.2 [M+H] +

[0360] Step 10-5:

[0361]

[0362] At room temperature, 48 (150 mg), 10 (95.7 mg, WO2018119286), Pd(dppf)Cl2 / DCM (18.8 mg) and Na2CO3 (48.8 mg) were placed in a reaction flask, degassed under vacuum, dioxane / H2O (6 mL, 5:1) was injected with a syringe, and after degassing again, the reaction was heated at 100 °C for 3 hours. TLC showed that the raw materials reacted completely. The reaction solution was washed with water, extracted with EA, and purified by column chromatography to obtain 150 mg of a yellow solid. MS-APCI: 854.2 [M+H] +

[0363] Step 10-6:

[0364]

[0365] At room temperature, 9 (150 mg) was dissolved in THF (2 ml), TBAF / THF (0.2 mL, 1 M) was added, and the reaction was carried out at room temperature for 2 hours. Solids precipitated in the reaction solution. It was filtered, the solid cake was dissolved in MeOH, and passed through a cation exchange column to obtain 20.7 mg of a yellow solid. MS-APCI: 616.2 [M+H] +

[0366] 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 8.2, 1.3 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.48–7.40 (m, 2H), 7.39–7.30 (m, 2H), 7.19 (d, J = 5.8 Hz, 1H), 6.95 (dd, J = 7.5, 1.3 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 4.85 (t, J = 5.4 Hz, 1H), 4.73 (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).

[0367] Synthesis of Compound LW1005-011 in Example 11

[0368]

[0369] Step 11-1:

[0370]

[0371] 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). The reaction mixture was heated and stirred at 140 °C in an oil bath for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, an aqueous sodium hydroxide solution (2 M) was added to the reaction mixture to adjust the pH to 6 - 7. The mixture was extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography. 370 mg of white solid was obtained with a yield of 76.3%. MS-APCI: 305 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 1.0 Hz, 1H), 8.60 (d, J = 5.4 Hz, 1H), 8.28 (dd, J = 5.4, 1.0 Hz, 1H), 7.87 (dd, J = 8.0, 1.3 Hz, 1H), 7.77 (dd, J = 7.8, 1. Hz, 1H), 7.38 (m, 1H), 2.63 (s, 3H).

[0372] Step 11-2:

[0373]

[0374] Substrate 53 (2.88 g, 9.44 mmol) and m-CPBA (3.83 g, 0.0188 mol) were dissolved in DCM (40 mL), and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, the pH was adjusted to 6 - 7 with an aqueous sodium hydroxide solution (2 M), and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 2.23 g of a brownish-yellow solid with a yield of 73.5%. MS-APCI: 321 [M+H] +

[0375] Step 11-3:

[0376]

[0377] Compound 4 (2.2 g, 6.94 mmol) was added to a single-necked flask containing acetic anhydride (30 mL, 0.38 mol). Then the reaction mixture was heated and stirred at 140 °C for 2 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to 80 °C, and then methanol (12 mL) and water (3.6 mL) were added to the reaction mixture, and the mixture was stirred at 80 °C for 30 minutes. The reaction mixture was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered, washed with ethyl acetate (10 mL x 3), and dried under reduced pressure to obtain 1.6 g of a tea-white solid with a yield of 71.8%. MS-APCI: 321 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 6.6 Hz, 1H), 7.42 (t, J = 6.4 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H), 2.61 (s, 3H).

[0378] Step 11-4:

[0379]

[0380] 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-necked flask containing DMF (30 mL). Then the reaction mixture was stirred at room temperature overnight, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and purified by column chromatography to give 2.3 g of a tea-white solid with a yield of 94%. MS-APCI [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.48–7.32 (m, 7H), 7.28 (t, J = 7.4 Hz, 4H), 7.06 (d, J = 7.1 Hz, 1H), 4.25 (t, J = 4.8 Hz, 2H), 3.94 (t, J = 4.9 Hz, 2H), 2.62 (s, 3H).

[0381] Step 11-5:

[0382]

[0383] Compound 56 (500 mg, 0.83 mmol) and TBAF (650 mg, 2.5 mmol) were added to a single-necked flask containing THF (10 mL). Then the reaction mixture was stirred at room temperature for 15 minutes, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and purified by column chromatography to give 340 mg of a tea-white solid with a yield of more than 100% (containing TBAF). MS-APCI [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 7.5, 5.4 Hz, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.10 (t, J = 5.5 Hz, 2H), 3.70 (q, J = 5.5 Hz, 2H), 2.60 (s, 3H).

[0384] Step 11-6:

[0385]

[0386] Compound 57 (240 mg, 0.657 mmol), B2Pin2 (333 mg, 1.31 mmol), potassium acetate (129 mg, 1.31 mmol) and Pd(dppf)2Cl2 . DCM (54 mg, 0.0657 mmol) were added to a single-necked flask containing 1,4-dioxane (10 mL) under nitrogen protection. Then the reaction mixture was stirred at 100 °C for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled, filtered, silica gel was added for mixing, and column chromatography was carried out to obtain 150 mg of a tea-white solid with a yield of 55.3%. LC-MS: 413 MS-APCI [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 7.4, 1.5 Hz, 1H), 7.74 (dd, J = 7.7, 1.5 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 4.90 (s, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.70 (d, J = 5.0 Hz, 2H), 2.67 (s, 3H), 1.34 (s, 12H).

[0387] Step 11-7:

[0388]

[0389] 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) was added to a single-necked flask containing 1,4-dioxane (10 mL) and water (2 mL) under nitrogen protection. Then the reaction solution was 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 purified by column chromatography. Then, a pale new green solid (6 mg) was obtained by preparative reverse-phase column chromatography. MS-APCI [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.1 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 6.0 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 4.67 (br, 2H), 4.48 (br, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.70 (t, J = 5.6 Hz, 2H), 2.41–2.25 (m, 4H), 2.08 (s, 3H), 2.03–1.95 (m, 1H), 1.92–1.82 (m, 1H).

[0390] Synthesis of Compound LW1005-012 in Example 12

[0391] [[ID=,10]]

[0392] Step 12-1:

[0393]

[0394] Compound 54 (1 g, 1.66 mmol) and NCS (221 mg, 1.66 mmol) were added to a single-necked flask containing DMF (15 mL). Then the reaction solution was stirred at 60 °C for 45 minutes, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was evaporated to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain an oil (600 mg) with a yield of 56.6%. LC-MS: 637 [M+H] + ; 1HNMR(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).

[0395] Step 12-2:

[0396]

[0397] Compound 57 (680 mg, 1.066 mmol) and TBAF (1.28 mL, 1 M THF solution) were added to a single-necked flask containing THF (10 mL). Then the reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, extracted with ethyl acetate / water, dried over anhydrous sodium sulfate, and purified by column chromatography to give 230 mg of a tea-white solid in 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).

[0398] Step 11-3:

[0399]

[0400] Compound 58 (230 mg, 0.575 mmol), B2Pin2 (154 mg, 0.606 mmol), potassium acetate (141 mg, 1.43 mmol) and Pd(dppf)2Cl2 . DCM (47 mg, 0.0575 mmol) were added to a single-necked flask containing 1,4-dioxane (10 mL) under nitrogen protection. Then the reaction mixture was stirred at 110 °C for 2 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography to give 210 mg of a brown-yellow oil in a yield of 81.7%. LC-MS: 447 [M+H] +;

[0401] Step 12-4:

[0402]

[0403] 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-necked flask containing 1,4-dioxane (8 mL) and water (2 mL) under nitrogen protection. Then the reaction mixture was stirred at 100 °C for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography. Then LW1005-066 was prepared using a reverse-phase column. LC-MS: 653 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.11 (s, 1H), 8.54 (s, 1H), 8.09 (s, 1H), 8.01 (d, J = 9.8 Hz, 2H), 7.81 (dd, J = 7.9, 1.3 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.6, 1.3 Hz, 1H), 7.25 (d, J = 6.2 Hz, 1H), 7.17–7.04 (m, 1H), 4.78–4.59 (m, 3H), 4.57–4.39 (m, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.70 (t, J = 5.4 Hz, 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).

[0404] Synthesis of Compound LW1005-013 in Example 13

[0405]

[0406] Step 13-1:

[0407]

[0408] Compound 7 (1.5 g, 2.55 mmol) and NCS (400 mg, 3.06 mmol) were added to a single-necked flask containing DMF (15 mL). Then the reaction mixture was stirred at 60 °C for 45 minutes, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, washed with ethyl acetate / water (1:1, 50 mL) by stirring, filtered, and dried to obtain 1.2 g of a white solid with a yield of 75.7%. LC-MS: 621 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.49–7.26 (m, 11H), 4.26 (d, J = 5.3 Hz, 2H), 3.95 (t, J = 4.5 Hz, 2H), 2.80 (s, 3H), 0.98 (s, 9H).

[0409] Step 13-2:

[0410]

[0411] 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-necked flask containing 1,4-dioxane (20 mL). Under nitrogen protection, the reaction mixture was stirred at 110 °C for 4 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography to obtain 518 mg of a white solid with a yield of 96.3%. LC-MS: 669.2 [M+H]+.

[0412] Step 13-3:

[0413]

[0414] 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-necked flask containing 1,4-dioxane (15 mL) and water (5 mL). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 3 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography to obtain 267 mg of a pale yellow solid with a yield of 40%. LC-MS: 875 [M+H] + .

[0415] Step 13-4:

[0416]

[0417] Compound 62 (267 mg, 0.305 mmol) and TBAF (0.311 mL, 1 M THF solution, 0.311 mmol) were added to a single-necked flask containing THF (3 mL). Then the reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, triturated, and purified by column chromatography. The resulting solid was freeze-dried with distilled water and methanol to obtain a pale yellow solid. LC-MS: 637 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.19 (s, 1H), 8.10–8.04 (m, 3H), 7.53 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 5.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 4.92 (t, J = 5.5 Hz, 1H), 4.72 (s, 1H), 4.30–4.17 (m, 1H), 4.12 (t, J = 5.6 Hz, 2H), 3.82 (d, J = 10.8 Hz, 1H), 3.68 (q, J = 5.5 Hz, 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).

[0418] Synthesis of Compound LW1005-014 in Example 14

[0419]

[0420] Step 14-1:

[0421]

[0422] Compound 1 (1 g, 4.69 mmol) and triethylamine (0.66 mL, 4.69 mmol) were added to a single-necked flask containing acetonitrile (15 mL), and the mixture was 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, the temperature was raised to room temperature and the mixture was stirred for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered, rinsed with ethyl acetate, the organic layer was dried by evaporation and mixed with the sample, and column chromatography was performed to obtain 1.03 g of a pale yellow oil, with a yield of 91.8%. LC-MS: 140 [M - Boc + 2H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 3.85 (t, J = 6.2 Hz, 2H), 2.66 (t, J = 6.2 Hz, 2H), 1.48 (s, 9H).

[0423] Step 14-2:

[0424]

[0425] Compound 64 (640 mg, 2.99 mmol) and Rh2(OAc)4 (33 mg, 0.075 mmol) were added to a single-necked flask containing 1,2-dichloroethane (5 mL). Then, the reaction solution was refluxed and stirred at 81 °C. A solution of 2 (1 g, 4.18 mmol) in 1,2-dichloroethane (10 mL) was added dropwise to the above reaction solution. After the addition, the mixture was refluxed and stirred overnight. After the reaction was complete, the reaction solution was dried by evaporation, mixed with the sample, and column chromatography was performed to obtain 650 mg of a white solid, with a yield of 51.1%. LC-MS: 425 [M + H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.91 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.49–7.44 (m, 1H), 7.21 (t, J = 7.9 Hz, 1H), 3.76 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 6.3 Hz, 2H), 2.44 (s, 3H), 1.46 (s, 9H).

