5, 6-dihydrothieno [3, 4-h] quinazoline compound

Abstract

The invention discloses a series of 5, 6-dihydrothieno [3, 4-h] quinazoline compounds, and particularly discloses a compound as shown in a formula (P) and pharmaceutically acceptable salts thereof.

Description

[0001] This application is application number 202280011925.9, filed on January 26, 2022, and entitled "5,6-Dihydrothiophene[3,4- h Divisional application for quinazoline compounds.

[0002] This invention claims the following priority:

[0003] CN202110172946.6, application date: February 8, 2021;

[0004] CN202110655630.2, application date: June 11, 2021;

[0005] CN202110864387.5, application date: July 29, 2021;

[0006] CN202111137961.3, application date: September 27, 2021;

[0007] CN202111473661.2, application date: November 29, 2021. Technical Field

[0008] This invention relates to a series of 5,6-dihydrothiophene[3,4-] h Quinazoline compounds, specifically those represented by formula (P) and their pharmaceutically acceptable salts. Background Technology

[0009] Polo-like kinases (PLKs) are a class of highly conserved serine / threonine protein kinases, each possessing a highly homologous serine / threonine kinase domain at its N-terminus and a characteristic polobox domain (PBD) at its C-terminus that regulates PLK activity and subcellular dynamic localization. The PLK family has many members, with four isoforms in humans: PLK1, PLK2, PLK3, and PLK4, all playing crucial roles in the regulation of various phases of the cell cycle. Among these four family members, PLK1 has been the most thoroughly studied. Therefore, PLK1 is a target of widespread interest in tumor diagnosis and treatment.

[0010] Cardiff Oncology (formerly Trovagene), under license from Nerviano, is developing onvansertib (PCM-075; NMS-P937; nms-1286937; NMS-937), a fumarate, which is an oral Polo kinase-1 (PLK1) inhibitor. Onvansertib is a potential oral cancer treatment with indications including metastatic colorectal cancer (mCRC), solid tumors, acute myeloid leukemia (AML), and anti-metastatic castration prostate cancer. PLK1 is an effective therapeutic target that is overexpressed in most cancers, and onvansertib is a novel, highly selective PLK1 inhibitor.

[0011] Onvansertib, a PLK1 inhibitor, was the first to enter clinical trials. Early clinical results showed that 88% of KRAS-mutant mCRC patients experienced clinical benefit, and the inhibitor demonstrated acceptable safety. Compared to KRASG12C inhibitors, PLK1 inhibitors showed a higher response rate in CRC patients and were effective against all KRAS mutation subtypes. CRC is the third leading cause of cancer death after lung and breast cancer, with a global market valued at approximately $25 billion in 2018. Therefore, the search for highly active, selective, and metabolically stable small-molecule PLK1 inhibitors for cancer treatment is crucial. Summary of the Invention

[0012] This invention provides compounds of formula (P) or pharmaceutically acceptable salts thereof. , in, T1 is selected from CR1 and N; T2 is selected from CH and N; R1 is selected from H; R2 is selected from H, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 alkynyl group, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 alkynyl group, C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl groups are optionally surrounded by 1, 2 or 3 R groups. breplace; R3 is selected from C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups, wherein the C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups are optionally surrounded by 1, 2, or 3 R groups. c replace; R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. d replace; R5 is selected from H and OH; Alternatively, R1 and R3 can form rings with the adjacent atoms, creating structural fragments. Selected from ; Each R b Each of the following is independently selected from F, Cl, Br, I, OH, and OCH3; Each R c Selected independently from =O and C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 The alkylamino and heterocyclic butyl groups may be optionally substituted with 1, 2 or 3 R groups; Each R d They were each independently selected from F, Cl, Br, and I; Each R is independently selected from F, Cl, Br, I, and OH; The heteroatoms of the “heterocyclic butyl” and “7-9 membered heterocyclic alkyl” are selected from N, O and S.

[0013] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, , and The SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, , and Choose 1, 2, or 3 Rs b Replacement, other variables as defined in this invention.

[0014] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH2OH, S(=O)2CH3, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, CH3, CH2CH2OH, CH2OCH3, cyclopropyl, , and Other variables are as defined in this invention.

[0015] In some embodiments of the present invention, the R c Selected from =O, CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 may be replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0016] In some embodiments of the present invention, the R c Selected from =O, CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in this invention.

[0017] In some embodiments of the present invention, R3 is selected from CH2CH2CH3, , , and The CH2CH2CH3, , and Choose 1, 2, or 3 Rs c Replacement, other variables as defined in this invention.

[0018] In some embodiments of the present invention, R3 is selected from... , , , , , , , and Other variables are as defined in this invention.

[0019] The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from CH3, OCH3, OCHF2 and OCF3, and other variables are as defined in this invention.

[0020] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof. , in, T1 is selected from CR1 and N; T2 is selected from CH and N; R1 is selected from H; R2 is selected from H, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 alkynyl group, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 alkynyl group, C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl groups are optionally surrounded by 1, 2 or 3 R groups. b replace; R3 is selected from C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups, wherein the C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups are optionally surrounded by 1, 2, or 3 R groups. c replace; R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. d replace; Alternatively, R1 and R3 can form rings with the adjacent atoms, creating structural fragments. Selected from ; Each R b Each of the following is independently selected from F, Cl, Br, I, OH, and OCH3; Each R c Selected independently from =O and C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 The alkylamino and heterocyclic butyl groups may be optionally substituted with 1, 2 or 3 R groups; Each R d They were each independently selected from F, Cl, Br, and I; Each R is independently selected from F, Cl, Br, I, and OH; The heteroatoms of the “heterocyclic butyl” and “7-9 membered heterocyclic alkyl” are selected from N, O and S.

[0021] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, , and The SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, , and Choose 1, 2, or 3 Rs b Replacement, other variables as defined in this invention.

[0022] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH2OH, S(=O)2CH3, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, CH3, CH2CH2OH, CH2OCH3, cyclopropyl, , and Other variables are as defined in this invention.

[0023] In some embodiments of the present invention, the R c Selected from CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 may be replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0024] In some embodiments of the present invention, the R c Selected from CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in this invention.

[0025] In some embodiments of the present invention, R3 is selected from CH2CH2CH3, , , and The CH2CH2CH3, , and Choose 1, 2, or 3 Rs c Replacement, other variables as defined in this invention.

[0026] In some embodiments of the present invention, R3 is selected from... , , , , , , , and Other variables are as defined in this invention.

[0027] In some embodiments of the present invention, R4 is selected from CH3, OCH3, OCHF2 and OCF3, and other variables are as defined in the present invention.

[0028] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof. , in, T1 is selected from CR1 and N; T2 is selected from CH and N; R1 is selected from H; R2 is selected from H, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio and C 3-5 The cycloalkyl group is optionally surrounded by 1, 2 or 3 Rs. b replace; R3 is selected from C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups, wherein the C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups are optionally surrounded by 1, 2, or 3 R groups. c replace; R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. d replace; Alternatively, R1 and R3 can form rings with the adjacent atoms, creating structural fragments. Selected from ; Each R a They are independently selected from F, Cl, Br, I, CH3 and CF3, respectively; Each R b Each of the following is independently selected from F, Cl, Br, I, OH, and OCH3; Each R c Selected independently from =O and C 1-3 Alkyl, C1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 The alkylamino and heterocyclic butyl groups may be optionally substituted with 1, 2 or 3 R groups; Each R d They were each independently selected from F, Cl, Br, and I; Each R is independently selected from F, Cl, Br, I, and OH; The heteroatoms of the “heterocyclic butyl” and “7-9 membered heterocyclic alkyl” are selected from N, O and S.

[0029] In some embodiments of the present invention, the R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, and cyclopropyl, wherein the SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, and cyclopropyl are optionally replaced by 1, 2, or 3 Rs. b Replacement, other variables as defined in this invention.

[0030] In some embodiments of the present invention, R2 is selected from H, CN, SCH3, SCH2CH2OH, OCH2CH3, OCH2CH2OH, CH3, CH2CH2OH, CH2OCH3 and cyclopropyl, and other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the R c Selected from CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 may be replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0032] In some embodiments of the present invention, the R c Selected from CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in this invention.

[0033] In some embodiments of the present invention, R3 is selected from CH2CH2CH3, , , and The CH2CH2CH3, , and Choose 1, 2, or 3 Rs c Replacement, other variables as defined in this invention.

[0034] In some embodiments of the present invention, R3 is selected from... , , , , , , , and Other variables are as defined in this invention.

[0035] In some embodiments of the present invention, R4 is selected from CH3, OCH3, OCHF2 and OCF3, and other variables are as defined in the present invention.

[0036] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof. , in, T1 is selected from CR1 and N; T2 is selected from CH and N; R1 is selected from H; R2 is selected from C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylthio, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 The alkylthio group can be optionally surrounded by 1, 2, or 3 R groups. b replace; R3 is selected from C 1-4 alkyl and piperazine groups, the C 1-4 The alkyl and piperazine groups are optionally surrounded by 1, 2, or 3 R groups. c replace; R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. d replace; Alternatively, R1 and R3 form a pyrroloalkyl group with the attached atoms, wherein the pyrroloalkyl group is optionally... replace; Each R a They are independently selected from F, Cl, Br, I, CH3 and CF3, respectively; Each R b Each of the following is independently selected from F, Cl, Br, I, and OH; Each R c Selected independently from C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C1-3 Alkyl, C 1-4 The alkylamino and heterocyclic butyl groups may be optionally substituted with 1, 2 or 3 R groups; Each R d They were each independently selected from F, Cl, Br, and I; Each R is independently selected from F, Cl, Br, I, and OH; The heteroatom of the heterocyclic butyl group is selected from N, O and S.

[0037] In some embodiments of the present invention, the R2 is selected from SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, and CH(CH3)2, wherein the SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, and CH(CH3)2 are optionally represented by one, two, or three R2s. b Replacement, other variables as defined in this invention.

[0038] In some embodiments of the present invention, R2 is selected from SCH3, SCH2CH2OH, OCH2CH3 and CH2CH2OH, and other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the R c Selected from CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 may be replaced by 1, 2 or 3 Rs, and other variables are as defined in this invention.

[0040] In some embodiments of the present invention, the R c Selected from CH3, CH2CH2OH, N(CH3)2 and Other variables are as defined in this invention.

[0041] In some embodiments of the present invention, R3 is selected from CH2CH2CH3 and The Choose 1, 2, or 3 Rs c Replacement, other variables as defined in this invention.

[0042] In some embodiments of the present invention, R3 is selected from... , , , and Other variables are as defined in this invention.

[0043] In some embodiments of the present invention, R4 is selected from CH3, OCH3 and OCF3, and other variables are as defined in the present invention.

[0044] In some embodiments of the invention, R1 and R3 form a pyrroloalkyl group with the attached atoms, making the structural segment... Selected from Other variables are as defined in this invention.

[0045] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from... , Wherein, R2 and R3 are as defined in this invention.

[0046] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from... , Among them, R2 and R c As defined in this invention.

[0047] In some embodiments of the present invention, R2 is selected from C. 1-3 Alkoxy, C 1-3 Alkylthio and -OC 3-5 cycloalkyl, the C 1-3 Alkoxy, C 1-3 Alkylthio and -OC 3-5 The cycloalkyl group is optionally surrounded by 1, 2 or 3 Rs. b Replacement, other variables as defined in this invention.

[0048] In some embodiments of the present invention, R2 is selected from SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2, and... , the SCH3, SCH2CH3, SCH(CH3)2, OCH3, OCH2CH3, OCH(CH3)2 and Choose 1, 2, or 3 Rs b Replacement, other variables as defined in this invention.

[0049] In some embodiments of the present invention, R2 is selected from SCH3, SCH2CH2OH, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, and Other variables are as defined in this invention.

[0050] In some embodiments of the present invention, the R c Selected from CH3 and CH2CH2OH.

[0051] The present invention also provides compounds of formula (P-3) or pharmaceutically acceptable salts thereof. , in, R c As defined in this invention; L1 is selected from O and S; R6 is selected from C 1-3 Alkyl and C 3-5 Cycloalkyl.

[0052] In some embodiments of the present invention, R6 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl and cyclobutyl.

[0053] The present invention also includes some solutions derived from arbitrary combinations of the above variables.

[0054] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, wherein the compounds are selected from... .

[0055] The present invention also provides the use of the said compound or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating solid tumors.

[0056] The present invention also provides the use of the said compound or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating selective PLK1 inhibitor-associated solid tumors.

[0057] In some embodiments of the present invention, the solid tumor refers to colorectal cancer.

[0058] Related definitions

[0059] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0060] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0061] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0062] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0063] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, ( R )- and( S - Enantiomers, diastereomers, (D )-Isomer, ( L (Isomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, are all within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.)

[0064] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0065] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0066] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0067] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0068] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0069] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site decreases accordingly with the number of chemical bonds connected, resulting in a group with the corresponding valence. When the group has a fused, spiro, or bridged ring structure, and this fused, spiro, or bridged ring structure is connected to other groups by non-directional chemical bonds, any one or more sites of the fused, spiro, or bridged ring can be connected to other groups by chemical bonds. The chemical bonds connecting the sites to other groups can be straight solid line bonds (…). Straight dashed key ( ), or wavy lines ( () indicates that the oxygen atom in the group is bonded to another group. For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in the group is bonded to another group. The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... , , , Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a single chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a corresponding monovalent piperidinyl group. This indicates that any connectable site on this group can be linked to other groups via a single chemical bond, including at least... , , , , , , and These are the 8 connection methods.

[0070] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0071] Unless otherwise specified, the term "7-9 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated cyclic group consisting of 7 to 9 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, with regard to the “7-9 membered heterocyclic alkyl,” the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 7-9 membered heterocyclic alkyl group includes 7-, 8-, and 9-membered heterocyclic alkyl groups. Examples of 7-9 membered heterocyclic alkyl groups include, but are not limited to, those mentioned above. , and wait.

[0072] Unless otherwise specified, "C 3-5 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic system. 3-5 Cycloalkyl groups include C 3-4 and C 4-5 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0073] Unless otherwise specified, the terms "5-membered heteroaryl" and "5-membered heteroaryl" are used interchangeably in this invention. The term "5-membered heteroaryl" refers to a monocyclic group consisting of five ring atoms with a conjugated π-electron system, wherein one, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). A 5-membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. Examples of such 5-membered heteroaryl groups include, but are not limited to, pyrrole groups (including...). N -pyrroleyl, 2-pyrroleyl and 3-pyrroleyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazoleyl (including... N -imidazolium, 2-imidazolium, 4-imidazolium and 5-imidazolium, etc.), oxazolium (including 2-oxazolium, 4-oxazolium and 5-oxazolium, etc.), triazolium (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl and 4 H -1,2,4-triazolyl, tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), and thienyl (including 2-thienyl and 3-thienyl, etc.).

[0074] Unless otherwise specified, the term "C" 1-4 "Alkylamino" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-4 Alkylamino groups include C 1-3 C 1-2 C 2-4 C4, C3, and C2 alkylamino groups, etc. C 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0075] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0076] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via a sulfur atom. The C 1-3 Alkyl thio groups include C1-3 C 1-2 And C3 alkylthio groups, etc. C 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0077] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including...). n -propyl and isopropyl), butyl (including n -Butyl, Isobutyl s -Butyl and t (-Butyl) etc.

[0078] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including...). n -propyl and isopropyl, etc.

[0079] Unless otherwise specified, "C 2-3 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, acetylenyl and propynyl.

[0080] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0081] The structures of the compounds of this invention can be confirmed using conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After collecting relevant data by scanning / ω, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0082] The solvent used in this invention is commercially available. Attached Figure Description

[0083] Figure 1 In vivo pharmacodynamic study of a human colon cancer HCT-116 cell subcutaneous xenograft tumor model; tumor volume map; Figure 2 In vivo pharmacodynamic study of a human colon cancer HCT-116 cell subcutaneous xenograft tumor model, showing changes in body weight.

[0084] Technical effect

[0085] The compounds of this invention exhibit good inhibitory activity against PLK1, and can selectively inhibit PLK1, demonstrating good inhibitory activity against cell proliferation. In in vivo pharmacodynamic studies, they showed significant antitumor activity and were well tolerated in animals. The compounds of this invention also possess excellent pharmacokinetic properties. Detailed Implementation

[0086] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0087] Example 1

[0088] Step 1: Synthesis of Compounds 1-2

[0089] Compound 1-1 (500 mg, 1.85 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and tert-butoxybis(dimethylamino)methane (966.93 mg, 5.55 mol, 3 eq) was added at 20 °C. After the addition was complete, the temperature was raised to 90 °C and reacted for 12 hours. After the starting material disappeared as detected by LCMS, the temperature was lowered to 20 °C, and the solvent was removed by vacuum concentration using an oil pump to obtain compound 1-2. This crude product was directly used in the next reaction.

[0090] Characterization of compounds 1-2: 1 H NMR (400 MHz, CDCl3) d : 1.30 (t, J = 7.04 Hz, 3 H), 2.51 (s, 3 H), 2.78 - 2.82 (m, 2 H), 3.05 (s, 6 H), 3.07 - 3.11 (m, 2 H), 4.25 (q, J = 7.04Hz, 2H), 7.52 (s, 1H).

[0091] Step 2: Synthesis of compounds 1-4

[0092] Compounds 1-2 (180 mg, 553.09 µmol, 1 eq) and 1-3 (193.05 mg, 608.40 µmol, 1.1 eq) were dissolved in N,N-dimethylformamide (4 mL) sequentially, and the mixture was heated to 110 °C and reacted for 20 hours. After the disappearance of starting material 1-2 was detected by LCMS, the system was diluted with water (20 mL) and ethyl acetate (20 mL) was added. 3) Extract, separate, combine the organic phases and wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to obtain crude product, and separate the crude product by thin-layer chromatography (developing solvent: dichloromethane:methanol=20:1) to obtain compounds 1-4.

[0093] Characterization of compounds 1-4: LCMS: m / z (ESI) = 580.17 [M+H] + .

[0094] 1 H NMR (400 MHz, CDCl3) d: 1.46 - 1.50 (m, 3 H), 2.30 (s, 3 H), 2.53 (s, 4 H), 2.58 - 2.62 (m, 3 H), 2.66 - 2.70 (m, 2 H), 3.09 - 3.32 (m, 6 H), 4.25 - 4.29 (m, 2 H), 6.35 - 6.45 (m, 1 H), 7.03 - 7.07 (m, 1 H), 7.24 (s, 1H), 8.21 (s, 1 H), 8.32 - 8.36 (m, 1 H).

[0095] Step 3: Synthesis of Compound 1

[0096] Compounds 1-4 (90 mg, 155.26 µmol, 1 eq) were dissolved in tetrahydrofuran (1 mL), cooled to 0°C, and ammonium chloride (49.83 mg, 931.59 µmol, 6.0 eq) was added. A 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (1.55 mL, 10 eq) was then added. After the addition was complete, the temperature was raised to 25°C, and the reaction was carried out at this temperature for 2 hours. The reaction was quenched by adding ethanol (2 mL), and the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (HPLC) (Phenomenonex preparative chromatograph; column: C18 80). 40 mm 3 µm; mobile phase A: aqueous solution containing 0.05% ammonia, mobile phase B: acetonitrile; running gradient: B%: 38%-68%, run for 8 min. ), yielding compound 1.

[0097] Characterization of compound 1: LCMS: m / z (ESI) = 551.15 [M+H] + .

[0098] 1 H NMR (400 MHz, CDCl3) d: 2.22 (s, 3 H), 2.43 - 2.46 (m, 4 H), 2.54 (s, 3 H), 2.72 - 2.76 (m, 2 H), 3.08 - 3.18 (m, 6 H), 6.68 - 6.73 (m, 1 H),7.15 - 7.21 (m, 1 H), 7.44 (s, 2 H), 7.48 - 7.54 (m, 1 H), 8.33 (s, 1 H), 8.48 (s, 1 H).

