A cdK degrader and uses thereof

Abstract

The present application relates to a kind of bifunctional CDK degradation agent (W-L-T) and its use;Wherein, W is the targeting group of CDK, T is the ligand group of E3 ubiquitin ligase, L is the bivalent connecting group that makes the chemical connection of targeting group (W) and ligand group (T). The bifunctional compound disclosed in the present application and its composition show pharmacological activity related to the degradation, inhibition of target protein, and can be used for treating, inhibiting or preventing CDK-related diseases or disorders.

Description

Technical Field

[0001] This invention relates to bifunctional compounds with a WLT structure, or pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers thereof, and their use as CDK degrading agents in the preparation of medicaments for the treatment, inhibition, or prevention of CDK-related conditions. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are kinases that play important regulatory roles at different stages of cell division and proliferation. CDKs bind to cyclins to form cyclin-CDK complexes, which are subsequently activated by phosphorylation by CDK-activating kinases (CAKs). Activated cyclin-CDK complexes, such as cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, and cyclin D / CDK6, are important regulators of cell cycle progression and also participate in regulating transcription, DNA repair and differentiation, and apoptosis.

[0003] Studies have shown that tumor development may be related to CDK activation, and CDK inhibitors have proven to be an effective cancer treatment. For example, CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved by the FDA for the treatment of breast cancer. Although CDK4 / 6 inhibitors have broad potential and significant clinical efficacy in hormone receptor (ER)-positive metastatic breast cancer, approximately 10%–15% of patients develop primary resistance to CDK4 / 6 inhibitors, and most patients develop acquired resistance, which limits the clinical application of CDK4 / 6 inhibitors (Turner et al., J ClinOncol 37:1169-117, 2019).

[0004] Cyclin E comprises cyclin E1 and cyclin E2, encoded by the genes CCNE1 and CCNE2, respectively. It is frequently overexpressed in cancers, and this overexpression has been reported to be associated with poor prognosis in breast cancer. As a regulatory subunit of CDK2, the Cyclin E / CDK2 complex plays a crucial role in regulating the G1 / S phase transition, histone biosynthesis, and centrosome replication. Studies have identified CDK2 activity as being associated with tumor growth in many cancer types, and CDK2 overexpression has been shown to occur in the aberrant regulation of the cell cycle. When CDK4 / 6 is inhibited, CDK2 activation can contribute to drug resistance as a compensatory mechanism for cell cycle progression. Therefore, inhibiting CDK4 / 6 while simultaneously inhibiting CDK2 may help control tumor drug resistance and potentially benefit more patients with indications for which CDK4 / 6 inhibitors are not yet approved.

[0005] Protein degradation-targeting chimeras (Protac) are a novel technology in drug discovery in recent years, as cited in Angew. Chem. Int. Ed. 2016, 55, 807–810, J. Med. Chem. 2018, 61, 444-452. Protac is not a traditional enzyme inhibitor; instead, it exerts its protein degradation effect by inducing selective intracellular proteolysis. Protac is a heterobifunctional small molecule composed of two active domains and a linker, capable of removing specific unwanted proteins. One of the two active domains of Protac binds to an E3 ubiquitin ligase, and the other binds to the target protein to be degraded. Recruiting the E3 ligase to the target protein leads to ubiquitination, followed by proteasome degradation. Protac offers many advantages over traditional small molecule inhibitors. For diseases or conditions related to CDK2 / 4 / 6, small molecule formulations that can target and degrade CDK4 / 6 are highly significant. Currently, there are reports of Protac degraders targeting CDK4 / 6 overcoming resistance to clinical CDK4 / 6 inhibitors. Summary of the Invention

[0006] The main technical problem solved by this invention is to provide a bifunctional compound capable of accumulating E3 ubiquitin ligase near a target protein for degradation. As a CDK degrading agent, it can be used as a targeted ubiquitination regulator for various peptides or proteins, thereby degrading or inhibiting the targeted peptide or protein. The bifunctional compound disclosed in this invention, or its pharmaceutically acceptable salt, ester, hydrate, solvate, stereoisomer, isotope derivative, or prodrug, comprises a CDK targeting group W, an E3 ubiquitin ligase ligand group T, and a bivalent linker group (L) chemically linking the targeting group (W) and the ligand group (T), thereby enabling the target protein (CDK) to be located near the E3 ubiquitin ligase, thus affecting or inhibiting the degradation of the protein.

[0007] The quantities and positions of W and T described in this invention are shown as examples only and are not intended to limit the compounds. In practice, those skilled in the art can adjust or change them as needed.

[0008] In some embodiments, the bifunctional compound comprises a targeting group W and a ligand group T of E3 ubiquitin ligase, wherein W and T are covalently linked to corresponding sites of the bivalent linker L, respectively, to form a protein degradation targeting chimera, which is represented by the following general formula:

[0009] WLT.

[0010] In some embodiments, the bifunctional compound comprises only the targeting group W and the ligand group T of the E3 ubiquitin ligase, i.e., it is presented in the form of WT.

[0011] In some embodiments, the targeting group W of the CDK has a structure selected from formula (Ia), (Ib), or (Ic):

[0012]

[0013] Where X and Y are independently selected from N, -CH- or –C(CN)-;

[0014] Z is selected independently

[0015] Z 1 Independently selected from N or -CH-;

[0016] Z 2 Independently selected from substituted or unsubstituted C3-C8 membered divalent cyclic hydrocarbon groups or heterocyclic hydrocarbon groups, substituted or unsubstituted C3-C8 membered divalent aryl or heteroaryl groups, substituted or unsubstituted divalent pyridinyl or piperidinyl groups, -S(=O)2- or not present;

[0017] Z 3Independently selected from substituted or unsubstituted carbonyl groups, -S(=O)2-, O, –NH– or absent;

[0018] R 1 The hydrocarbon is selected from H, halogens, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted 3-8 membered cyclic hydrocarbon or heterocyclic hydrocarbon, wherein the substituted C1-C6 alkyl or C1-C6 alkoxy is optionally substituted by 1-6 substituents independently selected from F, Cl, Br, –CN, -NH2, -OH or mercapto, wherein the heterocycle in the heterocyclic hydrocarbon includes substituted or unsubstituted monocyclic, spirocyclic or fused rings; preferably, R 1 It is an unsubstituted C1-C6 alkyl group, especially a C1-C4 alkyl group, more preferably, R 1 Isopropyl

[0019] Each R 2 Independently selected from H, F, Cl, Br, -CN, -NH2, -OH, mercapto or substituted or unsubstituted alkyl groups (such as halomethyl);

[0020] R 3 R 4 It is independently selected from H, halogen, halomethyl (monohalomethyl, dihalomethyl, and trihalomethyl), amino, hydroxyl, or mercapto;

[0021] n is an integer independently selected from 0 to 2, specifically 0, 1, and 2;

[0022] m is selected from an integer between 0 and 3, specifically 0, 1, 2, and 3.

[0023] In some embodiments, R 3 Selected from halogens (fluorine, chlorine, bromine), more preferably, R 3 Selected from fluorine.

[0024] In some embodiments, R 4 Selected from halogens (fluorine, chlorine, bromine), more preferably, R 4 Selected from fluorine.

[0025] In some embodiments, the targeting group W of the CDK has a structure selected from those shown in formulas (IIa)-(IIf):

[0026]

[0027] In some embodiments, when the structure has a chiral center, its three-dimensional structure is independently selected from the R-configuration, the S-configuration, or a mixture of the R- and S-configurations.

[0028] In some embodiments, the ligand group T of the E3 ubiquitin ligase is selected from ligands that can bind to VHL (Von Hippel-Lindau), CRBN (Cereblon), MDM2, clAP, AhR, Nimbolide, CCW16, KB02, or KEAP1.

[0029] In some embodiments, the ligand T of the E3 ubiquitin ligase is selected from T1 or T2:

[0030]

[0031] Among them, R 7 R 8 It is independently selected from O, N, piperidinyl or substituted pyridinyl, or is a bond.

[0032] Furthermore, the ligand group T of the E3 ubiquitin ligase can be a ligand capable of binding to VHL, as shown below:

[0033]

[0034] The ligand group T of E3 ubiquitin ligase can also be a ligand that can bind to CRBN, as shown below:

[0035]

[0036] In some embodiments, the ligand group T of the E3 ubiquitin ligase can also be a ligand capable of binding to CRBN, as shown below:

[0037]

[0038] Furthermore, the ligand T of the E3 ubiquitin ligase is selected from:

[0039]

[0040] The substitution on the benzene ring can occur at any substituted site.

[0041] In one specific embodiment, the ligand T of the E3 ubiquitin ligase may be of formula T1 selected from the following structures:

[0042]

[0043] In one specific embodiment, the ligand T of the E3 ubiquitin ligase may be of formula T2 selected from the following structures:

[0044]

[0045] In some embodiments, the structure of the bivalent linker L is selected from one or more combinations of substituted or unsubstituted hydrocarbon groups, alkyloxy groups, oxyalkyl groups, cyclic hydrocarbon groups, heterocyclic hydrocarbon groups, acyl hydrocarbon groups, alkyl acyl groups, carbonyl hydrocarbon groups, alkyl carbonyl groups, amide hydrocarbon groups, alkyl amide groups, aryl groups, and oligopeptide groups having dual linking sites. The bivalent linker (L) connects W and T by chemical covalent bonds to form a complete target molecule. The hydrocarbon group includes, but is not limited to, saturated hydrocarbon groups, unsaturated hydrocarbon groups, aromatic hydrocarbon groups, oxane hydrocarbon groups, nitrogenane hydrocarbon groups, sulfurane hydrocarbon groups, phosphorusane hydrocarbon groups, and mixed heteroane hydrocarbon groups with different heteroatoms. The chain length of the hydrocarbon group or heteroane group is 1 to 20 atoms. When it is a heteroane group, the heteroane group contains 1 to 5 heteroatoms, and the chemical valence of the heteroatoms is satisfied by hydrogen, oxygen, nitrogen, etc., in a corresponding bonding manner as needed.

[0046] Furthermore, the chemical linking group L is selected from the following structures:

[0047]

[0048]

[0049]

[0050] Where p = 0 to 0, specifically, it can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. In some embodiments, p = 0 to 15; in some embodiments, p = 0 to 10, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10;

[0051] Where q = 0 to 6, specifically, it can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In some embodiments, q = 0 to 5, such as 0, 1, 2, 3, 4, 5.

[0052] i = 0 to 3, preferably i = 1 or i = 0.

[0053] In some embodiments, the bivalent linker L has L 1 -L 2 -L 3 The structure, where L 1 L 2 L 3 They can exist simultaneously, or one or both of them can exist; and

[0054] L 1 L 2 L 3A bivalent group independently selected from one or more of the following groups: substituted or unsubstituted hydrocarbon groups, hydrocarbon oxy groups, oxy hydrocarbon groups, cyclic hydrocarbon groups, heterocyclic hydrocarbon groups, acyl hydrocarbon groups, hydrocarbon acyl groups, carbonyl hydrocarbon groups, hydrocarbon carbonyl groups, amide hydrocarbon groups, hydrocarbon amide groups, aryl groups, and oligopeptide groups, which have dual linkage sites.

[0055] The hydrocarbon groups include saturated hydrocarbon groups, unsaturated hydrocarbon groups, aromatic hydrocarbon groups, oxane hydrocarbon groups, nitrogen hydrocarbon groups, sulfur hydrocarbon groups, phosphorus hydrocarbon groups, and mixed hydrocarbon groups with different heteroatoms. The chain length of the hydrocarbon group or the hydrocarbon group is 1 to 20 atoms, and when it is a hydrocarbon group, the hydrocarbon group contains 1 to 5 heteroatoms.

[0056] The heterocycles in the heterocyclic hydrocarbon group include substituted or unsubstituted monocyclic, spirocyclic, or fused rings.

[0057] In some embodiments, L 1 Selected from oxygen, nitrogen, or the structures shown in formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), and (IIIk):

[0058]

[0059] In some embodiments, L 1 Selected from:

[0060]

[0061] Or it doesn't exist;

[0062] Where p = 0 to 20, specifically, it can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. In some embodiments, p = 0-15; in some embodiments, p = 0-10, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; preferably 0 to 5, more particularly 1 to 2.

[0063] In some embodiments, L 2 L 3 Selected independently from:

[0064] Or it doesn't exist;

[0065] Among them, L 2 and L 3 They may not exist simultaneously;

[0066] Where p = 0 to 20, specifically, it can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, preferably 0 to 10; m = 0 to 3, specifically, it can be 0, 1, 2, 3; q = 0 to 10, specifically, it can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, preferably q = 0 to 5.

[0067] In some embodiments, the chemical linking groups L, i.e., L1+L2+L3 together, form a structure selected from the following:

[0068]

[0069]

[0070] In some embodiments, the chemical linking group L is selected from the following structures:

[0071]

[0072] In some embodiments, the bifunctional compound includes compounds shown in Table 1 below or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope derivatives, or prodrugs.

[0073] Table 1

[0074]

[0075]

[0076] In some embodiments, the bifunctional compound includes compounds shown in Table 2 below, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope derivatives, or prodrugs.

[0077] Table 2

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] The above-mentioned compounds possess good biological activity and can be used to treat CDK-related diseases or conditions, preferably, to treat diseases or conditions related to CDK1 / 2 / 4 / 6. In some embodiments, they can be used to treat diseases or conditions related to CDK1. In some embodiments, they can be used to treat diseases or conditions related to CDK2. In some embodiments, they can be used to treat diseases or conditions related to CDK4. In some embodiments, they can be used to treat diseases or conditions related to CDK6. In some embodiments, they can be used to treat at least one disease or condition related to CDK1, CDK2, CDK4, and CDK6. In some embodiments, they can be used to treat at least two or more diseases or conditions related to CDK1, CDK2, CDK4, and CDK6.

[0090] In some embodiments, the compounds provided in this application, as CDK degraders, exert a therapeutic effect in CDK-related tumors or cancers by degrading CDK proteins. In some embodiments, the compounds provided in this application can be used to degrade at least one of CDK1, CDK2, CDK4, and CDK6.

[0091] In some embodiments, the compounds provided in this application may be compounds with natural abundance or with isotopic substitution, and the isotopes may be... 1 H, D, T, 18 O、 17 O、 15 N and 13 C, etc.

[0092] The present invention also provides a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotope derivative or prodrug thereof.

[0093] Furthermore, it also includes at least one pharmaceutically acceptable excipient, carrier, or diluent.

[0094] Furthermore, pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and flow aids.

[0095] Furthermore, pharmaceutically acceptable carriers include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

[0096] Furthermore, the composition is suitable for oral or injectable administration.

[0097] This application also provides the use of any of the compounds described above, or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope derivatives, prodrugs, or pharmaceutical compositions, in the preparation of drugs for treating, inhibiting, or preventing CDK-related conditions. Preferably, this application also provides the use of any of the compounds described above, or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope derivatives, prodrugs, or pharmaceutical compositions, in the preparation of drugs for treating, inhibiting, or preventing CDK-related conditions. This application also provides a method for treating, inhibiting, or preventing CDK-related conditions, comprising administering an effective amount of the compounds and / or pharmaceutical compositions described above to a subject, thereby achieving a therapeutic effect on the related disease.

[0098] In some implementations, cancer and / or other proliferative disorders are CDK-related diseases.

[0099] Furthermore, the disease is selected from proliferative disorders and their associated malignancies or cancers, including tumors with amplified or overexpressed Cyclin D or CCNE1 / 2.

[0100] In some implementations, the malignant tumor is cancer, including one or more of the following: bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, skin cancer, lymphatic hematopoietic tumors, myeloid hematopoietic tumors, thyroid follicular carcinoma, tumors originating from stromal cells, tumors of the central or peripheral nervous system, melanoma, glioma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma or Kaposi's sarcoma, and leukemia.

[0101] This application also provides a kit comprising any of the compounds described above or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope derivatives or prodrugs, or any of the compositions described above, for the preparation of a medicament for the treatment, inhibition or prevention of CDK-related diseases.

[0102] The compounds provided in this application, or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, isotope derivatives, or prodrugs, have excellent inhibitory or degradation effects on CDK proteins and can be used in the preparation of drugs for the treatment, inhibition, or prevention of CDK-related diseases. Attached Figure Description

[0103] Figure 1 : Nuclear magnetic resonance (NMR) spectrum of compound 5. Detailed Implementation

[0104] To provide a clear and consistent understanding of the terminology used in this specification, some definitions are provided below. Furthermore, unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0105] When used in conjunction with the term "comprising" in the claims and / or specification, the word "a" can mean "one," but it is also known to mean "one or more," "at least one," and "one or more." Similarly, the word "another" can mean at least a second or more.

[0106] As used in this specification and claims, the words “comprising” (and any form of inclusion, such as “comprising” and “including”), “having” (and any form of having, “having,” “including,” and “containing”) are inclusive and open-ended and do not exclude additional unlisted elements or processing steps. The terms “about” or “approximately” are used to indicate that the value includes errors introduced by the instruments and methods used in determining the value.

[0107] The CDK degrading agent disclosed in this invention is a bifunctional compound comprising a CDK targeting group W and an E3 ubiquitin ligase ligand group T. Unless the context otherwise requires, the terms W and T are used in an inclusive sense. For example, the term W includes all parts that may target and recognize CDK proteins. It can be a single molecule capable of targeting and recognizing CDK proteins or a group generated by a molecular reaction. It can also be a molecule that includes the targeting and recognizing molecule and binds to other structures or a group generated by a molecular reaction. In other words, W includes all molecules or groups capable of partially or wholly recognizing CDK proteins, especially CDK1 / 2 / 4 / 6 proteins. The term T includes all parts that may be used as ligands for E3 ubiquitin ligases. It can be a single ligand capable of adapting to E3 ubiquitin ligases, or it can be a molecule or group that includes a ligand molecule or group and also contains other structures. In other words, T includes all molecules or groups capable of partially or wholly adapting to E3 ubiquitin ligases.

[0108] The L disclosed in this invention is a bivalent linker used to chemically link a target group (W) to a ligand group (T). The L disclosed in this invention is used to link W and T, thereby combining W and T together. In some embodiments, W and T are directly linked, i.e., L may not be present. In most cases, L is present. The scope and specific structure of L provided in this application are not intended to be limiting; it can be any structure that links W and T.

[0109] The term "pharmaceuticalally acceptable" as used in this invention means that the drug, pharmaceutical product, inert ingredient, etc., described by the term is suitable for contact with the tissues of humans and lower animals without abnormal toxicity, incompatibility, instability, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio.