[0426] Step 14-3:

[0427]

[0428] Triphenylphosphine (123 mg, 0.47 mmol), iodine (120 mg, 0.47 mmol) and triethylamine (0.13 mL, 0.94 mmol) were successively added to a single-necked flask containing DCM (10 mL), and the mixture was stirred at room temperature for 10 minutes. Then, a solution of 66 (100 mg, 0.235 mmol) in DCM (5 mL) was added dropwise to the above reaction solution. After the addition was complete, the mixture was continuously stirred at room temperature for 2 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was evaporated to dryness, mixed with silica gel, and purified by column chromatography to obtain 37 mg of a white solid with a yield of 38.8%. LC-MS: 307 [M - Boc + 2H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 6.4 Hz, 2H), 1.49 (s, 9H).

[0429] Step 14-4:

[0430]

[0431] Compound 67 (290 mg, 0.172 mmol) and TFA (0.16 mL, 2.136 mmol) were successively added to DCM (10 mL), and the mixture was 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, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 170 mg of a white solid with a yield of 78%. LC-MS: 307 [M + H]+; 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 3.55 (td, J = 7.2, 2.6 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H).

[0432] Step 14-5:

[0433]

[0434] Compound 68 (100 mg, 0.326 mmol), O-TBS-bromoethanol (0.14 mL, 0.651 mmol) and NaH (26 mg, 0.651 mmol) were successively added to DMF (5 mL), protected by nitrogen, and stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to dryness, then extracted with ethyl acetate / water, and the organic layer was dried over anhydrous sodium sulfate. Column chromatography gave 70 mg of a white solid with a yield of 46.1%. LC-MS: 465 [M+H]+;

[0435] Step 14-6:

[0436]

[0437] 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-necked flask containing 1,4-dioxane (4 mL) and water (1 mL), protected by nitrogen, and then 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 chromatographed to give 70 mg of a pale yellow solid with a yield of 64.9%. LC-MS: 719 [M+H] + .

[0438] Step 14-7:

[0439]

[0440] Compound 70 (110 mg, 0.162 mmol) and TBAF (0.1 mL, 0.107 mmol) were added to a single-necked flask containing 1,4-dioane (2 mL), protected by nitrogen, and then the reaction solution was stirred at room temperature for 24 hours. The reaction was detected by TLC. After the reaction was complete, it was purified by preparative reverse-phase column, and then freeze-dried to give 1.1 mg of a pale yellow solid. LC-MS: 605 [M+H]+; 11H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 8.07 (d, J = 5.8 Hz, 1H), 7.93 (dd, J = 7.8, 1.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.39–7.28 (m, 2H), 7.19 (d, J = 5.8 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.73 (d, J = 5.6 Hz, 2H), 4.24 (s, 1H), 3.89–3.73 (m, 4H), 3.57 (q, J = 5.8 Hz, 2H), 3.49 (t, J = 6.5 Hz, 2H), 3.18 (t, J = 7.2 Hz, 2H), 2.80–2.72 (m, 1H), 2.68 (dd, J = 3.9, 2.0 Hz, 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).

[0441] Synthesis of Compound LW1005-015 in Example 15

[0442]

[0443] Step 15-1:

[0444]

[0445] Dissolve raw material 5 (5.0 g, WO2018119286) in DCM (100 mL), add imidazole (3.2 g), stir evenly, add TBDPSCl (5.9 g), and react at room temperature for 3 hours. After the reaction is completed, wash with saturated brine, extract with DCM, dry, concentrate, and purify by column chromatography to obtain 3.7 g of yellow solid. MS-APCI: 699 [M+H]+

[0446] Step 15-2:

[0447]

[0448] Mix raw material 71 (1.97 g), 33 (3.3 g), Pd(dppf)Cl2 / DCM (431 mg), and Na2CO3 (1.12 g), displace with nitrogen, add Dioxane / H2O (4:1) (50 mL), and react at 95 °C for 3 hours. After the reaction is completed, wash with water, extract with EA, dry, concentrate, and purify by column chromatography to obtain 2.7 g of yellow solid. MS-APCI: 866 [M+H]+

[0449] Step 15-3:

[0450]

[0451] Add compound 72 (140 mg, 0.162 mmol) to a single-necked flask containing DCM (15 mL). Add Dess-Martin Reagent (240 mg, 0.567 mmol) to a plastic test tube containing DMF (3 mL), and shake once. Then, add the Dess-Martin Reagent / DMF solution dropwise to the compound 1 / DCM solution, and complete the addition within 1-2 minutes. Stir the reaction mixture at room temperature for 10 minutes. After the reaction is complete, add saturated sodium bicarbonate (5 mL) and 10% sodium thiosulfate solution (5 mL) to the reaction mixture. Extract with DCM, dry over anhydrous sodium sulfate, and rotary evaporate to remove some of the solvent until approximately 15 mL of solvent remains. Set aside for use without further purification directly in the next reaction. MS-APCI: 864 [M+H]+

[0452] Step 15-4:

[0453]

[0454] Dissolve 3-azetidinecarboxylic acid (23 mg, 0.23 mmol) in AcOH (0.25 mL), then add this solution dropwise to the DCM solution of the above compound 73, and then add triethylamine (0.3 mL). Stir the reaction mixture at room temperature for 1 hour. Then, add sodium triacetoxyborohydride (49 mg, 0.23 mmol) to the reaction mixture, and stir the reaction mixture at room temperature overnight. Quench with water, extract with DCM / water, dry the organic layer over anhydrous sodium sulfate, and obtain 78 mg of a pale yellow solid by column chromatography. The two-step yield is 50.7%. LC-MS: 949 [M+H] + 。

[0455] Step 15-5:

[0456]

[0457] Add compound 74 (78 mg, 0.082 mmol) and TBAF (1 M in THF, 0.1 mL, 0.1 mmol) to a single-necked flask containing THF (2 mL), and then stir the reaction mixture at room temperature overnight. After the reaction is complete, evaporate the reaction mixture to dryness, add water (20 mL) and stir. Filter to collect the residue, and obtain 17.4 mg of a pale yellow solid by preparative reverse-phase column chromatography. LC-MS: 711 [M+H] + ; 1 1H 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,1H),8.05(s,1H),7.57(t,J=7.8Hz,1H),7.48–7.38(m,2H),7.25(s,1H),7.05(s,1H),4.79–4.61(m,2H),4.53–4.41(m,1H),4.40–4.19(m,5H),3.71–3.51(m,5H),3.37–3.26(m,2H),2.44(s,3H),2.33(s,1H),2.06(s,3H),2.01(br,1H),1.87(s,1H).

[0458] Synthesis of Compound LW1005-016 in Example 16

[0459]

[0460] Step 16-1:

[0461]

[0462] Add 73 (300 mg, 1.0 eq) to a reaction flask and dissolve it in 20 mL of DCM. Add a DMSO (0.5 mL) solution of 3-hydroxyacridine hydrochloride (109.9 mg, 2 eq) to the above solution, and then add dropwise Et3N (35.1 mg, 1.0 eq). Stir at room temperature for 1 h. Add sodium triacetoxyborohydride (147.2 mg, 2.0 eq) and stir at room temperature overnight. Monitor the reaction by TLC until it is completed. Wash the reaction solution with saturated sodium bicarbonate, dry, concentrate, and perform column chromatography to obtain 200 mg of a yellow solid. MS-APCI: 921 [M+H] +

[0463] Step 16-2:

[0464]

[0465] Add 75 (150 mg, 1.0 eq) to a reaction flask, dissolve it in THF, and add dropwise a TBAF / THF solution (1 M in THF, 2 mL). Stir at room temperature for 1 h. Monitor the reaction by TLC until it is completed. Concentrate, perform column chromatography, prepare, and pass through an ion exchange column to obtain 25.60 mg of a bright yellow solid. MS-APCI: 683 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.73 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.20 (s, 1H), 8.07 (d, J = 6.7 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 5.8 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 4.28–4.17 (m, 1H), 4.09–3.98 (m, 2H), 3.90–3.74 (m, 1H), 3.61–3.50 (m, 2H), 2.78–2.71 (m, 7H), 2.42 (s, 3H), 2.41–2.29 (m, 2H), 2.09 (s, 3H), 2.08–1.95 (m, 1H), 1.65–1.51 (m, 1H).

[0466] Synthesis of Compound LW1005-017 in Example 17

[0467]

[0468] Step 17-1:

[0469]

[0470] Dissolve (R)-pyrrolidine-3-carboxylic acid (44 mg, 0.384 mmol) in AcOH (0.25 mL), then add this solution dropwise to a DCM solution of Compound 73 (150 mg), then add triethylamine (0.3 mL), and stir the reaction mixture at room temperature for 1 hour. Then add sodium triacetoxyborohydride (163 mg, 0.768 mmol) to the reaction mixture and stir at room temperature overnight. Quench with water, extract with DCM / water, dry the organic layer over anhydrous sodium sulfate, and obtain 75 mg of a pale yellow solid by column chromatography with a two-step yield of 40.6%. LC-MS: 963 [M+H] + .

[0471] Step 17-2:

[0472]

[0473] Compound 76 (75 mg, 0.078 mmol), TBAF (1 M in THF, 0.1 mL, 0.1 mmol) were added to a single-necked flask containing THF (2 mL). Then the reaction mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was evaporated to dryness, water (20 mL) was added, stirred, filtered, and purified by reverse-phase column chromatography to obtain 12.57 mg of a pale yellow solid. LC-MS: 725 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 8.22 (br, 1H), 8.13–8.04 (m, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.47–7.37 (m, 2H), 7.24 (s, 1H), 7.03 (s, 1H), 4.79–4.61 (m, 3H), 4.53–4.39 (m, 3H), 4.10–3.61 (m, 7H), 3.44–3.38 (m, 2H), 3.34–3.29 (m, 2H), 2.44 (s, 3H), 2.34 (s, 1H), 2.07 (s, 3H), 2.00 (br, 1H), 1.86 (s, 1H).

[0474] Synthesis of Compound LW1005-018 in Example 18

[0475]

[0476] Step 18-1:

[0477]

[0478] 8 (1.72 g, 1.0 eq) and Et3N (1.00 g, 2.0 eq) were added to a reaction flask containing 30 mL of DCM and 1 mL of DMF. The temperature was lowered to 0 °C, and a solution of BzCl / DCM was added dropwise. After addition, the temperature was raised to room temperature and stirred overnight. Monitored by TLC, when the reaction was completed, the reaction mixture was washed with saturated sodium bicarbonate solution and saturated brine, dried, and concentrated. The obtained solid was slurried with a solution of EA:PE = 1:10 (200 mL) for 2 h. Filtered by suction, the filter cake was washed with PE and dried to obtain 1.39 g of a white solid. MS-APCI: 453 [M+H] + ;

[0479] 11H NMR (400 MHz, DMSO-d6) δ 8.04–7.91 (m, 4H), 7.87 (dt, J = 8.1, 1.7 Hz, 2H), 7.71–7.62 (m, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.36 (td, J = 7.9, 3.6 Hz, 2H), 6.95 (d, J = 7.3 Hz, 1H), 4.60 (t, J = 5.7, 4.1 Hz, 2H), 4.48 (t, J = 5.0 Hz, 2H), 2.78 (s, 3H).