[0099] Example 2

[0100] Step 1: Synthesis of Compound 2-2

[0101] Sodium tert-butoxide (127.13 mg, 1.32 mmol, 2 eq) was dissolved in tetrahydrofuran (1.6 mL). Ethanol (154 µL, 1.32 mmol, 1.9 eq) was added at 20 °C. After stirring for 30 minutes, the system was cooled to 0 °C, and compound 2-1 (200 mg, 661.45 µmol, 1 eq) was added. The reaction was continued for 1 hour after the addition was complete. After the reaction was finished, water (20 mL) was added to quench the reaction, and ethyl acetate (30 mL) was used to quench the reaction. 3) Extraction, combining the organic phases, washing the organic phases with saturated brine (50 mL), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain compound 2-2.

[0102] Characterization of compound 2-2: 1 H NMR (400 MHz, CDCl3) d: 1.38 - 1.42 (m, 3 H), 1.62 - 1.67 (m, 3 H), 2.02 - 2.14 (m, 2 H), 2.49 - 2.60 (m, 2 H), 3.20 - 3.27 (m, 2 H), 4.34 - 4.38 (m, 4 H).

[0103] Step 2: Synthesis of compounds 2-3

[0104] Compound 2-2 (80 mg, 298.14 µmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL), and tert-butoxybis(dimethylamino)methane (156.4 mg, 894.10 µmol, 3 eq) was added. The mixture was heated to 90 °C and reacted for 12 hours. After the reaction was completed, the temperature was lowered to 20 °C, and the solvent was removed by vacuum concentration using an oil pump to obtain compound 2-3. This crude product was used directly in the next reaction step.

[0105] Characterization of compounds 2-3: 1 H NMR (400 MHz, CDCl3) d : 1.26 - 1.32 (m, 3 H), 1.45 - 1.52 (m, 3 H), 2.73 - 2.76 (m, 2 H), 3.00 - 3.07 (m, 8 H), 4.19 - 4.25 (m, 4 H), 7.51 (s, 1H).

[0106] Step 3: Synthesis of compounds 2-4

[0107] Compounds 2-3 (10 mg, 30.92 µmol, 1 eq) and 1-3 (8.33 mg, 26.26 µmol, 0.849 eq) were dissolved sequentially in N,N-dimethylformamide (0.5 mL), and the mixture was heated to 110 °C and reacted for 12 hours. After the reaction was completed, the system was diluted with water (2 mL) and then diluted with ethyl acetate (2 mL). 3) Extract, combine the organic phases and wash with saturated brine (3 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain crude product, separate the crude product by thin-layer chromatography (developing solvent: dichloromethane:methanol=20:1) to obtain compounds 2-4.

[0108] Characterization of compounds 2-4: LCMS: m / z (ESI) = 578.20 [M+H] + .

[0109] 1 H NMR (400 MHz, CDCl3) d : 1.30 - 1.33 (m, 3 H), 1.45 - 1.50 (m, 3 H),2.30 (s, 3 H), 2.53 (s, 4 H), 2.68 - 2.72 (m, 2 H), 3.15 - 3.25 (m, 6 H),4.25 - 4.29 (m, 4 H), 4.36 - 4.43 (m, 1 H), 7.01 - 7.08 (m, 1H), 7.24 (s, 1H), 8.21 (s, 1H), 8.30 - 8.37 (m, 1H).

[0110] Step 4: Synthesis of Compound 2

[0111] Compound 2-4 (80 mg, 138.50 µmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL), and ammonium chloride (45 mg, 831.00 µmol, 6 eq) was added. The system was then cooled to 0 °C, and a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (1.39 mL, 1.39 mmol, 10 eq) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 20 °C, and the reaction was carried out at this temperature for 2 hours. The reaction was quenched by adding ethanol (3 mL), and the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (HPLC) (Phenomenonex preparative chromatograph; column: C18 80). 40 mm 3 µm; mobile phase A: aqueous solution containing 0.05% ammonia, mobile phase B: acetonitrile; running gradient: B%: 36%-66%, run for 8 min. ), yielding compound 2.

[0112] Characterization of compound 2: LCMS: m / z (ESI) = 549.19 [M+H] + .

[0113] 1 H NMR (400 MHz, CDCl3) d : 1.27 - 1.37 (m, 3 H), 2.22 (s, 3 H), 2.34 (s, 3 H), 2.68 (s, 2 H), 3.04 - 3.20 (m, 7 H), 4.19 - 4.26 (m, 2 H), 6.67 (s, 1 H), 7.17 (s, 1 H), 7.35 (s, 2 H), 7.84 (s, 1 H), 8.16 - 8.24 (m, 1 H), 8.32 (s, 1 H).

[0114] Example 3

[0115] Step 1: Synthesis of compound 3-2

[0116] Compound 2-1 (450 mg, 1.49 mmol, 1 eq) was dissolved in ethanol (5 mL), and 2-mercaptoethanol (151.17 mg, 1.93 mmol, 134.97 µL, 1.3 eq) and triethylamine (301.19 mg, 2.98 mmol, 414.29 µL, 2 eq) were added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was then diluted with water (10 mL) and further diluted with ethyl acetate (10 mL). 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-70:30) to obtain compound 3-2.

[0117] The characterization of compound 3-2 is as follows: LCMS: m / z (ESI) = 301.0 [M+H] + .

[0118] 1 H NMR (400 MHz, CDCl3) d : 4.30 - 4.39 (m, 2 H), 3.99 - 4.05 (m, 2 H), 3.26 - 3.34 (m, 2 H), 3.17 - 3.24 (m, 2 H), 2.53 - 2.61 (m, 2 H), 2.06 - 2.11(m, 2 H), 1.34 - 1.42 (m, 3H).

[0119] Step 2: Synthesis of compound 3-3

[0120] Compound 3-2 (260 mg, 865.53 µmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and tert-butoxybis(dimethylamino)methane (452.54 mg, 2.60 mmol, 536.18 µL, 3 eq) was added. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was then cooled to 20 °C, diluted with water (20 mL), and then ethyl acetate (10 mL) was added. The mixture was stirred, filtered, and the filter cake was slurried with ethanol (10 mL) for 0.5 hours. After filtration, the filter cake was concentrated under reduced pressure using an oil pump to remove any remaining solvent, yielding compound 3-3.

[0121] Characterization of compound 3-3: 1 H NMR (400 MHz, CDCl3) d : 7.65 (s, 1 H), 4.28 - 4.37 (m, 2 H), 3.88 -3.98 (m, 2 H), 3.21 - 3.28 (m, 2 H), 3.15 - 3.20 (m, 2 H), 3.14 (s, 6 H),2.82 - 2.91 (m, 2 H), 1.32 - 1.43 (m, 3 H).

[0122] Step 3: Synthesis of compounds 3-4

[0123] Compound 3-3 (300 mg, 843.95 µmol, 1 eq) was dissolved in N,N-dimethylaminoformamide (5 mL), and compound 1-3 (267.79 mg, 843.95 µmol, 1 eq) was added. The mixture was stirred at 110 °C for 16 hours. Saturated brine (15 mL) was added to the reaction system, and ethyl acetate (5 mL) was used as a distillate. 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compounds 3-4.

[0124] Characterization of compounds 3-4: LCMS: m / z (ESI) = 610.20 [M+H] + .

[0125] 1 H NMR (400 MHz, CD3OD) d: 8.29 (s, 1 H), 7.88 - 7.93 (m, 1 H), 7.15 -7.22 (m, 1 H), 6.66 - 6.76 (m, 1 H), 4.29 - 4.36 (m, 2 H), 3.79 - 3.89 (m, 2H), 3.26 - 3.30 (m, 6 H), 3.21 - 3.25 (m, 4 H), 2.78 - 2.85 (m, 2 H), 2.69 (s, 3 H), 2.39 - 2.44 (m, 2 H), 1.33 - 1.39 (m, 3 H).

[0126] Step 4: Synthesis of compounds 3-5

[0127] Compounds 3-4 (100 mg, 164.02 µmol, 1 eq) were dissolved in dichloromethane (2 mL), followed by the addition of triethylamine (24.90 mg, 246.03 µmol, 34.24 µL, 1.5 eq) and 4-dimethylaminopyridine (2.00 mg, 16.40 µmol, 0.1 eq), and then tert-butyldimethylchlorosilane (29.67 mg, 196.82 µmol, 24.12 µL, 1.2 eq). The mixture was stirred at 20 °C for 20 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product, which was purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compounds 3-5.

[0128] Characterization of compounds 3-5: LCMS: m / z (ESI) = 724.30 [M+H] + .

[0129] 1 H NMR (400 MHz, CD3OD) d: 8.29 (s, 1 H), 7.94 - 8.00 (m, 1 H), 7.12 -7.20 (m, 1 H), 6.65 - 6.73 (m, 1 H), 4.27 - 4.36 (m, 2 H), 3.91 - 3.99 (m, 2H), 3.25 - 3.29 (m, 6 H), 3.21 - 3.25 (m, 2 H), 2.78 - 2.87 (m, 2 H), 2.60 -2.70 (m, 4 H), 2.37 (s, 3 H), 1.32 - 1.40 (m, 3 H), 0.84 (s, 9 H), -0.01 (s,6 H).

[0130] Step 5: Synthesis of compounds 3-6

[0131] Compound 3-5 (70 mg, 96.69 µmol, 1 eq) was dissolved in tetrahydrofuran (1 mL), and ammonium chloride (31.03 mg, 580.16 µmol, 6 eq) was added. The mixture was then cooled to 0 °C, and a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (966.93 µL, 10 eq) was added. The mixture was then heated to 20 °C and stirred for 4 hours. Water (5 mL) was added to the reaction system, followed by ethyl acetate (5 mL). 3) Extract, separate, combine organic phases, dry organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure to remove solvent to obtain compounds 3-6.

[0132] Characterization of compounds 3-6: LCMS: m / z (ESI) = 695.20 [M+H] + .

[0133] 1 H NMR (400 MHz, CD3OD) d : 8.29 (s, 1 H), 7.99 - 8.03 (m, 1 H), 7.14 -7.21 (m, 1 H), 6.64 - 6.71 (m, 1 H), 3.90 - 3.96 (m, 2 H), 3.24 - 3.29 (m, 6H), 3.21 - 3.24 (m, 2 H), 2.79 - 2.86 (m, 2 H), 2.58 - 2.65 (m, 4 H), 2.37 (s, 3 H), 0.84 (s, 9 H), -0.02 (s, 6 H).

[0134] Step 6: Synthesis of Compound 3

[0135] Compound 3-6 (60 mg, 86.34 µmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL), followed by the addition of a 1 M tetrabutylamine tetrahydrofuran solution (172.69 µL, 2 eq). The resulting reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was washed with water (10 mL), followed by the addition of ethyl acetate (10 mL). 3) Extraction, separation, and drying of the combined organic phases with anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure to obtain the crude product. The crude product was then separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: C18 100). 30 mm 10 µm; Mobile phase A: 10 mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia), Mobile phase B: acetonitrile; Running gradient: B%: 25%-55%, run for 8 min. ), yielding compound 3.

[0136] Characterization of compound 3: LCMS: m / z (ESI) = 581.30 [M+H] + .

[0137] 1 H NMR (400 MHz, DMSO- d 6) d : 8.43 (s, 1 H), 8.32 (s, 1 H), 7.40 - 7.48 (m, 3 H), 7.13 - 7.20 (m, 1 H), 6.68 - 6.75 (m, 1 H), 5.02 - 5.09 (m, 1 H), 3.63 - 3.71 (m, 2 H), 3.12 - 3.17 (m, 4 H), 3.04 - 3.11 (m, 4 H), 2.71 - 2.76 (m, 2 H), 2.42 - 2.46 (m, 4 H), 2.07 (s, 3 H).

[0138] Example 4

[0139] Step 1: Synthesis of compound 4-2

[0140] Compound 4-1 (10 g, 45.87 mmol, 1 eq) was dissolved in dichloromethane (300 mL), and N,N-diisopropylethylamine (8.90 g, 68.89 mmol, 12.00 mL, 1.50 eq) and chloromethyl methyl ether (4.47 g, 55.52 mmol, 4.22 mL, 1.21 eq) were added. The mixture was stirred at 20 °C for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, and water (150 mL) and dichloromethane (150 mL) were added to the crude product. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 4-2.

[0141] The characterization of compound 4-2 is as follows: 1 H NMR (400 MHz, CDCl3) d : 3.53 (s, 3 H), 5.29 (s, 2 H), 7.20 – 7.28 (m, 1 H), 7.61 (s, 1 H), 7.92 – 7.99 (m, 1 H).

[0142] Step 2: Synthesis of Compound 4-3

[0143] Compound 4-2 (2 g, 7.63 mmol, 1 eq) was dissolved in toluene (12 mL) and dimethyl sulfoxide (4 mL), followed by the addition of N-methylmorpholine (1.15 g, 11.45 mmol, 1.27 mL, 1.5 eq), cesium carbonate (7.46 g, 22.90 mmol, 3 eq), tris(dibenzylacetone)palladium (139.77 mg, 152.64 µmol, 0.02 eq), and (S)-(-)-2,2-bis(di-p-tolylphosphine)-1,1-binaphthyl (207.22 mg, 305.28 µmol, 0.04 eq). The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was filtered through a funnel lined with diatomaceous earth. The filter cake was washed with ethyl acetate (150 mL). The filtrate was concentrated to dryness under reduced pressure. Then, ethyl acetate (50 mL) and saturated brine (50 mL) were added to the crude product. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to give compounds 4-3.

[0144] The characterization of compound 4-3 is as follows: LCMS: m / z (ESI) = 282.0 [M+H] + .

[0145] 1 H NMR (400 MHz, CDCl3) d : 2.37 (s, 3 H), 2.55 - 2.61 (m, 4 H), 3.14 -3.24 (m, 4 H), 3.53 (s, 3 H), 5.20 (s, 2 H), 7.09 (s, 1 H), 7.22 - 7.26 (m, 1H), 7.30 -7.36 (m, 1 H).

[0146] Step 3: Synthesis of compound 4-4

[0147] Compound 4-3 (950 mg, 3.38 mmol, 1 eq) was dissolved in dichloromethane (10 mL), followed by the addition of methanol (8.4 mL) and 12 M concentrated hydrochloric acid (1.6 mL, 5.69 eq). The mixture was stirred at 15 °C for 16 hours. The temperature was then raised to 35 °C and stirred for 8 hours. The solvent was concentrated to dryness under reduced pressure to obtain the hydrochloride salt of compound 4-4.

[0148] The hydrochloride salt of compound 4-4 is characterized as follows: LCMS: m / z (ESI) = 238.1 [M+H] + .

[0149] Step 4: Synthesis of compounds 4-5

[0150] The hydrochloride salt of compound 4-4 (400 mg, 1.46 mmol, 1 eq) was dissolved in dichloromethane (8 mL), cooled to 0°C in an ice bath, and then a mixed solution of potassium hydroxide (491.95 mg, 8.77 mmol, 6 eq) and water (2.4 mL) was added. Then, (bromodifluoromethyl)trimethylsilane (605.72 mg, 2.92 mmol, 2 eq) was added at 0°C, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was extracted with dichloromethane (5 mL) and water (5 mL), separated, dried over anhydrous sodium sulfate on the organic phase, filtered, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 4-5.

[0151] The characterization of compounds 4-5 is as follows: 1 H NMR (400 MHz, CDCl3) d : 2.44 - 2.54 (m, 3 H), 2.67 - 2.84 (m, 4 H), 3.37 (s, 4 H), 6.26 - 6.75 (m, 1 H), 7.06 - 7.10 (m, ,1 H), 7.26 (s, 1 H),7.30- 7.40 (m, 1H).

[0152] Step 5: Synthesis of compounds 4-6

[0153] 10% pure wet palladium on carbon (50 mg), methanol (5 mL), and compound 4-5 (30 mg, 104.43 µmol, 1 eq) were added sequentially under a micro-argon gas flow. The reaction solution was reacted at 15 °C for 2 hours under hydrogen (15 psi). The reaction solution was directly filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 4-6.

[0154] The characterization of compounds 4-6 is as follows: 1 H NMR (400 MHz, CD3OD) d : 2.92 (s, 3 H), 3.05 - 3.71 (m, 8 H), 6.26 -6.32 (m, 1 H), 6.36 - 6.78 (m, 2 H), 6.91 -6.95 (m, 1 H).

[0155] Step 6: Synthesis of compounds 4-7

[0156] Compound 4-6 (18 mg, 69.96 µmol, 1 eq) was dissolved in 6 M hydrochloric acid aqueous solution (180.00 µL, 15.44 eq), followed by the addition of aminonitrile (61.92 mg, 1.40 mmol, 61.92 µL, 20 eq), and stirred at 60 °C for 1 hour. Water (5 mL) and dichloromethane (5 mL) were added to the reaction solution, and the mixture was separated. Sodium hydroxide was added to the aqueous phase to adjust the pH to greater than 12, and then ethyl acetate (5 mL) was added. 2) Extract, separate, combine organic phases, dry organic phase with anhydrous sodium sulfate, filter, concentrate solvent under reduced pressure to dryness to obtain compounds 4-7.

[0157] The characterization of compounds 4-7 is as follows: LCMS: m / z (ESI) = 300.1 [M+H] + .

[0158] Step 7: Synthesis of compounds 4-8

[0159] Compounds 1-2 (20 mg, 44.68 µmol, 2.4 eq) were dissolved in N,N-dimethylformamide (0.5 mL), followed by the addition of compound 4-7 (6.26 mg, 18.62 µmol, 1 eq). The reaction mixture was stirred at 110 °C for 12 hours. Saturated saline solution (5 mL) and water (5 mL) were then added to the reaction mixture, followed by ethyl acetate (5 mL). 6) Extract, separate, combine the organic phases, and rinse the organic phases with saturated saline (5 mL). 6) Wash, dry with anhydrous sodium sulfate, filter, and concentrate the solvent under reduced pressure to dryness to obtain the crude product. The crude product is then separated and purified by high-performance liquid chromatography (HPLC) (Phenomenex preparative chromatograph; column: C18 75). 30mm 3µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 55%-85%, run for 12 min. ), to obtain compounds 4-8.

[0160] The characterization of compounds 4-8 is as follows: LCMS: m / z (ESI) = 562.2 [M+H] + .

[0161] 1 H NMR (400 MHz, CD3OD) d : 1.20- 1.28 (m, 3 H), 2.36 (s, 3 H), 2.58 -2.65 (m, 7 H), 2.80 -2.86 (m, 2 H), 3.19 - 3.26 (m, 4 H), 3.25 -3.30 (m, 2H), 4.30 -4.36 (m, 2 H), 6.69 -6.73 (m, 2 H), 7.04 - 7.13 (m, 1 H), 8.00 -8.05 (m, 1 H), 8.28 (s, 1 H).

[0162] Step 8: Synthesis of Compound 4

[0163] Compound 4-8 (2 mg, 3.56 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (1 mL), and ammonium chloride (38.09 mg, 712.17 µmol, 200 eq) and a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (1.42 mL, 400 eq) were added. The mixture was stirred at 20 °C for 3 hours. The reaction solution was quenched with methanol (5 mL), and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: C18 100). 25mm 5µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 20%-55%, run for 10 min. ), yielding compound 4.

[0164] The characterization of compound 4 is as follows: LCMS: m / z (ESI) = 533.2 [M+H] + .

[0165] 1 H NMR (400 MHz, CD3OD) d : 2.36 (s, 3 H), 2.59 - 2.69 (m, 5 H), 2.82 -2.86 (m, 2 H), 3.11 - 3.27 (m, 8 H), 6.50 - 6.93 (m, 2 H), 7.05 - 7.25 (m, 1H), 8.03 (d, J =2.86 Hz, 1 H), 8.29 (s, 1 H).