[0110] A "pharmaceutically acceptable stereoisomer" of a compound refers to an isomer resulting from different spatial arrangements of atoms in a molecule. More specifically, isomers arising from the same order of connection of atoms or groups of atoms in a molecule but different spatial arrangements are called stereoisomers. These are mainly divided into two categories: stereoisomers caused by bond lengths, bond angles, the presence of double bonds, or the presence of rings are called configuration stereoisomers. Generally, configuration stereoisomers cannot or are very difficult to interconvert. Stereoisomers resulting solely from the rotation of single bonds are called conformational stereoisomers, sometimes also called rotational stereoisomers. When rotation in a rotational isomer is hindered and cannot occur, it becomes a "stereoisomer." For example, in the biphenyl structure, when there are large and different substituents at the α- and α'- positions, the rotation of the single bond between the two benzene rings cannot rotate freely due to the obstruction between the substituents, thus producing two stereoisomers.

[0111] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable compound. An ideal salt (basic, acidic, or charged functional group) can retain or improve the biological activity and properties of the parent compound as defined in this invention, and is not biologically undesirable. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic segments using conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric base or acid in water, an organic solvent, or a mixture of both. Salts can be prepared in situ during the final separation or purification of the pharmaceutical preparation, or by reacting the purified compound of this invention in free acid or base form separately with the desired corresponding base or acid and separating the resulting salt. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing cationic groups covalently bonded to anionic groups; these are referred to as "internal salts."

[0112] As used in this invention, the term "ester" refers to a group or segment that can be represented by the general formula RCOOR', typically obtained by reacting a carboxylic acid with an alcohol (eliminating one molecule of water). R is, for example, a lower alkyl or aryl group, such as methylene, ethylene, isopropylene, phenylene, etc., but not limited thereto; R' is, for example, a lower alkyl or aryl group, such as methyl, ethyl, propyl, isopropyl, butyl, phenyl, etc., but not limited thereto. The term "alkyl ester" means that R' is an alkyl group, with one end directly bonded to an oxygen atom on the ester and the other end covalently bonded to at least one carbon or heteroatom in the compound or segment.

[0113] The terms "substituted" or "having substituents" refer to a parent compound or part having at least one substituent group. The terms "unsubstituted" or "not having substituents" refer to a parent compound or part having no other substituents except for an undetermined valence chemically saturated with hydrogen atoms.

[0114] Unless otherwise indicated, a “substituted” group has a substituent at one or more substituted positions of the group, and the substituent is either the same or different at each position when substituting more than one position in any given structure.

[0115] As described herein, "substituent" or "substituent group" refers to a group selected from halogens (F, Cl, Br or I), hydroxyl, mercapto, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, thionyl, sulfonyl, phosphonyl, or other organic moieties conventionally used and accepted in organic chemistry.

[0116] Ubiquitin (Ub) is a small protein with a molecular weight of approximately 8.5 kDa, composed of 76 amino acids. It is widely distributed in all eukaryotic cells and its sequence is highly conserved, differing from yeast to humans by only 3 amino acids. Ubiquitination refers to the process by which ubiquitin covalently binds to a target protein under the catalysis of a series of enzymes. The ubiquitination process typically requires the synergistic action of three ubiquitin-activating enzymes: E1 ubiquitin activator, E2 ubiquitin conjugate, and E3 ubiquitin ligase. Common E3 ubiquitin ligases include VHL (Von Hippel-Lindau), CRBN (Cereblon), MDM2, clAP, AhR, Nimbolide, CCW16, KB02, and KEAP1.

[0117] As used in this invention, the terms "aryl" and "aromatic" refer to an aromatic group having "4n+2" (π) electrons and 6 to 14 ring atoms in a conjugated monocyclic or polycyclic system (fused or unfused), where n is an integer from 1 to 3. Polycyclic systems include at least one aromatic ring. Aryl groups can be directly linked or linked via C1-C3 alkyl groups (also called arylalkyl or aralkyl groups). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indene, benzocyclooctenyl, benzocycloheptenyl, azulel, acenaphthel, fluorenyl, phenanthrene, anthracene, etc. The term aryl includes both unsubstituted and substituted aryl groups. Aryl groups linked by hydrocarbon groups are also called arylalkyl groups.

[0118] The term "hydrocarbon group" includes, but is not limited to, saturated hydrocarbon groups, unsaturated hydrocarbon groups, aromatic hydrocarbon groups, oxane hydrocarbon groups, nitrogen hydrocarbon groups, sulfur hydrocarbon groups, phosphorus hydrocarbon groups, and mixed hydrocarbon groups with different heteroatoms. The chain length of the hydrocarbon group or the hydrocarbon group is 1 to 20 atoms. When it is a hydrocarbon group, the hydrocarbon group contains 1 to 5 heteroatoms, and the chemical valence of the heteroatoms is satisfied by hydrogen, oxygen, nitrogen, etc., in a corresponding bonding manner as needed.

[0119] The terms "cyclogroup," "alicyclic," "cyclohydrogroup," and their equivalents refer to groups that contain saturated or partially unsaturated carbon rings in monocyclic, spirocyclic (sharing a single atom), or fused (sharing at least one bond) carbocyclic systems, wherein the carbocyclic system has 3 to 15 carbon atoms. The term "cyclohydrogroup" includes composite groups consisting of cyclogroups and hydrocarbon groups.

[0120] As used in this invention, the term "heterocyclic" and its equivalents refer to a group comprising a saturated or partially unsaturated carbocyclic ring in a monocyclic, spirocyclic (sharing a single atom), or fused (sharing at least one bond) carbocyclic system, having 3 to 15 carbon atoms, including groups with 1 to 6 heteroatoms (e.g., N, O, S, P) or containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl, or cycloalkyl), PO2, SO, SO2, etc.). The heterocyclic hydrocarbon group may be connected to a C atom or to a heteroatom (e.g., through a nitrogen atom). "Heterocyclic" or "heterocyclic" includes heterocyclic alkyl and heteroaryl groups. Examples of heterocycles include, but are not limited to, acridine, acridine, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, 4αH-carbazolyl, carbaolinyl, benzodihydropyranyl, chromenyl, cenolinyl, decahydroquinolinyl, 2H,6H-1,5,2-diathiazinyl, dihydrofurano[2,3-b]tetrahydrofuran, and furan. Furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, dihydroindolyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, oxazolyl, pyrimidinyl, phenanthridine, phenanthrolinyl , phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinoneyl, 4-piperidinoneyl, piperinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolylyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridinium-imidazazole, pyridothiazazole, pyridinyl, substituted pyridinyl, pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxolinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl Tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiaanthryl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 3,4-triazolyl, xanthonyl, etc. The term "heterocyclic" includes both unsubstituted and substituted heterocyclic groups. The term "heterocyclic hydrocarbon group" refers to a combination of a heterocycle and a hydrocarbon group.

[0121] As used in this invention, the term "acyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on a -C=O group. The terms "amine" or "amino" as used in this invention refer to an unsubstituted or substituted fragment of the general formula -NR-, where R can be hydrogen or a hydrocarbon group. The term "amide" refers to the structure -C(=O)-NR- where an amino group is directly connected to an acyl group. The term "acyl-alkyl group" refers to a combination group of an acyl group and a hydrocarbon group, i.e., where the carbon atom on the acyl group is connected to a hydrocarbon group.

[0122] The term "carbonyl" refers to the -C=O- segment formed by carbon and oxygen atoms linked by a double bond. "Carbonyl" is a component of functional groups such as aldehydes, ketones, and acids.

[0123] The terms "amide hydrocarbon group" or "hydroalkyl amide group" refer to a group formed by the combination of a hydrocarbon group and an amide group. The terms "acyl hydrocarbon group" or "hydroalkyl acyl group" refer to a group formed by the combination of a hydrocarbon group and an acyl group. The terms "carbonyl hydrocarbon group" or "hydroalkyl carbonyl group" refer to a group formed by the combination of a hydrocarbon group and a carbonyl group.

[0124] As used in this invention, the term "alkoxy" or "lower alkoxy" refers to a structure in which an alkyl group is bonded to an oxygen atom. Representative alkoxy groups include those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, etc. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "alkoxy" includes unsubstituted or substituted alkoxy groups, as well as perhaloalkoxy groups. Similarly, the term "hydrocarbonyl" or "oxycarbonyl" refers to a group or structure in which a hydrocarbon group is bonded to an oxygen atom.

[0125] A “pharmaceutically acceptable salt” of a compound refers to a salt of a pharmaceutically acceptable compound. Ideally, the salt of a compound (basic, acidic, or charged functional group) should retain or improve the biological activity and properties of the parent compound as defined in this invention, and should not be biologically undesirable. Pharmaceutically acceptable salts can be those mentioned by Berge et al. in “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1-19 (1977). These include, but are not limited to:

[0126] (1) Salts formed by adding acids to basic or positively charged functional groups. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, carbonates, etc. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, neopentanoic acid, tert-butylacetic acid, β-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylamino Sulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, lauryl sulfate, oleic acid, palmitic acid, stearic acid, lauric acid, pyruvic acid, pantothenic acid, lactobionic acid, alginic acid, galactobionic acid, galacturonic acid, gluconic acid, glucoheponic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, mucoconic acid, etc.

[0127] (2) When the parent compound contains an acidic proton or is replaced by a metal ion, a base can be added to obtain a salt. The metal ions include basic metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium), or other metal ions such as aluminum, zinc, and iron. Organic bases include, but are not limited to, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, aminobutanetriol, N-methylglucosamine, piperazine, chloroprocaine, procaine, choline, and lysine.

[0128] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic fragments using conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric base or acid in water, an organic solvent, or a mixture of both. Salts can be prepared in situ during the final separation or purification of the pharmaceutical preparation, or by reacting a purified compound of the invention in free acid or base form separately with the desired corresponding base or acid and then separating the resulting salt. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing cationic groups covalently bonded to anionic groups, which are referred to as "internal salts." The compounds of the present invention include all acids, salts, bases, and other ionic and nonionic forms. For example, if the compound in the present invention is an acid, the salt form of that compound is also included. Similarly, if the compound in the present invention is a salt, the acidic and / or base forms of that compound are also included.

[0129] The present invention also provides pharmaceutical compositions, in one embodiment of which the pharmaceutical composition comprises: a compound disclosed herein or a pharmaceutically acceptable salt or ester or isomer or hydrate thereof, and a pharmaceutically acceptable excipient or carrier or diluent.

[0130] Specifically, pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and flow aids. Pharmaceutically acceptable carriers or diluents include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

[0131] "Pharmaceutical composition" means comprising compounds as described herein, and at least one component depending on the requirements of the route of administration and dosage form, including pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or loads, such as preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antimicrobial agents, antifungal agents, lubricants, and dispersants. "Prevention" or "protection" is used to indicate at least a reduction in the likelihood of acquiring a disease or condition (or susceptibility) or developing a disease or disorder (i.e., preventing the development of clinical symptoms of at least one disease in patients who may be exposed to or susceptible to the disease but have not yet experienced or displayed symptoms of the disease).

[0132] The term "subject" refers to both animals and humans, including mammals and non-mammals, including but not limited to rats, dogs, and monkeys.

[0133] The term "prodrug" or its equivalents refer to a reagent that is directly or indirectly converted into its active form in vitro or in vivo (see, for example, R. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs," 360pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and..."). Rewards, XVIII, 1470p. Springer. Prodrugs can be used to alter the biodistribution (e.g., preventing the drug from normally entering protease reaction sites) or pharmacokinetics of a specific drug. A variety of groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphate esters / salts, etc. When a prodrug is administered to a subject, the group is cleaved away enzymatically or non-enzymatically, reductively, oxidatively, or hydrolyzed, or otherwise releases the active compound. As used herein, “prodrug” includes pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, and any of the crystalline forms described above.

[0134] The term "peptide" or "oligopeptide" refers to a compound formed by the dehydration condensation of two or more amino acid molecules linked together by amide bonds. Generally, the number of amino acids that make up a peptide ranges from 2 (dipeptide) to 20 (eicoseptide).

[0135] The term "residue" refers to the main part of a molecule after a certain group is removed, such as amino acid residues (e.g., the structure H2NCH2CO-, i.e., glycyl group, which is the part after removing a hydroxyl group from glycine) and peptide residues.

[0136] In other embodiments, the present invention provides methods for inhibiting, treating, and / or preventing immune-related diseases, disorders, and conditions, diseases with inflammatory components, and related disorders using at least one of the bifunctional compounds or combinations thereof provided by the present invention.

[0137] Other diseases, disorders, and conditions that can be treated or prevented, either wholly or partially, by degrading CDK proteins are also candidate indications for the bifunctional compounds and compositions thereof provided in this invention.

[0138] The term "treatment" refers to the initiation of action, after a disease, disorder, or symptom has been diagnosed or observed, in order to temporarily or permanently eliminate, alleviate, suppress, slow down, or improve at least one underlying cause of the disease, disorder, or symptom afflicting the subject, or symptoms associated with the disease, disorder, or symptom afflicting the subject. Therefore, treatment includes suppressing (e.g., preventing or alleviating the development or further development of the disease, disorder, or symptom or its associated clinical symptoms) an active disease. Specifically, as used herein, the term "treatment" specifically refers to administering a therapeutic agent comprising a compound or composition according to the invention to a patient already suffering from an infection. The term "treatment" also relates to administering a compound or composition according to the invention, optionally together with one or more anticancer agents, to reduce or alleviate one or more symptoms associated with CDK; or slow the development of one or more symptoms associated with CDK; or reduce the severity of one or more symptoms associated with CDK; or suppress the clinical manifestations of CDK; or suppress the manifestation of adverse symptoms associated with CDK.

[0139] The term "prevention" refers to the temporary or permanent prevention, suppression, inhibition, or reduction of a subject's risk of developing a disease, disorder, condition, or symptom (as determined by, for example, the absence of clinical symptoms) or the delay of its onset in subjects susceptible to a particular disease, disorder, or symptom. In some cases, the term also refers to slowing the progression of a disease, disorder, or symptom or inhibiting its development into a harmful or other undesirable state. Specifically, as used herein, the term "prevention" is used to indicate the application of a compound or composition according to the invention to prevent the occurrence of CDK-related diseases.

[0140] As used herein, the term "CDK-related disease" refers to any disease, condition, or other pathological symptom involving a CDK-related target, including at least one of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, or CDK9. Therefore, in some embodiments, this application relates to treating or alleviating the severity of one or more diseases in which a known CDK plays a role. Specifically, CDK-related diseases are proliferative disorders and their associated malignancies or cancers, including tumors with Cyclin D or CCNE1 / 2 amplification or overexpression.

[0141] In some embodiments, the malignant tumor or cancer is selected from: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxomas, rhabdomyosarcomas, fibromas, lipomas, and teratomas; lungs: bronchial carcinomas (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinomas, bronchial adenomas, sarcomas, lymphomas, chondromas, mesotheliomas; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucosidoma, gastrinoma, carcinoid tumor, vasodilator peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma). Large intestine (adenocarcinoma, tubular adenoma, villonoma, hematoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampoule carcinoma, bile duct carcinoma; bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular lymphoma). Cellular sarcoma), multiple myeloma, malignant giant cell tumor, string tumor, osteochondroma, benign chondroma, chondroblastoma, chondromycinoma, osteomyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, gliomatosis), Brain (astrocytoma, myeloma, glioma, epididymal tumor, germ cell tumor (pineal tumor), various forms of glioblastoma, oligodendroglioma, glioma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology: Uterus (endometrial cancer (serous bladder cancer, mucinous bladder cancer, unclassified carcinoma), granulosa cell tumor Serum: stromal tumors, dysplasia, malignant teratomas); vulva: squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma; vagina: clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonic rhabdomyosarcoma); fallopian tubes: cancer; hematology: blood: myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse's nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal glands: neuroblastoma.

[0142] In some implementations, the malignant tumor or cancer is selected from: bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, skin cancer, lymphatic hematopoietic tumors, myeloid hematopoietic tumors, thyroid follicular carcinoma, tumors originating from interstitial cells, tumors of the central or peripheral nervous system, melanoma, glioma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma or Kaposi's sarcoma, and leukemia.

[0143] In some embodiments, the invention further provides the use of the bifunctional compounds and compositions described herein in combination with one or more additional agents. These additional agents may have CDK-modifying activity and / or they may act through different mechanisms of action. In some embodiments, such agents comprise radiation (e.g., local or total radiotherapy) and / or other therapeutic forms of non-pharmacological nature. When using combination therapy, the bifunctional compound and an additional agent may be in the form of a single composition or multiple compositions, and the treatment may be administered simultaneously, sequentially, or through some other regimen. For example, in some embodiments, an implementation is provided where a chemotherapy phase follows a radiation phase. Combination therapy may have additive or synergistic effects.

[0144] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, capsules, lozenges, sugar tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions can contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically acceptable formulation. Tablets, capsules, etc., typically contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier or excipient suitable for manufacturing tablets. These carriers or excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0145] In some embodiments, the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.

[0146] In some embodiments, the pharmaceutical composition is contained in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector), while in other embodiments, it is contained in a reusable container (e.g., a reusable vial).

[0147] The formulation may also include a carrier to protect the composition from rapid degradation or disappearance from the body, such as controlled-release formulations, including liposomes, hydrogels, and microencapsulated delivery systems. For example, delayed-release materials, such as glyceryl monostearate or glyceryl stearate alone, or in combination with waxes, may be used. Any drug delivery device can be used to deliver bifunctional compounds, including implants (e.g., implantable pumps) and catheter systems, slow-infusion pumps, and devices. All of these are well known to those skilled in the art.

[0148] Pharmaceutical compositions can also be in the form of sterile injectable aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned in this application, according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), alcohols, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (such as oleic acid) can be used to prepare injectable formulations. Prolonged absorption of specific injectable formulations can be achieved by including agents that delay absorption (e.g., aluminum monostearate or gelatin).

[0149] The bifunctional compounds and compositions provided by this invention can be administered to a subject in any suitable manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisional, intra-articular, intracranial (within the brain parenchyma and ventricles; nasal cavity; vagina; sublingual; intraocular; rectal; local (e.g., transdermal); oral and inhalation. Accumulation injection, which is generally administered subcutaneously or intramuscularly, can also be used to release the bifunctional compounds disclosed in this application within a defined time period.

[0150] This invention also provides kits comprising bifunctional compounds or compositions. Kits are typically in the form of a physical structure containing various components and can be used, for example, to implement the methods provided in this application. For example, a kit may include one or more bifunctional compounds disclosed in this invention (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. Bifunctional compounds may be provided in ready-to-use form (e.g., tablets or capsules) or in form requiring, for example, reconstitution or dilution before administration (e.g., powder). When the bifunctional compound is in a form requiring reconstitution or dilution by the user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together with or separately from the bifunctional compound. When using combination therapy, the kit may contain several therapeutic agents independently, or they may already be combined in the kit. Each component of the kit may be packaged in a separate container, and all the various containers may be in a single package. The kits of this invention may be designed to maintain the components contained therein under the conditions required (e.g., refrigeration or freezing).