[0480] Step 18-2:

[0481]

[0482] Add 77 (200 mg) to the reaction flask, protect with N2, add 5 mL of POCl3, heat to 85 °C, stir for 2 h, rotary evaporate the excess POCl3, and cool to -20 °C. Dilute 20 mL of ammonia water to 50 mL with ice and add dropwise to the reaction flask. White smoke is released. Raise the temperature to room temperature and stir for 30 min. Extract twice with ethyl acetate. Wash the organic phase with brine, dry, concentrate, and perform column chromatography. Obtain 67.2 mg of a pale yellow solid. MS-APCI: 452 [M+H][[ID=***]] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.20 (s, 1H), 8.06–7.89 (m, ));

[0483] Step 18-3:

[0484]

[0485] Add 78 (200 mg, 1.0 eq), 5 (240 mg, 1.2 eq), Na2CO3 (120 mg, 2.5 eq) and Pd(dppf)2Cl2 (50 mg, 0.1 eq) to the reaction flask, protect with N2, add 1,4-dioxane / H2O (10 ml / 2 ml) to dissolve, heat to 100 °C, and stir for 3 h. Monitor the reaction by LC-MS until it is completed, cool down, wash the reaction solution with water, dry, concentrate, and perform column chromatography. Obtain 14.06 mg of a yellow solid. MS-APCI: 602 [M+H] + ; 1 It should be noted that there seems to be an incomplete part in the original text for item . The translated content is based on the available text.1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.34 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 8.10–8.03 (m, 2H), 7.82 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.46–7.32 (m, 2H), 7.20 (d, J = 5.8 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 4.31 (t, 2H), 4.23 (s, 1H), 3.82 (d, J = 10.9 Hz, 2H), 3.76 (t, 2H), 2.79–2.61 (m, 3H), 2.45 (s, 4H), 2.38 (dd, J = 9.8, 3.6 Hz, 2H), 2.09 (s, 3H), 2.02 (dt, J = 14.3, 7.2 Hz, 2H), 1.62–1.54 (m, 1H).

[0486] Synthesis of Compound LW1005 - 019 in Example 19

[0487]

[0488] Step 19 - 1:

[0489]

[0490] Add 77 (1.0 g) to the reaction flask, protect with N2, add POCl3 (15 mL), heat to 100 °C, stir for 2 h, rotary evaporate the excess POCl3, and cool to -20 °C. NH2OH (50% aqueous solution) (1.46 g, 10 eq) was added dropwise to the reaction flask, white smoke was released, and the mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC until completion, and extracted twice with DCM (poor solubility). The organic phase was washed with brine, dried, and concentrated to obtain 2 g of a yellow solid. MS - APCI: 468 [M + H] +

[0491] Step 19 - 2:

[0492]

[0493] Add 79 (2.0 g, 1.0 eq) and imidazole (1.45 g, 10.0 eq) to the reaction flask, disperse with DMF, add TBSCl, and stir at RT for 1 h. The reaction was monitored by TLC until completion, extracted with EA / water, the organic phase was washed with brine, dried, concentrated, and purified by column chromatography to obtain 2.65 g of a golden yellow solid. MS - APCI: 582 [M + H]+

[0494] Step 19-3:

[0495]

[0496] Disperse 80 (300 mg, 1.0 eq) in methanol, add K2CO3 (200 mg, 3.0 eq), and stir overnight at room temperature. Monitor the reaction by TLC until completion. Extract the reaction mixture with ethyl acetate / water, back-extract the aqueous phase twice, wash the organic phase with brine, dry over anhydrous sodium sulfate, concentrate in vacuo, and purify by column chromatography to obtain 200 mg of a pale yellow solid. MS-APCI: 478 [M+H] +

[0497] Step 19-4:

[0498]

[0499] Add 81 (177.5 mg, 1.0 eq), 5 (256.2 mg, 1.5 eq), K3PO4 (196.9 mg, 2.5 eq), and Pd(PPh3)4 (42.8 mg, 0.1 eq) to a reaction flask in sequence under N2 protection. Dissolve them in 1,4-dioxane / H2O (10 ml / 2 ml), heat to 100 °C, and stir for 3 h. Monitor the reaction by TLC until completion. Cool the reaction mixture, wash it with water, dry over anhydrous sodium sulfate, concentrate in vacuo, and purify by column chromatography to obtain 187.6 mg of a golden yellow solid. MS-APCI: 732 [M+H] +

[0500] Step 19-5:

[0501]

[0502] Add 82 (72.5 mg) to a reaction flask, dissolve it in 2 mL of methanol, and add dropwise a methanol solution of hydrogen chloride (4.567 mol / L, 0.4 ml). Stir at room temperature for 30 min. Monitor the reaction by TLC until completion. Prepare the reaction mixture directly to obtain 23.15 mg of a bright yellow solid. MS-APCI: 618 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.03 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.22–8.16 (m, 2H), 8.07 (d, J = 5.8 Hz, 1H), 7.97–7.90 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.39–7.27 (m, 3H), 7.21 (dd, J = 11.0, 6.6 Hz, 2H), 6.91 (d, J = 7.4 Hz, 1H), 6.12 (d, J = 7.4 Hz, 1H), 4.85 (s, 1H), 4.74 (s, 1H), 4.22 (s, 1H), 3.89–3.78 (m, 4H), 3.68 (d, J = 5.3 Hz, 2H), 2.75 (dd, J = 9.6, 6.2 Hz, 2H), 2.37 (s, 3H), 2.09 (s, 3H), 2.02 (dt, J = 14.5, 7.1 Hz, 2H).

[0503] Synthesis of Compound LW1005 - 020 in Example 20

[0504]

[0505] Step 20 - 1:

[0506]

[0507] 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 - necked flask containing DMF (6 mL). Then the reaction mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, extracted with ethyl acetate / water, and the organic layer was dried over anhydrous sodium sulfate. Column chromatography gave 70 mg of a pale yellow solid. LC - MS: 582 [M + H] + 。

[0508] [[ID=,20]]Step 20 - 2:

[0509]

[0510] Compound 84 (70 mg, 0.12 mmol), 5 (70 mg), potassium phosphate (95 mg, 0.45 mmol) and Pd(PPh3)4 (17 mg, 0.015 mmol) were added to a single-necked flask containing 1,4-dioxane (4 mL) and water (1 mL) under nitrogen protection. Then the reaction mixture was stirred at 100 °C for 3 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was cooled, filtered, and silica gel was added for sample mixing. Column chromatography was performed to obtain 30 mg of a pale yellow solid, and then 11.5 mg of a pale yellow solid was obtained by preparative reverse-phase column chromatography. LC-MS: 734 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.15 (s, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 7.9, 1.4 Hz, 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 = 7.3 Hz, 1H), 5.06 (s, 2H), 4.79–4.61 (m, 2H), 4.56–4.40 (m, 1H), 3.93 (t, J = 5.4 Hz, 1H), 3.65 (t, J = 5.2 Hz, 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)

[0511] Synthesis of Compound LW1005-021 in Example 21

[0512]

[0513] Step 21-1:

[0514]

[0515] The starting material 77 (18 g) and NIS (10.7 g) were successively added to MeCN (230 mL), and 5 mL of TFA was added dropwise. The mixture was stirred in an oil bath at 55 °C for 1.5 hours. After the reaction was completed as monitored by TLC, it was cooled, filtered, and dried to obtain 13.8 g of a yellow solid. MS-APCI: 579 [M+H] + .

[0516] Step 21-2:

[0517]

[0518] Compound 85 (1.0 g, 1.73 mmol) was added to POCl3 (15 mL), and the reaction was carried out at 90 °C for 1 hour. After concentration to dryness, it was ready for use. NH2OMe / HCl (10 g) was dissolved in 6 mL of water, NaOH (4.79 g) was added, and the mixture was stirred for 10 minutes. After filtration, the filtrate was cooled in an ice bath and then poured into the residue after the reaction. Stirring was carried out in an ice bath, and a solid appeared. The solid was filtered out and dried to obtain 1 g of crude product solid. MS-APCI: 608 [M+H] + .

[0519] Step 21-3:

[0520]

[0521] Compound 86 (3 g, 4.9 mmol) was dissolved in MeOH / THF (30 mL / 30 mL), 5N sodium methoxide solution (2.5 mL, 12.3 mmol) was added, and the mixture was stirred at room temperature while monitoring by TLC plate. After the reaction was completed, water was added to quench the reaction, the solvent was rotary evaporated, a solid appeared, and it was filtered. The solid was dried to obtain 2.7 g of pale yellow solid. MS-APCI: 504 [M+H] + .

[0522] Step 21-4:

[0523]

[0524] Raw material 87 (7.8 g, 15.5 mmol), Zn(CN)2 (1.09 g, 9.28 mmol), Xantphos-PdCl2 (1.17 g, 1.55 mmol), and Cs2CO3 (7.56 g, 23.2 mmol) were mixed in a 250 mL three-necked flask. After replacing with N2 three times, 150 mL of DMF was injected, and the mixture was stirred at 90 °C for 2 h. The reaction was detected to be complete by LCMS. After filtration, the filtrate was concentrated to dryness, and the solid was slurried with (DCM / MeOH = 100 mL / 2 mL) to obtain 4.5 g of pale yellow solid. MS-APCI: 403 [M+H] + .

[0525] Step 21-5:

[0526]

[0527] Compound 88 (80 mg, 0.198 mmol), 5 (76 mg, 0.2 mmol), Pd(dppf)2Cl2 (17 mg,), and Na2CO3 (53 mg, 0.5 mmol) were placed in a reaction flask, degassed and protected with N2. 3 mL of dioxane / 0.6 mL of water was injected into the reaction flask, and the reaction was carried out at 90 °C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was washed with water, extracted with ethyl acetate, dried, concentrated by evaporation, and purified by column chromatography to obtain 23 mg of a yellow solid. MS-APCI: 657 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 5.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.32 (dd, J = 11.5, 7.6 Hz, 2H), 7.16 (d, J = 5.8 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.94 (s, 1H), 4.70 (s, 1H), 4.19 (s, 1H), 3.96 (t, J = 5.1 Hz, 2H), 3.86–3.66 (m, 7H), 2.72 (dd, J = 9.7, 6.1 Hz, 1H), 2.63 (q, J = 7.6 Hz, 1H), 2.37–2.29 (m, 4H), 2.06 (s, 3H), 1.99 (dd, J = 13.7, 7.0 Hz, 1H), 1.59–1.50 (m, 1H).

[0528] Synthesis of Compound LW1005-022 in Example 22

[0529]

[0530] Step 22-1:

[0531]

[0532] Raw material 77 (1.0 g) was added to POCl3 (10 mL), and the reaction was carried out at 100 °C for 1 hour. After concentration to dryness, aqueous methylamine solution was added to the residue, and the mixture was stirred in an ice bath. A green solid appeared, which was filtered and dried to obtain 960 mg of a solid. MS-APCI: 592 [M+H] + .

[0533] Step 22-2:

[0534]

[0535] The raw material 89 (960 mg) and K2CO3 (770 mg) were successively added to MeOH (20 mL), stirred at 55 °C, monitored by TLC. After the reaction was completed, it was filtered and dried to obtain 900 mg of green solid. MS-APCI: 488 [M+H] + .

[0536] Step 22-3:

[0537]

[0538] The raw materials 90 (48 mg), ZnCN2 (22 mg), Pd2(dba)3 (11 mg), and dppf (15 mg) were mixed in a 50 mL single-necked flask, protected by N2, 5 mL of DMF was added, and it was stirred at 95 °C for 16 hours. The reaction was monitored by TLC. The reaction solution was filtered, the filtrate was washed with water, and extracted with EA. Column chromatography was carried out to obtain 28 mg of green solid. MS-APCI: 387 [M+H] + .

[0539] Step 22-4:

[0540]

[0541] Compound 1 (100 mg, 0.156 mmol), 5 (71 mg, 0.187 mmol), Pd(dppf)2Cl2 (13 mg) and Na2CO3 (51 mg, 0.48 mmol) were placed in a reaction flask, degassed and protected by N2. 3 mL of dioxane / 0.6 mL of water was injected into the reaction flask, and the reaction was carried out at 90 °C for 2 hours. The reaction was monitored by TLC spotting. The reaction solution was washed with water, extracted with EA, dried, concentrated by rotary evaporation, and column chromatography was carried out (DCM:MeOH = 10:1). Purification by reverse-phase column chromatography gave 25 mg of yellow solid. MS-APCI: 641 [M+H] + ; 11H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.79 (s, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 5.9 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 7.61 (s, 1H), 7.43–7.31 (m, 2H), 6.98 (d, J = 5.9 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.39 (s, 1H), 4.24 (s, 2H), 3.95 (s, 2H), 3.85 (s, 2H), 3.65 (s, 3H), 2.98–2.89 (m, 1H), 2.77–2.72 (m, 2H), 2.68–2.62 (m, 2H), 2.47 (s, 3H), 2.44–2.38 (m, 1H), 2.26–2.19 (m, 1H) 2.18 (s, 3H), 1.54–1.45 (m, 1H).