[0166] Example 5

[0167] Step 1: Synthesis of Compound 5-2

[0168] Compound 5-1 (2 g, 8.26 mmol, 1 eq) was dissolved in toluene (20 mL), and N-methylpiperazine (827.81 mg, 8.26 mmol, 916.73 µL, 1.00 eq), sodium tert-butoxide (1.19 g, 12.40 mmol, 1.5 eq), tris(dibenzylacetone)palladium (378.41 mg, 413.23 µmol, 0.05 eq) and (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (257.31 mg, 413.23 µmol, 0.05 eq) were added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction mixture was quenched with water (5 mL) and then quenched with ethyl acetate (5 mL). 3) Extract, separate, combine the organic phases, and concentrate the organic phase under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to obtain compound 5-2.

[0169] The characterization of compound 5-2 is as follows: LCMS: m / z (ESI) = 262.30 [M+H] + .

[0170] 1 H NMR (400 MHz, CDCl3) d : 8.07 - 8.14 (m, 1 H), 7.32 - 7.39 (dd, J =9.2 Hz, 1 H), 6.57 - 6.67 (d, J = 9.2 Hz, 1 H), 3.52 - 3.61 (t, J = 5.2 Hz, 4H), 2.46 - 2.58 (t, J = 5.2 Hz, 4 H), 2.36 (s, 3 H).

[0171] Step 2: Synthesis of Compound 5-3

[0172] Under nitrogen protection at -78°C, compound 5-2 (500 mg, 1.91 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), followed by the addition of 2 M diisopropylaminolithium tetrahydrofuran solution (1.44 mL, 1.5 eq). The reaction mixture was stirred at -78°C for 2 hours. Then, anhydrous tetrahydrofuran solution (2 mL) containing iodine (728.65 mg, 2.87 mmol, 1.5 eq) was added, and the reaction mixture was stirred at -78°C for 2 hours. Subsequently, the reaction system was heated to 80°C and stirred for 16 hours. The reaction was quenched by adding water (10 mL) and quenched with ethyl acetate (15 mL). 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to obtain compound 5-3.

[0173] Characterization of compound 5-3: LCMS: m / z (ESI) = 388.00 [M+H] + .

[0174] 1 H NMR (400 MHz, CDCl3) d : 7.99 - 8.06 (m, 1 H), 7.09 (s, 1 H), 3.55 -3.67 (m, 4 H), 2.48 - 2.65 (m, 4 H), 2.40 (s, 3 H).

[0175] Step 3: Synthesis of Compounds 5-4

[0176] Compound 1-2 (300 mg, 921.81 µmol, 1 eq) was dissolved in N,N-dimethylformamide (5 mL), and guanidine carbonate (415.20 mg, 2.30 mmol, 2.5 eq) was added. The mixture was stirred at 110 °C for 3 hours. Water (10 mL) was added to the reaction solution, and the mixture was stirred for 0.5 hours. The mixture was filtered, and the filter cake was washed with methanol (10 mL). The solvent residue was removed under reduced pressure using an oil pump to obtain compound 5-4.

[0177] Characterization of compound 5-4: LCMS: m / z (ESI) = 321.90 [M+H] + .

[0178] 1 H NMR (400 MHz, DMSO- d6) d : 8.13 (s, 1 H), 6.31 - 6.39 (m, 2 H), 4.22- 4.31 (m, 2 H), 3.14 - 3.21 (m, 2 H), 2.65 - 2.72 (m, 2 H), 2.61 (s, 3 H),1.25 - 1.33 (m, 3H).

[0179] Step 4: Synthesis of compound 5-5

[0180] Compound 5-4 (49.81 mg, 154.98 µmol, 1 eq) was dissolved in 1,4-dioxane (2 mL). Under nitrogen protection, tris(dibenzylacetone)dipalladium (14.19 mg, 15.50 µmol, 0.1 eq), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (8.97 mg, 15.50 µmol, 0.1 eq), cesium carbonate (100.99 mg, 309.97 µmol, 2 eq), and compound 5-3 (60 mg, 154.98 µmol, 1 eq) were added. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was quenched with water (10 mL) and then quenched with ethyl acetate (10 mL). 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to obtain compound 5-5.

[0181] Characterization of compound 5-5: LCMS: m / z (ESI) = 581.20 [M+H] + .

[0182] 1 H NMR (400 MHz, CDCl3) d : 1.40 -1.46 (m, 3 H), 2.38 (3 H), 2.53 -2.65 (m, 4 H), 2.67 (s, 3 H), 2.83 -2.86 (m, 2 H), 3.23 - 3.37 (m, 6 H), 4.35-4.39 (m, 2 H), 6.50 - 6.55 (m, 1 H), 7.12 -7.16 (m, 1 H), 8.24 -8.30 (m, 1H), 8.30 (s, 1 H).

[0183] Step 5: Synthesis of Compound 5

[0184] Compound 5-5 (90 mg, 155.00 µmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and ammonium chloride (49.75 mg, 930.00 µmol, 6 eq) was added. Under nitrogen protection, a 1 M solution of lithium di(trimethylsilyl)aminotetrahydrofuran (3.10 mL, 20 eq) was added at 0 °C, and the mixture was stirred at 20 °C for 3 hours. The reaction was quenched by adding water (10 mL), followed by the addition of ethyl acetate (15 mL). 3) Extraction, separation, and combination of organic phases. The organic phase is concentrated under reduced pressure to obtain the crude product. The crude product is then separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: C18 100). 30mm 10µm; Mobile phase A: 10mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia), Mobile phase B: acetonitrile; Running gradient: B%: 30%-60%, run for 8 min. ), yielding compound 5.

[0185] Characterization of compound 5: LCMS: m / z (ESI) = 552.20 [M+H] + .

[0186] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.77 (s, 1 H), 8.48 (s, 1 H), 8.02 - 8.06 (m, 1 H), 7.70 (s, 1 H), 7.47 (s, 2 H), 3.45 - 3.53 (m, 4 H), 3.10 - 3.19 (m, 2 H), 2.77 - 2.84 (m, 2 H), 2.61 (s, 3 H), 2.36 - 2.41 (m, 4 H), 2.20 (s, 3H).

[0187] Example 6

[0188] Step 1: Synthesis of Compound 6-2

[0189] Potassium carbonate (51.77 g, 374.58 mmol, 2 eq) was dissolved in dimethyl sulfoxide (200 mL), and then compound 6-1 (21 g, 187.29 mmol, 1 eq) was added. The mixture was stirred at 20 °C for 10 minutes. Carbon disulfide (15.69 g, 206.02 mmol, 12.45 mL, 1.1 eq) was added, and the mixture was stirred at 20 °C for 10 minutes. Then, a mixed solution of ethyl bromoacetate (31.28 g, 187.29 mmol, 20.71 mL, 1 eq) and methyl iodoform (26.58 g, 187.29 mmol, 11.66 mL, 1 eq) was added at 0 °C, while maintaining the temperature at 15–20 °C. After the addition was complete, the mixture was stirred at 20 °C for 1 hour. Add water (500 mL) and saturated saline solution (300 mL) to the reaction solution, and then add ethyl acetate (500 mL). 3) Extract, separate, combine the organic phases, wash with saturated brine (500 mL), separate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness to obtain crude product, purify the crude product by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain product, then slurry with methyl tert-butyl ether (15 mL) for 1 hour, filter, collect the filter cake to obtain compound 6-2.

[0190] The characterization of compound 6-2 is as follows: LCMS: m / z (ESI) = 343.0 [M+H] + .

[0191] 1 H NMR (400 MHz, CDCl3) d : 1.28 - 1.34 (m, 3 H), 1.34 - 1.42 (m, 3 H), 1.92 - 2.16 (m, 2 H), 2.48 - 2.68 (m, 2 H), 3.18 - 3.26 (m, 2 H), 3.86 (s, 2H), 4.18 - 4.44 (m, 4 H).

[0192] Step 2: Synthesis of Compound 6-3

[0193] Raney nickel (5.20 g, 60.70 mmol, 4.00 eq) and ethanol (150 mL) were added under a micro-argon flow, followed by compound 6-2 (5.2 g, 15.19 mmol, 1 eq). The reaction mixture was reacted at 30 °C for 48 hours under hydrogen (50 psi). The reaction mixture was passed through a funnel lined with diatomaceous earth, and the filter cake was washed with ethanol (800 mL). The filtrate was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain the product. The product was dissolved in methyl tert-butyl ether (20 mL), followed by the addition of petroleum ether (30 mL). After stirring for 1 hour, the mixture was filtered, and the filter cake was collected to obtain compound 6-3.

[0194] The characterization of compound 6-3 is as follows: 1 H NMR (400 MHz, CDCl3) d : 1.40 -1.50 (m, 3 H), 1.96 - 2.24 (m, 2 H), 2.41 - 2.75 (m, 2 H), 3.23 -3.26 (m, 2 H), 4.34 - 4.40 (m, 2 H), 8.29 (s, 1H).

[0195] Step 3: Synthesis of Compound 6-4

[0196] Compound 6-3 (1 g, 4.46 mmol, 1 eq) was dissolved in anhydrous ethanol (20 mL), and sodium borohydride (280 mg, 7.40 mmol, 1.66 eq) was added. The mixture was stirred at 20 °C for 2 hours. Water (10 mL) was added to the reaction solution, and the pH was adjusted to 6 with 1 M dilute hydrochloric acid solution. The solution was then concentrated under reduced pressure until the solvent level no longer decreased. Water (10 mL) and saturated saline solution (10 mL) were added to the crude product, and the solution was further concentrated with ethyl acetate (40 mL). 2) Extract, separate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the solvent under reduced pressure to dryness. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to give compounds 6-4.

[0197] The characterization of compound 6-4 is as follows: LCMS: m / z (ESI) = 209.1 [M-17] + .

[0198] 1 H NMR (400 MHz, CDCl3) d: 1.34 – 1.40 (m, 3 H), 1.54 – 1.83 (m, 3 H), 1.92 – 2.12 (m, 2 H), 3.03 – 3.09 (m, 2 H), 4.33 – 4.38 (m, 2 H), 4.74 – 4.87 (m, 1 H), 7.53 (s, 1 H).

[0199] Step 4: Synthesis of compounds 6-5

[0200] Compound 6-4 (8 g, 35.35 mmol, 1 eq) was dissolved in dichloromethane (110 mL), followed by the addition of acetyl chloride (11.10 g, 141.41 mmol, 10.09 mL, 4 eq), 4-dimethylaminopyridine (431.90 mg, 3.54 mmol, 0.1 eq), and pyridine (13.98 g, 176.76 mmol, 14.27 mL, 5 eq). The mixture was stirred at 20 °C for 2 hours. The solvent was concentrated under reduced pressure to one-third of its original volume, and water (30 mL) was added. The mixture was separated, and the organic phase was washed with water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-85:15) to obtain compound 6-5.

[0201] The characterization of compound 6-5 is as follows: LCMS: m / z (ESI) = 209.0 [M-59] + .

[0202] 1 H NMR (400 MHz, CDCl3) d : 1.37 -1.40 (m, 3 H), 1.78 - 2.01 (m, 4 H), 2.08 (s, 3 H), 2.76 - 3.30 (m, 2 H), 4.33 -4.38 (m, 2 H), 5.93 -6.00 (m, 1H), 7.52 (s, 1 H).

[0203] Step 5: Synthesis of Compound 6-6

[0204] Compound 6-5 (3.1 g, 11.55 mmol, 1 eq) was dissolved in N,N-dimethylformamide (31 mL), followed by the addition of N-bromosuccinimide (6.37 g, 35.81 mmol, 3.1 eq), and the mixture was stirred at 50 °C for 16 hours. Ethyl acetate (50 mL) and saturated brine (50 mL) were added to the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-95:5) to give compound 6-6.

[0205] The characterization of compound 6-6 is as follows: LCMS: m / z (ESI) =286.9,288.9 [M-59] + .

[0206] 1 H NMR (400 MHz, CDCl3) d : 1.31 - 1.40 (m, 3 H), 1.71 - 1.89 (m, 3 H), 2.09 (s, 3 H), 2.19 (s, 1 H), 2.64 - 2.79 (m, 1 H), 3.29 - 3.49 (m, 1 H), 4.32 -4. 39 (m, 2 H), 5.86 - 6.20 (m, 1 H).

[0207] Step 6: Synthesis of compounds 6-7

[0208] Compound 6-6 (3.7 g, 10.66 mmol, 1 eq) was dissolved in ethanol (37 mL), followed by the addition of potassium carbonate (1.47 g, 10.66 mmol, 1 eq). The mixture was stirred at 40 °C for 16 hours, then heated to 60 °C and stirred for 4 hours. The reaction mixture was filtered, and the filter cake was washed with ethanol (500 mL). The filtrate was collected and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 6-7.

[0209] The characterization of compounds 6-7 is as follows: LCMS: m / z (ESI) =286.9,288.8 [M-17] + .

[0210] 1 H NMR (400 MHz, CDCl3) d: 1.36 -1.42 (m, 3 H), 1.77 - 1.80 (m, 4 H), 2.02 - 2.20 (m, 1 H), 2.61 - 2.81 (m, 1 H), 3.24 - 3.44 (m, 1 H), 4.32 -4.40 (m, 2 H), 4.88 -4.93 (m, 1 H).

[0211] Step 7: Synthesis of compounds 6-8

[0212] Compounds 6-7 (1.76 g, 5.77 mmol, 1 eq) were dissolved in dichloromethane (30 mL), followed by the addition of pyridinium chlorochromate (3.73 g, 17.30 mmol, 3 eq) and sodium acetate (1.42 g, 17.30 mmol, 3 eq). The mixture was stirred at 20 °C for 2 hours. The reaction solution was filtered through a funnel lined with diatomaceous earth, washed with ethyl acetate (50 mL) and dichloromethane (50 mL), and the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-80:20) to give compounds 6-8.

[0213] The characterization of compounds 6-8 is as follows: LCMS: m / z (ESI) =302.9,304.9 [M+H] + .

[0214] 1 H NMR (400 MHz, CDCl3) d : 1.38 – 1.42 (m, 3 H), 2.10 -2.15 (m, 2 H), 2.59 – 2.65 (m, 2 H), 3.27 –3.30 (m, 2 H), 4.35 – 4.40 (m, 2 H).

[0215] Step 8: Synthesis of compounds 6-10

[0216] Compound 6-8 (203 mg, 669.59 µmol, 1 eq), compound 6-9 (332.79 mg, 1.34 mmol, 2 eq), 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (62.49 mg, 133.92 µmol, 0.2 eq), bis(acetonitrile)palladium(II) chloride (17.37 mg, 66.96 µmol, 0.1 eq), and cesium carbonate (654.49 mg, 2.01 mmol, 3 eq) were added to the reaction flask. Then, a mixed solution of water (1 mL) and tert-butanol (1 mL) was added. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. Ethyl acetate (100 mL), saturated saline solution (50 mL), and water (50 mL) were added to the reaction solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 6-10.

[0217] The characterization of compounds 6-10 is as follows: LCMS: m / z (ESI) = 375.0 [M+Na] + .

[0218] 1 H NMR (400 MHz, CDCl3) d : 1.38 -1.43 (m, 3 H), 1.54 - 1.57 (m, 6 H), 2.07 - 2.10 (m, 2 H), 2.47 - 2.62 (m, 2 H), 3.23 -3.30 (m, 2 H), 3.59 -3.62(m, 6 H), 4.34 -4.37 (m, 2 H), 4.66 -4.70 (m, 1 H).

[0219] Step 9: Synthesis of compounds 6-11

[0220] Compound 6-10 (283 mg, 802.96 µmol, 1 eq) was dissolved in ethanol (10 mL), and p-toluenesulfonic acid monohydrate (158.48 mg, 833.15 µmol, 1.04 eq) was added. The mixture was stirred at 20 °C for 1 hour. The solvent was concentrated under reduced pressure to dryness to obtain a crude product, which was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-80:20) to give compound 6-11.

[0221] The characterization of compound 6-11 is as follows: LCMS: m / z (ESI) = 268.9 [M+H] + .

[0222] 1 H NMR (400 MHz, CDCl3) d : 1.38 – 1.41 (m, 3 H), 1.80 (s, 1 H), 2.01 -2.17 (m, 2 H), 2.49 - 2.63 (m, 2 H), 3.24 -3.30 (m, 2 H), 3.51 -3.56 (m, 2H), 3.95 -4.06 (m, 2 H), 4.34 – 4.38 (m, 2 H).

[0223] Step 10: Synthesis of compounds 6-12

[0224] Compound 6-11 (50 mg, 186.34 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (7.5 mL), and then tert-butoxybis(dimethylamino)methane (162.38 mg, 931.70 µmol, 192.39 µL, 5 eq) was added. The mixture was stirred at 80 °C for 12 hours. The solvent was concentrated to dryness under reduced pressure to give compound 6-12.

[0225] The characterization of compound 6-12 is as follows: LCMS: m / z (ESI) = 297.0 [M-26] + .

[0226] Step 11: Synthesis of compounds 6-13

[0227] Compound 6-12 (60 mg, 185.53 µmol, 1 eq) was dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of compound 1-3 (58.87 mg, 185.53 µmol, 1 eq). The mixture was stirred at 110 °C for 12 hours. Ethyl acetate (10 mL), water (5 mL), and saturated brine (5 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane:methanol = 100:0-90:10) to obtain compound 6-13.

[0228] The characterization of compound 6-13 is as follows: LCMS: m / z (ESI) = 578.1 [M+H] + .

[0229] Step 12: Synthesis of Compound 6

[0230] Compound 6-13 (8 mg, 13.85 µmol, 1 eq) was dissolved in tetrahydrofuran (0.8 mL), and the mixture was kept under nitrogen protection at 0 °C. Ammonium chloride (30 mg, 560.84 µmol, 40.49 eq) and a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (567.85 µL, 41 eq) were then added, and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with methanol (5 mL), and the solvent was concentrated to dryness under reduced pressure. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: Prep Sunfire C18 100). 30mm 10 µm; Mobile phase A: 10 mM ammonium bicarbonate aqueous solution, Mobile phase B: acetonitrile; Running gradient: B%: 35%-50%, run for 8 min. ), yielding compound 6.

[0231] The characterization of compound 6 is as follows: LCMS: m / z (ESI) = 549.3 [M+H] + .

[0232] 1H NMR (400 MHz, DMSO- d 6 ) d : 2.18 - 2.26 (m, 3 H), 2.29 - 2.38 (m, 4H), 2.40 - 2.46 (m, 4 H), 2.68 - 2.81 (m, 4 H), 3.02 - 3.17 (m, 4 H), 4.55 -4.70 (m, 1 H), 6.66 - 6.87 (m, 1 H), 7.11 - 7.27 (m, 2 H), 7.32 - 7.51 (m, 2H), 8.27 - 8.37 (m, 1 H), 8.62 - 8.74 (m, 1 H).

[0233] Example 7

[0234] Step 1: Synthesis of Compound 7-2

[0235] Compound 7-1 (4 g, 15.62 mmol, 1 eq) was dissolved in tetrahydrofuran (40 mL), and 2-dicyclohexylphospho-2-(N,N-dimethylamine)-biphenyl (491.90 mg, 1.25 mmol, 0.08 eq), tris(dibenzylacetone)dipalladium (1.14 g, 1.25 mmol, 0.08 eq) were added. Under nitrogen protection, a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (37.50 mL, 2.4 eq) and 1-Boc-piperazine (4.36 g, 23.44 mmol, 1.5 eq) were added. The resulting reaction mixture was stirred at 80 °C for 3 hours under nitrogen protection. The reaction mixture was quenched with water (60 mL) and quenched with dichloromethane (50 mL). 3) Extract, separate, combine the organic phases and dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane:methanol = 100:0-98:2) to obtain compound 7-2.

[0236] The characterization of compound 7-2 is as follows: LCMS: m / z (ESI) = 362.10 [M+H] + .