[0151] To better understand the present invention and to more clearly demonstrate how to implement it, features of embodiments according to the present invention are now described by way of example and in conjunction with the accompanying drawings.

[0152] Example

[0153] The invention will be more readily understood by referring to the following embodiments, which are used to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

[0154] Unless otherwise defined or the context clearly requires, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should be understood that any methods and materials similar to or equivalent to those described in this application may be used in the practice or testing of this invention. Unless otherwise stated, all materials and instruments used in this application are commercially available.

[0155] Preparation example:

[0156] The compounds disclosed in this invention can be synthesized stepwise or modularly. Specifically, Scheme A discloses methods for synthesizing some exemplary intermediates, and Scheme B discloses the synthesis steps of exemplary compounds. Different intermediates or starting materials can be selected for each compound by referring to the synthesis of the exemplary compounds and the design of the compound itself.

[0157] Option A:

[0158] Synthesis of Intermediate 1

[0159]

[0160] Step A: At room temperature, compound I (5.00 g, 28.90 mmol, 1.00 eq.) was added to a solution of dioxane / H₂O (75 / 37.5 mL), followed by compound II (8.97 g, 29.01 mmol, 1.00 eq.), Na₂CO₃ (9.19 g, 86.70 mmol, 3.00 eq.), and PdCl₂(Ph₃P)₂ (1.01 g, 1.44 mmol, 0.05 eq.). After the additions, the reaction flask was purged with N₂ three times. The reaction was stirred overnight at 100 °C. After the reaction, it was cooled to room temperature. The reaction mixture was separated by saturated NH₄Cl (75 mL) and ethyl acetate (30 mL), and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give a pale yellow solid of compound III (6.40 g, yield: 82%).

[0161] Step B: Palladium on carbon (0.60 g) and compound III of formula above (6.40 g, 23.24 mmol, 1.00 eq.) were added to 60 mL of methanol. The reaction flask was then purged with H2 three times. The reaction was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered to remove the palladium on carbon. The concentrate was used to obtain intermediate 1 (5.90 g, yield: 91.5%) as a white solid.

[0162] Synthesis of intermediate 2

[0163]

[0164] Step A: Compound I (20.00 g, 82.21 mmol, 1.00 eq.) was added to EtOH (800 mL), followed by SnCl2 (79.53 g, 411.03 mmol, 98% purity, 5.00 eq.). The mixture was stirred at 80 °C for 3 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, poured onto ice, and the pH was adjusted to 7-8 using 5N NaOH solution. The mixture was filtered, and the aqueous phase was extracted with ethyl acetate (2 x 400 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound II (13.00 g, yield: 76.76%), which was used for the next step without further purification. m / z (ESI): 206 [M+H] + .

[0165] Step B: Compound II of Formula II (600.00 mg, 2.91 mmol, 1.00 eq.) was added to dichloromethane (24.68 mL), followed by acetone (253.73 mg, 4.37 mmol, 320.77 μL, 1.50 eq.), and then CH3COOH (874.49 mg, 14.56 mmol, 5 eq.) was added at 0 °C. The reaction mixture was stirred at the same temperature for 10 minutes. Then sodium borohydride acetate (1.23 g, 5.82 mmol, 2.00 eq.) was added at 0 °C, and the reaction mixture was stirred overnight at 0 °C. The reaction was monitored by TLC and MS. After the reaction was complete, the reaction was quenched with ice water and the aqueous phase was extracted with ethyl acetate (2 × 100 mL). The organic phases were combined, washed three times with water, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound III (650 mg, yield: 90%), which was used for the next reaction without any further purification. m / z (ESI): 248 [M+H] + .

[0166] Step C: Intermediate III (650.00 mg, 2.62 mmol, 1.00 eq.) was added to chloroform (10 mL), followed by NaHCO3 (1.10 g, 13.10 mmol, 5.00 eq.), and then TEBA (596.76 mg, 2.62 mmol, 1.00 eq.) at 0 °C. The reaction mixture was stirred at the same temperature for 5 min. Then, chloroacetyl chloride (295.90 mg, 2.62 mmol, 1.00 eq.) was added at 0 °C, and the reaction mixture was stirred overnight at 60 °C. The reaction was monitored by TLC and MS. After the reaction was complete, the reaction was quenched with ice water and extracted twice with dichloromethane (2 × 50 mL). The organic phases were combined, washed three times with water, then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the desired product, compound IV (400 mg, yield: 53%). m / z (ESI): 288 [M+H] + .

[0167] Step D: Compound IV (400.00 mg, 1.39 mmol, 1.00 eq.) was added to THF (10 mL), and BH3·DMS (10 M, 555.34 μL, 4.00 eq.) was added dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 5 min. Then the reaction mixture was stirred at 80 °C for 1 h. The reaction was monitored by TLC and MS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The reaction was then quenched with saturated NaHCO3 at 0 °C, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired crude product, compound V (300 mg, yield: 79%). This crude product was used for the next reaction without any further purification. m / z (ESI): 274 [M+H] + .

[0168] Step E: Compound V (200.00 mg, 729.58 μmol, 1.00 eq.) was added to 1,4-dioxane (10 mL), followed by pinacol diboronate (203.80 mg, 802.54 μmol, 1.10 eq.), and then AcOK (214.80 mg, 2.19 mmol, 3.00 eq.) and PdCl2 (DPPF) (26.69 mg, 36.48 μmol, 0.05 eq.) at room temperature. After completion, the reaction flask was purged with N2 three times. The reaction was stirred overnight at 80 °C. The reaction was monitored by TLC and MS. After the reaction was complete, 1,4-dioxane was removed under reduced pressure. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the desired product, compound VI (80 mg, yield: 34%). m / z (ESI): 323 [M+H] + .

[0169] Step F: Compound VI (80.00 mg, 249.07 μmol, 1.00 eq.) and 2,4-dichloro-5-fluoropyrimidine (41.59 mg, 249.07 μmol, 1.00 eq.) were added to THF:H2O (10 mL), followed by K2CO3 (68.85 mg, 498.14 μmol, 2.00 eq.) and Pd(Ph3P)4 (2.88 mg, 2.49 μmol, 0.01 eq.). After completion, the reaction flask was purged with N2 three times. The reaction was stirred overnight at 80 °C. The reaction was monitored by TLC and MS. After the reaction was complete, THF was removed under reduced pressure. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the desired product, compound VII (60 mg, yield: 74%). m / z (ESI): 326 [M+H] + .

[0170] Step G: Compound VII (2.00 g, 6.14 mmol, 1 eq.) and compound VIII (1.87 g, 6.75 mmol, 1.10 eq.) were added to 1,4-dioxane (20 mL), followed by BINAP (152.92 mg, 245.59 μmol, 0.04 eq.), cesium carbonate (3.00 g, 9.21 mmol, 1.50 eq.), and Pd(Ph3P)4 (141.90 mg, 122.80 μmol, 0.02 eq.). After completion, the reaction flask was purged with N2 three times, then heated to 100 °C and stirred overnight. The reaction was monitored by TLC and MS. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate (50 mL × 2). The organic phase was concentrated under reduced pressure. The crude product was then added to ethyl acetate and heated to reflux. The crude product was cooled to room temperature, recrystallized, and filtered to obtain compound IX (2.2 g, yield: 63%) with a purity of 86%. m / z (ESI): 567 [M+H] + .

[0171] Step H: Compound IX (0.50 g, 882.39 μmol, 1.00 eq.) was added to EA (15 mL), cooled to 0 °C, and ethyl acetate hydrochloride solution (2 M, 15 mL) was added dropwise. The mixture was then stirred overnight at room temperature. The reaction was monitored by TLC and MS. After completion, the mixture was filtered and dried under vacuum to give crude intermediate 2 hydrochloride (0.45 g, yield: 94%). The crude product was used for the next step without any further purification. m / z (ESI): 467 [M+H] + .

[0172] Option B

[0173] Example 1: Synthesis of Compound 1 of the present invention

[0174]

[0175] Compound 1 is synthesized by proceeding through steps A to B according to the above reaction route.

[0176] Step A: Compound I-1 (600.00 mg, 2.19 mmol, 1.00 eq.) was added to DMF (10 mL), followed by the addition of 1,9-dibromononane (1.25 g, 4.38 mmol, 2.00 eq.), KI (363.20 mg, 2.19 mmol, 1.00 eq.), and sodium bicarbonate (551.43 mg, 6.56 mmol, 3.00 eq.). The mixture was heated to 90 °C and stirred overnight. The reaction was monitored by TLC. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH: dichloromethane = 1 / 50) to give compound II-1 (260.00 mg, yield: 24.79%). m / z (ESI): 479 [M+H] + .

[0177] Step B: Intermediate 2 (194.64 mg, 417.22 μmol, 1.00 eq.) and compound II-1 obtained in Step A (200.00 mg, 417.22 μmol, 1.00 eq.) were added to DMF (6 mL), followed by K2CO3 (172.99 mg, 1.25 mmol, 3.00 eq.) and KI (34.63 mg, 208.61 μmol, 0.50 eq.). The mixture was heated to 90 °C and stirred overnight. The reaction was monitored by TLC and MS. After completion, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain approximately 400 mg of crude product. The crude product was purified by column chromatography (MeOH: dichloromethane = 1 / 50) to give the final product compound 1 (43.90 mg, yield: 12.16%, purity: 98.33%).

[0178] 1H-NMR (400MHz, DMSO-d6): δ11.12(s,1H),9.98(s,1H),8.63(d,J=3.9Hz,1H),8.23–8.15(m,2H),7.82(dd,J=8.5,7.3Hz,1H),7.61(d,J =8.7Hz,1H),7.52(d,J=8.5Hz,1H),7.49(d,J=2.0Hz,1H),7.45(d,J=7.2Hz,1H),7.23–7.17(m,1H),5.09(dd,J=12.8,5.4Hz,1H),4.31 (dd,J=5.1,3.6Hz,2H),4.21(t,J=6.3Hz,2H),4.19–4.12(m,1H),2.99(s,2H),2.89(ddd,J=16.7,13.7,5.3Hz,2H),2.64–2.56(m,1H), 2.09–1.88(m,5H),1.77(p,J=6.5Hz,2H),1.67(s,2H),1.47(d,J=8.3Hz,2H),1.33(s,9H),1.21(d,J=6.5Hz,6H).m / z(ESI): 866.3[M+H] + .

[0179] Example 2: Synthesis of Compound 2

[0180]

[0181] Compound 2 was synthesized by proceeding through steps A to E according to the reaction route.

[0182] Step A: Compound I-2 (15.00 g, 99.89 mmol, 1.00 eq.) was dissolved in dichloromethane (1 L), stirred in an ice-water bath, and tetrabromomethane (72.87 g, 219.75 mmol, 2.20 eq.) was added. The mixture was stirred at 0 °C for 15 min, and then PPh3 (52.40 g, 199.77 mmol, 2.00 eq.) was added. The reaction was carried out at 0 °C for 30 min, then raised to room temperature and stirred overnight. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound II-2 (20.00 g, yield: 72.56%).

[0183] Step B: The above-mentioned compound II-2 (20.00 g, 72.47 mmol, 1.00 eq.) was dissolved in DMF (150 mL), and potassium N-phthalimide (13.42 g, 72.47 mmol, 1.00 eq.) was added at room temperature. The mixture was heated to 80 °C and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (2 × 180 mL). The organic phases were combined, washed with brine (1 × 180 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH: dichloromethane = 1 / 50) to give compound III-2 (14.00 g, yield: 56.45%), m / z (ESI): 342 [M+H]. + .

[0184] Step C: Intermediate 2 (272.67 mg, 584.48 μmol, 1.00 eq.), compound III-2 (200.00 mg, 584.48 μmol, 1.00 eq.), DIEA (453.23 mg, 3.51 mmol, 610.82 μL, 6.00 eq.), K2CO3 (242.34 mg, 1.75 mmol, 3.00 eq.), and KI (97.02 mg, 584.48 μmol, 1.00 eq.) were stirred in DMF (10 mL) and reacted at 90 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature and poured into water (200 mL). The mixture was extracted with ethyl acetate (3 × 80 mL), the organic phases were combined, washed with saturated brine (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the product was purified by column chromatography (MeOH: dichloromethane = 1 / 50) to give compound IV-2 (300.00 mg, yield: 70.52%), m / z (ESI): 728.3 [M+H]. + .

[0185] Step D: Compound IV-2 (300.00 mg, 412.20 μmol, 1.00 eq.) was dissolved in EtOH (30 mL), and hydrazine hydrate (41.27 mg, 824.40 μmol, 2.00 eq.) was added. The mixture was reacted at 80 °C for 1 h. After the reaction was complete as detected by TLC, a white solid was filtered off, and the solvent was removed by concentration under reduced pressure. Dichloromethane (20 mL) was added to the residue. The mixture was filtered, and the solvent was removed under reduced pressure. The product was purified by column chromatography (MeOH:dichloromethane = 1 / 50) to obtain compound V-2 (170.00 mg, yield: 69.00%). m / z (ESI): 598.3 [M+H] + .

[0186] Step E: Compound V-2 (160 mg, 267.69 μmol, 1.00 eq.), compound VI-2 (88.73 mg, 321.23 μmol, 1.20 eq.), K2CO3 (110.99 mg, 803.08 μmol, 3.00 eq.), and KI (44.44 mg, 267.69 μmol, 1.00 eq.) were stirred in DMF (10 mL) and heated to 90 °C for 16 h. The mixture was poured into water (100 mL), extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, washed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified by column chromatography (MeOH: dichloromethane = 1 / 50) to give compound 2 (16.50 mg, yield: 7.22%, purity 98.36%).

[0187] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.97(s,1H),8.62(d,J=3.9Hz,1H),8.20–8.11(m,2H),7.64–7.55(m,2H),7.49(s,1H),7. 22–7.17(m,1H),7.16(d,J=8.6Hz,1H),7.05(d,J=7.0Hz,1H),6.62(t,J=5.8Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),4.31(t,J=4.3 Hz, 2H), 4.16 (p, J = 6.5Hz, 1H), 3.65 (t, J = 5.3Hz, 3H), 3.61 (s, 4H), 3.49 (t, J = 5.6Hz, 3H), 3.31 (t, J = 4.3Hz, 2H), 2.89 (ddd, J = 17. 4,14.1,5.5Hz,2H),2.57(dd,J=15.8,11.9Hz,3H),2.09–1.95(m,3H),1.85(s,4H),1.24(d,J=3.7Hz,3H),1.20(d,J=6.5Hz,6H). m / z(ESI):854.3[M+H] + .

[0188] Example 3: Synthesis of Compound 3

[0189]

[0190] Compound 3 was synthesized by proceeding through steps A to B according to the above reaction route.

[0191] Step A: Compound I-3 (600.00 mg, 2.19 mmol, 1.00 eq.), 1,6-dibromohexane (533.79 mg, 2.19 mmol, 1.00 eq.), sodium bicarbonate (551.43 mg, 6.56 mmol, 3.00 eq.), and KI (363.20 mg, 2.19 mmol, 1.00 eq.) were added to DMF (10 mL). The mixture was stirred at 80 °C for 16 h. After stirring, the mixture was cooled to room temperature and poured into 80 mL of water. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with brine (1 × 40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound II-3 as a pale yellow solid (475.00 mg, yield: 49.65%), m / z (ESI): 438 [M+H]. + .

[0192] Step B: Intermediate 2 (213.37 mg, 457.37 μmol, 1.00 eq.), compound II-3 (200.00 mg, 457.37 μmol, 1.00 eq.), DIEA (354.66 mg, 2.74 mmol, 477.98 μL, 6.00 eq.), K2CO3 (189.64 mg, 1.37 mmol, 3.00 eq.), and KI (75.92 mg, 457.37 μmol, 1.00 eq.) were stirred in DMF (10 mL) at 90 °C for 16 h. After stirring, the mixture was cooled to room temperature and poured into 100 mL of water. The mixture was extracted with ethyl acetate (3 × 80 mL). The organic phases were combined and washed with brine (1×80mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the product was purified by column chromatography (MeOH: dichloromethane = 0%-2% as eluent) to obtain compound 3 of the present invention (33.80mg, yield: 8.98%, purity 98.58%).

[0193] 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),9.99(s,1H),8.63(d,J=3.9Hz,1H),8.24–8.14(m,2H),7.83(dd,J=8.5,7.3Hz,1H),7.62(d,J=8.3Hz,1H),7 .54(d,J=8.6Hz,1H),7.51–7.43(m,2H),7.19(dd,J=11.2,1.8Hz,1H),5. 09(dd,J=12.7,5.4Hz,1H),4.35–4.29(m,2H),4.23(t,J=6.2Hz,2H),4.1 7(p,J=6.6Hz,1H),3.32(d,J=4.4Hz,2H),2.89(ddd,J=16.6,13.7,5.3Hz ,2H),2.66–2.53(m,2H),2.03(tdd,J=12.3,6.3,3.1Hz,2H),1.95(d,J=2 0.0Hz,3H),1.84–1.75(m,3H),1.67(s,2H),1.52(dq,J=15.7,8.1,7.5Hz ,3H),1.41(q,J=7.8Hz,3H),1.24(d,J=3.9Hz,3H),1.20(d,J=6.5Hz,6H). m / z(ESI):823.2[M+H] + .

[0194] Example 4: Synthesis of Compound 5

[0195]

[0196] Compound 5 was synthesized by proceeding through steps A to H according to the above reaction route.

[0197] Step A: Compound I-4 (10.00 g, 50.96 mmol, 1.00 eq.) was added to dichloromethane (200 mL), followed by 2-(2-benzyloxyethoxy)ethanol (10.00 g, 50.96 mmol, 1.00 eq.), tert-butyl bromoacetate (39.76 g, 203.83 mmol, 4.00 eq.), and tetrabutylammonium chloride (14.16 g, 50.96 mmol, 1.00 eq.). NaOH solution (200.00 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was complete, the organic phase was retained. The aqueous phase was extracted with dichloromethane (200 mL × 2), the organic phases were combined, washed with water and brine, filtered, and dried over Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (MeOH: dichloromethane = 0%-2% as eluent) to give compound II-4 (6.1 g, yield: 38%).

[0198] Step B: Compound II-4 (6.10 g, 19.65 mmol, 1.00 eq.) was added to methanol (100 mL), followed by the addition of Pd / C (2.00 g) and H2 replacement three times. The mixture was then stirred overnight at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered, and methanol (100 mL) was removed under reduced pressure to give crude compound III-4 (6 g, yield: 98%). This crude compound was used for the next step without any further purification.