[0542] Synthesis of Compound LW1005-023 in Example 23

[0543]

[0544] Step 23-1:

[0545]

[0546] Add 92 (9.1 g, 1.0 eq; EP2848622) and Cs2CO3 (41.56 g, 3.0 eq) into a reaction flask, dissolve them with DMF, add 2-bromoethanol (6.03 mL, 2.0 eq) dropwise, and stir at 50 °C for 18 h. Monitor by LC-MS until the reaction is completed. Rotavap the DMF, add 100 mL of water and stir for 1 h. Filter by suction, and wash the filter cake with 50 mL of water and 100 mL of n-heptane. Obtain 9.0 g of a coffee-colored solid. MS-APCI: 258 [M+H] +

[0547] Step 23-2:

[0548]

[0549] 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), and Pd(PPh3)4 (2.02 g, 0.05 eq) were added to a reaction flask. Under N2 protection, 1,4 - dioxane / water was added for dissolution, and the mixture was stirred at 100 °C for 3 h. Monitored by LC - MS, the reaction was completed. The reaction solution was washed with water, washed with brine, dried, concentrated, and purified by column chromatography to obtain 10.1 g of a solid. MS - APCI: 348 [M + H] +

[0550] Step 23 - 3:

[0551]

[0552] 95 (5.0 g, 1.0 eq) and Et3N (6 mL, 3.0 eq) were added to dichloromethane. BzCl was added dropwise at RT, and the mixture was stirred at RT for 2 h. Monitored by TLC, the reaction was completed. The reaction solution was washed with saturated sodium bicarbonate solution and saturated brine, dried, concentrated, and purified by column chromatography. 6.4 g of a pale yellow to off - white solid was obtained. MS - APCI: 452 [M + H] +

[0553] Step 23 - 4:

[0554]

[0555] 96 (11.0 g, 1.0 eq) was dissolved in acetonitrile. NIS was added, and TFA was added dropwise at RT. After addition, the mixture was stirred at 55 °C for 3 h, and a large amount of solid precipitated. Monitored by TLC, the reaction was completed. The mixture was filtered by suction, the filter cake was washed with n - heptane, the filtrate was concentrated by rotary evaporation, extracted with EA / water, washed with 10% Na2S2O3 solution, dried, concentrated, and purified by column chromatography together with the filter cake. 13 g of an off - white solid was obtained. MS - APCI: 578 [M + H] +

[0556] Step 23 - 5:

[0557]

[0558] 97 (1.0 g) was added to a reaction flask, 5 mL of POCl3 was added, and the mixture was stirred at 90 °C for 1.5 h. The mixture was concentrated by rotary evaporation and pumped with an oil pump until it became a foamy solid. 30% aqueous methylamine solution (20 mL, 100 eq) was added, dissolved in DCM, and stirred at rt for 15 min. Monitored by TLC, the raw material was completely converted. The layers were separated, the organic phase was washed with brine, dried, concentrated, and purified by column chromatography to obtain 1.0 g of a coffee - colored solid. MS - APCI: 591 [M + H] +

[0559] Step 23-6:

[0560]

[0561] Disperse 98 (1.0 g, 1.0 eq) in methanol / THF, add solid K2CO3 (700 mg, 3.0 eq), and stir at room temperature for 3 h. TLC shows a large amount of starting material remaining. Add additional K2CO3 (700 mg, 3.0 eq) and continue stirring at room temperature overnight. TLC shows that the starting material has reacted almost completely. Evaporate the solvent under reduced pressure, extract with DCM / water, wash the organic phase with brine, dry, concentrate, and perform column chromatography. Obtain 700 mg of a coffee-colored solid. MS-APCI: 487 [M+H] +

[0562] Step 23-7:

[0563]

[0564] Add 99 (2.7 g, 1.0 eq), Zn(CN)2 (299.4 mg, 0.46 eq), Cs2CO3 (2.17 g, 1.2 eq), and Xantphos-PdCl2 (418 mg, 0.1 eq) to a reaction flask, protect with N2, dissolve in DMF, and stir at 90 °C for 2 h. Monitor by LC-MS. After the reaction is complete, evaporate the DMF under reduced pressure, extract with DCM / water, wash the organic phase with brine, dry, concentrate, and perform column chromatography. Obtain 2.2 g of a coffee-colored solid. MS-APCI: 386 [M+H] +

[0565] Step 23-8:

[0566]

[0567] Add 100 (300 mg, 1.0 eq), 5 (352.5 mg, 1.2 eq), Na2CO3 (164.6 mg, 2.0 eq), and Pd(dppf)2Cl2 (41 mg, 0.1 eq) to a reaction flask, protect with N2, dissolve in 1,4-dioxane / water, and stir at 90 °C for 2 h. Monitor by LC-MS. After the reaction is complete, extract the reaction mixture with DCM / water, wash the organic phase with brine, dry, concentrate, and perform column chromatography to obtain 40 mg of a pale yellow solid. MS-APCI: 640 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.87–8.81 (m, 1H), 8.43 (d, J = 7.1 Hz, 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 = 9.0 Hz, 1H), 7.31 (s, 1H), 7.24–7.12 (m, 2H), 6.88 (s, 1H), 4.20 (s, 1H), 4.04 (d, J = 5.2 Hz, 2H), 3.79 (q, J = 13.5 Hz, 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).

[0568] Synthesis of Compound LW1005-024 in Example 24

[0569]

[0570] Step 24-1:

[0571]

[0572] Compound 97 (1.5 g, 2.59 mmol) was added to POCl3 (30 mL), and the reaction was carried out at 90 °C for 2 hours. After concentration to dryness, it was reserved for use. NH2OMe / HCl (22 g) was dissolved in 10 mL of water, NaOH (10.36 g) was added, and the mixture was stirred for 10 minutes. After filtration, the filtrate was cooled in an ice bath and then poured into the residue after the reaction of 1. Stirring was carried out in an ice bath, and a solid appeared. The solid was filtered out and dried to obtain 1.5 g of crude product. MS-APCI: 607 [M+H] + .

[0573] Step 24-2:

[0574]

[0575] Compound 101 (300 mg, 0.49 mmol) was dissolved in MeOH / THF (30 mL / 30 mL), K2CO3 (28 mg, 0.98 mmol) was added, and the mixture was stirred at room temperature. TLC was used to monitor the reaction. After the reaction was completed, the solvent was evaporated to dryness, a solid appeared, and it was filtered. The solid was dried to obtain 200 mg of a pale yellow solid. MS-APCI: 503 [M+H] + .

[0576] Step 24-3:

[0577]

[0578] Mix raw material 102 (135 mg, 0.268 mmol), Zn(CN)2 (16 mg, 0.137 mmol), Xantphos-PdCl2 (20 mg, 0.0268 mmol), and Cs2CO3 (131 mg, 0.402 mmol) in a 50 mL three-necked flask. Replace the air with N2 three times, inject 10 mL of DMF, stir at 90 °C for 2 h, and detect the completion of the reaction by LC-MS. Filter, concentrate the filtrate to dryness, mix with silica gel, and perform column chromatography to obtain 4.5 g of a pale yellow solid. MS-APCI: 402 [M+H] + .

[0579] Step 24-4:

[0580]

[0581] Place compound 103 (100 mg, 0.249 mmol), 5 (100 mg, 0.261 mmol), Pd(dppf)2Cl2 (21 mg), and Na2CO3 (79 mg, 0.746 mmol) in a reaction flask, protect with N2 degassing, inject 3 mL of dioxane / 0.6 mL of water into the reaction flask, react at 90 °C for 2 h, and monitor the completion of the reaction by TLC spotting. Wash the reaction mixture with water, extract with EA, dry, evaporate to dryness, and pass through a column (DCM:MeOH = 10:1) to obtain 11 mg of a yellow solid. MS-APCI: 656 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 8.04 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 5.8 Hz, 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 = 5.2 Hz, 2H), 3.78 (d, J = 16.2 Hz, 5H), 3.69 (t, J = 4.3 Hz, 2H), 2.72 (dd, J = 9.6, 6.1 Hz, 1H), 2.63 (q, J = 7.6 Hz, 1H), 2.36 (dd, J = 9.7, 3.7 Hz, 1H), 2.15 (s, 3H), 2.07 (s, 3H), 2.00 (dq, J = 13.9, 7.3 Hz, 1H), 1.60–1.50 (m, 1H).

[0582] Synthesis of Compound LW1005-025 in Example 25

[0583]

[0584] Step 25-1:

[0585]

[0586] Dissolve compound 103 (50 mg, 0.124 mmol) in DCM (120 mL), and then add Dess-Martin Reagent (158 mg, 0.373 mmol) to the above solution at one time. Stir the mixture at room temperature for 30 minutes and monitor the reaction by TLC. After the reaction is complete, quench the reaction with water, and then wash the reaction solution with saturated sodium bicarbonate, 10% sodium thiosulfate solution and saturated brine in sequence. Dry the organic layer with anhydrous sodium sulfate, filter, and pour the organic layer into a 250 mL single-neck flask. Add methyl 4-piperidinecarboxylate (0.05 mL, 0.373 mmol), acetic acid (1 drop) and sodium cyanoborohydride (79 mg, 0.373 mmol) to the above solution in sequence. Stir the mixture at room temperature for 2 hours and monitor the reaction by TLC. After the reaction is complete, quench the reaction with water, and then wash the reaction solution with saturated sodium bicarbonate and saturated brine in sequence. Dry the organic layer with anhydrous sodium sulfate and perform column chromatography to obtain 20 mg of a pale yellow solid. MS-APCI: 527 [M+H] + .

[0587] Step 25-2:

[0588]

[0589] Dissolve raw material 104 (230 mg, 0.436 mmol) in 10 mL of THF / H2O (2:1), add LiOH (21 mg, 0.872 mmol), react at room temperature for 2 hours, and monitor the reaction by TLC. After the reaction is complete, add TFA (0.08 mL, 1.135 mmol) to adjust the solution to neutral, rotary evaporate THF, add water and stir to wash, precipitate solids, filter, and dry the solids to obtain 200 mg of pale yellow solid. MS-APCI: 513 [M+H] + .

[0590] Step 25-3:

[0591]

[0592] Place compound 105 (200 mg), 5 (148 mg), Pd(dppf)2Cl2 (34 mg) and Na2CO3 (170 mg) in a reaction flask, degas and protect with N2, inject 3 mL of dioxane / 0.6 mL of water into the reaction flask, react at 90 °C for 2 hours, and monitor the reaction by TLC spotting. Wash the reaction solution with water, extract with EA, dry, rotary evaporate, and column chromatograph (DCM:MeOH = 10:1) to obtain 22.2 mg of yellow solid. MS-APCI: 767 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 8.04 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.35 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 5.8 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.71 (s, 1H), 4.20 (s, 1H), 3.93 (t, J = 6.2 Hz, 2H), 3.87–3.74 (m, 6H), 2.82 (d, J = 11.0 Hz, 2H), 2.73 (dd, J = 9.7, 6.1 Hz, 1H), 2.62 (dt, J = 17.7, 6.9 Hz, 3H), 2.38 (dd, J = 9.7, 3.5 Hz, 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).