[0237] 1 H NMR (400 MHz, CDCl3) d : 7.00 - 7.06 (m, 1 H), 6.26 - 6.35 (m, 2 H), 3.78 - 3.86 (m, 2 H), 3.53 - 3.58 (m, 4 H), 3.02 - 3.14 (m, 4 H), 1.49 (s, 9H).

[0238] Step 2: Synthesis of Compound 7-3

[0239] Compound 7-2 (2 g, 5.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (60 mL) solution, and sodium nitrite (1.53 g, 22.14 mmol, 4 eq) was added. Then, 45% hydroiodic acid aqueous solution (3.78 g, 13.28 mmol, 2.22 mL, 2.4 eq) was added dropwise at 20 °C. The reaction temperature was then increased to 35 °C and stirred for 16 hours. Water (60 mL) was added to dilute the reaction mixture, followed by the addition of ethyl acetate (50 mL). 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-80:20) to obtain compound 7-3.

[0240] Characterization of compound 7-3: LCMS: m / z (ESI) = 473.00 [M+H] + .

[0241] 1 H NMR (400 MHz, CDCl3) d : 7.32 - 7.34 (m, 1 H), 7.11 - 7.16 (m, 1 H), 6.85 - 6.91 (m, 1 H), 3.55 - 3.61 (m, 4 H), 3.09 - 3.16 (m, 4 H), 1.49 (s, 9H).

[0242] Step 3: Synthesis of Compound 7-4

[0243] Compound 5-4 (180.36 mg, 561.16 µmol, 1 eq) was dissolved in 1,4-dioxane (8 mL) solution. Tris(dibenzylacetone)dipalladium (51.39 mg, 56.12 µmol, 0.1 eq), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (32.47 mg, 56.12 µmol, 0.1 eq), and cesium carbonate (365.67 mg, 1.12 mmol, 2 eq) were added under nitrogen protection. Compound 7-3 (265 mg, 561.16 µmol, 1 eq) was added after three nitrogen purgings. The resulting reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was quenched with water (20 mL), followed by the addition of ethyl acetate (20 mL). 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-80:20) to obtain compound 7-4.

[0244] Characterization of compound 7-4: LCMS: m / z (ESI) = 666.20 [M+H] + .

[0245] 1 H NMR (400 MHz, CDCl3) d: 8.31 (s, 1 H), 8.27 - 8.30 (m, 1 H), 7.09 -7.19 (m, 1 H), 6.48 - 6.56 (m, 1 H), 5.28 - 5.35 (m, 1 H), 4.32 - 4.42 (m, 2H), 3.53 - 3.63 (m, 4 H), 3.28 - 3.37 (m, 2 H), 3.12 - 3.24 (m, 4 H), 2.83 (t, J=7.2 Hz, 2 H), 2.66 (s, 3 H), 1.49 (s, 9 H), 1.38 - 1.43 (m, 3 H).

[0246] Step 4: Synthesis of Compounds 7-5

[0247] Compound 7-4 (300 mg, 450.62 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (10 mL), and ammonium chloride (144.63 mg, 2.70 mmol, 6 eq) was added. The reaction was carried out under nitrogen protection, and the temperature was lowered to 0 °C. A 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (9.01 mL, 20 eq) was added, and the resulting reaction mixture was stirred at 20 °C for 3 hours. The reaction was quenched with water (15 mL) and quenched with ethyl acetate (20 mL). 3) Extract, separate, combine organic phases, concentrate the organic phase to dryness under reduced pressure, and separate the crude product by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 7-5.

[0248] Characterization of compound 7-5: LCMS: m / z (ESI) = 637.20 [M+H] + .

[0249] 1 H NMR (400 MHz, CDCl3) d : 8.25 - 8.31 (m, 1 H), 8.14 - 8.24 (m, 1 H), 7.13 - 7.21 (m, 1 H), 6.52 - 6.63 (m, 1 H), 5.50 - 5.59 (m, 2 H), 3.54 - 3.65 (m, 4 H), 3.25 - 3.33 (m, 2 H), 3.13 - 3.25 (m, 4 H), 2.81 - 2.90 (m, 2 H), 2.64 (s, 3 H), 1.49 (s, 9 H).

[0250] Step 5: Synthesis of Compound 7

[0251] Compound 7-5 (100 mg, 157.06 µmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3.85 g, 33.77 mmol, 2.50 mL, 214.99 eq) was added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC method: Waters Xbridge Prep OBD preparative chromatograph; column: C18 150). 40mm 10µm; Mobile phase A: 10mM ammonium bicarbonate aqueous solution (0.05% ammonia), Mobile phase B: acetonitrile; Running gradient: B%: 20%-50%, run for 8 min. ), yielding compound 7.

[0252] Characterization of compound 7: LCMS: m / z (ESI) = 537.10 [M+H] + .

[0253] 1 H NMR (400 MHz, DMSO- d 6) d : 8.46 (s, 1 H), 8.32 (s, 1 H), 7.47 - 7.51 (m, 1 H), 7.41 - 7.46 (m, 2 H), 7.13 - 7.20 (m, 1 H), 6.66 - 6.71 (m, 1 H), 3.08 - 3.15 (m, 2 H), 2.95 - 3.05 (m, 4 H), 2.79 - 2.84 (m, 4 H), 2.71 - 2.76 (m, 2 H), 2.54 (s, 3 H).

[0254] Example 8

[0255] Step 1: Synthesis of Compound 8-1

[0256] Compound 7 (80 mg, 149.09 µmol, 1 eq) was dissolved in a mixed solution of anhydrous tetrahydrofuran (5 mL) and dimethyl sulfoxide (2.5 mL). The pH was adjusted to 7-8 with triethylamine (15.09 mg, 149.09 µmol, 20.75 µL, 1 eq), and then adjusted to 5-6 with acetic acid (35.81 mg, 596.36 µmol, 34.11 µL, 4 eq). At 0 °C, (tert-butyldimethylsiloxy)acetaldehyde (64.97 mg, 372.72 µmol, 71.01 µL, 2.5 eq) was added and stirred for 0.5 h. At 0 °C, sodium triacetoxyborohydride (69.52 mg, 328.00 µmol, 2.2 eq) was added, and the resulting reaction solution was stirred at 20 °C for 2 h. Add water (3 mL) to the reaction system, then add ethyl acetate (5 mL). 3) Extract, separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 8-1.

[0257] The characterization of compound 8-1 is as follows: LCMS: m / z (ESI) = 695.20 [M+H] + .

[0258] 1 H NMR (400 MHz, CDCl3) d : 8.31 (s, 1 H), 8.20 - 8.27 (m, 1 H), 7.32 -7.38 (m, 1 H), 7.12 - 7.20 (m, 1 H), 6.47 - 6.56 (m, 1 H), 5.65 - 5.75 (m, 2H), 3.86 - 4.01 (m, 2 H), 3.37 - 3.44 (m, 2 H), 3.21 - 3.35 (m, 4 H), 2.81 -2.99 (m, 6 H), 2.66 (s, 3 H), 1.24 - 1.29 (m, 2 H), 0.90 (s, 9 H), 0.09 (s, 6H).

[0259] Step 2: Synthesis of Compound 8

[0260] Compound 8-1 (100 mg, 143.90 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (0.5 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (287.81 µL, 2 eq) was added. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was washed with water (20 mL) and precipitated with ethyl acetate (25 mL). 3) Extraction, separation, and combination of organic phases; drying of the organic phase with anhydrous sodium sulfate; filtration; and concentration under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge Prep OBD preparative chromatograph; column: C18 150). 40mm 10µm; Mobile phase A: 10mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia), Mobile phase B: acetonitrile; Running gradient: B%: 20%-50%, run for 8 min. Compound 8 was obtained.

[0261] Characterization of compound 8: LCMS: m / z (ESI) = 581.20 [M+H] + .

[0262] 1 H NMR (400 MHz, DMSO- d 6) d : 8.44 - 8.48 (m, 1 H), 8.31 (s, 1 H), 7.49- 7.52 (m, 1 H), 7.40 - 7.46 (m, 2 H), 7.13 - 7.19 (m, 1 H), 6.68 - 6.72 (m, 1 H), 4.39 - 4.45 (m, 1 H), 3.49 - 3.56 (m, 2 H), 3.29 (s, 3 H), 3.09 - 3.17 (m, 6 H), 2.71 - 2.77 (m, 2 H), 2.52 -2.60 (m, 4 H), 2.40 - 2.46 (m, 2 H).

[0263] Example 9

[0264] Step 1: Synthesis of Compound 9-2

[0265] Compound 9-1 (2.4 g, 11.06 mmol, 1 eq), dichlorobis(triphenylphosphine)palladium(II) (194.06 mg, 276.47 µmol, 0.025 eq), and cuprous iodide (105.31 mg, 552.94 µmol, 0.05 eq) were added to a reaction flask, followed by diethylamine (25 mL) and 1-dimethylamino-2-propyne (1.15 g, 13.82 mmol, 1.47 mL, 1.25 eq). The mixture was stirred at 60 °C for 3 hours under nitrogen protection. After the reaction was complete, the temperature was lowered to 20 °C, and the reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 100:0-0:100) to give compound 9-2.

[0266] The characterization of compound 9-2 is as follows: LCMS: m / z (ESI) = 220.0 [M+H] + .

[0267] 1 H NMR (400 MHz, CDCl3) d : 2.38 (s, 6 H), 2.84 (s, 3 H), 3.51 (s, 2H), 8.24 -8.26 (m, 1 H), 8.69 -8.75 (m, 1 H).

[0268] Step 2: Synthesis of Compound 9-3

[0269] Raney nickel (1.4 g, 16.34 mmol, 2.56 eq), ethanol (50 mL), and compound 9-2 (1.4 g, 6.39 mmol, 1 eq) were added under a micro-argon flow. The reaction mixture was stirred at 25°C for 4 hours under hydrogen (15 psi). The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to give compound 9-3.

[0270] The characterization of compound 9-3 is as follows: LCMS: m / z (ESI) = 194.1 [M+H] + .

[0271] Step 3: Synthesis of compound 9-4

[0272] Compound 9-3 was dissolved in 6 M hydrochloric acid aqueous solution (517.36 µL, 6 eq), and then aminonitrile (174.00 mg, 4.14 mmol, 174.00 µL, 8 eq) was added. The mixture was stirred at 60 °C for 1 hour. Water (5 mL) and dichloromethane (5 mL) were added to the reaction solution, and the mixture was separated. Sodium hydroxide solid was added to the aqueous phase to adjust the pH to greater than 12, and the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography (HPLC) (HPLC preparation method: Waters XbridgePrep OBD preparative chromatograph; column: C18 150). 40mm 10µm; Mobile phase A: 10mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia), Mobile phase B: acetonitrile; Running gradient: B%: 1%-15%, run for 8 min. ), yielding compound 9-4.

[0273] The characterization of compound 9-4 is as follows: LCMS: m / z (ESI) = 236.3 [M+H] + .

[0274] 1 H NMR (400 MHz, DMSO- d 6) d : 1.56 - 1.63 (m, 2 H), 2.08 (s, 6 H), 2.10-2.18 (m, 5 H), 2.40 -2.47 (m, 2 H), 5.08 (s, 4 H), 6.77 (s, 1 H), 7.82 (s, 1H).

[0275] Step 4: Synthesis of Compound 9-5

[0276] Compound 9-4 (40 mg, 169.98 µmol, 1 eq) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of compound 1-2 (76.09 mg, 169.98 µmol, 1 eq). The mixture was stirred at 110 °C for 12 hours. Ethyl acetate (10 mL), saturated saline solution (5 mL), and water (5 mL) were added to the reaction mixture. The mixture was separated, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: C18 100). 30mm 10µm; mobile phase A: 0.04% hydrochloric acid aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 30%-50%, run for 8 min. ), yielding compound 9-5.

[0277] The characterization of compound 9-5 is as follows: LCMS: m / z (ESI) = 498.2 [M+H] + .

[0278] 1 H NMR (400 MHz, DMSO- d 6) d : 1.09 - 1.23 (m, 3 H), 1.92 - 2.07 (m, 2H), 2.33 - 2.36 (m, 3 H), 2.54 - 2.57 (m, 3 H), 2.59 - 2.67 (m, 2 H), 2.68 -2.72 (m, 6 H), 2.73 - 2.81 (m, 2 H), 2.95 - 3.02 (m, 2 H), 3.04 - 3.13 (m, 2H), 4.02 - 4.17 (m, 2 H), 8.01 - 8.14 (m, 1 H), 8.24 - 8.36 (m, 1 H), 8.43 -8.55 (m, 1 H).

[0279] Step 5: Synthesis of Compound 9

[0280] Compound 9-5 (24 mg, 48.22 µmol, 1 eq) was dissolved in a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (964.49 µL, 20 eq), followed by the addition of ammonium chloride (25.80 mg, 482.24 µmol, 10 eq). The mixture was stirred at 20°C for 16 hours under nitrogen protection. After quenching with methanol (5 mL), the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (Preparative HPLC method: Waters Xbridge BEH preparative chromatograph; column: C18 100). 30mm 10µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 15%-45%, run for 8 min. ), yielding compound 9.

[0281] The characterization of compound 9 is as follows: LCMS: m / z (ESI) = 469.1 [M+H]+ .

[0282] 1 H NMR (400 MHz, CDCl3) d : 1.76 - 1.84 (m, 2 H), 2.24 (s, 6 H), 2.33 -2.37 (m, 2 H), 2.49 (s, 3 H), 2.55 (s, 3 H), 2.58 -2.63 (m, 2 H), 2.70 - 2.80 (m, 2 H), 3.15 -3.23 (m, 2 H), 5.49 (s, 2 H), 6.72 (s, 1 H), 8.00 (s, 1 H), 8.20 (s, 1 H), 8.29 (s, 1 H).

[0283] Example 10

[0284] Step 1: Synthesis of Compound 10

[0285] Compound 7 (10 mg, 18.64 µmol, 1 eq) was dissolved in dichloroethane (0.5 mL), followed by the addition of 3-oxetane (1.48 mg, 20.50 µmol, 1.1 eq), then tetraethoxytitanium (4.25 mg, 18.64 µmol, 3.86 µL, 1 eq). The resulting reaction mixture was stirred at 20 °C for 1 hour, then sodium triacetoxyborohydride (4.34 mg, 20.50 µmol, 1.1 eq) was added, and the mixture was stirred at 20 °C for 12 hours. Water (5 mL) was then added to the reaction system, resulting in the precipitation of a large amount of white flocculent material. Ethyl acetate (5 mL) was then added. 5) Extract, separate, combine the organic phases and dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain the crude product. The crude product is then separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: Prep Sunfire C18 100). 30mm 10µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 35%-50%, run for 8 min. ), yielding compound 10.

[0286] Characterization of compound 10: LCMS: m / z (ESI) = 593.20 [M+H] + .

[0287] 1 H NMR (400 MHz, CD3OD) d : 8.29 (s, 1 H), 7.95 - 7.99 (m, 1 H), 7.16 -7.21 (m, 1 H), 6.66 - 6.72 (m, 1 H), 4.70 - 4.75 (m, 2 H), 4.62 - 4.66 (m, 2H), 3.53 - 3.59 (m, 1 H), 3.27 -3.30 (m, 4 H), 3.21 (t, J=7.20 Hz, 2 H), 2.80- 2.85 (m, 2 H), 2.60 - 2.65 (m, 3 H), 2.49 - 2.55 (m, 4 H).

[0288] Example 11

[0289] Step 1: Synthesis of Compound 11-2

[0290] Compound 11-1 (2 g, 10.30 mmol, 1 eq) and potassium carbonate (2.85 g, 20.60 mmol, 2 eq) were dissolved in tetrahydrofuran (20 mL). The reaction mixture was cooled to 0 °C under nitrogen protection, and then bromoacetyl bromide (3.12 g, 15.45 mmol, 1.34 mL, 1.5 eq) was added. The mixture was stirred at 0 °C for 10 minutes, followed by the addition of a 40% aqueous solution of dimethylamine (3.48 g, 30.90 mmol, 3.91 mL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 10 minutes. The reaction mixture was slowly quenched in ice water (200 mL) and then quenched with ethyl acetate (100 mL). 3) Extract, separate, and combine the organic phases. Separate the organic phases with saturated saline solution (100 mL). 3) After washing, the product was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-95:5) to obtain compound 11-2.

[0291] The characterization of compound 11-2 is as follows: 1 H NMR (400 MHz, CDCl3) d: 8.67 (s, 1 H), 6.92 (s, 1 H), 4.26 (t, J=8.60 Hz, 2 H), 3.92 (s, 3 H), 3.16 - 3.32 (m, 4 H), 2.41 (s, 6 H).

[0292] Step 2: Synthesis of compound 11-3

[0293] 10% wet palladium on carbon (1 g) was added under a micro-argon flow, followed by anhydrous methanol (2 mL), and then compound 11-2 (1 g, 3.58 mmol, 1 eq). The reaction mixture was stirred at 40°C for 12 hours under hydrogen (15 psi). The reaction mixture was passed through a funnel lined with diatomaceous earth, and the filter cake was filtered with methanol (50 mL). 2) Elute and collect the filtrate. Concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate + 0.5% ammonia = 100:0-0:100) to obtain compound 11-3.

[0294] Characterization of compound 11-3: 1 H NMR (400 MHz, DMSO- d 6) d : 7.55 (s, 1 H), 6.70 (s, 1 H), 4.63 (s, 2H), 3.95 - 4.19 (m, 2 H), 3.65 - 3.71 (m, 3 H), 3.13 (s, 2 H), 2.87 - 3.04(m, 2 H), 2.25 (s, 6 H).

[0295] Step 3: Synthesis of compound 11-4

[0296] Compound 11-3 (200 mg, 802.22 µmol, 1 eq) was dissolved in 6 M hydrochloric acid aqueous solution (802.22 µL, 6 eq), followed by the addition of aminonitrile (269.80 mg, 6.42 mmol, 269.80 µL, 8 eq). The mixture was heated to 100 °C and stirred for 2 hours, then aminonitrile (134.90 mg, 3.21 mmol, 134.90 µL, 4 eq) was added, and the reaction mixture was stirred at 100 °C for 12 hours. Water (10 mL) and dichloromethane (10 mL) were added to the reaction mixture, followed by extraction. The aqueous phase was collected separately, and the pH of the aqueous phase was adjusted to 11 with saturated sodium hydroxide aqueous solution and then concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters 2767 / QDa preparative chromatograph; column: Waters Xbridge BEH C18 100). 25mm 5µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 1%-25%, run for 10 min. ), yielding compound 11-4.

[0297] Characterization of compound 11-4: 1 H NMR (400 MHz, DMSO- d 6) d : 7.61 (s, 1 H), 6.84 (s, 1 H), 5.50 (s, 3H), 4.12 (t, J=8.40 Hz, 2 H), 3.67 (s, 3 H), 3.14 (s, 2 H), 3.05 (t, J=8.40Hz, 2 H), 2.25 (s, 6H).

[0298] Step 4: Synthesis of Compound 11-5

[0299] Compound 1-2 (67.02 mg, 205.94 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of compound 11-4 (60 mg, 205.94 µmol, 1 eq). The mixture was stirred at 110 °C for 16 hours. The reaction solution was quenched in water (30 mL), and then ethyl acetate (15 mL) was added. 3) Extract, separate, and combine the organic phases. Separate the organic phases with saturated saline solution (15 mL). 3) After washing, the product was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 11-5.

[0300] Characterization of compound 11-5: 1 H NMR (400 MHz, CDCl3) d : 9.25 (s, 1 H), 8.32 (s, 1 H), 6.76 (s, 1H), 4.35 (q, J=7.20 Hz, 2 H), 4.18 (t, J=8.20 Hz, 2 H), 3.82 - 3.95 (m, 3 H), 3.60 (s, 1 H), 3.25 - 3.36 (m, 2 H), 3.16 - 3.25 (m, 2 H), 3.09 - 3.16 (m, 1H), 2.98 - 3.09 (m, 1 H), 2.73 - 2.89 (m, 2 H), 2.65 (s, 3 H), 2.39 (s, 6 H),1.40 (t, J=7.20 Hz, 3 H).