[0199] Step C: The obtained compound III-4 (500.00 mg, 2.27 mmol, 1.00 eq.) was added to dichloromethane (10 mL), followed by Et3N (459.41 mg, 4.54 mmol, 2.00 eq.). The reaction was cooled to 0 °C, and 4-methylbenzenesulfonyl chloride (519.34 mg, 2.72 mmol, 1.20 eq.) was added dropwise. The mixture was then reacted overnight at 0 °C. The reaction was monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed successively with water and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH: dichloromethane = 0%–2% as eluent) to give the desired product, compound IV-4 (230 mg, yield: 69%).

[0200] Step D: The obtained compound IV-4 (216.11 mg, 1.47 mmol, 1.10 eq.) and K₂CO₃ (553.65 mg, 4.01 mmol, 3.00 eq.) were added to DMF (5 mL). The reaction mixture was then heated to 90 °C and reacted at this temperature overnight. The reaction was monitored by TLC and MS. After completion, the reaction mixture was extracted with ethyl acetate (50 × 2), the organic phases were combined, washed with water and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH: dichloromethane = 0%–2% as eluent) to give the desired product, compound V-4 (120 mg, 23%). m / z (ESI): 350 [M + H] +

[0201] Step E: The obtained compound V-4 and hydrazine hydrate (143.28 mg, 2.29 mmol, 80% purity, 2.00 eq.) were added to methanol (10 mL). The reaction mixture was heated to reflux overnight with stirring. The reaction was monitored by TLC and MS. After completion, the solvent was removed under reduced pressure to obtain the crude compound VI-4. The crude product was purified with HCl / EA and used in the next step.

[0202] Step F: The obtained compound VI-4 (1.00 g, 4.56 mmol, 1.00 eq.) was added to DMF (10 mL), followed by compound VII-4 (1.26 g, 4.56 mmol, 1.00 eq.) and K₂CO₃ (1.89 g, 13.68 mmol, 3.00 eq.). The mixture was heated to 90 °C and reacted overnight. The reaction was monitored by TLC and MS. After completion, the mixture was extracted with ethyl acetate (100 × 3), the organic phases were combined, washed with water and brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH: dichloromethane = 0%–2% as eluent) to give the product compound VIII-4 (375 mg, yield: 17%). m / z (ESI): 476 [M+H] + .

[0203] Step G: The obtained compound VIII-4 (375.00 mg, 788.66 μmol, 1.00 eq.) was added to dichloromethane (15 mL). The mixture was cooled to -10 °C, and then TFA (11.51 g, 100.97 mmol, 7.5 mL, 128.03 eq.) was added dropwise. The reaction mixture was then allowed to react at room temperature for 2 h. The reaction was monitored by TLC and MS. After completion, the solvent was removed under reduced pressure to give crude compound IX-4 (360 mg, 96%), which was used for the next step without further purification. m / z (ESI): 419 [M+H]+ .

[0204] Step H: The obtained compound IX-4 (180.00 mg, 429.20 μmol, 1.00 eq.) was added to DMF (10 mL), followed by DIEA (221.88 mg, 1.72 mmol, 299.03 μL, 4.00 eq.) and HATU (242.89 mg, 643.80 μmol, 1.50 eq.). The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC and MS. After completion, water was added to the reaction mixture to precipitate the crude product. Compound 5 (10 mg, yield: 15%, purity 96.87%) was obtained as a pale yellow solid by preparative HPLC (acetonitrile / water system).

[0205] 1 H-NMR: (400MHz, DMSO-d6): δ11.10(s,1H),9.88(s,1H),8.60(d,J=4.0Hz,1H) ,8.17(d,J=2.4Hz,1H),8.10(d,J=8.6Hz,1H),7.61–7.57(m,1H),7.57–7.53(m ,1H),7.47(s,1H),7.22–7.15(m,1H),7.13(d,J=8.6Hz,1H),7.02(d,J=7.0Hz ,1H),6.60(t,J=5.8Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.48(d,J=12.9Hz,1 H),4.30(dd,J=5.1,3.6Hz,2H),4.21(d,J=13.8Hz,1H),4.16(d,J=2.9Hz,1H) ,4.14(d,J=6.8Hz,1H),3.90(d,J=13.3Hz,1H),3.67–3.60(m,6H),3.47(t,J=5 .5Hz,4H),2.94–2.72(m,2H),2.05–1.94(m,2H),1.78(t,J=14.6Hz,2H),1.59 (d, J=11.8Hz, 1H), 1.46 (d, J=11.6Hz, 1H), 1.24 (s, 2H), 1.19 (d, J=6.5Hz, 6H). m / z (ESI): 869.3 [M+H] + .

[0206] Example 5: Synthesis of Compound 6

[0207]

[0208] Compound 6 of the present invention was synthesized by proceeding through steps A to E according to the reaction route.

[0209] Step A: Compound I-5 (15.00 g, 77.23 mmol, 1.00 eq.) was dissolved in dichloromethane (800 mL) and stirred in an ice bath. Tetrabromomethane (56.35 g, 169.91 mmol, 2.20 eq.) was added, and the mixture was stirred in an ice bath for 15 min. Then, PPh3 (40.51 g, 154.46 mmol, 2.00 eq.) was added. The reaction was carried out in an ice bath for 30 min; the mixture was then transferred to room temperature and reacted overnight. The solvent was removed by concentration under reduced pressure, and the product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound II-5 (19.00 g, yield: 76.88%).

[0210] Step B: The obtained compound II-5 (19.00 g, 59.37 mmol, 1.00 eq.) was dissolved in DMF (100 mL), and potassium N-phthalimide (11.00 g, 59.37 mmol, 1.00 eq.) was added at room temperature. The mixture was heated to 8 °C and reacted for 6 h. After cooling to room temperature, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 × 80 mL). The organic phases were combined, washed with brine (1 × 180 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound III-5 (13.00 g, yield: 56.69%), m / z (ESI): 386 [M+H]. + .

[0211] Step C: Intermediate 2 (300.00 mg, 643.05 μmol, 1.00 eq.), the obtained compound III-5 (248.37 mg, 643.05 μmol, 1.00 eq.), DIEA (498.65 mg, 3.86 mmol, 672.03 μL, 6.00 eq.), K2CO3 (266.63 mg, 1.93 mmol, 3.00 eq.), and KI (106.75 mg, 643.05 μmol, 1.00 eq.) were stirred in DMF (10 mL) and stirred at 90 °C for 16 h. The mixture was then poured into 200 mL of water and extracted with ethyl acetate (3 × 80 mL). The organic phases were combined, washed with brine (1 × 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound IV-5 (220.00 mg, yield: 44.32%), m / z (ESI): 772.3 [M+H). + .

[0212] Step D: The obtained compound IV-5 (220.00 mg, 285.03 μmol, 1.00 eq.) was dissolved in ethanol (30 mL), and hydrazine hydrate (28.54 mg, 570.06 μmol, 2.00 eq.) was added. The mixture was reacted at 80 °C for 1 h. After the reaction was complete as detected by TLC, a white solid was filtered off, the solvent was removed by rotary evaporation, and 20 mL of dichloromethane was added to the residue. The insoluble solid was filtered off, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (MeOH: dichloromethane = 0%-2% as eluent) to obtain compound V-5 (128.00 mg, yield: 69.98%) m / z (ESI): 642.3 [M+H] + .

[0213] Step E: The obtained compound V-5 (70.00 mg, 109.08 μmol, 1.00 eq.), compound VI (36.16 mg, 130.89 μmol, 1.20 eq.), K₂CO₃ (45.23 mg, 327.23 μmol, 3.00 eq.), and KI (18.11 mg, 109.08 μmol, 1.00 eq.) were stirred in DMF (10 mL) and stirred at 90 °C for 16 h. The reaction was incomplete. The mixture was poured into 100 mL of water. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined and washed with brine (1×50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the crude product was purified by column chromatography (MeOH / dichloromethane = 0%-2% as eluent) to give compound 6 (17.80 mg, yield: 18.17%, purity 98.92%).

[0214] 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.98(s,1H),8.63(d,J=3.9Hz,1H),8.23–8.15(m,2H),7.82(dd,J=8.5,7.3Hz,1H),7.61( d,J=8.7Hz,1H),7.52(d,J=8.5Hz,1H),7.49(d,J=2.0Hz,1H),7.45(d,J=7.2Hz,1H),7.23–7.17(m,1H),5.09(dd,J=12.8,5.4Hz, 1H),4.31(dd,J=5.1,3.6Hz,2H),4.21(t,J=6.3Hz,2H),4.19–4.12(m,1H),2.99(s,2H),2.89(ddd,J=16.7,13.7,5.3Hz,2H),2.6 4–2.56(m,1H),2.09–1.88(m,5H),1.77(p,J=6.5Hz,2H),1.67(s,2H),1.47(d,J=8.3Hz,2H),1.33(s,9H),1.21(d,J=6.5Hz,6H). m / z(ESI):898.3[M+H] + .

[0215] Example 6: Synthesis of Compound 7

[0216]

[0217] Compound 7 of the present invention was synthesized by proceeding through steps A to B according to the reaction route.

[0218] Step A: At room temperature, compound I-6 (105.00 mg, 442.79 μmol, 1.20 eq.), compound II-6 (172.14 mg, 368.99 μmol, 1.00 eq.), HATU (208.82 mg, 553.51 μmol, 1.50 eq.), and DIEA (143.46 mg, 1.11 mmol, 193.34 μL, 3.01 eq.) were added to 3 mL of DMF. The reaction flask was then purged with N2 three times. The reaction was stirred at 25 °C for 12 h. After the reaction was complete, the mixture was filtered and concentrated. It was then extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (MeOH / dichloromethane = 0%–2% as eluent) to give compound III-6 (100.00 mg, yield: 39%) as a yellow solid.

[0219] Step B: The obtained compound III-6 (100.00 mg, 145.85 μmol, 1.00 eq.), compound IV-6 (40.00 mg, 145.85 μmol, 1.00 eq.), and K2CO3 (60.47 mg, 437.55 μmol, 3.00 eq.) were added to DMF (5 mL). The reaction flask was then purged with N2 three times. The reaction was stirred at 90 °C for 4 h. After the reaction was complete, the mixture was filtered and concentrated. It was then extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by TLC (dichloromethane / MeOH = 10 / 1) to give compound 7 of the present invention as a yellow solid (30.00 mg, yield: 23%, purity 95.99%).

[0220] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),9.91(s,1H),8.61(d,J=4.0Hz,1H),8.19(d,J=2.4Hz,1H),8.12(d,J=8.6Hz,1H),7.69–7.56(m,2H),7.49( s,1H),7.31(d,J=7.1Hz,1H),7.25(d,J=8.4Hz,1H),7.22–7.14(m,1H), 4.56(d,J=12.8Hz,1H),4.30(dd,J=5.1,3.6Hz,2H),4.21–4.06(m,1H),3 .99(d,J=13.5Hz,1H),3.68–3.59(m,2H),3.17(d,J=4.9Hz,1H),3.09(t ,J=12.8Hz,1H),2.97(ddd,J=17.0,14.0,5.3Hz,1H),2.83–2.67(m,2H), 2.33(dd,J=9.1,5.7Hz,2H),2.02(ddd,J=15.0,9.8,4.9Hz,1H),1.80(t,J=12.5Hz,2H),1.62–1.38(m,9H),1.27(s,11H),1.19(d,J=6.6Hz,6H). m / z(ESI):881.3[M+H] + .

[0221] Example 7: Synthesis of Compound 9

[0222]

[0223] Compound 9 was synthesized by proceeding through steps A to C according to the reaction route.

[0224] Step A: Compound I-7 (200.00 mg, 428.70 μmol, 1.0 eq.), DIEA (221.62 mg, 1.71 mmol, 4.0 eq.), and KI (71.16 mg, 428.70 μmol, 1.0 eq.) were placed in a reaction flask, and 5 mL of DMF was added. Compound A (101.66 mg, 428.70 μmol, 1.0 eq.) was added dropwise to the above system. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (MeOH / dichloromethane = 0%–2% as eluent) to give compound II-7 (150.00 mg, yield: 56.19%), m / z (ESI): 622 [M+H). + .

[0225] Step B: Dissolve the obtained compound II-7 (150.00 mg, 240.87 μmol, 1.0 eq.) in 6 mL of dichloromethane. Add 2 mL of TFA dropwise to the solution at 0 °C. Allow the system to return to room temperature and stir for 16 h. After the reaction is complete, concentrate the reaction solution and remove the solvent to obtain a crude compound III-7 in oily form. This crude product can be used directly in the next step without purification.

[0226] Step C: 90.00 mg of the crude compound III-7 from the previous step was placed in 5 mL of DMF. HATU (89.88 mg, 238.25 μmol, 1.5 eq.) and DIEA (82.11 mg, 635.32 μmol, 4.0 eq.) were added to the above system, and the mixture was stirred at room temperature for 0.5 h. VHL ligand (84.74 mg, 190.60 μmol, 1.2 eq.) was added to the mixture, and the mixture was stirred at room temperature for 3 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (MeOH / dichloromethane = 0%–2% as eluent) to give compound 9 (15.20 mg, yield: 9.64%, purity 99.19%).

[0227] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.99(s,1H),8.64(d,J=3.9Hz,1H),8.43–8.36(m,2H),8.20(d,J=8.7Hz,1H),7.89–7.79(m,2H), 7.49(d,J=2.2Hz,1H),7.45–7.37(m,4H),7.23–7.17(m,1H),6.20(s,1H),5.13(s,1H),4.91(q,J=7.1Hz,1H),4.54(d,J=9.3Hz,1H),4.4 3(t,J=8.1Hz,1H),4.34–4.26(m,3H),4.17(p,J=6.6Hz,1H),3.61(s,2H),3.32(d,J=4.5Hz,5H),2.46(s,3H),2.35–2.13(m,3H),2.00(d ,J=8.1Hz,1H),1.80(ddd,J=12.9,8.5,4.7Hz,1H),1.53(s,5H),1.38(d,J=7.0Hz,4H),1.24(s,3H),1.20(d,J=6.5Hz,6H),0.95(s,9H). m / z(ESI):992.4[M+H] + .

[0228] Example 8: Synthesis of Compound 11

[0229]

[0230] Compound 11 of the present invention was synthesized by proceeding through steps A to C according to the reaction route.

[0231] Step A: Intermediate 2 (300.00 mg, 643.05 μmol, 1.0 eq.) was placed in a reaction flask, followed by 12 mL of methanol and 3 mL of tetrahydrofuran. Then, compound I-8 (169.28 mg, 707.36 μmol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 1 h. Separately, NaBH3CN (80.82 mg, 1.29 mmol, 2.0 eq.) was added to the above system, and the temperature was raised to 50 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was extracted with 30 mL of water and ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (MeOH: dichloromethane = 0%-2% as eluent) to give compound II-8 (200.00 mg, yield: 45.09%), m / z (ESI): 690 [M+H] + .

[0232] Step B: The obtained compound II-8 (200.00 mg, 289.92 μmol, 1.0 eq.) was dissolved in 9 mL of dichloromethane. 3 mL of TFA was added dropwise to the solution at 0 °C. The system was allowed to return to room temperature and stirred for 16 h. After the reaction was complete, the reaction solution was concentrated, and the solvent was removed under reduced pressure to obtain a crude compound III-8 in oily form. This crude compound was used directly in the next reaction without purification.

[0233] Step C: Take the crude compound III-8 obtained in the previous step (180.00 mg, 305.23 μmol, 1.0 eq.) and DIEA (157.79 mg, 1.22 mmol, 4.0 eq.) into a reaction flask, add 5 mL of DMF, and separately add compound M (92.74 mg, 335.75 μmol, 1.10 eq.) to the above system. Heat to 80 °C and stir for 16 h. After the reaction is complete, cool to room temperature, add 50 mL of water, and extract with ethyl acetate (3 × 30 mL). Combine the organic phases, wash with saturated brine (30 mL), dry to anhydrous Na2SO4, filter, and concentrate the filtrate. Purify the residue by column chromatography (MeOH / dichloromethane = 0%-2% as eluent) to give compound 11 (51.00 mg, yield: 19.75%, purity 99.33%).

[0234] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.00(s,1H),8.63(d,J=3.9Hz,1H),8.23–8.14(m,2H),7.65(dd,J=15.0,8.4 Hz,2H),7.49(s,1H),7.35(s,1H),7.30–7.15(m,2H),5.09–4.98(m,1H),4.31(t,J=4.3Hz,2H),4.17(p,J=6.6Hz,1H) ,3.50(d,J=7.0Hz,2H),3.42(d,J=6.1Hz,4H),3.31(d,J=4.6Hz,2H),2.89(ddd,J=17.2,14.0,5.5Hz,3H),2.63–2.5 3(m,2H),2.19(s,3H),2.09–1.86(m,6H),1.66(s,4H),1.25–1.22(m,2H),1.21(d,J=6.5Hz,6H).m / z(ESI): 846[M+H] + .

[0235] Example 9: Synthesis of Compound 12

[0236]

[0237] Compound 12 was synthesized by proceeding through steps A to C according to the reaction route.

[0238] Step A: Compound I-9 (1.00 g, 3.66 mmol, 1.0 eq.) and potassium carbonate (1.52 g, 10.98 mmol, 3.0 eq.) were placed in a reaction flask, and 30 mL of DMF was added. Separately, tert-butyl bromoacetate (856 mg, 4.39 mmol, 1.2 eq.) was added dropwise to the above system. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound II-9 (1.00 g, yield: 70.92%), m / z (ESI): 388 [M+H]. + .

[0239] Step B: Dissolve the obtained compound II-9 (229 mg, 0.59 mmol, 1.0 eq.) in 10 mL of dichloromethane. Add 0.3 mL of TFA dropwise to the solution at 0 °C. Allow the system to return to room temperature and stir for 2 hours. After the reaction is complete, concentrate the reaction solution and remove the solvent to obtain a crude product of compound III-9 in oily form. This crude product can be used directly in the next reaction without further purification.

[0240] Step C: Take 0.2 g of the crude compound III-9 from the previous step into 15 mL of DMF. Separately add HATU (308 mg, 0.81 mmol, 1.5 eq.) and DIEA (209 mg, 1.62 mmol, 3 eq.) to the above system and stir at room temperature for 1 hour. Separately add intermediate 2 (253 mg, 0.54 mmol, 1.0 eq.) to the system and stir at room temperature for 12 hours. After the reaction is complete, add 80 mL of water and extract with ethyl acetate (3 × 30 mL). Combine the organic phases, wash with saturated brine (40 mL), dry to anhydrous Na2SO4, filter, and concentrate the filtrate. Purify the residue by column chromatography (MeOH / dichloromethane = 0%-2% as eluent) to obtain compound 12 of the present invention (12 mg, yield: 2.85%, purity 98.32%).