[0593] Synthesis of Compound LW1005-026 in Example 26

[0594]

[0595] Step 26-1:

[0596]

[0597] Compound 97 (1.3 g) was added to POCl3 (15 mL), and the mixture was heated to 90 °C and reacted for 1 hour. The raw material was completely reacted as monitored by TLC. The reaction solution was rotary evaporated to about 5 mL remaining, and then dropped into ammonia water (100 mL) with a pipette, and a yellow solid precipitated. After filtration, the solid was rotary evaporated to dryness to obtain 1.0 g of product 3, a black-gray solid. MS-APCI: 578 [M + H] + ;

[0598] Step 26-2:

[0599]

[0600] Compound 104 (1.0 g) was suspended in MeOH (15 mL), and K2CO3 (478 mg) was added at room temperature. After the suspension was stirred for 1 hour, the reaction was completed as detected by LCMS. The reaction solution was evaporated to dryness. The remaining solid was dissolved in DMF. The DMF solution was poured into water, and a solid precipitated out. After filtration and drying of the solid, 600 mg of a gray solid was obtained. MS-APCI: 474 [M+H] + ;

[0601] Step 26-3:

[0602]

[0603] Raw material 107 (300 mg), Zn(CN)2 (116 mg), Xantphos-PdCl2 (80 mg), and Cs2CO3 (200 mg) were mixed in a 50 mL three-necked flask. After three replacements with N2, 10 mL of DMF was injected, and the mixture was stirred at 90 °C for 2 h. The reaction was completed as detected by LC-MS. After filtration, the filtrate was concentrated to dryness, mixed with a sample, and purified by column chromatography to obtain 160 mg of a pale yellow solid. MS-APCI: 402 [M+H] + .

[0604] Step 26-4:

[0605]

[0606] Compound 108 (35 mg), 5 (40 mg), Pd(dppf)2Cl2 (12 mg), and Na2CO3 (22 mg) were placed in a reaction flask. After degassing and protection with N2, 3 mL of dioxane / 0.6 mL of water was injected into the reaction flask, and the reaction was carried out at 90 °C for 2 hours. The reaction was complete as detected by TLC spotting. The reaction solution was washed with water, extracted with EA, dried, evaporated to dryness, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 12 mg of a yellow solid. MS-APCI: 627 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.57 - 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, 1.4 Hz, 1H), 8.08 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.50 (dd, J = 7.6, 1.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 5.50 (s, 1H), 5.18 (s, 1H), 4.75 - 4.58 (m, 2H), 4.51 - 4.37 (m, 3H), 3.83 - 3.77 (m, 3H), 3.35 - 3.25 (m, 3H), 2.43 (s, 3H), 2.07 (s, 3H), 2.03 - 1.98 (m, 1H), 1.91 - 1.81 (m, 2H).

[0607] Synthesis of Compound LW1005 - 027 in Example 27

[0608]

[0609] Step 27 - 1:

[0610]

[0611] Take raw material 109 (6.8 g, 1.0 eq; Organic Syntheses, 2007, 84, 262 - 271) and add it to DMAc (70 ml). After dissolving clearly, add potassium carbonate (9.12 g, 2.0 eq), and dropwise add methyl iodide (7 g, 1.5 eq). React at room temperature overnight; Treatment: Add water (50 ml), ammonia water (20 ml), extract with EA (100 ml * 3), and elute by column chromatography: ethyl acetate / n - heptane = 15 / 85 to obtain 6.05 g of yellow solid (yield: 83.4%). LCMS: found 221 [M + H] + ; 1 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 6.1 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.26 (s, 1H), 6.97–6.83 (m, 1H), 4.11 (s, 3H), 4.04 (s, 3H), 3.91 (s, 3H).

[0612] Step 27 - 2:

[0613]

[0614] Add raw material 110 (5 g, 1.0 eq) to acetic acid (82 g, 30 eq), add 47% aqueous hydrobromic acid solution (55 g, 30 eq), heat to 95 °C after dissolution and clear, and react for 2 hours; Treatment: Concentrate to obtain 9 g of pale yellow solid (yield: quantitative), and directly charge it to the next step. LCMS: found 193 [M+H] +

[0615] Step 27-3:

[0616]

[0617] Add raw material 111 (4.36 g, 1.0 eq) to methanol (90 ml), it is insoluble, add concentrated sulfuric acid (5 g, 1.0 eq), reflux and react overnight at an external bath temperature of 85 °C; Treatment: Under ice bath, dropwise add 70 ml of saturated sodium bicarbonate, pH = 7-8, a solid precipitates, filter, wash the solid with water, and dry to obtain 4.43 g of white solid (yield: 94.8%). LCMS found: 207 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 7.24 (s, 1H), 7.20 (t, J = 6.5 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H).

[0618] Step 27-4:

[0619]

[0620] Add raw material 112 (4.2 g, 1.0 eq) to DMAc (50 ml), under argon protection, add cesium carbonate (13.3 g, 2.0 eq), add silanol raw material 8 (9.62 g, 1.3 eq), and react overnight at room temperature; Treatment: Add water (100 ml), adjust the pH to 5-6 with 1 M hydrochloric acid (80 ml); Extract 3 times with EA, column chromatography: Elute with 20% EA / n-heptane, concentrate to obtain 4.5 g of white solid, yield: 45.4%. LCMS found: 489 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.3 Hz, 4H), 7.39 (t, J = 7.5 Hz, 2H), 7.32–7.23 (m, 5H), 6.66 (d, J = 7.5 Hz, 1H), 4.13 (t, J = 5.0 Hz, 2H), 3.95 (s, 3H), 3.86 (t, J = 5.0 Hz, 2H), 3.83 (s, 3H), 0.93 (s, 9H).

[0621] Step 27-5:

[0622]

[0623] Dissolve Compound 113 (300 mg) and Compound 114 (149 mg) in 15 mL of THF. Under nitrogen protection and in an ice-salt bath, add dropwise 2.5 mL of NaHMDS (2 M). After the addition, keep the reaction at a certain temperature for 20 min; monitor the reaction by LC-MS. After the reaction is complete, quench with water, extract with EA, combine the organic phases, wash with brine, dry, evaporate to dryness, mix with silica gel, and purify by column chromatography to obtain 160 mg of a light yellow solid. LC-MS found: 699[M+H]+

[0624] Step 27-6:

[0625]

[0626] Dissolve Compound 115 (160 mg) in 2 mL of methanol, add 100 mg of 10% Pd / C. After the addition, displace with hydrogen and react at room temperature for 30 min, monitor the reaction by TLC. After the reaction is complete, filter through diatomaceous earth, take the filtrate and evaporate to dryness to obtain 140 mg of a grayish-white solid crude product, which is directly used in the next step. LC-MS found: 669[M+H]+

[0627] Step 27-7:

[0628]

[0629] Dissolve Compound 113 (55 mg) and Compound 116 (75 mg) in 3.8 mL of THF. Under nitrogen protection and in an ice-salt bath, add dropwise 0.45 mL of NaHMDS (2 M). After the addition, keep the reaction at a certain temperature for 1 h, monitor the reaction by LC-MS.

[0630] After the reaction is complete, quench with water, extract with EA, combine the organic phases, wash with brine, dry, evaporate to dryness, mix with silica gel, and purify by column chromatography to obtain 53 mg of a yellow solid. LC-MS found: 1125[M+H] +

[0631] Step 27-8:

[0632]

[0633] Dissolve Compound 117 (53 mg) in 2.5 mL of THF, add 2.5 mL of triethylamine trihydrofluoride. After the addition, react at room temperature for 2 h, monitor the reaction by TLC. After the reaction is complete, evaporate THF at low temperature, and purify the resulting residue by preparative reverse-phase column chromatography to obtain 6.1 mg of a white solid. LC-MS found: 1125[M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.55 (s, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.62 (d, J = 7.5 Hz, 1H), 4.00 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.62 (t, J = 5.6 Hz, 2H), 1.96 (s, 4H), 1.24 (s, 1H).

[0634] Synthesis of Compound LW1005-028 in Example 28

[0635]

[0636] Step 28-1:

[0637]

[0638] Add 118 (7.6 g, 51.0 mmol, 1.0 eq) to the reaction flask in sequence, freshly distilled anhydrous THF, protected by inert gas; cool to -78 °C with dry ice-acetone; add dropwise n-BuLi (30.5 mL, 76.5 mmol, 1.5 eq, 2.5 M); stir at low temperature for ~30 min; introduce carbon dioxide dried by concentrated sulfuric acid and anhydrous calcium chloride into the reaction solution; react for 3 h, slowly warm up to ~0 °C; quench with saturated ammonium chloride solution; add water and ethyl acetate; separate the organic phase; wash the aqueous phase with ethyl acetate once; adjust the pH of the aqueous phase to ~2; a large amount of solid precipitates, filter and dry to obtain 9.4 g of solid, with a yield of 95.5%. LCMS found: 194 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 6.0 Hz, 1H), 7.60 (s, 1H), 7.39 (dd, J = 6.0, 0.9 Hz, 1H), 4.02 (s, 3H).

[0639] Step 28-2:

[0640]

[0641] Add compound 119 (9.0 g, 46.6 mmol, 1.0 eq), ethanol (270 mL) and concentrated sulfuric acid (11.5 mL) to the reaction flask, heat to reflux; stir overnight, distill off ethanol, cool the residue with an ice-water bath, add water dropwise to precipitate solid; filter and dry to obtain 7.4 g of solid, with a yield of 76.7%. LCMS found: 208 [M+H] + ;1 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.31 (td, J = 7.1, 2.9 Hz, 3H).

[0642] Step 28-3:

[0643]

[0644] Add 120 (7.0 g, 33.8 mmol, 1.0 eq), 70 mL of DMAc, cesium carbonate (22.0 g, 67.5 mmol, 2.0 eq) and compound 5 (14.7 g, 40.5 mmol, 1.2 eq) into a reaction flask, stir at room temperature for 2 h, add water and ethyl acetate, separate the ethyl acetate layer, extract the aqueous layer with ethyl acetate once, combine the organic layers, wash with saturated sodium chloride solution, and concentrate by rotary evaporation to obtain compound 121 without purification, which is directly carried forward to the next step without purification. LCMS: found 490 [M+H] +

[0645] Step 28-4:

[0646]

[0647] Add the crude product of compound 121 from the previous step, ethanol (70 mL) and water (18 mL) into a 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 layer; cool the aqueous layer in an ice 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 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 0.9 Hz, 1H), 7.48–7.34 (m, 7H), 7.29 (t, J = 7.3 Hz, 4H), 6.80 (dd, J = 7.5, 0.9 Hz, 1H), 4.19 (t, J = 4.9 Hz, 2H), 3.88 (t, J = 4.9 Hz, 2H), 0.92 (s, 9H).

[0648] Step 28-5:

[0649]

[0650] Substrate 123 (600 mg; WO2018119286), 124 (1 g), TsOH (365 mg) were added to isopropanol (10 mL), and the mixture was stirred at 85 °C overnight. TLC detected the disappearance of the starting materials. The reaction solution was concentrated in vacuo, washed with water, extracted with EtOAc, and purified by column chromatography to obtain 350 mg of a pale yellow solid. LC-MS: 540 [M+H] +

[0651] Step 28-6:

[0652]

[0653] 125 (190 mg) was added to 4N HCl / dioxane (1 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. TLC detected the complete reaction of the starting materials. The reaction solution was concentrated in vacuo to obtain 190 mg of a grey crude solid, which was directly used in the next step. LC-MS: 440 [M+H] +

[0654] Step 28-7:

[0655]

[0656] 126 (150 mg), 122 (102 mg), and HATU (108 mg) were dissolved in DMF (1 mL) at room temperature, then DIEA (85 mg) was added, and the reaction was continued at room temperature overnight. TLC detected the reaction. After the reaction was complete, the reaction solution was washed with water, extracted with EtOAc, the organic phase was washed with saturated NaCl, dried, concentrated in vacuo, and purified by column chromatography to obtain 70 mg of a yellow solid. LC-MS: 883 [M+H]+

[0657] Step 28-8:

[0658]

[0659] At room temperature, 127 (70 mg) was dissolved in THF (0.5 ml), 0.1 mL of TBAF / THF (1 N) was added, and the mixture was stirred for 1 hour. TLC detection showed that the raw materials disappeared. The reaction solution was directly passed through a column, and the obtained 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 (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.31 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J = 5.7 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.18 (d, J = 5.8 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 4.89 (t, J = 5.4 Hz, 1H), 4.72 (d, J = 4.5 Hz, 1H), 4.23 (s, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.83 (q, J = 13.8 Hz, 2H), 3.66 (q, J = 5.5 Hz, 2H), 2.75 (dd, J = 9.6, 6.0 Hz, 1H), 2.67 (d, J = 7.0 Hz, 1H), 2.44–2.37 (m, 1H), 2.09 (s, 3H), 1.99 (m, 4H), 1.59 (m, 1H), 1.24 (s, 2H).