[0301] Step 5: Synthesis of Compounds 11-6

[0302] Compound 11-5 (50 mg, 90.30 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4 mL) and anhydrous ethanol (1 mL). Lithium hydroxide monohydrate (18.95 mg, 451.51 µmol, 5 eq) was dissolved in water (1 mL) and added to the reaction mixture. The mixture was stirred at 40 °C for 5 hours. The pH of the reaction mixture was adjusted to 7 with 1 M dilute hydrochloric acid, and then freeze-dried to obtain compound 11-6.

[0303] Characterization of compound 11-6: 1 H NMR (400 MHz, DMSO- d 6) d: 10.35 (s, 1 H), 8.82 (s, 1 H), 8.54 (s, 1H), 8.34 (s, 1 H), 7.07 (s, 1 H), 4.45 (d, J=4.40 Hz, 2 H), 4.10 (t, J=8.20Hz, 2 H), 3.80 (s, 3 H), 3.17 - 3.24 (m, 4 H), 2.88 (d, J=4.40 Hz, 6 H), 2.79 (t, J=7.00 Hz, 2 H), 2.56 (s, 3 H).

[0304] Step 6: Synthesis of Compound 11

[0305] Compound 11-6 (110 mg, 209.27 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and then N,N-diisopropylethylamine (81.14 mg, 627.80 µmol, 109.35 µL, 3 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (103.44 mg, 272.05 µmol, 1.3 eq), and ammonium bicarbonate (49.63 mg, 627.80 µmol, 51.70 µL, 3 eq) were added sequentially. The mixture was stirred at 20°C for 2 hours under nitrogen protection. The reaction solution was directly filtered, and the filtrate was collected. The filtrate was then separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters 2767 / QDa preparative chromatograph; column: Phenomenex C18 80). 40mm 3µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 30%-60%, run for 8 min. ), yielding compound 11.

[0306] Characterization of compound 11: LCMS: m / z (ESI) = 525.30 [M+H] + .

[0307] 1 H NMR (400 MHz, DMSO- d 6) d: 8.67 (s, 1 H), 8.29 (s, 1 H), 7.84 (s, 1H), 7.42 (s, 2 H), 6.96 (s, 1 H), 4.16 (t, J=8.20 Hz, 2 H), 3.79 (s, 3 H), 3.17 (s, 2 H), 3.11 (t, J=7.20 Hz, 4H), 2.70 - 2.77 (m, 2H), 2.53 (s, 3H), 2.26 (s, 6H).

[0308] Example 12

[0309] Step 1: Synthesis of Compound 12-1

[0310] Compound 6-3 (200 mg, 891.76 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4 mL), and then tert-butoxybis(dimethylamino)methane (466.25 mg, 2.68 mmol, 552.43 µL, 3 eq) was added. The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The solvent was concentrated to dryness under reduced pressure to give compound 12-1.

[0311] The characterization of compound 12-1 is as follows: LCMS: m / z (ESI) = 253.2 [M-26] + .

[0312] Step 2: Synthesis of Compound 12-2

[0313] Compound 12-1 (100 mg, 357.97 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of compound 1-3 (113.59 mg, 357.97 µmol, 1 eq). The mixture was stirred at 110 °C for 16 hours. Ethyl acetate (20 mL), water (10 mL), and saturated brine (10 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 12-2.

[0314] The characterization of compound 12-2 is as follows: LCMS: m / z (ESI) = 534.3 [M+H] + .

[0315] 1H NMR (400 MHz, CDCl3) d : 1.42 (t, J=7.2 Hz, 3 H), 2.39 (s, 3 H), 2.62 (s, 4 H), 2.89 (t, J=7.2 Hz, 2 H), 3.26 - 3.43 (m, 6 H), 4.39 (q, J=7.2Hz, 2 H), 6.50 -6.55 (m, 1 H), 7.15 -7.20 (m, 1 H), 7.35 (s, 1 H), 8.25 (s, 1H), 8.37 (s, 1 H), 8.40 -8.46 (m, 1 H).

[0316] Step 3: Synthesis of Compound 12

[0317] Compound 12-2 (135 mg, 253.02 µmol, 1 eq) was dissolved in a 1 M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (2 mL, 7.90 eq), followed by the addition of ammonium chloride (54.14 mg, 1.01 mmol, 4 eq). The mixture was stirred at 20°C for 1 hour. The reaction solution was directly concentrated to dryness under reduced pressure, and methanol (2 mL) was added. The solution was then further concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative high-performance liquid chromatography (HPLC) (Preparative HPLC method: Waters 2767 / QDa preparative chromatograph; column: Phenomenex C18 80). 40mm 3µm; Mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 25%-55%, run for 8 min. Compound 12 was obtained.

[0318] The characterization of compound 12 is as follows: LCMS: m / z (ESI) = 505.1 [M+H] + .

[0319] 1 H NMR (400 MHz, CDCl3) d: 2.39 (s, 3 H), 2.57 - 2.69 (m, 4 H), 2.90(t, J=7.15 Hz, 2 H), 3.26 - 3.38 (m, 6 H), 5.65 (d, J=5.77 Hz, 2 H), 6.55(dd, J=9.03, 3.01 Hz, 1 H), 7.16 (dd, J=8.91, 1.51 Hz, 1 H), 7.36 (s, 1 H), 8.18 (s, 1 H), 8.37 (s, 1 H), 8.41 (d, J=2.89 Hz, 1 H).

[0320] Example 13

[0321] Step 1: Synthesis of Compound 13-1

[0322] Compound 6-8 (300 mg, 989.54 µmol, 1 eq) was dissolved in N,N-dimethylformamide (4.5 mL), followed by the addition of cuprous cyanide (265.88 mg, 2.97 mmol, 648.49 µL, 3 eq) and potassium iodide (32.85 mg, 197.91 µmol, 0.2 eq). The mixture was stirred at 140 °C for 0.5 h under nitrogen protection. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, which was then filtered. The filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to give compound 13-1.

[0323] The characterization of compound 13-1 is as follows: LCMS: m / z (ESI) = 250.2 [M+1] + .

[0324] 1 H NMR (400 MHz, CDCl3) d : 1.41 (t, J=7.2 Hz, 3 H), 2.15 (t, J=6.8 Hz, 2 H), 2.59 - 2.77 (m, 2 H), 3.27 (t, J=6.8 Hz, 2 H), 4.41 (q, J=7.2 Hz, 2 H).

[0325] Step 2: Synthesis of Compound 13-2

[0326] Compound 13-1 (145 mg, 581.66 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (6 mL), and then tert-butoxybis(dimethylamino)methane (304.12 mg, 1.74 mmol, 360.33 µL, 3 eq) was added. The mixture was stirred at 80 °C for 3 hours. The solvent was then directly concentrated under reduced pressure to dryness to give compound 13-2.

[0327] The characterization of compound 13-2 is as follows: LCMS: m / z (ESI) = 305.2 [M+H] + .

[0328] Step 3: Synthesis of Compound 13-3

[0329] Compound 13-2 (177 mg, 581.54 µmol, 1 eq) was dissolved in DMF (4.5 mL), followed by the addition of compound 1-3 (184.53 mg, 581.54 µmol, 1 eq). The mixture was stirred at 110 °C for 16 hours. Ethyl acetate (20 mL), water (10 mL), and saturated brine (10 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 13-3.

[0330] The characterization of compound 13-3 is as follows: LCMS: m / z (ESI) = 559.3 [M+H] + .

[0331] 1 H NMR (400 MHz, CDCl3) d : 1.43 (t, J=7.2 Hz, 3 H), 2.38 (s, 3 H), 2.62 (s, 4 H), 2.89 (t, J=7.2 Hz, 2 H), 3.17 - 3.44 (m, 6 H), 4.42 (q, J=6.8Hz, 2 H), 6.51 -6.62 (m, 1 H), 7.10 -7.19 (m, 1 H), 7.39 (s, 1 H), 8.15 (d, J=2.8 Hz, 1 H), 8.46 (s, 1 H).

[0332] Step 4: Synthesis of Compound 13-4

[0333] Compound 13-3 (200 mg, 358.05 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and then lithium hydroxide monohydrate (45.07 mg, 1.07 mmol, 3 eq) and water (1 mL) were added. The mixture was stirred at 40 °C for 1 hour, and the solvent was directly concentrated to dryness to obtain compound 13-4.

[0334] The characterization of compound 13-4 is as follows: LCMS: m / z (ESI) = 531.1 [M+1] + .

[0335] Step 5: Synthesis of Compound 13

[0336] Compound 13-4 (200 mg, 376.99 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of N,N-diisopropylethylamine (146.17 mg, 1.13 mmol, 196.99 µL, 3 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (215.01 mg, 565.48 µmol, 1.5 eq), and ammonium bicarbonate (89.41 mg, 1.13 mmol, 93.13 µL, 3 eq). The mixture was stirred at 20 °C for 5 hours. Ethyl acetate (10 mL), water (5 mL), and saturated brine (5 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters 2767 / QDa preparative chromatograph; column: Phenomenex C18 75). 30mm 3µm; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 25%-55%, run for 8 min. Compound 13 was obtained.

[0337] The characterization of compound 13 is as follows: LCMS: m / z (ESI) = 530.1 [M+1] + .

[0338] 1 H NMR (400 MHz, CDCl3) d: 2.35 (s, 3 H), 2.52 - 2.70 (m, 4 H), 2.85 -2.92 (m, 2 H), 3.12 - 3.43 (m, 6 H), 5.81 (s, 2 H), 6.49 - 6.61 (m, 1 H),7.10 - 7.20 (m, 1 H), 7.46 (s, 1 H), 8.05 - 8.19 (m, 1 H). 8.47 (s, 1 H).

[0339] Example 14 Step 1: Synthesis of Compound 14-2 Compound 14-1 (2 g, 7.81 mmol, 1.1 eq) was dissolved in 1,4-dioxane (30 mL), followed by the addition of 1-methyl-3-oxoperpiperazine (810.63 mg, 7.10 mmol, 1 eq). The mixture was purged with nitrogen three times, and then cesium carbonate (4.63 g, 14.20 mmol, 2 eq) was added. Following this nitrogen purging, N,N-dimethylethylenediamine (626.02 mg, 7.10 mmol, 775.73 µL, 1 eq) was added. Finally, cuprous iodide (676.26 mg, 3.55 mmol, 0.5 eq) was added under nitrogen purging. The mixture was stirred at 120 °C for 16 hours. Add 1-methyl-3-oxoperazine (810.63 mg, 7.10 mmol, 1 eq) and cuprous iodide (676.26 mg, 3.55 mmol, 0.5 eq), and continue stirring at 120°C for 24 hours. Add water (50 mL) to the reaction system, separate the layers, and use ethyl acetate (70 mL) for the aqueous phase. 3) Extract, separate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 14-2.

[0340] The characterization of compound 14-2 is as follows: LCMS: m / z (ESI) = 290.0 [M+H] + .

[0341] 1 H NMR (400 MHz, CDCl3) d: 2.41 (s, 3 H), 2.71 - 2.85 (m, 2 H), 3.23 -3.32 (m, 2 H), 3.62 - 3.72 (t, J =5.20 Hz, 2 H), 3.94 (s, 2 H), 6.58 - 6.66(dd, J =8.8, 2.4 Hz, 1 H), 6.73 - 6.80 (d, J =2.4 Hz, 1 H), 7.10 - 7.15 (dd, J=8.8, 1.2 Hz, 1 H).

[0342] Step 2: Synthesis of Compound 14-3

[0343] Compound 14-2 (300 mg, 1.04 mmol, 1 eq) was added to a 6 M aqueous hydrochloric acid solution (1.20 mL, 6.94 eq), followed by the addition of an aminonitrile (348.82 mg, 8.30 mmol, 348.82 µL, 8 eq). The mixture was stirred at 60 °C for 16 hours. The reaction mixture was then diluted with 2 mL of water and 5 mL of ethyl acetate. 2) Extraction and separation. Adjust the pH of the aqueous phase to 13 with 1 M potassium hydroxide solution, and then extract with ethyl acetate (5 mL). 3) Extraction, separation, drying the organic phase with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain compound 14-3.

[0344] The characterization of compound 14-3 is as follows: LCMS: m / z (ESI) = 332.0 [M+H] + .

[0345] 1 H NMR (400 MHz, DMSO- d 6) d : 2.26 (s, 3 H), 2.65 - 2.73 (m, 2 H), 3.08 (s, 2 H), 3.60 - 3.67 (t, J =5.20 Hz, 2 H), 5.27 - 5.34 (m, 2 H), 5.36 - 5.45 (m, 2 H), 6.81 - 6.89 (m, 2 H), 7.14 - 7.20 (m, 1 H).

[0346] Step 3: Synthesis of compound 14-4

[0347] Compound 1-2 (200 mg, 603.70 µmol, 1 eq) was added to N,N-dimethylformamide (2 mL) containing compound 14-3 (196.47 mg, 603.70 µmol, 1 eq), and the mixture was stirred at 110 °C for 16 hours. The reaction mixture was washed with water (5 mL), and then ethyl acetate (5 mL) was added. 3) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain the crude product. The crude product was separated by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain compound 14-4.

[0348] The characterization of compound 14-4 is as follows: LCMS: m / z (ESI) = 594.1 [M+H] + .

[0349] 1 H NMR (400 MHz, DMSO- d 6) d : 1.26 - 1.33 (m, 3 H), 2.28 (s, 3 H), 2.59 (s, 3 H), 2.60 - 2.70 (m, 2 H), 2.76 - 2.82 (m, 2 H), 3.11 (s, 2 H), 3.22 (t, J=7.2 Hz, 2 H), 3.63 - 3.69 (t, J=5.2 Hz, 2 H), 4.18 - 4.28 (q, J=7.2 Hz, 2 H), 7.07 - 7.14 (d, J=8.4 Hz, 1 H), 7.35 - 7.42 (d, J=8.4 Hz, 1 H), 8.12 -8.20 (m, 1 H), 8.39 (s, 1 H), 8.82 (s, 1 H).

[0350] Step 4: Synthesis of Compounds 14-5

[0351] Compound 14-4 (80 mg, 134.76 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (1.6 mL), followed by the addition of anhydrous ethanol (0.4 mL) and water (0.4 mL), and then lithium hydroxide monohydrate (28.28 mg, 673.81 µmol, 5 eq). The mixture was purged with nitrogen three times. After the addition was complete, the temperature was raised to 45 °C and stirred for 5 hours. The pH of the reaction system was adjusted to 7 with 1 M hydrochloric acid aqueous solution. The organic solvent in the system was then evaporated to dryness using a water pump, and the remaining aqueous solution was freeze-dried to obtain the crude product. Methanol (5 mL) was added to the crude product, and the mixture was sonicated for five minutes. After filtration, the filter cake was dried using a water pump to obtain compound 14-5.

[0352] The characterization of compound 14-5 is as follows: LCMS: m / z (ESI) = 566.0 [M+H] + .

[0353] 1 H NMR (400 MHz, DMSO- d 6) d : 2.55 (s, 3 H), 2.67 (s, 3 H), 2.75 - 2.80 (m, 4 H), 3.14 (s, 2 H), 3.20 (t, J=7.2 Hz, 2 H), 3.77 - 3.85 (m, 2 H), 7.08- 7.15 (m, 1 H), 7.40 - 7.48 (m, 1 H), 8.05 - 8.13 (m, 1 H), 8.37 (s, 1 H).

[0354] Step 5: Synthesis of Compounds 14-6

[0355] Compound 14-5 (30 mg, 53.04 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (0.5 mL), and oxaloyl chloride (53.86 mg, 424.34 µmol, 37.14 µL, 8 eq) was added at 0 °C. The mixture was purged with nitrogen three times, and then N,N-dimethylformamide (387.71 µg, 5.30 µmol, 4.08e-1 µL, 0.1 eq) was added. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was then poured into 25% ammonia solution (5 mL) at 20 °C and stirred for 0.5 h. Ethyl acetate (15 mL) was added to the reaction mixture. 4) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain the crude product. The crude product was then separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: Phenomenex C18 100). 30mm 10 µm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient B%: 20%-55%, 10 min), to obtain compound 14.

[0356] The characterization of compound 14 is as follows: LCMS: m / z (ESI) = 565.1 [M+H] + .

[0357] 1 H NMR (400 MHz, DMSO- d 6) d : 2.29 (s, 3 H), 2.56 (s, 3 H), 2.69 - 2.79 (m, 4 H), 3.07 - 3.16 (m, 4 H), 3.63 - 3.70 (t, J=5.2 Hz, 2H), 7.06 - 7.12(m, 1 H), 7.36 - 7.42 (m, 1 H), 7.42 - 7.49 (m, 2 H), 8.19 - 8.24 (d, J=2.4Hz, 1 H), 8.38 (s, 1 H), 8.75 (s, 1 H).

[0358] Example 15

[0359] Step 1: Synthesis of Compound 15-3

[0360] Compound 15-1 (1 g, 2.73 mmol, 1 eq), compound 15-2 (540.37 mg, 2.73 mmol, 1 eq), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (157.70 mg, 272.55 µmol, 0.1 eq), tris(dibenzylacetone)dipalladium (249.58 mg, 272.55 µmol, 0.1 eq), and sodium tert-butoxide (785.80 mg, 8.18 mmol, 3 eq) were dissolved in anhydrous toluene (20 mL). The reaction mixture was stirred at 60°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-90:10) to obtain compound 15-3.

[0361] The characterization of compound 15-3 is as follows: LCMS: m / z (ESI) = 381.0, 383.0 [M-55] + .

[0362] 1 H NMR (400 MHz, CDCl3) d : 7.18 - 7.22 (m, 1 H), 6.92 (d, J=3.0 Hz, 1H), 6.62 - 6.66 (m, 1 H), 4.31 (d, J=5.0 Hz, 2 H), 3.67 - 4.04 (m, 2 H), 3.27 (d, J=10.4 Hz, 2 H), 2.68 - 2.72 (m, 1 H), 1.48 (d, J=8.7 Hz, 1 H), 1.39 (s, 9 H).

[0363] Step 2: Synthesis of Compound 15-4

[0364] Compound 5-4 (240 mg, 746.69 µmol, 1 eq), compound 15-3 (391.79 mg, 896.03 µmol, 1.2 eq), palladium acetate (8.38 mg, 37.33 µmol, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (21.60 mg, 37.33 µmol, 0.05 eq), and cesium carbonate (729.86 mg, 2.24 mmol, 3 eq) were dissolved in 1,4-dioxane (12 mL), and stirred at 110°C for 40 hours under nitrogen atmosphere. Ethyl acetate (10 mL), water (5 mL), and saturated brine (5 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, compound 15-4.

[0365] Characterization of compound 15-4: LCMS: m / z (ESI) = 678.2 [M+H] + .

[0366] 1 H NMR (400 MHz, CDCl3) d : 8.30 (s, 1 H), 7.92 (s, 1 H), 7.30 - 7.41 (m, 1 H), 7.15 - 7.19 (m, 1 H), 6.32 -6.44 (m, 1 H), 4.19 - 4.46 (m, 4 H), 3.71 - 4.14 (m, 2 H), 3.21 - 3.47 (m, 4 H), 2.83 (t, J=7.2 Hz, 2 H), 2.65 (s, 4 H), 1.49 (d, J=8.4 Hz, 1 H), 1.36 - 1.43 (m, 12 H).

[0367] Step 3: Synthesis of Compound 15-5

[0368] Compound 15-4 (150 mg, 221.32 µmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (770.00 mg, 6.75 mmol, 0.5 mL, 30.51 eq), and stirred at 20°C for 16 hours. The solvent was concentrated to dryness under reduced pressure. Water (10 mL) and ethyl acetate (10 mL) were added to the crude product, and the pH was adjusted to greater than 8 with a saturated sodium bicarbonate aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated to dryness under reduced pressure to give compound 15-5.