[0241] 1H NMR (400MHz, DMSO-d6) δ8.68(d,J=2.4Hz,1H),8.30(t,1H),8.20(d,1H),7.56(d,J=8.5,Hz,2H),7.47(d,J=8.3Hz,1H),7.34(d, J=8.6Hz,1H),7.07(d,1H),7.02(d,J=11.2,1.8Hz,1H),5.23(d,J=12.7,1H),4.75(d,J=6.3Hz,2H),4.35(s,2H),4.20(m,J=6.6H z,2H),3.37(d,J=4.4Hz,2H),3.01(m,J=5.3Hz,2H),2.85(dd,J=5.2,6.8,2H),2.03(dd,J=12.3,6.3,Hz,2H),1.95(d,J=20.0Hz ,1H),1.84–1.75(m,1H),1.67(m,J=12.5Hz,2H),1.51(dq,J=15.7,8.1,7.5Hz,3H),1.41(d,J=5.3Hz,6H),1.21(d,J=3.9Hz,1H). m / z(ESI):780.3[M+H] + .

[0242] Example 10: Synthesis of Compound 13

[0243]

[0244] Compound 13 was synthesized by proceeding through steps A to B according to the reaction route.

[0245] Step A: Dissolve 5.00 g (23.44 mmol, 1.0 eq.) of compound I-10 in 30 mL of dichloromethane. Add 10 mL of TFA dropwise to the solution at 0 °C. Allow the system to return to room temperature and stir for 2 h. After the reaction is complete, concentrate the reaction solution and remove the solvent to obtain a crude product of compound II-10 in oily form. This crude product can be used directly in the next reaction without purification.

[0246] Step B: 1.00 g of the crude compound of formula II-10 was placed in 10 mL of DMF. DIEA (1.87 g, 14.48 mmol, 4.0 eq.) was added to the reaction flask, and the mixture was stirred at room temperature for 1 h. CRBN ligand 1 (1.00 g, 3.62 mmol, 1.0 eq.) was added to the above system, and the mixture was heated to 90 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (MeOH / dichloromethane = 0%-2% as eluent) to give compound III-10 (500.00 mg, yield: 37.43%). m / z (ESI): 370 [M+H] + .

[0247] Step C: Take 500.00 mg of the obtained compound III-10 in 15 mL of DMF, and separately take intermediate 2 (631.00 mg, 1.36 mmol, 1.0 eq.). Add acetic acid (163.00 mg, 2.71 mmol, 2.0 eq.) and sodium triacetylborohydride (574.00 mg, 2.71 mmol, 2.0 eq.) to the system at 0 °C, and maintain the temperature for 1 h. Then, raise the system to room temperature and stir, reacting for 16 h. After the reaction is complete, add 80 mL of water and extract with ethyl acetate (3 × 30 mL). Combine the organic phases, wash with saturated brine (40 mL), dry to anhydrous Na₂SO₄, filter, and concentrate the filtrate. Purify the residue by preparative HPLC (acetonitrile / 0.1% TFA water system) to obtain compound 13 of the present invention (10.00 mg, yield: 0.81%, purity 95.12%).

[0248] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.38(s,1H),8.68(d,J=3.8Hz,1H),8.47(s,1H),8.21(s,1H),7.99–7.93(m,1H),7.69(d,J=8.5H z,1H),7.48(s,1H),7.38(s,1H),7.29(dd,J=8.8,2.3Hz,1H),7.20(d,J=1.8Hz,1H),6.25(s,1H),5.08(dd,J=12.9,5.4Hz,1H),4.32(t, J=4.3Hz,2H),4.20–4.10(m,4H),3.32(t,J=4.4Hz,3H),3.14(d,J=6.1Hz,3H),3.03(t,J=12.5Hz,3H),2.91–2.81(m,3H),2.63–2.58(m, 1H),2.05–1.98(m,2H),1.89(t,J=16.2Hz,2H),1.30(d,J=10.8Hz,2H),1.27–1.22(m,3H),1.21(d,J=6.5Hz,6H).m / z(ESI): 819.9[M+H] + .

[0249] Example 11: Synthesis of Compound 15

[0250]

[0251] Compound 15 of the present invention was synthesized according to this reaction route. Details are as follows.

[0252] Step A: At room temperature, NBS (1.86 g, 10.48 mmol, 1.2 eq.) and AIBN (43.01 mg, 261.93 μmol, 0.03 eq.) were added sequentially to a CCl4 (20 mL) solution of compound I-11 (2.00 g, 8.73 mmol, 1.0 eq.). The reaction was carried out at 78 °C for 3 h. The reaction was monitored by TLC until complete, and LC-MS showed the formation of the target compound. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound II-11 (2.20 g, yield: 81.82%), which was a light brown oily substance. This crude product could be used directly in the next step without purification. m / z (ESI): 309 [M+H] + .

[0253] Step B: At room temperature, 3-aminopiperidine-2,6-dione (915.31 mg, 7.14 mmol, 1.0 eq.) and DIEA (4.62 g, 35.72 mmol, 6.22 mL, 5.0 eq.) were added sequentially to a MeCN (30 mL) solution of crude compound II-11 (2.20 g, 7.14 mmol, 1.0 eq.). The reaction was carried out at 90 °C for 12 h. The reaction was monitored by TLC (EA) until complete. The mixture was filtered, and the filter cake was washed with MTBE (3 × 10 mL) and dried under vacuum to obtain crude CRBN ligand 2 (1.80 g, yield: 77.98%) as a black solid. The crude product was used directly in the next step without purification. m / z (ESI): 323, 325 [M+H] + .

[0254] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),7.87((d,J=1.7Hz,1H),7.83(dd,J=8.1,1. 9Hz,1H),7.60(d,J=8.1Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.52–4.25(m,2H),

[0255] 2.98–2.83(m,1H),2.66–2.54(m,1H),2.39(qd,J=13.3,4.5Hz,1H),2.01(dtd,J=12.5,5.2,2.1Hz,1H).

[0256] Step C: To a DMF (3 mL) solution of intermediate 2 (200.00 mg, 428.70 μmol, 1.0 eq.), 7-octenoic acid (66.10 mg, 471.57 μmol, 1.1 eq.), HATU (323.47 mg, 857.40 μmol, 2.0 eq.), and DIEA (221.63 mg, 1.71 mmol, 298.69 μL, 4.0 eq.) were added sequentially. The reaction was carried out at room temperature for 4 h. 15 mL of water was added to the reaction solution, and a solid precipitated. The solid was filtered to obtain crude compound IV (180.00 mg, yield: 71.32%), a pale yellow solid. The crude compound was used directly in the next step. m / z (ESI): 589 [M+H] + .

[0257] Step D: At room temperature, CRBN ligand 2 (59.47 mg, 184.02 μmol, 1.0 eq.), (PPh3)2PdCl2 (12.92 mg, 18.40 μmol, 0.1 eq.), and CuI (7.01 mg, 36.80 μmol, 0.2 eq.) were added sequentially to a mixed solvent of DMF (1 mL) and TEA (1 mL) of the obtained compound IV (130.00 mg, 220.83 μmol, 1.2 eq.), and N2 was replaced three times. The reaction was carried out at 80 °C for 12 h. 15 mL of water was added to the reaction solution, and a solid precipitated. The crude product was obtained by filtration and purified by preparative HPLC (acetonitrile / water system) to obtain compound 15 (10.00 mg, purity: 95%, yield 6.21%).

[0258] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.75(s,1H),8.71(s,1H),8.36(d,J=10.8Hz,1H),8.02(d,J=6.1Hz,1H),7.65–7.61(m,2H),7 .59(d,J=4.5Hz,1H),7.56(dd,J=7.1,3.2Hz,1H),7.45(s,1H),7.20(d,J=11.8Hz,1H),6.27(d,J=3.1Hz,2H),5.10(dd,J=13.3,5.0H z,2H),4.46(dd,J=18.3,2.7Hz,1H),4.37–4.28(m,3H),4.20–4.16(m,2H),3.69(d,J=5.4Hz,3H),3.36–3.26(m,2H),2.99–2.81(m,2 H),2.69–2.52(m,2H),2.47–2.43(m,2H),2.41–2.31(m,2H),1.99(dd,J=11.9,6.7Hz,2H),1.67–1.39(m,6H),1.19(d,J=6.5Hz,6H). m / z(ESI):831[M+H] + .

[0259] Example 12: Synthesis of Compound 16

[0260]

[0261] Compound 16 was synthesized according to this reaction route. Details are as follows.

[0262] Step A: At room temperature, 5-hexyneic acid (52.88 mg, 471.57 μmol, 1.1 eq.), HATU (323.47 mg, 857.40 μmol, 2.0 eq.), and DIEA (221.63 mg, 1.71 mmol, 298.69 μL, 4.0 eq.) were added sequentially to a DMF (3 mL) solution of intermediate 2 (200.00 mg, 428.70 μmol, 1.0 eq.) at room temperature. The reaction was allowed to proceed for 4 h at room temperature. 15 mL of water was then added to the reaction solution, resulting in the precipitation of a solid. Filtration yielded a crude product of compound IV-12 (160.00 mg, yield: 66.57%), a pale yellow solid. This crude product was used directly in the next step. m / z (ESI): 561 [M+H] + .

[0263] Step B: At room temperature, the following substances were added sequentially: CRBN ligand 2 (48.03 mg, 148.64 μmol, 1 eq.), (PPh3)2PdCl2 (10.43 mg, 14.86 μmol, 0.1 eq.), and CuI (5.66 mg, 29.73 μmol, 0.2 eq.) prepared as in Example 11. The mixture was substituted with N2 three times and reacted at 80 °C for 12 h. 15 mL of water was added to the reaction solution, and a solid precipitated. The crude product was obtained by filtration and purified by preparative HPLC (acetonitrile / water system) to obtain compound 16 (10.00 mg, purity: 95%, yield 7.96%).

[0264] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.84(s,1H),8.71(d,J=3.4Hz,1H),8.36(d,J=11.1Hz,1H),8.08–7.97(m,1H ),7.67(d,J=6.7Hz,1H),7.65–7.59(m,2H),7.58–7.54(m,1H),7.45(s,1H),7.20(d,J=11.8Hz,1H),6.29(d,J=4.1Hz ,2H),5.10(dd,J=13.3,5.1Hz,2H),4.56–3.99(m,8H),3.38–3.24(m,3H),2.99–2.82(m,2H),2.69–2.51(m,6H),2.37 (td,J=13.2,4.4Hz,1H),2.06–1.94(m,1H),1.84(dt,J=12.8,6.7Hz,2H),1.19(d,J=6.5Hz,6H).m / z(ESI): 803[M+H] + .

[0265] Example 13: Synthesis of Compound 18

[0266]

[0267] Step A: A1 (2 g, 6.14 mmol, 1 eq) and A2 (1.87 g, 6.75 mmol, 1.1 eq) were dissolved in dioxane (20 ml), followed by the addition of BINAP (152.92 mg, 245.59 μmol, 0.04 eq), cesium carbonate (3.00 g, 9.21 mmol, 1.5 eq), and Pd(Ph3P)4 (141.90 mg, 122.80 μmol, 0.02 eq). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 12 hours. LC-MS showed the reaction was complete. After cooling to room temperature, water and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with water, dried over sodium sulfate, and concentrated to obtain the crude product. Ethyl acetate was added to the crude product, and the mixture was heated to reflux and then cooled to room temperature. The product precipitated and was filtered to obtain product A3 (3 g, 5.29 mmol, yield 86.23%).

[0268] Step B: Dissolve A3 in dichloromethane (14 ml), cool to 0°C in an ice bath, and then add trifluoroacetic acid (8.86 g, 77.67 mmol, 5.77 mL, 14.67 eq) dropwise. After the addition is complete, stir the reaction at room temperature for 12 hours. Monitor the reaction for completion by LCMS, and concentrate by rotary evaporation to obtain product A4 (2.4 g, 5.14 mmol, yield 97.17%).

[0269] Step C: A4 (2.25 g, 4.82 mmol, 1 eq) and A5 (1.5 g, 6.27 mmol, 1.3 eq) were dissolved in a mixed solvent of methanol (32 mL):tetrahydrofuran (8 mL), and sodium cyanoborohydride (605.97 mg, 9.64 mmol, 2 eq) was added at 0 °C. The reaction was stirred at 50 °C for 12 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was separated by column chromatography to obtain product A6 (2 g, 2.90 mmol, yield 60.13%).

[0270] Step D: Dissolve A6 (2g, 2.90mmol, 1eq) in dichloromethane (15mL), cool to 0℃, add trifluoroacetic acid (7.68g, 67.31mmol, 5mL, 23.22eq) dropwise, stir at room temperature for 12 hours, and concentrate by rotation to obtain crude product A7, which is used directly in the next reaction without purification.

[0271] Step E: A8 (359.21 mg, 1.22 mmol, 1.2 eq) was dissolved in dimethylformamide DMF (9.33 mL), and diisopropylethylamine (525.97 mg, 4.07 mmol, 708.86 μL, 4 eq) and A7 (600 mg, 1.02 mmol, 1 eq) were added. The reaction was stirred at 80 °C for 12 hours. Product formation was detected by LCMS. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography was used to separate the product compound 18 (100 mg, 115.75 μmol, yield 11.38%). 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.92(s,1H),8.61(d,J=3.9Hz,1H),8.20(d,J=2.4Hz,1H),8.14(d,J=8.6Hz,1H),7.70( d,J=11.4Hz,1H),7.63(dd,J=8.7,2.4Hz,1H),7.48(d,J=2.0Hz,1H),7.44(d,J=7.4Hz,1H),7.22–7.15(m,1H),5.11(dd,J=12. 8,5.4Hz,1H),4.38–4.27(m,2H),4.17(h,J=6.6Hz,1H),3.24–3.08(m,4H),2.89(ddd,J=16.4,13.6,5.2Hz,2H),2.66–2.53(m, 2H), 2.12–1.99 (m, 3H), 1.85–1.55 (m, 10H), 1.32 (d, J = 14.8Hz, 1H), 1.26 (d, J = 3.9Hz, 1H), 1.23 (s, 3H), 1.20 (d, J = 6.5Hz, 6H).

[0272] Example 14: Synthesis of Compound 19

[0273]

[0274] Step A: Dissolve B1 (1 g, 3.07 mmol, 1 eq) in dioxane (15 mL), add B2 (737.80 mg, 3.68 mmol, 1.2 eq), Pd(Ph3P)4 (70.95 mg, 61.40 μmol, 0.02 eq), and BINAP (76.46 mg, 122.80 μmol, 0.04 eq), purge with nitrogen, and react at 100 °C for 12 hours under nitrogen protection. TLC showed the reaction was complete. The reaction solution was concentrated to obtain a crude product, which was then subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 0-100%) to give a pale yellow oily product, B2 (700 mg, 1.43 mmol, yield 46.58%).

[0275] Step B: Dissolve B3 (700 mg, 1.43 mmol, 1 eq) in dichloromethane (20 mL), add trifluoroacetic acid (7.68 g, 67.31 mmol, 5 mL, 47.08 eq) at room temperature, and continue stirring for 3 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to give an oily product B4 (500 mg, 1.28 mmol, yield 89.79%), which was used directly in the next reaction without purification.

[0276] Step C: Dissolve B4 (500 mg, 1.28 mmol, 1 eq) in tetrahydrofuran (10 mL), add B5 (400.76 mg, 1.41 mmol, 1.1 eq) and diisopropylethylamine (414.83 mg, 3.21 mmol, 559.08 μL, 2.5 eq), and stir at room temperature for 3 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain a crude product, which was separated by column chromatography (silica gel, petroleum ether: ethyl acetate = 0-100%) to obtain product B6 (180 mg, 282.68 μmol, yield 22.02%).

[0277] Step D: Dissolve B6 (180 mg, 282.68 μmol, 1 eq) in dichloromethane (5 mL), add trifluoroacetic acid (3.07 g, 26.92 mmol, 2 mL, 95.25 eq), stir at room temperature for 3 hours, and TLC shows the reaction is complete. Concentrate the reaction solution to obtain an oily product B7 (150 mg, 279.52 μmol, yield 98.88%), which is used directly in the next reaction without purification.

[0278] Step E: Dissolve B7 (150 mg, 279.52 μmol, 1 eq) in dichloromethane (10 mL), add B8 (71.54 mg, 335.42 μmol, 1.2 eq) and sodium borohydride acetate (59.24 mg, 279.52 μmol, 1 eq), stir at room temperature for 12 hours, and TLC shows that the reaction is complete. The reaction solution is concentrated to obtain a crude product, which is separated by column chromatography (silica gel, petroleum ether: ethyl acetate = 0-100%) to give a light yellow oily product B9 (85 mg, 115.82 μmol, yield 41.43%).

[0279] Step F: Dissolve B9 (85 mg, 115.82 μmol, 1 eq) in dichloromethane (5 mL), add trifluoroacetic acid (3.07 g, 26.92 mmol, 2 mL, 232.47 eq), stir at room temperature for 3 hours, and TLC shows the reaction is complete. The reaction solution is concentrated to give a maroon oily product B10 (70 mg, 110.45 μmol, yield 95.36%), which is used directly in the next reaction without purification.

[0280] Step G: Dissolve B10 (70 mg, 110.45 μmol, 1 eq) in dimethylformamide (5 mL), add B11 (36.61 mg, 132.54 μmol, 1.2 eq) and diisopropylethylamine (71.37 mg, 552.23 μmol, 96.19 μL, 5 eq), and stir the reaction at 85 °C for 12 hours. TLC showed that the reaction was complete. Add water and ethyl acetate to the reaction solution, separate the organic layer, wash with water and saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. Thin-layer chromatography (silica gel, methanol:dichloromethane = 1:15) was used to separate the product into a light yellow solid compound 19 (6.7 mg, 7.53 μmol, yield 6.82%). 1 H NMR (400MHz, Chloroform-d): δ1.22(d,J=6.6Hz,6H),1.43(s,1H),1.64–1.55(m,4H),1.85(t,J=3.4Hz,2H),2.08–2.00(m,2H),2.14(dd, J=9.9,4.8Hz,2H),2.74–2.68(m,1H),2.88–2.76(m,2H),3.01–2.92(m,3H),3.14(t,J=11.4Hz,2H),3.32–3.26(m,2H),3.75(t,J=6.6Hz, 2H),3.82(d,J=13.0Hz,2H),3.95(d,J=13.3Hz,2H),4.15(dt,J=13.1,6.6Hz,1H),4.39–4.32(m,2H),4.94(dd,J=12.3,5.3Hz,1H),5.08( s,1H),7.04(dd,J=8.6,2.3Hz,1H),7.23(d,J=12.9Hz,1H),7.27(d,J=2.2Hz,1H),7.33(s,1H),7.67(d,J=8.5Hz,1H),8.19–8.12(m,2H).