[0660] Synthesis of Compound LW1005-029 in Example 29

[0661]

[0662] Step 29-1:

[0663]

[0664] Under an ice bath, 126 (120 mg) and 113 (86.5 mg) were dissolved in THF (2 ml). Under N2 protection, NaHMDS (0.7 mL) was added, and the reaction was continued in the ice bath for 1 hour. TLC showed that the raw materials reacted completely. The reaction was quenched with saturated NH4Cl, extracted with EA, and passed through a column to obtain 80 mg of a yellow solid of LW1005-011-3. LC-MS: 896 [M+H] +

[0665] Step 29-2:

[0666]

[0667] Substrate 128 (90 mg) was added to a mixture of THF and TEA / 3HF (2 mL, 1:1), and the reaction was carried out for 2 hours. TLC was used to detect the disappearance of the starting material. The reaction solution was adjusted to pH = 9 with saturated NaHCO3, extracted with EtOAc, dried by evaporation, and purified by preparative separation to obtain 12.4 mg of a yellow solid. LC-MS: 658 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (d, J = 94.5 Hz, 1H), 9.88 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.56 (s, 1H), 7.38 (ddd, J = 30.9, 13.6, 7.3 Hz, 4H), 7.26–7.17 (m, 1H), 7.08 (t, J = 6.5 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.4 Hz, 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).

[0668] Synthesis of Compound LW1005-030 in Example 30

[0669]

[0670] Step 30-1:

[0671]

[0672] Compound 128 (1 g, 1 eq; WO2012154213), CuI (0.03 g, 0.05 eq), and bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.05 eq) were added to a 50 ml reaction flask. The flask was purged with nitrogen three times, and anhydrous DMF (20 ml) was added. The system was clear and reddish-brown. Triethylamine (1.7 g, 5.0 eq) was added, and the system became clear and yellowish-brown. After purging with nitrogen three times and protecting from light, alkyne starting material 3 (0.52 g, 1.1 eq) was added. The reaction was carried out at room temperature, and TLC was used to monitor the reaction. After the reaction was complete, the reaction solution was poured into an ice-cold aqueous ammonium chloride solution, and extracted twice with MTBE. The organic layer was washed five times with saturated sodium chloride, and purified by column chromatography to obtain 1.03 g of an oily substance. LC-MS: 309 [M+H] + ; 11H NMR (400 MHz, Chloroform-d) δ 7.49 (dd, J = 8.0, 1.4 Hz, 1H), 7.40 (dd, J = 7.7, 1.3 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 2.57 (s, 3H), 1.06 (t, J = 7.9 Hz, 9H), 0.70 (q, J = 7.8 Hz, 6H).

[0673] Step 30-2:

[0674]

[0675] Add potassium phosphate (13 g, 2 eq) and palladium acetate (0.75 g, 0.03 eq) into a 500 ml reaction flask. Replace the air with nitrogen three times. Add a dioxane solution (75 ml) of 130 (10.5 g, 1.3 eq; LabNetwork), add a dioxane solution (75 ml) of compound 129 (9.5 g, 1 eq), add water (30 ml), and react at 100 °C in an external bath for 2 hours. The system turns dark brown. Monitor the reaction by TLC until it is complete. After the reaction is complete, quench with water, extract with MTBE, wash the organic layer with saturated brine, concentrate, and perform column chromatography to obtain 9.8 g of a liquid. LC-MS: 366 [M+H] + ; 1 1H NMR (400 MHz, Chloroform-d) δ 7.86 (dd, J = 7.8, 1.7 Hz, 1H), 7.55 (dd, J = 7.7, 1.4 Hz, 1H), 7.40–7.32 (m, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.06 (dd, J = 7.6, 1.4 Hz, 1H), 2.22 (s, 3H), 2.19 (s, 3H), 1.09 (t, J = 7.9 Hz, 9H), 0.72 (q, J = 7.9 Hz, 6H).

[0676] Step 30-3:

[0677]

[0678] Add raw material 131 (10.17 g, 1 eq) into THF (50 ml). The system is clear and light yellowish brown. Dropwise add a THF solution (50 ml) of TBAF (17.55 g, 2 eq) and react at room temperature for 30 minutes. After the reaction is complete, directly mix the sample and perform column chromatography to obtain 6.62 g of a solid. LC-MS: 252 [M+H] + ; 11H NMR (400 MHz, Chloroform-d) δ 7.54 (dd, J = 7.8, 1.4 Hz, 1H), 7.40–7.32 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.08 (dd, J = 7.7, 1.4 Hz, 1H), 3.32 (s, 1H), 2.19 (s, 3H), 2.16 (s, 3H).

[0679] Step 30-4:

[0680]

[0681] Add compound 132 (4.6 g, 1 eq), 133 (6.57 g, 1.15 eq; WO2014063199), bis(triphenylphosphine)palladium(II) chloride (0.64 g, 0.05 eq), CuI (0.15 g, 0.05 eq), and DIPEA (11.83 g, 5 eq) into a reaction flask. Replace the air with nitrogen three times, add DMF, and then replace the air with nitrogen again. The system is clear and reddish-brown. React at 55 °C in an external bath for 3 hours. After the reaction is complete, add 1000 ml of water under an ice bath, extract with EA (500 ml × 2 times), wash with saturated brine twice, and perform column chromatography to obtain 6.7 g. LCMS found 435 [M] + ; 1 1H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.91–7.83 (m, 2H), 7.46–7.36 (m, 3H), 7.19 (dd, J = 7.5, 1.4 Hz, 1H), 7.00 (s, 1H), 3.96 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H).

[0682] Step 30-5:

[0683]

[0684] Add compound 134 (6.76 g, 1 eq) into methanol (250 ml) and isopropyl acetate (600 ml), then add zinc powder (10 g, 10 eq) and ammonium chloride (8.3 g, 10 eq). Stir at room temperature for 1 hour. Filter, rinse the solid with isopropyl acetate, slurry the solid with EA, filter, concentrate the filtrate, and perform column chromatography to obtain 1.6 g of solid. LCMS found 406:408 = 3:1 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.85–7.69 (m, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.26–7.12 (m, 1H), 6.96 (t, J = 7.7 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.34 (d, J = 7.4 Hz, 1H), 4.92 (s, 2H), 3.89 (s, 3H), 2.19 (s, 3H), 1.77 (s, 3H).

[0685] Step 30-6:

[0686]

[0687] Add compound 135 (500 mg, 1 eq), palladium acetate (30 mg, 0.1 eq), BINAP (100 mg, 0.2 eq), and cesium carbonate (1000 mg, 2.5 eq) into a 50 ml reaction flask. Replace the air with nitrogen three times, add a toluene solution (20 ml) of chloro raw material 123 (700 mg), replace the air with nitrogen again, and react overnight at an external bath temperature of 100 °C. After the reaction is complete, filter, wash with EA, concentrate the filtrate, and purify by column chromatography to obtain 800 mg of a yellow solid. LCMS found 633 [M+H] + ;

[0688] Step 30-7:

[0689]

[0690] Add compound 136 (550 mg) into THF (5 ml) and methanol (4 ml). Add sodium borohydride (100 mg) and lithium chloride (100 mg) under an ice bath, and react overnight at room temperature. After the reaction is complete, add an aqueous ammonium chloride solution under an ice bath, extract twice with EA, concentrate, and purify by column chromatography to obtain 450 mg of a yellow solid. LCMS found: 605 [M+H] +

[0691] Step 30-8:

[0692]

[0693] Add compound 137 (420 mg) into DCM (8 ml). Add activated manganese dioxide (430 mg) and reflux for overnight reaction. After the reaction is complete, filter through diatomaceous earth, wash with DCM, concentrate the filtrate, and purify by column chromatography to obtain 320 mg of a yellow solid. LCMS found: 603 [M+H]+

[0694] Step 30-9:

[0695]

[0696] 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 reaction was carried out at room temperature for 1 hour. Sodium triacetoxyborohydride (600 mg) was added, and 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 the aqueous layer was extracted with DCM once. The organic phase was dried over sodium sulfate and purified by column chromatography to obtain 100 mg of a pale yellow solid. LCMS found: 702 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (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 = 6.0 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.83 (s, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.01 (d, J = 7.4 Hz, 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 = 46.4 Hz, 1H).

[0697] Synthesis of Compound LW1005-031 in Example 31

[0698]

[0699] Step 31-1:

[0700]

[0701] Compound 135 (510 mg, 1 eq), 122 (500 mg, 1.05 eq), HATU (825 mg, 2 eq), and DIEA (295 mg, 2.1 eq) were added to a reaction flask, and DMF (25 ml) was added. The solution was clear, and the mixture was stirred at room temperature overnight. Work-up: Water (30 ml) was added, and the mixture was extracted twice with EA and washed once with saturated brine. Purification by column chromatography gave 1.37 g of a yellow solid. LCMS found 849 [M+H]+

[0702] Step 31-2:

[0703]

[0704] The raw material 139 (910 mg, 1 eq) was added to freshly distilled THF (10 ml), and lithium borohydride (100 mg, 5 eq) was added under an ice bath. The reaction was carried out at room temperature for 6 hours, and monitored by TLC. After the reaction was complete, an aqueous ammonium chloride solution was added under an ice bath, and the mixture was extracted 3 times with EA and washed once with saturated brine, then concentrated and purified by column chromatography to obtain 690 mg of a yellow solid. LCMS found: 821 [M+H] +

[0705] Step 31-3:

[0706]

[0707] Compound 140 (490 mg, 1 eq) was added to DCM (45 ml), and the solution was slightly turbid. Then DMP (380 mg, 1.5 eq) was added, and the reaction was carried out at room temperature for 40 minutes, monitored by TLC. After the reaction was complete, saturated sodium sulfite was added and stirred for 5 minutes, then saturated sodium bicarbonate was added and stirred for 5 minutes. The mixture was extracted 2 times with DCM and washed once with saturated brine, then mixed with silica gel and purified by column chromatography to obtain 319 mg of a yellow solid. LCMS found: 819 [M+H] +

[0708] Step 31-4:

[0709]

[0710] Compound 141 (100 mg, 1 eq), a solution of R-3-carboxypyrrolidine (41 mg) in AcOH (0.25 mL) and triethylamine (0.4 mL) were successively added to DCM (5 mL). After reacting at room temperature for 1 hour, sodium triacetoxyborohydride (120 mg) was added, and the reaction was carried out overnight at room temperature, monitored by TCL. After the reaction was complete, saturated ammonium chloride was added, and the layers were separated. The mixture was extracted 2 times with DCM, mixed with silica gel and concentrated, then purified by column chromatography to obtain 130 mg of a white solid. LCMS found: 918 [M+H] +

[0711] Step 31-5:

[0712]

[0713] 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 reaction was carried out at room temperature for 30 minutes, monitored by TCL. After the reaction was complete, it was directly mixed with silica gel and purified by column chromatography to obtain 80 mg of a yellow solid. LCMS found: 680 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.62 (s, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.46–7.39 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 4.89 (s, 1H), 4.40 (s, 1H), 4.06 (t, J = 5.7 Hz, 2H), 3.66 (d, J = 5.4 Hz, 2H), 2.23 (s, 3H), 1.97 (s, 3H).