[0369] Characterization of compound 15-5: LCMS: m / z (ESI) = 578.2 [M+H] + .

[0370] 1 H NMR (400 MHz, CDCl3) d : 8.31 (s, 1 H), 7.93 (d, J=3.0 Hz, 1 H), 7.26 (s, 1 H), 7.18 – 7.22 (m, 1 H), 6.33 -6.35 (m, 1 H), 5.31 (s, 1 H), 4.36-4.40 (m, 2 H), 3.92 (d, J=5.8 Hz, 2 H), 3.51 - 3.73 (m, 4 H), 3.33 (t, J=7.2Hz, 2 H), 2.83 (t, J=7.2 Hz, 3 H), 2.64 (s, 3 H), 1.60 -1.65 (m, 1 H), 1.40 (t, J=7.2 Hz, 3H).

[0371] Step 4: Synthesis of Compounds 15-6

[0372] Compound 15-5 (120 mg, 207.74 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (6.5 mL), and a 37% pure formaldehyde aqueous solution (238.46 mg, 2.94 mmol, 218.77 µL, 14.14 eq) was added. Then, acetic acid (229.45 mg, 830.97 µmol, 218.52 µL, 4 eq) was added, and the mixture was stirred at 25°C for 15 minutes. Sodium borohydride acetate (176.12 mg, 830.97 µmol, 4 eq) was then added, and the mixture was stirred at 25°C for 45 minutes under nitrogen protection. Ethyl acetate (10 mL), water (5 mL), and a saturated sodium bicarbonate aqueous solution (5 mL) were added to the reaction mixture. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to give compound 15-6.

[0373] Characterization of compound 15-6: LCMS: m / z (ESI) = 592.2 [M+H] + .

[0374] 1 H NMR (400 MHz, CDCl3) d : 8.32 (s, 1 H), 8.03 (d, J=2.9 Hz, 1 H), 7.30 (s, 1 H), 7.20 -7.22 (m, 1 H), 6.34 -6.40 (m, 1 H), 4.36 – 4.40 (m, 2H), 4.04 (d, J=4.1 Hz, 2 H), 3.54 - 3.74 (m, 4 H), 3.33 (t, J=7.2 Hz, 2 H), 2.84 (t, J=7.2 Hz, 2 H), 2.64 (s, 3 H), 2.34 (s, 3 H), 1.76 (d, J=9.2 Hz, 1H), 1.40 (t, J=7.2 Hz, 3H).

[0375] Step 5: Synthesis of Compound 15

[0376] Compound 15-6 (90 mg, 152.11 µmol, 1 eq) and ammonium chloride (48.82 mg, 912.68 µmol, 6 eq) were dissolved in a 1 M solution of lithium bis(trimethylsilyl)amino in n-hexane (1.52 mL, 10 eq), and stirred at 20°C for 2 hours under nitrogen. The reaction mixture was quenched with methanol (3 mL), and the solvent was concentrated to dryness under reduced pressure. The crude product was separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: Phenomenex C18 100). 30mm 10 µm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: acetonitrile%: 15%-85%, 8 min), to obtain compound 15.

[0377] Characterization of compound 15: LCMS: m / z (ESI) = 563.2 [M+H] + .

[0378] 1H NMR (400 MHz, CD3OD) d : 8.30 (s, 1 H), 7.63 (d, J=2.8 Hz, 1 H), 7.21 (d, J=9.0 Hz, 1 H), 6.50 -6.55 (m, 1 H), 3.60 - 3.80 (m, 4 H), 3.44 -3.57 (m, 2 H), 3.23 (t, J=7.2 Hz, 2 H), 2.84 (t, J=7.2 Hz, 2 H), 2.50 - 2.72 (m, 4 H), 2.19 (s, 3 H), 1.70 (d, J=8.4 Hz, 1 H).

[0379] Example 16

[0380] Step 1: Synthesis of Compound 16-1

[0381] Compound 6-8 (400 mg, 1.32 mmol, 1 eq), cyclopropylboronic acid (147.33 mg, 1.72 mmol, 1.3 eq), potassium phosphate (1.01 g, 4.75 mmol, 3.6 eq), palladium acetate (29.62 mg, 131.94 µmol, 0.1 eq), and tricyclohexylphosphine (111.00 mg, 395.82 µmol, 128.32 µL, 0.3 eq) were added to a reaction flask. Then, anhydrous toluene (12 mL) and water (0.6 mL) were added. After three nitrogen purgings, the mixture was stirred at 80°C for 16 hours. After the reaction was completed, the solvent in the reaction solution was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 16-1.

[0382] The characterization of compound 16-1 is as follows: LCMS: m / z (ESI) = 265.1 [M+H] + .

[0383] 1 H NMR (400 MHz, CDCl3) d : 4.30 -4.38 (m, 2 H), 3.41 (s, 1 H), 3.21 (t, J=6.2 Hz, 2 H), 2.50 - 2.65 (m, 2 H), 2.05 (t, J=6.3 Hz, 2 H), 1.37 (t, J=7.2 Hz, 3 H), 1.25 - 1.32 (m, 2 H), 0.77 - 0.91 (m, 2 H).

[0384] Step 2: Synthesis of Compound 16-2

[0385] Compound 16-1 (225 mg, 851.18 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (4.5 mL), followed by the addition of tert-butoxybis(dimethylamino)methane (445.04 mg, 2.55 mmol, 527.30 µL, 3 eq). The mixture was stirred at 80°C for 20 hours. After the reaction was complete, the solvent was concentrated to dryness under reduced pressure to obtain crude compound 16-2, which was used directly in the next step without purification.

[0386] Characterization of compound 16-2: LCMS: m / z (ESI) = 293.1 [M-26] + .

[0387] Step 3: Synthesis of Compound 16-3

[0388] Compound 16-2 (270 mg, 845.29 µmol, 1 eq) was dissolved in N,N-dimethylformamide (3.5 mL), followed by the addition of compound 1-3 (268.22 mg, 845.29 µmol, 1 eq). The mixture was stirred at 110 °C for 20 hours. After the reaction was complete, ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 16-3.

[0389] Characterization of compound 16-3: LCMS: m / z (ESI) = 574.3 [M+H] + .

[0390] 1 H NMR (400 MHz, CDCl3) d : 8.35 (s, 1 H), 8.09 (d, J=2.8 Hz, 1 H), 7.11 - 7.16 (m, 2 H), 6.52 - 6.54 (m, 1 H), 4.34 (d, J=7.2 Hz, 2 H), 3.55 (s, 1 H), 3.28 -3.30 (m, 6 H), 2.79 -2.82 (m, 2 H), 2.57 - 2.73 (m, 4 H), 2.42 (s, 3 H), 1.38 (t, J=7.2 Hz, 3 H), 1.17 - 1.25 (m, 2 H), 0.82 - 0.90 (m, 2H).

[0391] Step 4: Synthesis of Compound 16

[0392] Compound 16-3 (120 mg, 209.19 µmol, 1 eq) and ammonium chloride (67.14 mg, 1.26 mmol, 6 eq) were dissolved in 1 M lithium di(trimethylsilyl)amino in hexane (2.09 mL, 10 eq), and then stirred at 20°C for 1 hour under nitrogen. After the reaction was complete, methanol (3 mL) was added to quench the reaction mixture, and the solvent was concentrated to dryness under reduced pressure. The crude product was separated and purified by high performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: Phenomenex C18 100). 30mm 10 µm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient B%: 15%-85%, 8 min), to obtain compound 16.

[0393] Characterization of compound 16: LCMS: m / z (ESI) = 545.3 [M+H] + .

[0394] 1H NMR (400 MHz, CD3OD) d : 8.32 (s, 1 H), 7.60 (m, 1 H), 7.19 -7.23(m, 1 H), 6.76 – 6.72 (m, 1 H), 3.39 -3.48 (m, 1 H), 3.25 (s, 4 H), 3.17 (t,J=6.8 Hz, 2 H), 2.80 (t, J=6.8 Hz, 2 H), 2.67 (s, 4 H), 2.40 (s, 3 H), 1.04 –1.10 (m, 2 H), 0.75 – 0.79 (m, 2 H).

[0395] Example 17

[0396] Step 1: Synthesis of Compound 17-2

[0397] Under nitrogen protection at -75°C, an anhydrous tetrahydrofuran solution (5 mL) of compound 17-1 (1.25 g, 8.65 mmol, 1 eq) was added to a 0.1 M tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidinium (172.94 mL, 2 eq), and stirred for 0.5 h. Then, iodine (2.59 g, 10.20 mmol, 2.06 mL, 1.18 eq) was added at -75°C, and the mixture was stirred for 3 h. The reaction mixture was washed with saturated ammonium chloride aqueous solution (150 mL), separated, and rinsed with ethyl acetate (100 mL). 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-95:5) yielded compound 17-2.

[0398] The characterization of compound 17-2 is as follows: LCMS: m / z (ESI) = 271.0 [M+H] + .

[0399] 1 H NMR (400 MHz, DMSO- d 6) d : 4.05 (s, 3 H), 8.44 (s, 1 H).

[0400] Step 2: Synthesis of Compound 17-3

[0401] To compound 17-2 (600 mg, 2.22 mmol, 1 eq) in dimethyl sulfoxide (12 mL), p-methoxybenzylamine (912.99 mg, 6.66 mmol, 861.31 µL, 3 eq) and potassium fluoride (386.66 mg, 6.66 mmol, 155.91 µL, 3 eq) were added, and the mixture was stirred at 120 °C for 3 hours. Water (10 mL) and ethyl acetate (10 mL) were then added to the reaction mixture. 3) Extract, separate, combine the organic phases and concentrate under reduced pressure. Purify by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-60:40) to obtain compound 17-3.

[0402] The characterization of compound 17-3 is as follows: LCMS: m / z (ESI) = 279.9 [M+H] + .

[0403] 1H NMR (400 MHz, DMSO- d 6) d : 3.71 (s, 3 H), 4.00 (s, 3 H), 4.28 - 4.38(d, J =6.4 Hz 2 H), 6.45 (s, 1 H), 6.85 - 6.92 (d, J =8.8 Hz, 2 H), 7.21 - 7.29 (d, J =8.8 Hz, 2 H), 7.50 - 7.58 (m, 1 H).

[0404] Step 3: Synthesis of Compound 17-4

[0405] Compound 17-3 (250 mg, 893.75 µmol, 1 eq) was dissolved in 1,4-dioxane (2 mL), followed by the addition of 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (208.53 mg, 446.87 µmol, 0.5 eq), (2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (373.75 mg, 446.87 µmol, 0.5 eq). The mixture was purged with nitrogen three times, and then sodium tert-butoxide (171.78 mg, 1.79 mmol, 2 eq) and N-methylpiperazine (179.04 mg, 1.79 mmol, 198.27 µL, 2 eq) were added. The mixture was stirred at 110°C for 4 hours. Water (10 mL) was added to the reaction mixture for washing, followed by washing with ethyl acetate (10 mL). 4) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) yielded compound 17-4.

[0406] The characterization of compound 17-4 is as follows: LCMS: m / z (ESI) = 344.2 [M+H] + .

[0407] 1 H NMR (400 MHz, CDCl3) d: 2.36 (s, 3 H), 2.49 - 2.63 (m, 4 H), 3.47 -3.50 (m, 4 H), 3.82 (s, 3 H), 4.08 (s, 3 H), 4.23 - 4.30 (d, J=5.2 Hz, 2 H), 5.93 (s, 1 H), 6.89 - 6.93 (d, J=8.8 Hz, 2H), 7.23 - 7.26 (d, J=8.8 Hz, 2H).

[0408] Step 4: Synthesis of Compound 17-5

[0409] Trifluoroacetic acid (6 mL) was added to compound 17-4 (190 mg, 553.25 µmol, 1 eq), and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain the crude product. Water (5 mL) was added to the mixture, followed by dichloromethane (5 mL). 3) Washing, adjusting the pH of the aqueous phase to 14 with 1 M sodium hydroxide aqueous solution, and adding dichloromethane (20 mL). 6) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain compound 17-5.

[0410] The characterization of compound 17-5 is as follows: LCMS: m / z (ESI) = 224.0 [M+H] + .

[0411] 1 H NMR (400 MHz, CD3OD) d : 2.35 (s, 3 H), 2.52 - 2.62 (m, 4 H), 3.40 -3.44 (m, 4 H), 3.99 (s, 3 H), 6.30 (s, 1 H).

[0412] Step 5: Synthesis of Compound 17-6

[0413] To 20 mL of ethylene glycol dimethyl ether containing compound 5-4 (200 mg, 622.24 µmol, 1 eq), cesium iodide (96.88 mg, 684.47 µmol, 59.43 µL, 1.1 eq), iodine (86.86 mg, 342.23 µmol, 68.94 µL, 0.55 eq), cuprous iodide (37.92 mg, 199.12 µmol, 0.32 eq), and amyl nitrite (116.63 mg, 995.59 µmol, 134.06 µL, 1.6 eq) were added sequentially, and the mixture was stirred at 70 °C for 18 hours. The reaction system was washed with 10 mL of ammonia water, followed by washing with 20 mL of saturated sodium thiosulfate aqueous solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 17-6 was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-90:10) to obtain compound 17-6.

[0414] The characterization of compound 17-6 is as follows: LCMS: m / z (ESI) = 432.9 [M+H] + .

[0415] Step 6: Synthesis of Compound 17-7

[0416] Compound 17-5 (50 mg, 223.94 µmol, 1.5 eq) was dissolved in 1,4-dioxane (2 mL), followed by compound 17-6 (64.54 mg, 149.29 µmol, 1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (3.46 mg, 5.97 µmol, 0.04 eq), and cesium carbonate (145.93 mg, 447.88 µmol, 3 eq). After purging with nitrogen three times, palladium acetate (670.35 µg, 2.99 µmol, 0.02 eq) was added, followed by purging with nitrogen three times. The mixture was stirred at 110 °C for 2 hours. Water (5 mL) was added to the reaction system, followed by ethyl acetate (10 mL). 3) Extraction, separation, and direct vacuum concentration of the organic phase to obtain the crude product. Purification by thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) yielded compound 17-7.

[0417] The characterization of compound 17-7 is as follows: LCMS: m / z (ESI) = 528.1 [M+H] + .

[0418] 1 H NMR (400 MHz, DMSO- d 6) d : 1.29 - 1.32 (m, 3 H), 2.31 - 2.35 (m, 4H), 2.41 (s, 3 H), 2.65 - 2.69 (m, 4 H), 2.71 (s, 3 H), 2.82 - 2.87 (m, 2 H), 3.24 - 3.27 (m, 2 H), 4.02 (s, 3 H), 4.27 - 4.31 (m, 2 H), 8.04 - 8.13 (m, 1H), 8.18 (s, 1 H), 8.56 (s, 1 H).

[0419] Step 7: Synthesis of Compound 17

[0420] Ammonium chloride (21.29 mg, 397.98 µmol, 6 eq) was added to an anhydrous tetrahydrofuran (3.5 mL) solution of compound 17-7 (35 mg, 66.33 µmol, 1 eq), followed by a 1 M tetrahydrofuran solution of bis(trimethylsilyl)aminolithium (663.30 µL, 10 eq). The mixture was stirred at 20 °C for 2 hours. A saturated aqueous solution of ammonium chloride (10 mL) was then added to the reaction system, followed by ethyl acetate (10 mL). 3) Extraction, separation, and drying of the combined organic phases with anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then separated and purified by high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: C18 100). 30mm 10 µm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient B%: 10%-40%, 8 min), to obtain compound 17.

[0421] The characterization of compound 17 is as follows: LCMS: m / z (ESI) = 499.2 [M+H] + .

[0422] 1 H NMR (400 MHz, DMSO- d 6) d: 2.22 (s, 3 H), 2.41 - 2.45 (m, 4 H), 2.66 (s, 3 H), 2.78 - 2.85 (m, 2 H), 3.10 - 3.17 (m, 2 H), 3.41 - 3.45 (m, 4 H), 4.02 (s, 3 H), 7.49 (s, 2 H), 8.03 (s, 1 H), 8.20 (s, 1 H), 8.53 (s, 1 H).

[0423] Example 18

[0424] Step 1: Synthesis of Compound 18-1

[0425] Under nitrogen protection at 0°C, sodium hydride (132.29 mg, 3.31 mmol, 2 eq) of 60% purity was added to an anhydrous tetrahydrofuran solution (8 mL) of cyclopropanol (192.08 mg, 3.31 mmol, 2 eq). The mixture was stirred at 0°C for 0.5 h, then compound 2-1 (500 mg, 1.65 mmol, 1 eq) was added, and the reaction was continued at 0°C for 1 h. After the reaction was complete, water (5 mL) and ethyl acetate (10 mL) were added. 2) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure to obtain crude product, separation by thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate = 100:0-60:40) to obtain compound 18-1.

[0426] The characterization of compound 18-1 is as follows: LCMS: m / z (ESI) = 280.9 [M+H] + .

[0427] 1H NMR (400 MHz, CDCl3) d : 0.90 - 0.97 (m, 2 H), 1.06 - 1.14 (m, 2H), 1.33 - 1.42 (t, J=7.2 Hz, 3 H), 1.96 - 2.06 (m, 2 H), 2.44 - 2.53 (t, J=6.0 Hz, 2 H), 3.16 - 3.23 (t, J=7.2 Hz, 2 H), 4.05 - 4.12 (m, 1 H), 4.28 -4.39 (q, J=7.2 Hz, 2 H).

[0428] Step 2: Synthesis of Compound 18-2

[0429] Compound 18-1 was dissolved in anhydrous toluene (10 mL), and tert-butoxybis(dimethylamino)methane (1.99 g, 11.41 mmol, 2.36 mL, 20 eq) was added. The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added to the reaction system. 3) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain compound 18-2.

[0430] The characterization of compound 18-2 is as follows: LCMS: m / z (ESI) = 308.9 [M-26] + .

[0431] Step 3: Synthesis of Compound 18-3

[0432] Compound 18-2 (150 mg, 447.20 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and compound 1-3 (141.90 mg, 447.20 µmol, 1 eq) was added. The mixture was stirred at 110 °C for 4 hours. After the reaction was complete, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system. 3) Extract, separate, combine organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain crude product, and purify by column chromatography (gradient eluent: dichloromethane / methanol = 100:0-90:10) to obtain compound 18-3.

[0433] The characterization of compound 18-3 is as follows: LCMS: m / z (ESI) = 590.1 [M+H] + .

[0434] 1 H NMR (400 MHz, CDCl3) d : 0.88 - 0.97 (m, 2 H), 1.05 - 1.14 (m, 2 H), 1.38 - 1.42 (t, J =7.2 Hz, 3 H), 2.41 (s, 3 H), 2.57 - 2.71 (m, 4 H), 2.78 –2.88 (t, J=7.2 Hz, 2 H), 3.26 - 3.36 (m, 6 H), 4.14 - 4.17 (m, 1 H), 4.31 -4.39 (m, 2 H), 6.46 - 6.52 (m, 1 H), 7.11 - 7.17 (m, 1 H), 7.30 (s, 1 H),8.28 (s, 1 H), 8.31 - 8.34 (d, J =2.8 Hz 1 H).

[0435] Step 4: Synthesis of compound 18-4

[0436] Compound 18-3 (100 mg, 169.60 µmol, 1 eq) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (4 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (35.58 mg, 847.99 µmol, 5 eq) was added, and the mixture was stirred at 45 °C for 3 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure to remove the organic solvent, and the pH was adjusted to 7 with 2 N HCl aqueous solution. Compound 18-4 was then directly concentrated under reduced pressure.

[0437] The characterization of compound 18-4 is as follows: LCMS: m / z (ESI) = 562.1 [M+H] + .