[0281] Example 15: Synthesis of Compound 20

[0282]

[0283] Step A: Under nitrogen protection, C1 (200 mg, 613.99 μmol, 1 eq), aniline (62.90 mg, 675.38 μmol, 1.1 eq), cesium carbonate (300.07 mg, 920.98 μmol, 1.5 eq), Pd(PPh3)4 (14.19 mg, 12.28 μmol, 0.02 eq), and BINAP (15.29 mg, 24.56 μmol, 0.04 eq) were dissolved in dioxane (10 mL), and the reaction was carried out at 100 °C for 16 hours. TLC showed that the reaction was complete. After concentration, the reaction solution was separated by column chromatography to obtain C2 (80 mg, 209.20 μmol, yield 34.07%).

[0284] Step B: Chlorosulfonic acid (487.52 mg, 4.18 mmol, 20 eq) was added to a 100 mL three-necked flask equipped with a mechanical stirrer. After cooling to 12-15 °C in an ice-water bath, C2 (80 mg, 209.20 μmol, 1 eq) was added dropwise while maintaining the temperature at 15 °C. After the addition was complete, the reaction mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and slowly added to 80 mL of water. The precipitated solid was filtered, washed with water, and dried to obtain product C3 (65 mg, 135.16 μmol, yield 64.61%).

[0285] Step C: 2-(2-propynoxy)ethylamine (14.74 mg, 148.68 μmol, 1.1 eq) and diisopropylethylamine (DIEA) (26.20 mg, 202.74 μmol, 35.31 μL, 1.5 eq) were dissolved in dichloromethane (15 mL), and C3 (65 mg, 135.16 μmol, 1 eq) was added. The mixture was stirred at room temperature for 6 hours. TLC showed that the reaction was complete. The reaction solution was concentrated and separated by column chromatography to obtain C4 (42 mg, 77.26 μmol, yield 57.17%).

[0286] Step D: C6 (100 mg, 362.03 μmol, 1 eq) and diisopropylethylamine (187.16 mg, 1.45 mmol, 252.23 μL, 4 eq) were dissolved in dimethylformamide (5 mL), and then C5 (69.37 mg, 398.23 μmol, 1.1 eq) was added. The mixture was reacted at 90 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate to obtain the crude product. Column chromatography was used to separate product C7 (48 mg, 111.52 μmol, yield 30.80%).

[0287] Step E: C7 (25.34 mg, 58.87 μmol, 1 eq), C4 (32 mg, 58.87 μmol, 1 eq), sodium ascorbate (23.32 mg, 117.74 μmol, 2 eq), and cuprous iodide (22.42 mg, 117.74 μmol, 2 eq) were dissolved in a mixed solvent of water (5 mL) and acetonitrile (5 mL). The mixture was stirred at room temperature for 20 hours under nitrogen protection, and TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted three times with 30 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by liquid chromatography to obtain compound 20 (17.5 mg, 17.97 μmol, yield 30.52%). 1 H NMR (400MHz, DMSO) δ11.08(s,1H),10.18(s,1H),8.64(d,J=3.9Hz,1H),8.00(s,1H),7.97–7.88(m,2H),7.73–7.66(m,2H),7.55(dd,J=8.6,7.0Hz, 2H),7.43(d,J=2.1Hz,1H),7.20–7.15(m,1H),7.10(d,J=8.6Hz,1H),7.0 2(d,J=7.0Hz,1H),6.57(s,1H),5.04(dd,J=12.9,5.3Hz,1H),4.47(t,J=5 .2Hz,2H),4.43(s,2H),4.30(dd,J=5.1,3.6Hz,2H),4.14(p,J=6.6Hz,1H ),3.79(t,J=5.2Hz,2H),3.56(t,J=5.4Hz,2H),3.41(t,J=5.8Hz,4H),3.3 0(t,J=4.4Hz,2H),2.92–2.81(m,3H),2.63–2.51(m,2H),2.49–2.41(m,1H ), 2.01(ddt,J=11.7,6.2,3.9Hz,1H),1.23(s,2H),1.19(d,J=6.5Hz,6H).

[0288] 19F NMR (376MHz, DMSO) δ-74.94 (d, J=4.5Hz), -136.38, -148.56.

[0289] Example 16: Synthesis of Compound 21

[0290]

[0291] Step A: A8 (200 mg, 679.79 μmol, 1 eq) and diisopropylethylamine (351.42 mg, 2.72 mmol, 473.62 μL, 4 eq) were dissolved in dimethylformamide (6 mL), and C6 (130.26 mg, 747.77 μmol, 1.1 eq) was added. The mixture was stirred at 90 °C for 3 hours. After the reaction was completed, 60 mL of water was added to the reaction solution, and the mixture was extracted three times with 80 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate to obtain the crude product. D1 (95 mg, 211.86 μmol, yield 31.17%) was separated by column chromatography.

[0292] Step B: D1 (45.37 mg, 101.18 μmol, 1.1 eq), D2 (50 mg, 91.98 μmol, 1 eq), sodium ascorbate (36.45 mg, 183.96 μmol, 2 eq), and cuprous iodide (35.04 mg, 183.96 μmol, 2 eq) were dissolved in a mixed solvent of water (6 mL) and acetonitrile (6 mL). The mixture was stirred at room temperature for 20 hours under nitrogen protection, and the reaction was confirmed by TLC. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by liquid chromatography to obtain compound 21 (60 mg, 60.48 μmol, yield 65.76%). 1 H NMR (400MHz, DMSO) δ11.07(s,1H),10.17(s,1H),8.64(d,J=3.9Hz,1H),8.00(s,1H),7.96–7.91(m,2H),7.72–7.67(m,2H),7. 57–7.52(m,2H),7.44(d,J=2.1Hz,1H),7.21–7.15(m,2H),6.78(s,1H),5.05(dd,J=12.9,5.4Hz,2H),4.50–4.44(m,4H),4.33 –4.27(m,2H),4.15(p,J=6.6Hz,1H),3.78(t,J=5.2Hz,2H),3.56(t,J=5.5Hz,3H),3.43(q,J=4.6Hz,5H),3.31(t,J=4.4Hz,2H ),2.93–2.82(m,3H),2.63–2.52(m,2H),2.46(d,J=4.4Hz,1H),2.01(ddt,J=12.4,5.6,3.6Hz,1H),1.20(d,J=6.5Hz,6H).19F NMR(376MHz, DMSO)δ-74.61,-126.71,-136.38,-148.56.

[0293] Example 17: Synthesis of Compound 22

[0294]

[0295] Step A: E1 (5 g, 24.84 mmol, 1 eq) was dissolved in dichloromethane (50 mL), and p-toluenesulfonyl chloride (5.21 g, 27.33 mmol, 1.1 eq) and triethylamine (3.77 g, 37.26 mmol, 1.5 eq) were added. The mixture was stirred at 20 °C for 48 hours. TLC showed product formation. The reaction solution was concentrated and separated by column chromatography (220 g silica gel, 0%-100% petroleum ether: ethyl acetate) to give product E2 (3.5 g, 39%).

[0296] Step B: E2 (2 g, 5.63 mmol, 1 eq) was dissolved in dimethylformamide (20 mL), and p-aminothiophenol (1.48 g, 11.82 mmol, 2.1 eq) and potassium carbonate (4.67 g, 33.76 mmol, 6 eq) were added. The reaction mixture was reacted at 70 °C for 12 hours. The reaction solution was diluted with ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography was used to separate the crude product into a grayish-white solid E3 (1.24 g, 71%).

[0297] Step C: E3 (1.24 g, 4.02 mmol, 1 eq) was dissolved in dichloromethane (50 mL), and m-chloroperoxybenzoic acid (2.08 g, 12.06 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 10 minutes. TLC showed that the starting material was dry and the product was formed. The reaction solution was diluted with sodium bicarbonate aqueous solution and dichloromethane. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography was used to separate the crude product into a pale yellow solid E4 (1.0 g, 73%).

[0298] Step D: At room temperature, a tetrahydrofuranose solution of bis(trimethylsilylaminolithium) (2.95 g, 17.62 mmol, 6 eq) was added to a solution of E4 (1 g, 2.94 mmol, 1 eq) in ethyl formate (10 mL). The reaction was then heated to 60 °C and stirred for 2 hours. LC-MS showed that the starting material disappeared and the product was formed. The reaction was quenched with ammonium chloride aqueous solution. The reaction solution was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was suspended in dichloromethane and filtered. The resulting grayish-white solid was product E5 (900 mg, 83%).

[0299] Step E: At 0°C, E5 (200 mg, 542.82 μmol, 1 eq) was dissolved in tetrahydrofuran (2 mL) and dimethylformamide (0.5 mL), and sodium hydride (65.13 mg, 1.63 mmol, 60% purity, 3 eq) was added. The resulting suspension was stirred at 0°C for 10 minutes, and E6 (175.53 mg, 542.82 μmol, 1 eq) was added. The mixture was stirred at 20°C for 2 hours, and LC-MS showed product formation. The reaction was quenched with ammonium chloride aqueous solution, and the reaction solution was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography was used to separate the crude product into a pale yellow solid, E7 (100 mg, 31%).

[0300] Step F: Add hydrochloric acid-dioxane solution (4M, 4mL) to a solution of E7 (400.00mg, 685.29μmol, 1eq) in dichloromethane (4mL), stir at 20°C for 5 minutes, a yellow solid precipitates, pour off the solution, add petroleum ether to the remaining solid, stir for 10 minutes, and filter to obtain product E8 (200mg, 60%).

[0301] Step G: Sodium cyanoborohydride (7.80 mg, 124.07 μmol, 3 eq) was added to a methanol (1 mL) solution of E8 (20 mg, 41.36 μmol, 1 eq) and E9 (17.10 mg, 41.36 μmol, 1 eq). The resulting reaction solution was stirred at 20 °C for 2 hours. LC-MS showed that the starting material disappeared. The reaction solution was diluted with acetonitrile-water and then separated by preparative liquid chromatography to obtain a light yellow solid product (10 mg, 26%). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.6(s,1H),8.93(s,1H),8.39(s,1H),8.04(d,J=8.6Hz,2H),7.9 3(d,J=9.3Hz,1H),7.81(d,J=8.5Hz,2H),7.70(d,J=11.4Hz,1H),7.43(d,J=7.4Hz,1H),6.51(d,J=9.3Hz ,1H),5.11(dd,J=12.7,5.5Hz,2H),4.82(s,1H),3.19(m,2H),3.11(m,2H),2.87(m,2H),2.63(m,3H),2. 04–1.96(m,8H),1.87(d,J=12.1Hz,4H),1.68(m,4H),1.59(d,J=6.5Hz,4H),1.48(m,J=2H),1.25(s,3H).

[0302] Example 18: Synthesis of Compound 23

[0303]

[0304] Step A: Sodium cyanoborohydride (13.00 mg, 206.79 μmol, 2 eq) was added to a methanol (1 mL) solution of F1 (50 mg, 103.40 μmol, 1 eq) and F2 (24.26 mg, 113.73 μmol, 1.1 eq). The mixture was stirred at room temperature for 1 hour, and LC-MS showed product formation. Product F3 (60 mg, 85%) was obtained by column chromatography.

[0305] Step B: Add dioxane hydrochloride (1 mL, 4 M) to F3 (60 mg, 88.12 μmol, 1 eq), stir at room temperature for 6 minutes, and LC-MS shows the starting material disappears. Concentrate the reaction solution to obtain crude product F4 (50 mg, 97%).

[0306] Step C: A8 (30.40 mg, 103.32 μmol, 1.2 eq) and F4 (50 mg, 86.10 μmol, 1 eq) were dissolved in dimethyl sulfoxide (1 mL), and stirred at 130 °C for 1 hour. LCMS (UV350) showed that the starting material disappeared and the product was formed. The reaction solution was diluted with acetonitrile-water and separated by preparative liquid chromatography to obtain a light yellow product (5.6 mg, 7.0%). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.93(s,1H),8.05(d,J=8.7Hz,2H),7.93(d,J=9.4Hz,1H),7.8 2(d,J=8.5Hz,2H),7.70(d,J=11.3Hz,1H),7.43(d,J=7.6Hz,1H),6.51(d,J=9.3Hz,1H),5.77(s,1H), 5.11(dd,J=12.7,5.4Hz,1H),3.59(m,1H),2.93–2.82(m,7H),2.63-2.58(m,2H),2.18(m,3H),1.95– 1.85(m,4H),1.81–1.75(m,7H),1.51(q,J=12.6Hz,4H),1.39–1.30(m,2H),1.28(s,2H),1.25(s,3H).

[0307] Example 19: Synthesis of Compound 24

[0308]

[0309] Step A: Palladium acetate (27.40 mg, 122.04 μmol, 0.2 eq), cesium carbonate (397.64 mg, 1.22 mmol, 2 eq), and BINAP (75.99 mg, 122.04 μmol, 0.2 eq) were added to a 10 mL solution of C1 (198.77 mg, 610.21 μmol, 1 eq). The reaction was carried out at 100 °C for 12 hours under nitrogen protection. LC-MS showed that the starting material disappeared and the product was formed. After the reaction solution was evaporated to dryness, column chromatography was used to separate the product and obtain a light yellow solid G1 (200 mg, 82%).

[0310] Step B: Add G2 (68.87 mg, 251.62 μmol, 2 eq) and diisopropylethylamine (48.78 mg, 377.43 μmol, 65.74 μL, 3 eq) to a solution of G1 (0.05 g, 125.81 μmol, 1 eq) in dichloromethane (1 mL). React at 25 °C for 12 hours. LC-MS showed that the starting material disappeared and the product was formed. The reaction solution was evaporated to dryness to obtain crude product G3 (100 mg, 91%).

[0311] Step C: Add hydrazine hydrate (573.47 μmol, 5 eq) to a 2 ml ethanol solution of G3 (100 mg, 114.69 μmol, 1 eq). Stir the reaction at 90 °C for 1 hour. LCMS showed that the starting material disappeared and the product was formed. The reaction solution was evaporated to dryness to obtain a crude product. Ethanol was added, and the mixture was stirred and filtered to obtain a filter cake of G4 (50 mg, 86%).

[0312] Step D: G5 (33.98 mg, 158.56 μmol, 2 eq), HATU (59.82 mg, 158.56 μmol, 2 eq), and diisopropylethylamine (30.74 mg, 237.83 μmol, 41.43 μL, 3 eq) were added to a solution of G4 (40 mg, 79.28 μmol, 1 eq) in 2 mL of dimethyl sulfoxide. The reaction was stirred at 25 °C for 2 hours. LC-MS showed that the starting material disappeared and the product was formed. The reaction solution was diluted with ethyl acetate / water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the crude product. Preparative liquid chromatography yielded a yellow solid (8 mg, 17%). 1H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.64(s,1H),8.57(d,J=4.1Hz,1H),7.78–7.68(m,3H),7.48(s,1H),7.18(dd,J=9. 8,3.0Hz,3H),4.31(t,J=4.3Hz,2H),4.16(p,J=6.6Hz,1H),3.89(d,J=14.9Hz,1H),3.76(d,J=14.9Hz,1H),3.52(tq,J=1 4.0,7.0Hz,2H),3.17(t,J=7.1Hz,2H),3.09(td,J=10.6,4.1Hz,1H),2.17(td,J=6.9,2.7Hz,1H),2.00(d,J=12.6Hz,1H ),1.63–1.50(m,2H),1.27–1.14(m,9H),0.98–0.85(m,4H),0.85–0.82(m,4H),0.82–0.73(m,2H),0.71(d,J=6.9Hz,3H).

[0313] Example 20: Synthesis of Compound 25

[0314]

[0315] Step A: N-Boc ethylenediamine (639.07 mg, 3.99 mmol, 2 eq) and diisopropylethylamine (257.77 mg, 1.99 mmol, 347.39 μL, 1 eq) were added to a solution of 4-nitrobenzenesulfonyl chloride (442 mg, 1.99 mmol, 1 eq) in dichloromethane (10 mL). The mixture was reacted at 25 °C for 1 hour. LC-MS showed that the starting material disappeared and the product was formed. The reaction solution was evaporated to dryness, methanol was added, the mixture was stirred, and filtered to obtain the filter cake as product H1 (450 mg, 65%).

[0316] Step B: Add iron powder (161.70 mg, 2.90 mmol, 5 eq) and ammonium chloride (154.88 mg, 2.90 mmol, 5 eq) to the ethanol (5 ml) and water (0.5 ml) solution of H1. React at 90 °C for 14 hours, monitoring the disappearance of the starting material by LCMS. Filter the reaction solution through a silica gel short column and evaporate to dryness to obtain crude product H2 (180 mg, 98%).

[0317] Step C: H3 (92.10 mg, 285.36 μmol, 1 eq) and H2 (90 mg, 285.36 μmol, 1 eq) were dissolved in dioxane (2 mL), and XantPhos (33.02 mg, 57.07 μmol, 0.2 eq), Pd2(dba)3 (26.13 mg, 28.54 μmol, 0.1 eq), and cesium carbonate (278.93 mg, 856.09 μmol, 3 eq) were added. The reaction was carried out at 110 °C for 4 hours under nitrogen protection. LC-MS showed product formation. The reaction solution was diluted with ethyl acetate / water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, then with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. Column chromatography was used to separate H4 (70 mg, 40%).

[0318] Step D: Add hydrochloric acid-dioxane (2 mL, 4 M) solution to H4 (70 mg, 116.34 μmol, 1 eq) and stir at 25 °C for 10 minutes. LCMS showed that the starting material disappeared and the product was formed. The reaction solution was evaporated to dryness to obtain crude product H5 (55 mg, 94%), which was used directly in the next reaction without purification.

[0319] Step E: Dissolve H6 (34.18 mg, 159.51 μmol, 2 eq) in pyridine (0.5 mL), add CDI (25.86 mg, 159.51 μmol, 2 eq), stir at 20 °C for 20 minutes, then add H5 (40 mg, 79.75 μmol, 1 eq), and continue stirring for 10 minutes. LCMS showed that the starting material disappeared and the product was formed. Preparative HPLC purification yielded a white foam (10 mg, 19%). 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.73(d,J=3.7Hz,1H),8.24(d,J=1.3Hz,1H),8.04–7.96(m,2H),7.75 –7.64(m,3H),7.55(q,J=5.8Hz,2H),4.87(h,J=6.9Hz,1H),3.85(d,J=14.9Hz,1H),3.73(d,J=14.9Hz,1H),3 .18(t,J=5.4Hz,1H),3.17–3.01(m,2H),2.79(q,J=6.5Hz,2H),2.65(s,3H),2.15(ddt,J=11.6,7.3,4.5Hz,1 H),1.97(d,J=11.9Hz,1H),1.63(d,J=6.9Hz,6H),1.60–1.47(m,2H),1.28–1.13(m,2H),0.95–0.66(m,12H).

[0320] Example 21: Synthesis of Compound 26

[0321]

[0322] Step A: J1 (0.3 g, 760.61 μmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by the addition of diisopropylethylamine (196.61 mg, 1.52 mmol, 264.97 μL, 2 eq), and then G2 (249.81 mg, 912.73 μmol, 1.2 eq). The mixture was stirred at 20 °C for 12 hours, and LC-MS showed product formation. The reaction solution was diluted with dichloromethane / water, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, then with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. Column chromatography yielded a pale yellow solid (50 mg, 10.4%).