[0714] Synthesis of Compound LW1005-032 in Example 32

[0715]

[0716] Step 32-1:

[0717]

[0718] Compound 143 (5.6 g, 300 mmol), K2CO3 (5.5 g, 40 mmol) and 123 (5.2 g, 20 mmol) were successively added into a single-necked flask containing DMF (100 mL), and then stirred overnight in an oil bath at 120 °C. The reaction was monitored by TLC. After the reaction was complete, the organic solvent was evaporated to dryness, washed with water by stirring, filtered, the solid was dried, mixed with a sample, and purified by column chromatography to obtain 3.1 g of a brown solid. LCMS found: 414 [M+H] +

[0719] Step 32-2:

[0720]

[0721] Raw material 144 (1 g, 2.4 mmol), bis(pinacolato)diboron (711 mg, 2.8 mmol), PdCl2(dppf)DCM (195 mg, 0.24 mmol), KOAc (470 mg, 4.8 mmol) were mixed in a 25 mL single-necked flask, purged with N2 three times, 10 mL of Dioxide was injected, and stirred at 95 °C for 16 hours. After washing with water, extraction, concentration, and purification by column chromatography, 850 mg of a solid was obtained. LCMS found: 462 [M+H] +

[0722] Step 32-3:

[0723]

[0724] Mix raw material 145 (248 mg, 0.54 mmol), raw material 33 (100 mg, 0.27 mmol), PdCl2(dppf)2 DCM (22 mg, 0.027 mmol), and Na2CO3 (57 mg, 0.54 mmol), displace with nitrogen, add Dioxane / H2O (8 mL), react at 95 °C for 3 hours, wash with water, and prepare 47 mg of white solid. LCMS found: 629 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 2.4 Hz, 1H), 8.72 (s, 1H), 8.65–8.58 (m, 1H), 8.16–8.06 (m, 2H), 7.63 (d, J = 5.7 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.50–7.38 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 5.60–5.44 (m, 1H), 4.79–4.64 (m, 2H), 4.47 (dd, J = 31.1, 4.5 Hz, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.70 (d, J = 5.2 Hz, 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).

[0725] Synthesis of Compound LW1005-033 in Example 33

[0726]

[0727] Step 33-1:

[0728]

[0729] Dissolve compound 146 (1.0 g) in DCM (30 mL), add 147 (1.16 g) and TEA (1.32 g), react at room temperature for 1 hour, and then add NaBH(OAc)3 (3.31 g) in batches. React for 1 hour, and monitor the reaction completion by TLC plate. Wash the reaction solution with water, extract with DCM, evaporate to dryness, and purify by column chromatography to obtain 1.0 g of yellow solid product. LCMS found: 306 [M+H] +

[0730] Step 33-2:

[0731]

[0732] Compound 148 (1.0 g), 149 (0.92 g) and TsOH (0.75 g) were added to isopropanol (30 mL), and the reaction was carried out at 85 °C overnight. TLC showed that the reaction was complete. Water was added to the reaction solution, isopropanol was removed by rotary evaporation, and impurities were extracted with EA. The aqueous phase was adjusted to pH = 7 with an aqueous NaHCO3 solution, a solid precipitated, and the solid was dissolved by extraction with DCM. DCM was rotary evaporated to obtain 1.24 g of a yellow solid. LCMS found: 455 [M+H] +

[0733] Step 33-3:

[0734]

[0735] Compound 33 (1 g), bis(pinacolato)diboron (815 mg), PdCl2(dppf)DCM (180 mg), and KOAc (420 mg) were mixed in a 25 mL single-necked flask. The flask was purged with N2 three times, and 10 mL of Dioxide was injected. The mixture was stirred at 95 °C for 16 hours, washed with water, extracted, concentrated, and purified by column chromatography to obtain 900 mg of a solid. LCMS found: 422 [M+H] +

[0736] Step 33-3:

[0737]

[0738] At room temperature, 150 (119 mg), 151 (100 mg), Pd(dppf)Cl2 / DCM (19.4 mg), and Na2CO3 (50 mg) were placed in a reaction flask. The flask was evacuated to remove air, and dioxane / H2O (6 mL, 5:1) was injected with a syringe. After evacuation again, the reaction was heated at 100 °C for 4 hours. TLC monitored that the raw materials reacted completely. The reaction solution was washed with water and purified by column chromatography (DCM:MeOH = 20:1) to obtain 50 mg of a crude product. The crude product was separated by preparative chromatography to obtain 20 mg of product 5, a yellow solid. LCMS found: 670 [M+H] +

[0739] Step 33-4:

[0740]

[0741] Compound 152 (10 mg) was dissolved in THF / H2O (1.3 mL, 1:0.3), and LiOH / H2O (1.3 mg) was added. The reaction was carried out at room temperature for 1 hour. TLC showed that the raw materials reacted completely. The reaction solution was separated by preparative chromatography to obtain 5 mg of a yellow solid product. LCMS found: 656 [M+H] +; 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.07 (s, 1H), 8.73 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 8.03 (s, 1H), 7.56 (t, J = 7.8 Hz, 18H), 7.42 (dd, J = 7.9, 4.9 Hz, 2H), 7.29–7.19 (m, 2H), 7.08 (s, 1H), 5.33 (t, J = 4.8 Hz, 1H), 4.68 (s, 2H), 4.16 (s, 2H), 3.69 (t, J = 5.3 Hz, 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).

[0742] Synthesis of Compound LW1005 - 034 in Example 34

[0743]

[0744] Step 34 - 1:

[0745]

[0746] Dissolve Compound 43 (8 g) in acetic acid (100 mL), cool down in an ice bath, and add methyl 2,2,2 - trichloroacetimidate (16 mL) dropwise. After the addition, stir at room temperature overnight and monitor the reaction by TLC. After the reaction is complete, pour the reaction solution into ice water, extract with EA, wash with saturated brine, dry, evaporate to dryness, mix with silica gel, and purify by column chromatography to obtain 10.5 g of a white solid. LCMS found: 280 [M + H] +

[0747] Step 34 - 2:

[0748]

[0749] Dissolve Compound 153 (10.4 g) in ethanol / water (110 mL; 10:1), add sodium carbonate (5.9 g), and heat to 75 °C for reaction for 24 h; monitor the reaction by TLC. After the reaction is complete, evaporate the solvent to dryness, directly mix with silica gel, and purify by column chromatography to obtain 4.8 g of a white solid. LCMS found: 236 [M + H]+

[0750] Step 34 - 3:

[0751]

[0752] Add raw material 154 (4.5 g, 1 eq) to an aqueous solution of 40% hydrobromic acid (45 ml) and acetic acid (50 ml), react at 86 °C in an external bath for 15 minutes, and detect the reaction by LC-MS. After the reaction is complete, under an external bath of 40 °C, dry it with an oil pump to obtain 3.16 g of a red-brown solid. LCMS found 222 [M+H]+

[0753] Step 34-4:

[0754]

[0755] Add raw material 155 (3 g, 1 eq) to DMAc (100 ml), it is clear, add the bromine raw material (10 g, 2 eq), add cesium carbonate (14 g, 3 eq), react at room temperature for 1 hour, and detect the reaction by LC-MS. After the reaction is complete, add ice water, extract once with EA (100 mL), and the organic phase is mixed with a sample and passed through a column to obtain 2.2 g of a white solid. LCMS found: 504 [M+H]+

[0756] Step 34-5:

[0757]

[0758] Add raw material 126 (200 mg, 2 eq) to freshly distilled THF (5 mL), cool down to about -15 °C, protect with argon, dropwise add a 2M solution of NaHMDS (1 mL, 4 eq), react for 5 minutes, then dropwise add a solution of raw material 156 (100 mg, 1 eq) in THF (3 mL), and react at room temperature for 2 hours, and detect the reaction by TLC. After the reaction is complete, directly mix with a sample and pass through a column to obtain 104 mg of a pale yellow solid. LCMS found: 897 [M+H]+

[0759] Step 34-6:

[0760]

[0761] Dissolve raw material 157 (50 mg) in THF (1 mL), then add 1M TBAF / THF (0.1 mL) to the solution, react at room temperature for 30 minutes, and detect the reaction by TLC. After the reaction is complete, extract with ethyl acetate / water, and prepare by reverse-phase column to obtain 11 mg of a yellow solid. LC-MS found: 659.2 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.32 (s, 1H), 8.88 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 8.07 (d, J = 5.7 Hz, 1H), 7.67–7.54 (m, 2H), 7.41–7.27 (m, 2H), 7.18 (d, J = 5.8 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 4.23 (s, 1H), 4.07 (d, J = 7.8 Hz, 5H), 3.84 (q, J = 13.7 Hz, 2H), 3.65 (s, 2H), 2.77 (t, J = 7.9 Hz, 1H), 2.69 (d, J = 8.1 Hz, 1H), 2.41 (d, J = 10.0 Hz, 1H), 2.10 (s, 3H), 2.04 (s, 4H), 1.59 (s, 1H),.

[0762] Synthesis of Compound LW1005-035 in Example 35

[0763]

[0764] Step 35-1:

[0765] Compound 104 (300 mg, 0.568 mmol), B2Pin2 (173 mg, 0.682 mmol), Pd(dppf)2Cl2 (46 mg, 0.0568 mmol) and KOAc (166 mg, 1.7 mmol) were successively added into a single-necked flask containing Dioxane (10 mL), protected by nitrogen, heated and stirred in an oil bath at 90 °C, and the reaction was monitored by LC-MS. After the reaction was complete, it was filtered, dried by evaporation and mixed with samples, and purified by column chromatography to obtain 200 mg of a pale yellow solid.

[0766] Step 35-2:

[0767] Using Compound 158 (200 mg) and 159 (218 mg, WO2019191707) as raw materials, according to the synthesis method of Step 33-3, 180 mg of a pale yellow solid was obtained.

[0768] Step 35-3:

[0769] Compound 160 (180 mg) and LiOH (16 mg) were successively added to a single-necked flask containing THF / MeOH / H2O (2:1:1, 4 mL), stirred at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was complete, a pale yellow solid (42 mg) was obtained by preparative reverse-phase column chromatography. LC-MS found: 819 [M+H] +

[0770] Synthesis of Compound LW1005-036 in Example 36

[0771]

[0772] Step 36-1:

[0773] Using Compound 158 (200 mg) and 161 (210 mg, WO2019191707) as starting materials, according to the synthesis method of Step 33-3, 175 mg of a pale yellow solid was obtained.

[0774] Step 36-2:

[0775] Using Compound 162 (175 mg) as the starting material, according to the synthesis method of Step 36-2, 38 mg of a pale yellow solid was obtained. LC-MS found: 784 [M+H] +

[0776] Synthesis of Compound LW1005-037 in Example 37

[0777]

[0778] Step 37-1:

[0779] Compound 163 (40 g, 230.7 mmol), 164 (58.5 g, 230.7 mmol, WO2012031004), Pd(dppf)Cl2 / DCM (10.2 g, 0.05 eq), and Na2CO3 (53 g, 2 eq) were successively added to dioxane / H2O (300 mL, 5:1), degassed three times, protected by N2, and reacted at 80 °C for 1 hour. TLC showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EA, and 500 mL of saturated brine was added to the EA. The layers were separated. The EA layer was dried and concentrated in vacuo. The resulting solid was triturated with EA / HEP (200 mL, 1:3), filtered, and 40 g of a yellow solid was obtained.

[0780] Step 37-2:

[0781] 165 (66 g, 249 mmol) was dissolved in 500 mL of THF and cooled to 0 °C. A solution of sodium methoxide (50 mL, 5 N in MeOH) was added dropwise. After the addition, the reaction was carried out at 0 °C for 30 minutes. At 0 °C, 4 N HCl / MeOH was added dropwise to the reaction mixture until the pH reached 7. THF was removed by rotary evaporation. The residue was dissolved in 1 L of DCM, washed with 2 L of water, and the layers were separated. The DCM layer was dried and evaporated to dryness. The resulting solid was triturated with EA / HEP (200 mL, 1:3), filtered, and 60 g of a yellow solid was obtained.