[0438] 1H NMR (400 MHz, DMSO- d 6 ) d : 0.71 - 0.81 (m, 4 H), 2.21 (s, 3 H), 2.44 - 2.46 (m, 4 H), 2.57 - 2.63 (m, 2 H), 3.09 - 3.15 (m, 4 H), 3.17 - 3.22(m, 2 H), 3.98 - 4.07 (m, 1 H), 6.57 - 6.68 (m, 1 H), 7.10 - 7.22 (m, 1 H),7.79 - 7.86 (d, J =2.8 Hz, 1 H), 7.97 (s, 1 H), 8.22 (s, 1 H).

[0439] Step 5: Synthesis of Compound 18

[0440] Compound 18-4 (171.77 mg, 1.35 mmol, 118.46 µL, 8 eq) was dissolved in anhydrous tetrahydrofuran (3 mL). Oxaloyl chloride (171.77 mg, 1.35 mmol, 118.46 µL, 8 eq) was added at 0 °C. After three nitrogen purgings, N,N-dimethylformamide (1.24 mg, 16.92 µmol, 1.30 µL, 0.1 eq) was added. The mixture was stirred at 0 °C for 0.5 h. Then, 25% ammonia solution (9 mL) was added, and the mixture was stirred at 20 °C for 0.5 h. After the reaction was complete, ethyl acetate (10 mL) was added to the reaction mixture. 3) Extraction, separation, drying of the organic phase with anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure to obtain the crude product, followed by separation and purification by high-performance liquid chromatography (HPLC preparation method: Waters Xbridge BEH preparative chromatograph; column: C1875). 30 mm 3 µm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; gradient B%: 30%-70%, 8 min), to obtain compound 18.

[0441] The characterization of compound 18 is as follows: LCMS: m / z (ESI) = 561.2 [M+H] + .

[0442] 1H NMR (400 MHz, DMSO- d 6 ) d : 0.79 - 0.85 (m, 4 H), 2.21 (s, 3 H), 2.43 - 2.47 (m, 4 H), 2.66 - 2.70 (t, J=7.2 Hz, 2 H), 3.04 - 3.09 (t, J=7.2Hz, 2 H), 3.11 - 3.15 (m, 4 H), 4.11 - 4.18 (m, 1 H), 6.65 - 6.71 (m, 1 H), 7.13 - 7.19 (d, J=8.8 Hz, 1 H), 7.35 (s, 2 H), 7.65 - 7.70 (d, J=2.8 Hz, 1H), 8.20 (s, 1 H), 8.29 (s, 1 H).

[0443] Example 19

[0444] Step 1: Synthesis of Compound 19-1

[0445] Compound 6-3 (1.2 g, 5.35 mmol, 1 eq), (2-bromoethynyl)triisopropylsilane (1.47 g, 5.62 mmol, 1.05 eq), silver acetate (893.06 mg, 5.35 mmol, 273.95 µL, 1 eq), and palladium acetate (120.13 mg, 535.06 µmol, 0.1 eq) were dissolved in acetonitrile (45 mL) and stirred at 80°C for 72 hours. After the reaction was completed, the mixture was cooled to 20°C, and the reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 100:0-98:2) to give compound 19-1.

[0446] The characterization of compound 19-1 is as follows: LCMS: m / z (ESI) = 405.2 [M+H] + .

[0447] 1H NMR (400 MHz, CDCl3) d : 4.30 - 4.39 (m, 2 H), 3.18 - 3.25 (m, 2H), 2.51 - 2.65 (m, 2 H), 1.97 - 2.14 (m, 2 H), 1.32 - 1.42 (m, 3 H), 1.17 (s, 21 H).

[0448] Step 2: Synthesis of Compound 19-2

[0449] Compound 19-1 (155 mg, 383.06 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (2.5 mL), followed by the addition of tert-butoxybis(dimethylamino)methane (211.00 mg, 1.21 mmol, 0.25 mL, 3.16 eq). After nitrogen evacuation, the mixture was stirred at 80°C for 2 hours. After the reaction was complete, the mixture was cooled to 20°C, and the solvent was concentrated to dryness under reduced pressure to obtain crude compound 19-2, which was directly used in the next reaction.

[0450] Characterization of compound 19-2: LCMS: m / z (ESI) = 433.2 [M-26] + .

[0451] Step 3: Synthesis of Compound 19-3

[0452] Compound 19-2 (170 mg, 369.79 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of compound 1-3 (117.34 mg, 369.79 µmol, 1 eq). The mixture was stirred at 110°C for 20 hours. After the reaction was complete, water (10 mL) and saturated brine (10 mL) were added to the reaction solution, followed by extraction with ethyl acetate (20 mL). The mixture was separated, dried over anhydrous sodium sulfate on the organic phase, filtered, and the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 19-3.

[0453] Characterization of compound 19-3: LCMS: m / z (ESI) = 714.3 [M+H] + .

[0454] 1 H NMR (400 MHz, CDCl3) d : 8.38 (s, 1 H), 8.20 (m, 1 H), 7.19 (s, 1H), 7.14 (m, 1 H), 6.52 (m, 1 H), 4.37 (m, 2 H), 3.19 - 3.40 (m, 6 H), 2.81( 2 H), 2.53 - 2.70 (m, 4 H), 2.39 (s, 3 H), 1.40 (t, J =7.2 Hz, 3 H), 1.09 -1.19 (m, 21 H).

[0455] Step 4: Synthesis of Compound 19-4

[0456] Compound 19-3 (60 mg, 84.04 µmol, 1 eq) and ammonium chloride (26.97 mg, 504.25 µmol, 6 eq) were dissolved in a 1 M solution of lithium bis(trimethylsilyl)amino in hexane (2.09 mL, 10 eq). The mixture was stirred at 20°C for 1 hour under nitrogen atmosphere. The reaction was quenched by adding methanol (3 mL) to the reaction solution. The solvent was concentrated to dryness under reduced pressure to obtain crude compound 19-4.

[0457] Characterization of compound 19-4: LCMS: m / z (ESI) = 685.3 [M+H] + .

[0458] Step 5: Synthesis of Compound 19

[0459] Compound 19-4 (55 mg, 80.31 µmol, 1 eq) and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (1.2 mL, 14.94 eq) were dissolved in anhydrous tetrahydrofuran (2 mL) and stirred at 20°C for 20 hours. Saturated saline solution (5 mL) and water (5 mL) were added to the reaction mixture, followed by ethyl acetate (10 mL). The solution was filtered, separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters 2767 / QDa preparative chromatograph; column: C18 75). 30mm 3µm; mobile phase A: H2O (containing 0.2% formic acid), mobile phase B: acetonitrile; running gradient: B%: 1%-40%, run for 8 min), to obtain the formate of compound 19.

[0460] Characterization of compound 19: LCMS: m / z (ESI) = 529.2 [M+H]+.

[0461] 1H NMR (400 MHz, CD3OD) d : 9.01 - 9.13 (m, 1 H), 8.41 - 8.55 (m, 1H), 7.98 - 8.09 (m, 1 H), 7.69 - 7.78 (m, 1 H), 7.08 - 7.24 (m, 1 H), 6.87 -6.98 (m, 1 H), 6.66 - 6.82 (m, 1 H), 4.53 - 4.64 (m, 1 H), 3.39 - 3.46 (m, 2H), 3.28 - 3.32 (m, 4 H), 3.05 - 3.12 (m, 2 H), 2.93 - 3.02 (m, 4 H), 2.54 -2.72 (m, 3H).

[0462] Example 20

[0463] Step 1: Synthesis of Compound 20-1

[0464] Compounds 6-8 (200 mg, 659.69 µmol, 1 eq), 2-(tributyltinyl)furan (235.59 mg, 659.69 µmol, 208.48 µL, 1 eq), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (48.27 mg, 65.97 µmol, 0.1 eq) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 120°C for 16 hours. Water (10 mL), saturated brine (10 mL), and ethyl acetate (20 mL) were added to the reaction mixture for extraction. The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 100:0-70:30) to give compound 20-1.

[0465] The characterization of compound 20-1 is as follows: LCMS: m / z (ESI) = 291.0 [M+H] + .

[0466] Step 2: Synthesis of compound 20-2

[0467] Compound 20-1 (145 mg, 499.43 µmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and then tert-butoxybis(dimethylamino)methane (6.12 g, 35.11 mmol, 7.25 mL, 70.30 eq) was added. The mixture was stirred at 80°C for 16 hours under nitrogen atmosphere. After the reaction was completed, the solvent was concentrated to dryness under reduced pressure to obtain compound 20-2.

[0468] Characterization of compound 20-2: LCMS: m / z (ESI) = 319.0 [M-26] + .

[0469] Step 3: Synthesis of compound 20-3

[0470] Compound 20-2 (170 mg, 492.17 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and compound 1-3 (156.17 mg, 492.17 µmol, 1 eq) was added. The mixture was stirred at 110°C for 20 hours. After the reaction was completed, the temperature was lowered to 20°C, and water (10 mL), saturated brine (10 mL), and ethyl acetate (20 mL) were added to the reaction solution for extraction. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient elution: dichloromethane / methanol = 100:0-98:2) to obtain compound 20-3.

[0471] Characterization of compound 20-3: LCMS: m / z (ESI) = 600.2 [M+H] + .

[0472] 1 H NMR (400 MHz, CDCl3) d : 8.41 (s, 1 H), 8.11 – 8.13 (m, 1 H), 7.40 -7.57 (m, 2 H), 7.23 (s, 1 H), 7.13 -7.16 (m, 1 H), 6.49 -6.52 (m, 1 H), 6.40– 6.45 (m, 1 H), 4.39 – 4.45 (m, 2 H), 3.33 -3.36 (m, 2 H), 3.04 – 3.16 (m, 4H), 2.82 – 2.86 (m, 2 H), 2.44 – 2.59 (m, 4 H), 2.34 (s, 3 H), 1.42 (t, J=7.2Hz, 3H).

[0473] Step 4: Synthesis of Compound 20

[0474] Compound 20-3 (130 mg, 216.80 µmol, 1 eq) and ammonium chloride (69.58 mg, 1.30 mmol, 6 eq) were dissolved in a 1 M solution of bis(trimethylsilyl)amino in n-hexane (1.73 mL, 8 eq), and stirred at 20°C for 2 hours under nitrogen. Methanol (5 mL) was added to the reaction mixture, and the solvent was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters 2767 / QDa preparative chromatograph; column: C1880). 40mm 3µm; mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; running gradient: B%: 25%-55%, run for 8 min), to obtain compound 20.

[0475] Characterization of compound 20: LCMS: m / z (ESI) = 571.2 [M+H] + .

[0476] 1H NMR (400 MHz, CDCl3) d : 8.41 (s, 1 H), 8.11 (s, 1 H), 7.45 (s, 2H), 7.24 (s, 1 H), 7.13 -7.16 (m, 1 H), 6.50 -6.55 (m, 1 H), 6.40 (s, 1 H), 5.66 (s, 2 H), 3.30 -3.36 (m, 2 H), 3.01 - 3.20 (m, 4 H), 2.82 - 2.90 (m, 2H), 2.54 -2.60 (m, 4 H), 2.36 (s, 3 H).

[0477] Example 21

[0478] Step 1: Synthesis of Compound 21-1

[0479] Compound 5-4 (50 mg, 155.56 µmol, 1 eq) was added to anhydrous dichloromethane (2 mL), cooled to 0°C, and then 85% pure m-chloroperoxybenzoic acid (63.17 mg, 311.12 µmol, 2 eq) was added. The mixture was heated to 25°C and stirred for 12 hours. After the reaction was complete, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (4 mL), followed by dichloromethane (4 mL). 2) Extraction, combining the organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain the crude product, and purifying it by silica gel column chromatography (gradient eluent: dichloromethane / methanol = 100:0-90:10) to obtain compound 21-1.

[0480] Characterization of compound 21-1: LCMS: m / z (ESI) = 354.1 [M+H] + .

[0481] 1H NMR (400 MHz, CDCl3) d: 8.29 (s, 1H), 5.05 (s, 2H), 4.40 (q, J =7.2 Hz, 2H), 3.76 (s, 3H), 3.33 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).

[0482] Step 2: Synthesis of compound 21-2

[0483] Compound 21-1 (50 mg, 141.48 µmol, 1 eq) and compound 7-3 (66.81 mg, 141.48 µmol, 1 eq) were added to 1,4-dioxane (2 mL), followed by tris(dibenzylacetone)palladium (12.96 mg, 14.15 µmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (8.19 mg, 14.15 µmol, 0.1 eq), and cesium carbonate (92.19 mg, 282.95 µmol, 2 eq). The mixture was heated to 100°C and stirred for 12 hours. After the reaction was complete, the reaction solution was slowly poured into water (3 mL) to quench the reaction, followed by ethyl acetate (3 mL). 3) Extract, combine organic phases, and add saturated saline (3 mL) 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain crude product, and separate by thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate = 100:100) to obtain compound 21-2.

[0484] Characterization of compound 21-2: LCMS: m / z (ESI) = 698.2 [M+H] + .

[0485] 1H NMR (400 MHz, CDCl3) d: 8.45 (s, 1H), 7.96 – 8.04 (m, 1H), 7.14 -7.20 (m, 1H), 7.07 - 7.13 (m, 1H), 6.56 - 6.65 (m, 1H), 4.34 - 4.56 (m, 2H), 3.58 - 3.66 (m, 4H), 3.53 - 3.57 (m, 3H), 3.32 - 3.39 (m, 2H), 3.17 - 3.24(m, 4H), 2.82 - 2.90 (m, 2H), 1.47 - 1.52 (m, 9H), 1.38 - 1.45 (m, 3H).

[0486] Step 3: Synthesis of the trifluoroacetate of compound 21-3

[0487] Compound 21-2 (80 mg, 114.66 µmol, 1 eq) was added to anhydrous dichloromethane (2 mL), followed by trifluoroacetic acid (273.78 mg, 2.40 mmol, 177.78 µL, 20.94 eq). The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of compound 21-3. The crude product was used directly in the next step.

[0488] Characterization of compound 21-3: LCMS: m / z (ESI) = 598.1 [M+H] + .

[0489] Step 4: Synthesis of compound 21-4

[0490] The trifluoroacetate of compound 21-3 (75 mg, 105.39 µmol, 1 eq) was added to anhydrous tetrahydrofuran (1 mL), followed by triethylamine (10.66 mg, 105.39 µmol, 14.67 µL, 1 eq), a 37% formaldehyde aqueous solution (34.21 mg, 421.55 µmol, 31.38 µL, 4 eq), and glacial acetic acid (25.32 mg, 421.55 µmol, 24.11 µL, 4 eq). The mixture was stirred at 25°C for 0.5 hours, then sodium triacetoxyborohydride (89.34 mg, 421.55 µmol, 4 eq) was added, and the mixture was stirred at 25°C for 12 hours. Finally, a saturated sodium bicarbonate aqueous solution (2 mL) and ethyl acetate (2 mL) were added to the reaction mixture. 2) Extraction, separation, drying, filtration, and concentration of the filtrate under reduced pressure to obtain the crude product, which was then purified by thin-layer chromatography (developing solvent: dichloromethane / methanol = 100:10) to obtain compound 21-4.

[0491] Characterization of compound 21-4: LCMS: m / z (ESI) = 612.2 [M+H] + .

[0492] 1H NMR (400 MHz, CDCl3) d : 8.41 - 8.46 (m, 1H), 7.91 - 7.95 (m, 1H), 7.09 - 7.18 (m, 2H), 6.55 - 6.63 (m, 1H), 4.34 - 4.44 (m, 2H), 3.50 - 3.56(m, 3H), 3.30 - 3.36 (m, 2H), 3.23 - 3.30 (m, 4H), 2.78 - 2.89 (m, 2H), 2.59 - 2.66 (m, 4H), 2.35 - 2.41 (m, 3H), 1.37 - 1.43 (m, 3H).

[0493] Step 5: Synthesis of compound 21-5

[0494] Compound 21-4 (60 mg, 98.09 µmol, 1 eq) was added to anhydrous tetrahydrofuran (1 mL) and water (1 mL), followed by lithium hydroxide monohydrate (12.35 mg, 294.28 µmol, 3 eq). The mixture was stirred at 25°C for 12 hours. After the reaction was complete, the solution was concentrated directly, and the pH was adjusted to 6-7 with 2 N hydrochloric acid. Then, the solution was dissolved in dichloromethane (3... Extract (3 mL), separate, combine organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and obtain compound 21-5.

[0495] Characterization of compound 21-5: LCMS: m / z (ESI) = 584.2 [M+H] + .

[0496] Step 6: Synthesis of Compound 21

[0497] Compound 21-5 (50 mg, 85.67 µmol, 1 eq) was added to anhydrous N,N-dimethylformamide (0.5 mL), followed by ammonium bicarbonate (8.80 mg, 111.38 µmol, 9.17 µL, 1.3 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (65.15 mg, 171.35 µmol, 2 eq), and N,N-diisopropylethylamine (33.22 mg, 257.02 µmol, 44.77 µL, 3 eq). The mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters 2767 / QDa preparative chromatograph; column: C18 80). 30mm 3µm; Mobile phase A: 10mM ammonium bicarbonate aqueous solution, Mobile phase B: acetonitrile; Running gradient: B%: 25%-55%, run for 8 min. ), yielding compound 21.

[0498] Characterization of compound 21: LCMS: m / z (ESI) = 583.2 [M+H] + .

[0499] 1 H NMR (400 MHz, DMSO- d 6) d : 8.75 - 8.84 (m, 1H), 8.44 - 8.50 (m, 1H), 7.77 - 7.99 (m, 2H), 7.18 - 7.24 (m, 1H), 7.12 - 7.16 (m, 1H), 6.82 - 6.87(m, 1H), 3.30 - 3.33 (m, 3H), 3.13 - 3.21 (m, 4H), 3.04 - 3.11 (m, 2H), 2.71 - 2.78 (m, 2H), 2.41 - 2.45 (m, 4H), 2.19 - 2.24 (m, 3H).

[0500] Example 22

[0501] Step 1: Synthesis of Compound 22-1

[0502] Ethylene glycol monomethyl ether (151.00 mg, 1.98 mmol, 156.47 µL, 2 eq) was dissolved in tetrahydrofuran solution (5 mL). The solution was cooled to 0°C, and 60% sodium hydride (79.37 mg, 1.98 mmol, 2 eq) was added. The reaction was carried out at 0°C for 0.5 hours. Compound 2-1 (300 mg, 992.18 µmol, 1 eq) was added, and the reaction was continued at 0°C for another 0.5 hours. After the reaction was complete, water (20 mL) and ethyl acetate (10 mL) were added. 3) Extraction, washing with saturated brine (20 mL), separation, drying the organic phase with anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure to obtain crude product, purification by column chromatography (gradient eluent: petroleum ether / ethyl methyl ester = 100:0-50:50) to obtain compound 22-1.

[0503] The characterization of compound 22-1 is as follows: LCMS: m / z (ESI) = 298.9 [M+H] + .

[0504] 1H NMR (400 MHz, CDCl3) d : 1.38 (t, J=7.09 Hz, 3 H), 1.98 - 2.08 (m,2 H), 2.42 - 2.58 (m, 2 H), 3.19 - 3.23 (m, 2 H), 3.46 - 3.55 (m, 3 H), 3.81- 3.95 (m, 2 H), 4.33 (q, J=7.09 Hz, 2H), 4.38 - 4.42 (m, 2H).

[0505] Step 2: Synthesis of compound 22-2

[0506] Compound 22-1 (100 mg, 335.17 µmol, 1 eq) was dissolved in toluene (3 mL), and tert-butoxybis(dimethylamino)methane (350.49 mg, 2.01 mmol, 415.27 µL, 6 eq) was added. The mixture was stirred at 90 °C for 12 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (5 mL) and ethyl acetate (3 mL) were added. 3) Extraction, separation, washing the organic phase with saturated sodium chloride aqueous solution (5 mL), drying with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain compound 22-2.