[0323] Step B: Dissolve J2 (40 mg, 63.33 μmol, 1 eq) in ethanol (5 mL), add hydrazine hydrate (47.68 mg, 1.27 mmol, 85% purity, 20 eq), and react at 90 °C for 0.5 hours. Dry the reaction solution to obtain crude J3 (30 mg, 94%).

[0324] Step C: J3 (40 mg, 79.75 μmol, 1 eq) was dissolved in dimethylformamide (1 ml), and H6 (34.18 mg, 159.51 μmol, 2 eq), HATU (45.13 mg, 119.63 μmol, 1.5 eq), and diisopropylethylamine (20.61 mg, 159.51 μmol, 27.78 μL, 2 eq) were added. The reaction mixture was stirred at 20 °C for 2 hours. Preparative liquid chromatography purification yielded a pale yellow solid (16 mg, 28.7%). 1H NMR (400MHz, DMSO-d6) δ9.82(s,1H),9.66(s,1H),8.65(d,J=4.0Hz,1H),8.28(d,J=1.3Hz,1H),7.78(d,J=8.9Hz,2H),7.74(t,J=5.9 Hz,1H),7.67(d,J=12.1Hz,1H),7.22(d,J=8.9Hz,2H),4.87(p,J=6.8Hz,1H),3.97–3.86(m,1H),3.77(d,J=15.0Hz,1H),3.53(dd,J=1 4.8,7.3Hz,2H),3.18(t,J=7.1Hz,2H),3.09(td,J=10.5,4.0Hz,1H),2.66(s,3H),2.22–2.11(m,1H),2.00(d,J=11.8Hz,1H),1.65(d ,J=6.9Hz,6H),1.58–1.50(m,2H),1.39–1.23(m,3H),0.94–0.85(m,3H),0.85–0.81(m,3H),0.81–0.73(m,2H),0.70(d,J=6.9Hz,3H).

[0325] Example 22: Synthesis of Compound 27

[0326]

[0327] Step A: Add hydrochloric acid-dioxane (4M, 5mL) solution to K1 (300mg, 612.80μmol, 1eq) and stir at 25°C for 10 minutes. LCMS showed product formation. The reaction solution was evaporated to dryness to give brown semi-solid K2 (240mg, 90%).

[0328] Step B: K2 (240 mg, 616.27 μmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by the addition of G2 (337.34 mg, 1.23 mmol, 2 eq) and then dropwise addition of (238.94 mg, 1.85 mmol, 322.03 μL, 3 eq). The reaction mixture was stirred at 25 °C for 4 hours, and LC-MS showed product formation. The reaction mixture was concentrated to obtain a crude product. Column chromatography purification yielded a pale yellow solid K3 (290 mg, 75%).

[0329] Step C: K3 (280 mg, 446.80 μmol, 1 eq) was dissolved in ethanol (5 mL), and hydrazine hydrate (168.45 mg, 4.47 mmol, 85% purity, 10 eq) was added. The reaction was stirred at 90 °C for 10 min, and LC-MS showed product formation. The reaction mixture was concentrated to dryness to obtain a crude product. The crude product was suspended in ethanol and filtered to obtain a grayish-white solid K4 (200 mg, 81%).

[0330] Step D: K4 (80 mg, 161.10 μmol, 1 eq) was dissolved in dimethylformamide DMF (1 ml), followed by the addition of H6 (69.05 mg, 322.21 μmol, 2 eq), HATU (121.56 mg, 322.21 μmol, 2 eq), and diisopropylethylamine (62.46 mg, 483.31 μmol, 84.18 μL, 3 eq). The reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed that the starting material was present and the product was formed. The reaction solution was diluted with ethyl acetate / water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, then with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. Preparative liquid chromatography purification yielded the product (41 mg, 36%). 1 H NMR (400MHz, DMSO-d6) δ8.39(d,J=4.0Hz,1H),7.72(t,J=6.0Hz,1H),7.35(s,1H),7.29(d,J=7.5Hz,1H),7.12(d,J =11.7Hz,1H),4.30(t,J=4.4Hz,2H),4.10(q,J=6.7Hz,2H),3.97(d,J=15.0Hz,2H),3.82(d,J=15.0Hz,2H),3.65–3 .46(m,4H),3.30(t,J=4.3Hz,3H),3.27–3.09(m,3H),2.98(t,J=11.4Hz,2H),2.26–2.18(m,1H),2.10–1.97(m,2H) ,1.61(t,J=16.2Hz,2H),1.29–1.21(m,2H),1.18(d,J=6.5Hz,6H),1.02–0.83(m,9H),0.78(dd,J=23.2,9.4Hz,3H).

[0331] Example 23: Synthesis of Compound 28

[0332]

[0333] Step A: Add starter I (600.00 mg, 2.19 mmol, 1.00 eq), 1,6-dibromohexane (533.79 mg, 2.19 mmol, 1.00 eq), sodium bicarbonate (551.43 mg, 6.56 mmol, 3.00 eq), and KI (363.20 mg, 2.19 mmol, 1.00 eq) to DMF (10 mL). Stir at 80 °C for 16 h. After stirring, cool to room temperature and pour into 80 mL of water. Extract the mixture with EtOAc (3 x 50 mL), wash with brine (3 x 40 mL), dry to anhydrous Na₂SO₄, filter, and concentrate the filtrate. Purify the residue by column chromatography to give a pale yellow solid intermediate II (475.00 mg, yield: 49.65%), m / z (ESI): 438 [M+H]. +

[0334] Step B: The starting material C8 (213.37 mg, 457.37 μmol, 1.00 eq), intermediate II (200.00 mg, 457.37 μmol, 1.00 eq), DIEA (354.66 mg, 2.74 mmol, 477.98 μL, 6.00 eq), K2CO3 (189.64 mg, 1.37 mmol, 3.00 eq), and KI (75.92 mg, 457.37 μmol, 1.00 eq) were stirred in DMF (10 mL) at 90 °C for 16 h. After stirring, the mixture was cooled to room temperature and poured into 100 mL of water. The mixture was then extracted with AcOEt (3 x 80 mL). The product was washed with brine (3 x 80 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give compound 28 (33.80 mg, yield: 8.98%, purity 98.58%). 1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.99(s,1H),8.63(d,J=3.9Hz,1H),8 .24–8.14(m,2H),7.83(dd,J=8.5,7.3Hz,1H),7.62(d,J=8.3Hz,1H),7.54(d ,J=8.6Hz,1H),7.51–7.43(m,2H),7.19(dd,J=11.2,1.8Hz,1H),5.09(dd,J =12.7,5.4Hz,1H),4.35–4.29(m,2H),4.23(t,J=6.2Hz,2H),4.17(p,J=6.6H z,1H),3.32(d,J=4.4Hz,2H),2.89(ddd,J=16.6,13.7,5.3Hz,2H),2.66–2. 53(m,2H),2.03(tdd,J=12.3,6.3,3.1Hz,2H),1.95(d,J=20.0Hz,3H),1.84– 1.75(m,3H),1.67(s,2H),1.52(dq,J=15.7,8.1,7.5Hz,3H),1.41(q,J=7.8 Hz,3H),1.24(d,J=3.9Hz,3H),1.20(d,J=6.5Hz,6H).m / z(ESI): 823.2[M+H] + .

[0335] Example 24: Synthesis of Compound 29

[0336]

[0337] Step A: Dissolve raw material I (1.00 g, 3.65 mmol, 1.0 eq) in 10 mL of DMF. Separately add tert-butyl bromoacetate (711 mg, 3.65 mmol, 1.0 eq), followed by anhydrous potassium carbonate (756 mg, 5.47 mmol, 1.5 eq). Stir the mixture overnight at room temperature. After the reaction is complete, add 50 mL of water and extract with ethyl acetate (3 x 50 mL). Wash the organic layer with saturated brine (3 x 40 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 1 g of solid product II. The crude product can be used directly in the next reaction without purification. m / z (ESI): 389 [M+H]+

[0338] Step B: Take 1g of crude raw material II and add it to 20mL of dichloromethane. Add 10mL of trifluoroacetic acid at 0℃. Bring the reaction mixture to room temperature and stir overnight. After the reaction is complete, remove the solvent to obtain 1g of white solid, which is 1g of trifluoroacetate salt of intermediate III. The crude product does not require purification and can be used directly in the next step of the reaction. m / z (ESI): 333[M+H]+

[0339] Step C: Take 1 g of crude raw material III into 15 mL of DMF, add N,N-diisopropylethylamine (1.56 g, 12.05 mmol, 4 eq) and HATU (1.37 g, 3.61 mmol, 1.2 eq), stir at room temperature for 30 minutes, then add N-tert-butoxycarbonyl-1,4-butanediamine (624 mg, 3.31 mmol, 1.1 eq) to the system, and react overnight at room temperature. After the reaction is complete, add 50 mL of water, extract with ethyl acetate (3 x 50 mL), wash the organic layer with saturated brine (3 x 40 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by column chromatography to give a yellow solid intermediate IV (700 mg, yield: 46.3%), m / z (ESI): 503.2 [M+H]. +

[0340] Step D: Take intermediate IV (700 mg, 1.39 mmol, 1.0 eq). Add 10 mL of trifluoroacetic acid to 10 mL of dichloromethane at 0 °C. Bring the reaction mixture to room temperature and stir overnight. After the reaction is complete, remove the solvent to obtain 600 mg of the trifluoroacetate salt of the yellow solid product V. The crude product can be used directly in the next reaction without purification. m / z (ESI): 403 [M+H] +

[0341] Step E: Take intermediate C8 (500 mg, 1.07 mmol, 1.0 eq), add 20 mL of tetrahydrofuran, add triethylamine (163 mg, 1.61 mmol, 1.5 eq), and under nitrogen protection, cool to -70 °C. Add bromoacetyl bromide (217 mg, 1.07 mmol, 1.0 eq) at -80 °C, and stir at -70 °C for 2 h. After the reaction is complete, remove the solvent, and purify the residue by column chromatography to give intermediate VI (180 mg, 0.31 mmol, yield: 28.7%), m / z (ESI): 587.2 [M+H]. +

[0342] Step F: Intermediate V (120 mg, 0.30 mmol, 1.0 eq) was added to 10 mL of DMF, and DIEA (154 mg, 1.19 mmol, 4.0 eq) was added. The mixture was stirred at room temperature for 20 min. Intermediate VI (174 mg, 0.30 mmol, 1.0 eq) was added to the mixture, and the mixture was heated to 90 °C and stirred overnight until the reaction was complete. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give a white solid compound 29 (20 mg, yield 4.71%, purity 95.68%). 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.89(s,2H),8.57(s,2H),8.19(d,J=2.2Hz,2H),8.09(d,J=8.4Hz,2H),7.95(s,1H),7.77(t,J=7.9Hz, 1H),7.56(s,2H),7.46(d,J=9.4Hz,3H),7.37(d,J=8.5Hz,1H),7.15(d,J=11.7Hz,2H),5.11(dd,J=12.8,5.4Hz,1H),4.76(s,2H),4.52(d,J=1 2.3Hz,2H),4.28(t,J=4.2Hz,4H),4.20(s,1H),4.13(q,J=6.7Hz,2H),3.39(s,2H),3.28(t,J=4.3Hz,5H),3.23–3.00(m,4H),2.78(s,3H),2. 59(d,J=17.1Hz,4H),2.01(d,J=8.3Hz,2H),1.81(d,J=12.4Hz,4H),1.60(d,J=12.7Hz,2H),1.47(s,6H),1.23(s,4H),1.17(d,J=6.5Hz,11H).

[0343] Example 25: Synthesis of Compound 30

[0344]

[0345] Step A: Dissolve raw material I (1.00 g, 3.65 mmol, 1.0 eq) in 10 mL of DMF. Separately add tert-butyl bromoacetate (711 mg, 3.65 mmol, 1.0 eq), followed by anhydrous potassium carbonate (756 mg, 5.47 mmol, 1.5 eq). Stir the mixture overnight at room temperature. After the reaction is complete, add 50 mL of water and extract with ethyl acetate (3 x 50 mL). Wash the organic layer with saturated brine (40 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain solid product II. The crude product can be used directly in the next reaction without purification. m / z (ESI): 389 [M+H] +

[0346] Step B: Take 1 g of crude raw material II and add it to 20 mL of dichloromethane. Add 10 mL of trifluoroacetic acid at 0 °C. Bring the reaction mixture to room temperature and stir overnight. After the reaction is complete, remove the solvent to obtain a white solid product III, trifluoroacetate. The crude product can be used directly in the next reaction without purification. m / z (ESI): 333 [M+H] +

[0347] Step C: Take starting material IV (2.00 g, 10.57 mmol, 1.0 eq) and add triethylamine (2.14 g, 21.13 mmol, 2 eq) to 20 mL of dichloromethane. Under nitrogen protection, add methanesulfonyl chloride (1.82 g, 15.85 mmol, 1.5 eq) to the system at 0 °C and react at room temperature for 2 hours. After the reaction is complete, add 50 mL of water and extract with ethyl acetate (3 x 50 mL). Wash the organic layer with saturated brine (40 mL), dry with anhydrous Na₂SO₄, filter, and concentrate the filtrate to obtain solid product V. The crude product can be used directly in the next reaction without purification.

[0348] Step D: Take crude product V (285.9 mg, 1.07 mmol, 1.0 eq). Separately, take C8 fragment (500 mg, 1.07 mmol, 1.0 eq) in 10 mL of DMF. Add anhydrous potassium carbonate (222 mg, 1.61 mmol, 1.5 eq), heat the system to 90 °C, and react overnight. After the reaction is complete, add 50 mL of water, extract with ethyl acetate (3 x 50 mL), wash the organic layer with saturated brine (40 mL), dry with anhydrous Na₂SO₄, filter, and concentrate the filtrate to obtain crude product VI. Purify the residue by column chromatography to obtain intermediate VI (200 mg, yield: 29.3%), m / z (ESI): 637.3 [M+H]. +

[0349] Step E: Take 200 mg of product VI, add 9 mL of dichloromethane, and add 10 mL of trifluoroacetic acid at 0 °C. Bring the reaction mixture to room temperature and stir overnight. After the reaction is complete, remove the solvent to obtain 165 mg of the trifluoroacetate salt of solid product VII. The crude product can be used directly in the next reaction without purification. m / z (ESI): 537.3 [M+H] +

[0350] Step F: Intermediate III (103.2 mg, 0.31 mmol, 1.0 eq) was added to 10 mL of DMF, along with DIEA (120.2 mg, 0.93 mmol, 3.0 eq), EDCI (71.3 mg, 0.37 mmol, 1.2 eq), and HOBt (62.8 mg, 0.47 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min. Intermediate VII (165 mg, 0.31 mmol, 1.0 eq) was added to the mixture, and the mixture was stirred overnight at room temperature until the reaction was complete. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 30 (20 mg, yield 7.57%). 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.93(s,1H),8.62(d,J=3.9Hz,1H),8.33–8.10(m,2H),8.04(s,1H),7.84(t,J= 7.9Hz,1H),7.62(d,J=8.7Hz,1H),7.55–7.35(m,3H),7.19(d,J=11.5Hz,1H),5.13(dd,J=12.9,5.4Hz,1H),4.80(s,2H ),4.24(dt,J=59.6,5.4Hz,3H),3.20(q,J=6.3Hz,5H),2.90(ddd,J=18.6,14.0,5.3Hz,2H),2.80–2.54(m,4H),2.04( dd,J=12.5,6.2Hz,2H),1.87(s,4H),1.60(s,2H),1.50(q,J=6.7Hz,3H),1.20(d,J=6.4Hz,7H).m / z(ESI): 852.3[M+H] +

[0351] Example 26: Synthesis of Compound 31

[0352]

[0353] Step A: Compound I (200 mg, 0.614 mmol, 1.0 eq) was dissolved in 5 mL of 1,4-dioxane. Sulfonamide (105.7 mg, 0.614 mmol, 1.0 eq), cesium carbonate (300 mg, 0.92 mmol, 1.5 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP, 30.6 mg, 0.049 mmol, 0.08 eq), and tetrakis(triphenylphosphine)palladium (28.4 mg, 0.025 mmol, 0.04 eq) were added under nitrogen protection. The system was heated to 90 °C and stirred overnight until the reaction was complete. 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 31 (10 mg), yield 3.53%, purity 96.06%.

[0354] 1H-NMR: (400MHz, DMSO-d6) δ10.14(s,1H),8.65(d,J=3.9Hz,1H),7.93(d,J=8.4Hz,2H),7.74(d,J=8.5Hz,2H),7.45(s, 1H),7.19(d,J=11.2Hz,3H),4.31(t,J=4.3Hz,2H),4.16(p,J=6.6Hz,1H),1.21(d,J=6.5Hz,6H).m / z(ESI): 462.1[M+H] +

[0355] Example 27: Synthesis of Compound 32

[0356]

[0357] Step A: 2-(2-propynoxy)ethylamine (1.75 g, 17.65 mmol, 1.0 eq.) was dissolved in dichloromethane (40 mL), and triethylamine (3.57 g, 35.31 mmol, 4.91 mL, 2.0 eq.) was added. The reaction mixture was cooled to 0 °C. Then, p-nitrobenzenesulfonyl chloride (3.91 g, 17.65 mmol, 1.0 eq.) was added with stirring, and stirring continued for 2 hours. After the reaction was complete, 40 mL of water was added, and the aqueous phase was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid as intermediate I. (4.6 g, 16.18 mmol, yield: 91.66%, m / z (ESI): 285.1 [M+H]) + ).