[0782] Step 37-3:

[0783] In a 3 L reaction flask with mechanical stirring, CuBr (45.4 g, 316.5 mmol) was added to HBr (500 mL) and cooled to 0 °C for standby. Then, compound 166 (55 g, 211 mmol) was suspended in HBr (500 mL), cooled to 0 °C, and an aqueous solution of NaNO2 (17.5 g, 253 mmol) (dissolved in 50 mL of water) was added dropwise. Brown fumes were generated. After the addition, the mixture was stirred for 30 minutes. The HBr solution of compound 3-4 was poured into the HBr solution of CuBr at once. The reaction mixture turned black and a large amount of bubbles were generated. After stirring for 1 h, TLC monitoring showed that SM1 disappeared and the product spot was formed. 2 L of water was added to the reaction mixture, followed by 2 L of EtOAc. The mixture was stirred and the solid dissolved. The layers were separated. The EA layer was dried and evaporated to dryness, and purified by column chromatography (EA:DCM:HEP = 1:1:4) to obtain 45 g of the product as a yellow solid.

[0784] Step 37-4:

[0785] Compound 167 (15 g) was suspended in HCl / MeOH (250 mL, 4 N) (in a sealed reaction flask) and heated at 60 °C overnight. The reaction mixture became clear. TLC detection showed that the reaction was complete. After the reaction mixture was cooled to room temperature, a yellow solid precipitated. The reaction mixture was evaporated to dryness. Saturated sodium bicarbonate (300 mL) was added to the remaining solid, and the mixture was extracted with EA (200 mL × 3). The EA layer was dried and evaporated to dryness. The resulting solid was triturated with EA / HEP (240 mL, 1:5). After filtration, the solid cake was evaporated to dryness to obtain 12 g of the product as a yellow solid.

[0786] Step 37-5:

[0787] Compound 168 (31 g, 86.7 mmol) was dissolved in anhydrous THF (300 mL), cooled to 0 °C, and LiBH4 (2.1 g, 95.4 mmol) was added portionwise. The reaction was carried out at 0 °C for 1 h. The reaction was monitored by TLC until completion. The reaction mixture was filtered. The filter cake was rinsed with DCM. The filtrate was concentrated in vacuo. 300 mL of water was added to the resulting solid, and the mixture was extracted with EA (200 mL × 3). The EA layer was dried and concentrated in vacuo. The resulting solid was triturated with EA / HEP (240 mL, 1:5). After filtration, the filter cake was dried in vacuo to obtain 24 g of the product as a yellow solid.

[0788] Step 37-6:

[0789] Compound 169 (32 g, 97.5 mmol) was dissolved in dioxane (500 mL), MnO2 (51 g, 585.4 mmol) was added, and the mixture was degassed under N2 protection and reacted at 95 °C for 5 h. The reaction was monitored by TLC until completion. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting solid was triturated with EA / HEP (180 mL, 1:5). After filtration, the filter cake was dried in vacuo to obtain 24 g of the product as a yellow solid.

[0790] Step 37-7:

[0791] Compound 170 (22 g, 67.5 mmol), R-3-hydroxypyrrolidine hydrochloride (16.6 g, 135 mmol), and TEA (20.5 g, 202.5 mmol) were added to DCM (300 mL). After reacting at room temperature for 1 h, NaBH(OAc)3 (21.5 g, 101.25 mmol) was added, and the reaction was continued for 1 h. The reaction was monitored by TLC until completion. Work-up: 300 mL of water was added to the reaction mixture, and the layers were separated. The DCM layer was washed with saturated brine. After separation, the DCM layer was dried and concentrated in vacuo, and purified by column chromatography (DCM:MeOH = 40:1) to obtain 15.3 g of the product as a brown oil.

[0792] Step 37-8:

[0793] Compound 171 (2.0 g, 5 mmol), Bpin2 (6.37 g, 25.1 mmol), Pd(PPh3)2Cl2 (352 mg, 0.5 mmol), and KOAc (984.6 mg, 10 mmol) were added to dioxane (40 mL). The mixture was degassed three times and protected with N2, and reacted at 90 °C overnight. After the reaction was complete, it was filtered. The filtrate was concentrated in vacuo. After dissolving in 30 mL of DCM, 50 g of silica gel was added for sample mixing. Purification by silica gel column chromatography, elution gradient: EA = 100% (500 mL), EA:MeOH = 40:1 (2050 mL). 900 mg of the product was obtained as a brown oil.

[0794] Step 37-9:

[0795] Using compound 172 (200 mg) and 104 (200 mg) as raw materials, according to the synthesis method of step 33-3, 186 mg of a pale yellow solid was obtained.

[0796] Step 37-10:

[0797] Using compound 173 (186 mg) as a raw material, according to the synthesis method of step 36-2, 52 mg of a pale yellow solid was obtained. LC-MS found: 733 [M+H] +

[0798] Synthesis of compound LW1005-038 in Example 38

[0799]

[0800] Step 38-1:

[0801] Compound 94 (1.9 g, 6.41 mmol, WO2016207226), 174 (1.1 g, 6.41 mmol, WO2018006795), sodium carbonate (1.36 g, 12.82 mmol) and tetrakis(triphenylphosphine)palladium (222 mg, 0.19 mmol) were successively added to a single-necked flask containing dioxane / H2O (4:1, 25 mL), protected by nitrogen, stirred at 80 °C in an oil bath for 3 hours, and the reaction was detected by LC-MS. After about 10% of the raw materials remained, the reaction was cooled, filtered, dried by evaporation, extracted with DCM / H2O, dried over anhydrous sodium sulfate, and column chromatography (eluted with pure PE) was carried out to obtain 650 mg of a pale yellow solid. ESI(APCI): 306 [M+H] + .

[0802] Step 38-2:

[0803] Compound 175 (200 mg, 0.653 mmol), R-3-hydroxypyrrolidine hydrochloride (121 mg, 0.98 mmol) and triethylamine (0.09 mL, 0.653 mmol) were successively added to a single-necked flask containing DCM (10 mL), stirred at room temperature for 2 hours, then NaBH(OAc)3 (415 mg, 1.96 mmol) was added to the reaction solution, and stirred at room temperature overnight. The reaction was detected by TLC. After the reaction was complete, it was quenched with water, washed with brine, dried over anhydrous sodium sulfate, and column chromatography was carried out to obtain 200 mg of an oil. ESI(APCI): 377 [M+H] + .

[0804] Step 38-3:

[0805] Using compound 176 (200 mg) and 158 (202 mg) as raw materials, according to the synthesis method of step 33-3, 150 mg of pale yellow solid was obtained.

[0806] Step 38-4:

[0807] Using compound 177 (150 mg) as raw material, according to the synthesis method of step 36-2, 47 mg of pale yellow solid was obtained. LC-MS found: 732 [M+H] +

[0808] According to the synthesis routes of LW1005-001 to LW1005-038, the following compounds were synthesized using the corresponding raw materials

[0809]

[0810]

[0811]

[0812] Biological test

[0813] Example A: PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay

[0814] The assay was performed in a standard black 384-well polystyrene plate with a final volume of 20 μL. First, the inhibitor was serially diluted with DMSO and added to the plate wells, and then other reaction components were added. The final concentration of DMSO in the assay was 1%. The assay was carried out in PBS buffer (pH 7.4) containing 0.05% Tween-20 and 0.1% BSA at 25 °C. Recombinant human PD-L1 protein (19-238) with a His 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). The PD-L1 and PD-1 proteins were diluted in the assay buffer and then 0.1 μl of the solution was taken and added to the plate wells. The plate was centrifuged and the proteins were pre-incubated with the inhibitor for 40 minutes. After incubation, 0.1 μl of HTRF detection buffer containing europium-conjugated anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His -Antibody conjugated with allophycocyanin (APC, PerkinElmer - AD0059H). After centrifugation, the microplate was incubated at 25 °C for 60 minutes. The data (665 nm / 620 nm ratio) was read in a PHERAstar FS microplate reader. The final concentrations in the assay were ~3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG, and 20 nM anti-His-allophycocyanin. The IC50 values of the inhibitors were obtained by fitting the activity data using GraphPad Prism 5.0 software.

[0815] The IC50 values of the compounds illustrated in the examples are expressed in the following manner: IC 50 : +=≤10 nM; ++ = 10 - 100 nM; +++ =>100 nM

[0816] Data for the example compounds obtained using the PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay described in Example A are provided in Table 1.

[0817] Compound <![CDATA[IC 50 > Compound <![CDATA[IC 50 > LW1005-001 + LW1005-051 ++ LW1005-002 + LW1005-052 + LW1005-003 + LW1005-135 + LW1005-004 + LW1005-136 + LW1005-005 + LW1005-137 + LW1005-006 + LW1005-138 + LW1005-007 + LW1005-139 + LW1005-008 + LW1005-140 + LW1005-009 + LW1005-141 + LW1005-010 + LW1005-142 + LW1005-011 + LW1005-143 + LW1005-012 ++ LW1005-144 + LW1005-013 + LW1005-145 + LW1005-014 + LW1005-146 + LW1005-015 + LW1005-147 + LW1005-016 + LW1005-148 + LW1005-017 + LW1005-149 + LW1005-018 + LW1005-150 + LW1005-019 + LW1005-151 + LW1005-020 ++ LW1005-152 + LW1005-063 + LW1005-153 + LW1005-022 + LW1005-154 + LW1005-023 + LW1005-155 + LW1005-024 + LW1005-156 +

[0818] LW1005-025 + LW1005-157 + LW1005-026 + LW1005-158 + LW1005-027 + LW1005-159 + LW1005-028 + LW1005-160 + LW1005-029 + LW1005-161 + LW1005-030 + LW1005-162 + LW1005-031 + LW1005-163 + LW1005-032 ++ LW1005-164 + LW1005-033 + LW1005-165 + LW1005-034 + LW1005-166 + LW1005-039 + LW1005-167 + LW1005-040 + LW1005-168 + LW1005-041 ++ LW1005-169 + LW1005-042 + LW1005-170 + LW1005-043 + LW1005-171 + LW1005-044 ++ LW1005-172 + LW1005-045 + LW1005-173 + LW1005-046 + LW1005-174 + LW1005-047 + LW1005-175 + LW1005-048 + LW1005-176 + LW1005-049 + LW1005-177 + LW1005-050 ++ LW1005-178 + LW1005-179 + LW1005-180 + LW1005-181 + LW1005-182 +

[0819] All documents mentioned in the present invention are incorporated herein by reference as if each individual document was specifically and individually incorporated by reference. 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 appended claims of this application.

Claims

1. A pharmaceutical composition, characterized in that, Comprising (1) a compound selected from the following group, or a pharmaceutically acceptable salt thereof; (2) a pharmaceutically acceptable carrier:

2. Use of the pharmaceutical composition according to claim 1, characterized in that, For preparing a pharmaceutical composition for preventing and / or treating a disease related to the activity or expression level of PD-1 / PD-L1.

3. The use according to claim 2, characterized in that, The pharmaceutical composition is used for treating a disease selected from the following group: cancer, infectious disease, autoimmune disease.

4. The use according to claim 3, characterized in that, The cancer is selected from the following group: pancreatic cancer, colorectal cancer, breast cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, melanoma, neuroendocrine cancer, central nervous system cancer, bone cancer, soft tissue sarcoma, colon cancer, skin cancer, lung cancer, urinary system tumor, hematological tumor, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, head and neck cancer.

5. The use according to claim 3, characterized in that, 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, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer or colon cancer, skin cancer, hematological tumor, glioma, lymphoma, brain tumor, head and neck cancer.

6. The use according to claim 3, wherein, The infectious disease is selected from bacterial infection, viral infection.

7. The use according to claim 3, characterized in that, The autoimmune disease is selected from organ-specific autoimmune disease, systemic autoimmune disease.

8. The use according to claim 2, characterized in that, The pharmaceutical composition further comprises at least one therapeutic agent selected from the following group: nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

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