[0507] The characterization of compound 22-2 is as follows: LCMS: m / z (ESI) = 327.0 [M-26] + .

[0508] Step 3: Synthesis of compound 22-3

[0509] Compound 22-2 (200 mg, 565.88 µmol, 1 eq) and compound 1-3 (179.56 mg, 565.88 µmol, 1 eq) were dissolved in N,N-dimethylformamide (2 mL) and reacted with stirring at 110 °C for 12 hours. After the reaction was completed, water (5 mL) was added to quench the reaction, followed by ethyl acetate (5 mL). 3) Extraction, combining the organic phases, washing with saturated sodium chloride solution (5 mL), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (HPLC preparation method: Waters Xbridge Prep OBD preparative chromatograph; column: C18 150). 40mm 10µm; mobile phase A: 10mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia), mobile phase B: acetonitrile; gradient B%: 50%-80%, 8min), to obtain compound 22-3.

[0510] The characterization of compound 22-3 is as follows: LCMS: m / z (ESI) = 608.3 [M+H] + .

[0511] 1H NMR (400 MHz, CD3OD) d : 1.38 (t, J=7.13 Hz, 3 H), 2.37 (s, 3 H), 2.59 - 2.68 (m, 4 H), 2.80 - 2.82 (m, 2 H), 3.24 - 3.31 (m, 9 H), 3.75 - 3.80 (m, 2 H), 4.33 (q, J=7.13 Hz, 2 H), 4.41 - 4.50 (m, 2 H), 6.60 - 6.70 (m J=9.07, 1 H), 7.15 - 7.23 (m, 1 H), 8.20 - 8.24 (m, 1 H), 8.32 (s, 1 H).

[0512] Step 4: Synthesis of compound 22-4

[0513] Compound 22-3 (40 mg, 65.83 µmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (0.25 mL), and water (0.25 mL). Lithium hydroxide monohydrate (13.81 mg, 329.14 µmol, 5 eq) was added, and the mixture was stirred at 40 °C for 12 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The pH was adjusted to 6-7 with 2 N hydrochloric acid. Ethyl acetate (2 mL) was then added. 3) Extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 22-4.

[0514] The characterization of compound 22-4 is as follows: LCMS: m / z (ESI) = 580.1 [M+H] + .

[0515] Step 5: Synthesis of Compound 22

[0516] Compound 22-4 (35 mg, 60.39 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (78.05 mg, 603.88 µmol, 105.18 µL, 10 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (137.77 mg, 362.33 µmol, 6 eq), and ammonium bicarbonate (47.74 mg, 603.88 µmol, 49.73 µL, 10 eq). The mixture was stirred at 20 °C for 12 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (2 mL) and ethyl acetate (2 mL) were added. 3) Extract, combine organic phases, wash with saturated brine (3 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness under reduced pressure to obtain crude product, and separate and purify by preparative high-performance liquid chromatography (HPLC method: Phenomenex preparative chromatograph; column: C18 75). 30mm 3µm; Mobile phase A: 10mM ammonium bicarbonate aqueous solution (containing 0.05% ammonia), mobile phase B: acetonitrile; running gradient: B%: 30%-55%, run for 8 min, to obtain compound 22.

[0517] The characterization of compound 22 is as follows: LCMS: m / z (ESI) = 579.1 [M+H] + .

[0518] 1H NMR (400 MHz, DMSO- d 6 ) δ: 2.25 (s, 3 H), 2.71 (s, 2 H), 3.00 -3.24 (m, 9 H), 3.35 (s, 4 H), 3.59 (s, 2 H), 4.26 (s, 2 H), 6.60 – 6.70 (m, 1H), 7.15 – 7.20 (m, 1 H), 7.38 (s, 2 H), 7.80 (s, 1 H), 8.21 (s, 1 H), 8.34 (s, 1 H).

[0519] Example 23

[0520] Step 1: Synthesis of Compound 23-1

[0521] Compounds 1-4 (14 g, 24.15 mmol, 1 eq) were added to a mixed solution of water (140 mL), tetrahydrofuran (70 mL), and methanol (70 mL), followed by the addition of lithium hydroxide monohydrate (3.04 g, 72.46 mmol, 3 eq). The mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to half its original volume under reduced pressure. 2-Methyltetrahydrofuran (30 mL) was added, and the pH was adjusted to 6-7 with 6 N hydrochloric acid. The mixture was stirred at 20°C for 2 hours, filtered, and dried to obtain compound 23-1.

[0522] LCMS: m / z (ESI) = 552.1 [M+H] + .

[0523] Step 2: Synthesis of compound 23-2

[0524] Compound 23-1 (50 mg, 90.64 µmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (68.93 mg, 181.29 µmol, 2 eq) and N,N-diisopropylethylamine (35.14 mg, 271.93 µmol, 47.36 µL, 3 eq). The mixture was stirred at 20°C for 0.5 hours, followed by the addition of O-(tetrahydro-2H-pyran)-2-hydroxylamine (21.24 mg, 181.29 µmol, 2 eq). The mixture was stirred at 20°C for another hour. After the reaction was complete, water (3 mL) was added to the reaction mixture, followed by filtration. The resulting filter cake was dried to obtain compound 23-2.

[0525] The characterization of compound 23-2 is as follows: LCMS: m / z (ESI) = 651.0 [M+H] + .

[0526] Step 3: Synthesis of Compound 23

[0527] Compound 23-2 (50 mg, 76.84 µmol, 1 eq) was dissolved in anhydrous methanol (5 mL), and p-toluenesulfonic acid (35.71 mg, 207.40 µmol, 2.70 eq) was added. The mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and water (5 mL) and ethyl acetate (5 mL) were added. 3) Extraction, separation, and drying of the combined organic phases with anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then separated and purified by preparative high-performance liquid chromatography (HPLC) (Phenomenonex Luna preparative chromatograph; column: C18 75). 30mm 3µm; mobile phase A: water (containing 0.05% formic acid), mobile phase B: acetonitrile; running gradient: B%: 20%-60%, run for 8 min, to obtain the formate of compound 23.

[0528] Characterization of compound 23: LCMS: m / z (ESI) = 567.1 [M+H] + .

[0529] 1 H NMR (400 MHz, DMSO- d 6 ) d: 10.53 - 10.85 (m, 1 H), 8.93 - 9.36 (m, 1H), 8.47 (s, 1 H), 8.32 (s, 1 H), 8.16 (s, 1 H), 7.50 (d, J=2.8 Hz, 1 H), 7.17 (dd, J=8.8, 1.6 Hz, 1 H), 6.71 (dd, J=9.2, 2.8 Hz, 1 H), 3.12 - 3.18 (m,4 H), 3.07 - 3.10 (m, 2 H), 2.73 (t, J=7.2 Hz, 2 H), 2.53 (s, 3 H), 2.43 -2.46 (m, 4 H), 2.22 (s, 3 H).

[0530] Biological test data: Experimental Example 1: Evaluation of in vitro PLK1 kinase activity use 33 P-isotope labeled kinase activity assay (Reaction Biology Corp) to determine IC50 50 The value is used to evaluate the inhibitory effect of the test compound on human PLK1 protein kinase.

[0531] Buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO

[0532] Experimental Procedure: At room temperature, dissolve the test compound in DMSO to prepare a 10 mM solution. Dissolve the substrate Casein in freshly prepared buffer (final concentration 20 µM), add the test PLK1 kinase (final concentration 12 nM) and mix well. Using an Echo 550 ultrasonic pipetting system, add the DMSO-dissolved test compound stock solution to the above-mixed reaction solution according to the set final concentration gradient (maximum final concentration 1 µM, 3-fold dilution, 10 gradients). After incubating at room temperature for 20 minutes, add... 33 After incubating p-ATP (30 µM) at room temperature for 120 minutes, the reaction solution was spotted onto P81 ion-exchange filter paper (Whatman # 3698-915). The filter paper was repeatedly washed with 0.75% phosphoric acid solution, and the level of residual radiophosphorylated substrate on the filter paper was measured. %kinase activity = kinase activity 受试化合物 / kinase activity 空白组（DMSO）The IC was obtained by curve fitting using Prism4 software (GraphPad) at a rate of ×100%. 50 The values ​​and experimental results are shown in Table 1.

[0533] Table 1: Results of in vitro PLK1 kinase activity screening test of the compounds of the present invention

[0534] Conclusion: The compounds of this invention generally exhibit good inhibitory activity against PLK1.

[0535] Experimental Example 2: Evaluation of in vitro PLK2 / PLK3 / PLK4 kinase activity

[0536] use 33 P-isotope labeled kinase activity assay (Reaction Biology Corp) to determine IC50 50 The values ​​are used to evaluate the inhibitory effect of the test compounds on human PLK family protein kinases PLK2 / PLK3 / PLK4.

[0537] Buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.

[0538] Experimental Procedure: At room temperature, dissolve the test compound in DMSO to prepare a 10 mM solution. Dissolve the substrate Casein in freshly prepared buffer (final concentration 20 µM), add the test PLK2 / PLK3 / PLK4 kinases (final concentrations of 15 / 10 / 150 nM respectively) and mix thoroughly. Using an Echo 550 ultrasonic pipetting system, add the DMSO-dissolved test compound stock solution to the above-mixed reaction solution according to the set final concentration gradient (maximum final concentration 1 µM, 3-fold dilution, 10 gradients). After incubating at room temperature for 20 minutes, add... 33 P-ATP (final concentrations of 30 / 50 / 10 µM) was incubated at room temperature for 120 minutes, and then the reaction solution was spotted onto P81 ion exchange filter paper (Whatman # 3698-915). After repeatedly washing the filter paper with 0.75% phosphoric acid solution, the level of residual radiophosphorylated substrate on the filter paper was measured. %kinase activity = kinase activity 受试化合物 / kinase activity 空白组（DMSO） The IC was obtained by curve fitting using Prism4 software (GraphPad) at a rate of ×100%. 50 The values ​​and experimental results are shown in Table 2.

[0539] Table 2: Selectivity test results of PLK family protein kinases in this invention

[0540] Conclusion: The compounds of this invention exhibit weak inhibitory activity against PLK2 / PLK3 / PLK4 kinases, meaning they show good PLK1 selectivity.

[0541] Experimental Example 3: Evaluation of HCT116 Cellular Activity in In Vitro

[0542] Experimental materials: McCoy's 5A medium and penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. HCT116 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision multilabel analyzer (PerkinElmer).

[0543] Experimental methods: HCT116 cells were seeded into 96-well U-shaped plates with ultra-low adsorption, with 80 μL of cell suspension per well containing 1000 HCT116 cells. The cell plates were incubated overnight in a CO2 incubator.

[0544] The test compound was diluted 5-fold to the 9th concentration using a multi-channel pipette, i.e., from 2 mM to 5.12 nM, and a double-dilution assay was performed. 78 μL of culture medium was added to the intermediate plate, and then 2 μL of the serially diluted compound was transferred to each well of the intermediate plate according to the corresponding positions. After mixing, 20 μL of the compound was transferred to each well of the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.0256 nM. The cell plate was incubated in a CO2 incubator for 5 days. A separate cell plate was prepared, and the signal value on the day of drug addition was recorded as the maximum value (Max value in the equation below) for data analysis.

[0545] Add 100 μL of chemiluminescent cell viability detection reagent to the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the values ​​using a multi-label analyzer.

[0546] Data Analysis: Using the equation (Sample-Min) / (Max-Min) 100% conversion of raw data into inhibition rate, IC 50The values ​​can be obtained by curve fitting using four parameters (obtained in GraphPad Prism using the "log(inhibitor) vs. response -- Variable slope" mode). Table 3 provides the inhibitory activity of the compounds of this invention on the proliferation of HCT116 cells.

[0547] Table 3: Results of in vitro screening tests of compounds of the present invention

[0548] Conclusion: The compounds of this invention exhibited good inhibitory activity against cell proliferation in the HCT116 cell line.

[0549] Experiment 4: Pharmacokinetic Study of Test Compounds by Oral and Intravenous Injection in Male CD-1 Mice

[0550] Experimental objective: This study aimed to investigate the pharmacokinetics of the test compound in the plasma of male CD-1 mice after intravenous and oral administration.

[0551] Experimental procedure: Intravenous injection group: An appropriate amount of the test compound was weighed, dissolved in a 20% SBE-b-CD aqueous solution, and the pH was adjusted to 4-5 with 6 M hydrochloric acid. The solution was vortexed for 2 minutes to obtain a clear solution. Then, the pH was adjusted to approximately 7 with 5 N sodium hydroxide, and the solution was vortexed for 1 minute to prepare a 1.5 mg / mL clear solution. The solution was filtered through a 0.22 μm microporous membrane for later use. Six- to ten-week-old male CD-1 mice were selected and administered the test compound solution intravenously. Samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.

[0552] Oral administration group: An appropriate amount of the test compound was weighed, dissolved in a 20% SBE-b-CD aqueous solution, and the pH was adjusted to 3-4 with 6 M hydrochloric acid. The solution was vortexed for 2 minutes to obtain a clear solution. Then, the pH was adjusted to approximately 7 with 5 N sodium hydroxide, and the solution was vortexed for 1 minute to prepare a 2.0 mg / mL clear solution for later use. Six- to ten-week-old male CD-1 mice were selected and orally administered the test compound. Samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours.

[0553] At each time point, approximately 50 μL of whole blood was collected via the jugular vein to prepare plasma for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were euthanized under CO2 anesthesia after the collection of PK samples at the last time point. Plasma concentrations were processed using a non-compartmental model of WinNonlin™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The experimental results are shown in Table 4.

[0554] Table 4: Pharmacokinetic Results of the Test Compounds

[0555] Experimental conclusion: The compound showed low drug clearance in CD-1 mouse pharmacokinetic studies, but reached peak levels rapidly after oral administration and exhibited high oral bioavailability.

[0556] Example 5: In vivo pharmacodynamic study of the test compound on a human colon cancer HCT116 cell subcutaneous xenograft model

[0557] 1. Experimental Objective

[0558] This study used a BALB / c Nude mouse model of human colon cancer HCT116 cells subcutaneously transplanted into tumors to evaluate the in vivo antitumor efficacy of the test compounds.

[0559] 2. Experimental Methods

[0560] 2.1 Model Establishment

[0561] HCT116 cell culture: Cells were cultured in McCoy's 5A medium with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and subcutaneously inoculated into female BALB / c Nude mice (6-7 weeks old).

[0562] 2.2 Grouping and Drug Administration Observation

[0563] Once the tumors have grown to a certain size, animals with tumors that are too large, too small, or irregularly shaped are culled, and those with tumors ranging from 103.12 to 174.35 mm in size are selected. 3 The animals were randomly divided into 6 groups of 6 mice each, based on tumor volume. The average tumor volume was approximately 147.12 mm. 3The experimental groups and dosing regimens are shown in Table 5 below. Animal health and mortality were monitored daily. Routine checks included observing the effects of tumor growth and drug treatment on daily behavior, such as activity levels, food and water intake, weight changes (measured twice weekly), tumor size (measured twice weekly), physical appearance, and any other abnormalities.

[0564] Table 5. Study protocol for human colon cancer HCT116 cell xenograft model in BALB / c Nude mice.

[0565] Solvent: Vehicle group, 20% SEB-β-CD

[0566] PO: Oral administration

[0567] QD: Once a day, give 5 days, then stop for 2 days.

[0568] 2.3 Evaluation Indicators

[0569] The formula for calculating tumor volume (TV) is: 1 / 2 a b 2 Where a and b are the length and width of the tumor, respectively. The tumor inhibition rate (TGI) (%) is calculated as follows: TGI (%) = [1 - (average tumor volume at the end of treatment in a certain treatment group - average tumor volume at the beginning of treatment in that treatment group) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0570] 2.4 Data Analysis

[0571] In this study, experimental data are expressed as Mean ± SEM. Statistical analysis was performed using IBM SPSS Statistics software based on RTV data at the end of the experiment. Comparisons between two groups were analyzed using the t-test; comparisons between three or more groups were analyzed using one-way ANOVA. If the variances were homogeneous (no significant difference in F-values), Tukey's test was used; if the variances were unequal (significant difference in F-values), the Games-Howell test was used. A p-value < 0.05 was considered statistically significant.

[0572] 3. Experimental Results and Discussion

[0573] This experiment evaluated the efficacy of compound 1, compound 2, and compound 8 in a BALB / c Nude mouse model of subcutaneous transplantation of human colon cancer HCT-116 cells. No animal deaths occurred in any of the experimental groups throughout the administration period, and the mice tolerated the treatment well. The experimental results are shown in Table 6 and... Figure 1 , Figure 2 As shown.

[0574] Table 6. Evaluation of the antitumor efficacy of the test compounds in a human colon cancer HCT116 cell subcutaneous xenograft model

[0575] (Calculated based on tumor volume on day 22 after drug administration)

[0576] Experimental conclusion: In this pharmacodynamic model, the compound of the present invention exhibits dose-dependent antitumor activity and has significant antitumor effects. The changes in animal body weight throughout the experiment were similar to those in the solvent group, and the animals showed good tolerance.

Claims

1. The compound represented by formula (P) or a pharmaceutically acceptable salt thereof, in, T1 is selected from CR1 and N; T2 is selected from CH and N; R1 is selected from H; R2 is selected from H, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 alkynyl group, C 3-5 cycloalkyl, -OC 3-5 cycloalkyl and 5-membered heteroaryl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2C 1-3 Alkyl, C 2-3 alkynyl group, C 3-5 cycloalkyl, -OC 3-5 Cycloalkyl and 5-membered heteroaryl groups are optionally surrounded by 1, 2 or 3 R groups. b replace; R3 is selected from C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups, wherein the C 1-4 Alkyl, piperazine, and 7-9 membered heterocyclic alkyl groups are optionally surrounded by 1, 2, or 3 R groups. c replace; R4 is selected from C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. d replace; R5 is selected from H and OH; Alternatively, R1 and R3 can form rings with the adjacent atoms, creating structural fragments. Selected from Each R b Each of the following is independently selected from F, Cl, Br, I, OH, and OCH3; Each R c Selected independently from =O and C 1-3 Alkyl, C 1-4 Alkylamino and heterocyclic butyl, the C 1-3 Alkyl, C 1-4 The alkylamino and heterocyclic butyl groups may be optionally substituted with 1, 2 or 3 R groups; Each R d They were each independently selected from F, Cl, Br, and I; Each R is independently selected from F, Cl, Br, I, and OH; The heteroatoms of the "heterocyclic butyl" and "7-9 membered heterocyclic alkyl" are selected from N, O and S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from H, CN, SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl. , and The SCH3, SCH2CH3, SCH(CH3)2, S(=O)2CH3, OCH3, OCH2CH3, OCH(CH3)2, CH3, CH2CH3, CH(CH3)2, cyclopropyl, , and Choose 1, 2, or 3 Rs b replace.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from H, CN, SCH3, SCH2CH2OH, S(=O)2CH3, OCH2CH3, OCH2CH2OH, OCH2CH2OCH3, CH3, CH2CH2OH, CH2OCH3, cyclopropyl. , and .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R c Selected from =O, CH3, CH2CH3, N(CH3)2 and The CH3, CH2CH3 and N(CH3)2 may be optionally replaced by 1, 2 or 3 Rs.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R c Selected from =O, CH3, CH2CH2OH, N(CH3)2 and .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from CH2CH2CH3. , , and The CH2CH2CH3, , and Choose 1, 2, or 3 Rs c replace.

7. The compound according to any one of claims 1, 4-6, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from , , , , , , , and .

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from CH3, OCH3, OCHF2, and OCF3.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... in, R2 and R3 are as defined in any one of claims 1 to 8.

10. The compounds shown below, or their pharmaceutically acceptable salts, are selected from... 。 11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 in the preparation of a medicament for treating solid tumors.

12. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 in the preparation of a medicament for treating solid tumors associated with selective PLK1 inhibitors.

13. The application according to claim 11 or 12, wherein, Solid tumors refer to colorectal cancer.

Images