[0358] Step B: Intermediate I (4.6 g, 16.18 mmol, 1 eq.) was dissolved in ethanol (20 mL). Reduced iron powder (9.04 g, 161.81 mmol, 10 eq.) and ammonium chloride (4.33 g, 80.90 mmol, 5.0 eq.) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was vacuum filtered, and the filtrate was collected. The filter cake was washed with ethyl acetate (2 x 30 mL). The filtrate was dried and then evaporated to dryness to obtain a light gray solid, which was intermediate II. (4 g, 15.73 mmol, yield: 97.21%, m / z (ESI): 255.4 [M+H]) + )

[0359] Step C: Phosgene (2.19 g, 19.03 mmol, 1.45 mL, 1.1 eq.) was dissolved in dichloromethane (25 mL), and a dichloromethane solution of intermediate II (4.4 g, 17.30 mmol, 1.0 eq.) (25 mL) was added. The mixture was stirred at room temperature for 16 hours. Subsequently, sodium cyanoborohydride (427 mg, 6.80 mmol, 10.0 eq.) was added in portions with stirring, and stirring was continued for 24 hours. After the extraction was complete, 50 mL of water was added, and the aqueous phase was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid as intermediate III. (4.4 g, 14.85 mmol, yield: 85.81%, m / z (ESI): 297.1 [M+H]) + )

[0360] Step D: Intermediate III (3 g, 10.12 mmol, 1.0 eq.) was dissolved in DMF (16 mL), and potassium hydroxide (624.78 mg, 11.13 mmol, 1.1 eq.) and 3,5-dimethylpyrazole-1-nitrimidylnitrate (2.24 g, 11.13 mmol, 1.1 eq.) were added to the reaction solution. The mixture was stirred at 55°C for 3 hours. After the reaction was complete, 30 mL of water was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid as intermediate IV. (3.6 g, 8.28 mmol, yield: 81.84%, 434.5 [M+H]) + )

[0361] Step E: Intermediate IV (3.6 g, 8.28 mmol, 1.0 eq) was dissolved in tetrahydrofuran (80 mL), and hydrazine hydrate was added to the reaction solution. The mixture was stirred at 55 °C for 3 hours. After the reaction was completed, the solvent was removed by rotary evaporation under vacuum, and the product was recrystallized in ethyl acetate to give a white solid as intermediate V. (2.1 g, 6.24 mmol, yield: 75.36%, m / z (ESI): 337.3 [M+H]) + )

[0362] Step F: Intermediate V (400 mg, 1.19 mmol, 1.0 eq.) and 3-methylthiophene-2-carboxylic acid (338.14 mg, 2.38 mmol, 2.0 eq.) were dissolved in DMF (20 mL), followed by the addition of HOBT (321.36 mg, 2.38 mmol, 2.0 eq.), EDCI (455.93 mg, 2.38 mmol, 2.0 eq.), and triethylamine (300.83 mg, 2.97 mmol, 413.23 μL, 2.5 eq.). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, 50 mL of ethyl acetate was added. The organic layers were combined, washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid as intermediate VI (370 mg, 0.803 mmol, Yield: 67.56%, m / z (ESI): 461 [M+H)). + )

[0363] Step G: 2-[2-(2-aminoethoxy)ethoxy]ethanol (907.38 mg, 6.08 mmol, 1.2 eq.) and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (1.4 g, 5.07 mmol, 1.0 eq.) were dissolved in DMF (2 mL), and N,N-diisopropylethylamine (1.31 g, 10.14 mmol, 1.77 mL, 2.0 eq.) was added. The mixture was stirred at 90 °C for 5 hours. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the product was purified by silica gel column chromatography to give a yellow solid, which was compound VII. (500mg, 1.23mmol, Yield: 24.33%, m / z (ESI): 406.4[M+H] + )

[0364] Step H: Intermediate VII (500 mg, 1.23 mmol, 1.0 eq.) was dissolved in anhydrous dichloromethane (20 mL), followed by the addition of triethylamine (374.41 mg, 3.70 mmol, 514.30 μL, 3.0 eq.) and methanesulfonyl chloride (169.54 mg, 1.48 mmol, 114.55 μL, 1.2 eq.). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated under vacuum, and the product was purified by silica gel column chromatography to give a yellow solid as intermediate VIII (550 mg, 1.14 mmol, yield: 92.33%).

[0365] Step I: Intermediate VIII (550 mg, 1.14 mmol, 1.0 eq.) was dissolved in anhydrous dichloromethane (20 mL), and sodium azide (110.93 mg, 1.71 mmol, 1.5 eq.) was added. The mixture was stirred at 70 °C for 2 hours. After the reaction was complete, 20 mL of water was added, and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a yellow solid as compound IX. (420 mg, 0.976 mmol, yield: 85.78%, m / z (ESI): 431.4 [M+H]) + )

[0366] Step J: Intermediate IX (400 mg, 0.912 mmol, 1.0 eq.) and intermediate VI (393 mg, 0.912 mmol, 1.0 eq.) were dissolved in DMF (8 mL), and copper sulfate pentahydrate (113.85 mg, 456.00 mmol, 0.5 eq.) was dissolved in tert-butanol (2.5 mL) and water (0.8 mL). The mixture was thoroughly combined, and then sodium vitamin C (542.03 mg, 2.74 mmol, 3.0 eq.) was added. The mixture was stirred at 70 °C for 3 hours. After stirring, the solvent was evaporated under vacuum, and the product was purified by silica gel column chromatography to give a yellow solid as compound 32 (450 mg, 0.505 mmol, yield: 55.38%). 1 H NMR(500MHz,DMSO-d6)δppm:2.02(s,1H),2.63(s,3H),2.87(d,J=6.1Hz,3H),3.41(d,J=4.9Hz,4H),3.51(s,4H ),3.55(d,J=5.1Hz,2H),3.79(s,2H),4.42(s,2H),4.46(d,J=4.9Hz,2H),5.04(dd,J=12.9,5.1Hz,1H),6.57(s ,1H),7.02(d,J=7.0Hz,1H),7.10(d,J=8.6Hz,1H),7.15(d,J=4.9Hz,1H),7.45(s,1H),7.56(t,J=7.6Hz,1H),7 .73(d,J=8.6Hz,2H),7.78-7.90(m,4H),7.99(s,1H),8.04(d,J=5.0Hz,1H),9.92(s,1H),11.08(s,1H); m / z(ESI + ):891.5(M+H)

[0367] Example 28: Synthesis of Compound 33

[0368]

[0369] Step A: Take starting material I (100 mg, 0.307 mmol, 1 eq), aniline (31.45 mg, 337.69 μmol, 1.1 eq), cesium carbonate (150.04 mg, 460.49 μmol, 1.5 eq), tetrakis(triphenylphosphine)palladium (7.10 mg, 6.14 μmol, 0.02 eq), and BINAP (7.65 mg, 12.28 μmol, 0.04 eq) into a reaction flask, add 1,4-dioxane (10 mL), and then stir at 100 °C for 16 h under nitrogen protection. TLC showed the reaction was complete. Cool to room temperature. The reaction solution was concentrated under vacuum to obtain a crude product, which was then purified by column chromatography to obtain compound 1 (96 mg, yield: 81.77%, m / z (ESI): 383 [M+H)). + )

[0370] Step B: Add chlorosulfonic acid (585.03 mg, 5.02 mmol, 20 eq) to the reaction flask and cool the system to 12-15 °C with ice water. While stirring, maintain the temperature at 15 °C and add starting material II (96 mg, 251.04 μmol, 1 eq) in portions. After addition, react the reaction mixture at 60 °C for 2 hours. Cool the reaction to room temperature and slowly pour it into 150 mL of water while stirring. Filter to collect the precipitate, wash with water, and dry to give compound III. (75 mg, yield: 62.12%, m / z (ESI): 481 [M+H]) + )

[0371] Step C: Add 4-formyl-N-Cbz-piperidine IV (100 mg, 0.404 mmol, 1 eq) to a reaction flask, add MeOH (10 mL), then add 1-tert-butoxycarbonylpiperazine (75.32 mg, 0.404 mmol, 1 eq), and stir the mixture at room temperature for 1 hour. Add sodium cyanoborohydride (50.82 mg, 0.808 mmol, 2 eq) to the above system and stir at room temperature for 18 hours. After the reaction is complete, remove the solvent under reduced pressure, add 30 mL of water to the residue, extract with ethyl acetate (3 × 30 mL), wash the organic layer with saturated brine (30 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify the residue by column chromatography to give compound V. (95 mg, yield: 56.26%, m / z (ESI): 418 [M+H)) + )

[0372] Step D: To a solution of compound V (95 mg, 0.228 mmol, 1.0 eq) in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The mixture was concentrated to give the trifluoroacetate of compound VI (72 mg, m / z (ESI): 318 [M+H)). + ).

[0373] Step E: Compound III (54.45 mg, 0.171 mmol, 1.1 eq), N,N-diisopropylethylamine (30.23 mg, 0.234 mmol, 1.5 eq), and dichloromethane (20 mL) were added to a reaction flask, followed by compound VI (75 mg, 156 mmol, 1.0 eq). The mixture was stirred at room temperature for 6 hours. After complete conversion, the reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography to obtain compound VII. (80 mg, yield: 67.33%, m / z (ESI): 762.3 [M+H]) + )

[0374] Step F: Compound VII (80 mg, 0.127 mmol) was dissolved in MeOH (10 mL), palladium on carbon (30 mg) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was concentrated to dryness under vacuum to give compound VIII. (53 mg, yield: 91.89%, m / z (ESI): 628 [M+H)) + )

[0375] Step G: Compound VIII (53 mg, 84.43 μmol, 1.0 eq), N,N-diisopropylethylamine (43.65 mg, 337.72 μmol, 58.82 μL, 4.0 eq), and DMF (5 mL) were added to a reaction flask, followed by the addition of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (25.65 mg, 92.87 μmol, 1.1 eq). The mixture was heated to 80 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and 20 mL of water was added. The mixture was extracted with ethyl acetate (3 x 20 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 33 (3.8 mg, yield: 5.09%).

[0376] 1H NMR (400MHz, DMSO) δ1.20(d,J=6.4Hz,6H),1.30(s,2H),1.57–1.37(m,3H),1.70(d,J=13.7Hz,2H),2.00(dt,J=10.2,6.2Hz,3H ),2.14(d,J=6.8Hz,2H),2.43(d,J=4.8Hz,3H),2.64–2.53(m,2H),2.99–2.80(m,5H),3.51(s,1H),3.94(d,J=13.0Hz,2H),4.16 (p,J=6.7Hz,1H),4.30(t,J=4.4Hz,2H),5.02(dd,J=12.9,5.4Hz,1H),5.32(t,J=5.0Hz,1H),6.55(s,1H),7.26–7.09(m,3H),7. 45(s,1H),7.62(dd,J=15.2,8.5Hz,3H),7.45(s,1H),8.02(d,J=8.6Hz,1H),8.65(d,J=3.7Hz,1H),10.22(s,1H),10.98(s,1H).

[0377] m / z (ESI): 884.3 [M+H] +

[0378] Example 29: Synthesis of Compound 34

[0379]

[0380] Step A: Starting material I (500 mg, 1.24 mmol, 1.00 eq) and 1-Boc-4-aminopiperidine (273 mg, 1.36 mmol, 1.10 eq) were dissolved in 30 mL of 2-methyltetrahydrofuran. The mixture was stirred at 60 °C for 16 h. After stirring, the mixture was cooled to room temperature and 60 mL of ethyl acetate was added. The organic layer was washed with brine (3 x 40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give intermediate II (358 mg, yield: 65%), a grayish-white solid, m / z (ESI): 444.3 [M+H]. +

[0381] Step B: Intermediate II (300 mg, 0.68 mmol, 1.00 eq) and N-chlorosuccinimide (182 mg, 1.36 mmol, 2.00 eq) were dissolved in 2-methyltetrahydrofuran (20 mL) and stirred at 50 °C for 16 h. After stirring, the mixture was cooled to room temperature and 60 mL of ethyl acetate was added. The organic layer was washed with brine (3 x 40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give a grayish-white solid intermediate III (293 mg, yield: 90%, 478.3 [M+H]). + ).

[0382] Step C: Intermediate III (250 mg, 0.52 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent and excess trifluoroacetic acid were distilled off under vacuum to obtain a viscous oily trifluoroacetate salt of intermediate IV (250 mg, yield: quant., 377.2 [M+H]). + ).

[0383] Step D: The trifluoroacetate of intermediate IV (250 mg, 0.51 mmol, 1.00 eq) and triethylamine (0.23 mL, 1.53 mmol, 3.00 eq) were dissolved in 2-methyltetrahydrofuran (20 mL). After stirring at room temperature for 10 minutes, 4-chlorothioylpiperidine carboxylate butyl ester was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 40 mL of ethyl acetate was added to the reaction mixture. The organic layer was washed with brine (3 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid intermediate V (214 mg, yield: 67%, m / z (ESI): 625.4 [M+H)). + ).

[0384] Step E: Intermediate V (200 mg, 0.32 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent and excess trifluoroacetic acid were distilled off under vacuum to obtain a viscous oily trifluoroacetate salt of intermediate VI (250 mg, yield: quant., 377.2 [M+H]). + ).

[0385] Step F: The trifluoroacetate of intermediate VI (100 mg, 0.19 mmol, 1.00 eq) and intermediate II (95 mg, 0.23 mmol, 1.20 eq) were dissolved in methanol / dichloromethane (15 mL, v / v = 1:1). Sodium triacetoxyborohydride (403 mg, 1.9 mmol, 10.00 eq) was added in portions with stirring at room temperature for 24 h. After stirring, 20 mL of water was added, and the mixture was stirred for another 10 min. The mixture was then extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give compound 34 (15.7 mg, yield: 9.0%).

[0386] 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.64(s,1H),8.14(s,2H),7.72(d,J=11. 4Hz,1H),7.45(d,J=7.3Hz,1H),5.12(dd,J=12.8,5.4Hz,1H),3.69(s,3H),3.14 (t,J=31.6Hz,8H),2.89(t,J=9.4Hz,3H),2.77–2.56(m,2H),2.11–1.87(m,11H ),1.72(d,J=9.1Hz,4H),1.66–1.51(m,8H),1.27(m,6H).m / z(ESI):922.5[M+H] +

[0387] Example 30: Synthesis of Compound 35

[0388]

[0389] Step A: Starting material I (500 mg, 1.72 mmol, 1.00 eq) and ethyl difluorobromoacetate (1.05 g, 5.15 mmol, 3.0 eq) were dissolved in anhydrous 1,4-dioxane (30 mL). Then, palladium di(acetonitrile)chloride (22.3 mg, 0.086 mmol, 0.05 eq), Xantphos (55.5 mg, 0.096 mmol, 0.08 eq), and anhydrous potassium carbonate (832 mg, 6.02 mmol, 3.5 eq) were added. Under nitrogen protection, the reaction mixture was stirred at 110 °C for 24 hours. After stirring, the mixture was cooled to room temperature and 60 mL of ethyl acetate was added. The organic layer was washed with brine (3 x 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give intermediate II (426 mg, 1.03 mmol, yield: 61%), a grayish-white solid, m / z (ESI): 413.2 [M+H].+

[0390] Step B: Intermediate II (400 mg, 0.968 mmol, 1.0 eq) was dissolved in methanol (10 mL), then cooled to 0 °C, and potassium carbonate (1.34 g, 9.68 mmol, 10.0 eq) was added. The mixture was stirred for 2 hours. After the reaction was complete, the pH was adjusted to 2 with 1.0 M hydrochloric acid solution, and then 60 mL of ethyl acetate was added to the reaction mixture. The organic layer was washed with brine (3 x 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a grayish-white solid intermediate III (354 mg, 0.92 mmol, yield: 95%, 386.3 [M+H]). + ).

[0391] Step C: Intermediate III (300 mg, 0.778 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (8 mL), followed by the addition of potassium fluoride (453 mg, 7.78 mmol, 10.0 eq). The mixture was stirred at 110 °C for 1.5 hours under nitrogen protection. After the reaction was complete, 60 mL of ethyl acetate was added to the mixture. The organic layer was washed with brine (3 x 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give a grayish-white solid intermediate IV (172 mg, 0.506 mmol, yield: 65%, 342.2 [M+H]). + ).

[0392] Step D: Intermediate IV (172 mg, 0.506 mmol, 1.00 eq) was dissolved in a mixed solvent of 2-methyltetrahydrofuran and water (20 mL, v / v = 1:1). Oxone (2.49 g, 4.05 mmol, 8.00 eq) was added in portions over one hour with stirring at room temperature, and stirring continued for 3 hours. After the reaction was complete, 40 mL of ethyl acetate was added to the reaction mixture. The organic layer was washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the product purified by silica gel column chromatography to give a white solid intermediate V (126 mg, 0.339 mmol, yield: 67%, m / z (ESI): 374.1 [M+H)). + ).

[0393] Step E: Intermediate VI (2.0 g, 4.15 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL), and 4 M dioxane hydrochloride solution (10 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solid precipitate was collected by vacuum filtration. The filter cake was washed with dichloromethane (2 x 20 mL) and dried to obtain a white solid, which was the hydrochloride salt of intermediate VII (1.71 g, 4.11 mmol, yield: quant., 382.4 [M+H]). + ).

[0394] Step F: The hydrochloride salt of intermediate VII (400 mg, 0.957 mmol, 1.0 eq) and intermediate VIII (395 mg, 0.957 mmol, 1.0 eq) were dissolved in methanol (20 mL), and a catalyst amount of acetic acid was added. The mixture was stirred at room temperature for 1 hour. Subsequently, sodium cyanoborohydride (360 mg, 5.74 mmol, 6.00 eq) was added in portions with stirring, and stirring continued for 24 hours. After the extraction was complete, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a yellow solid as compound IX (290 mg, 0.373 mmol, yield: 39.0%, m / z (ESI): 779.5 [M+H)). + ).

[0395] Step G: Intermediate IX (200 mg, 0.257 mmol, 1.00 eq) was dissolved in trifluoroacetic acid (3 mL) and stirred at 40 °C for 14 hours. Afterward, excess trifluoroacetic acid was distilled off under vacuum to obtain a yellow solid, which was the trifluoroacetate salt of intermediate X (192 mg, 0.253 mmol, yield: quant., 646.5 [M+H]). + ).

[0396] Step H: The trifluoroacetate of intermediate X (60 mg, 0.079 mmol, 1.0 eq) and intermediate V (30 mg, 0.079 mmol, 1.0 eq) were dissolved in DMSO (2 mL). N,N-diisopropylethylamine (52 mg, 0.395 mmol, 5.0 eq) was added using a pipette, and the mixture was stirred at room temperature for 10 minutes, followed by stirring at 40 °C for 1 hour. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give compound 35 (11.8 mg, 12.6 μmol, yield: 16.0%). 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.79(d,J=19.5Hz,1H),8.24(d,J=7.3Hz,1H),8.11(d,J=3.2Hz,1H),7.72(d,J =11.4Hz,1H),7.45(s,1H),6.90(d,J=54.4Hz,1H),5.88(t,J=8.2Hz,1H),5.13(dd,J=12.8,5.4Hz,1H),4.42(d,J=21. 2Hz,1H),4.06–3.91(m,1H),3.69(q,J=12.6Hz,2H),3.16(m,7H),2.99–2.82(m,3H),2.75–2.57(m,3H),2.31–2.14(m ,1H),2.08–1.84(m,9H),1.83–1.48(m,13H),1.41(s,1H),1.26(s,1H),1.01(d,J=13.6Hz,3H).m / z(ESI):938.5[M+H] +

[0397] Example 31: Synthesis of Compound 36

[0398]

[0399] Step A: The hydrochloride salt of intermediate I (400 mg, 0.957 mmol, 1.0 eq) and 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylic acid (261 mg, 1.15 mmol, 1.2 eq) were dissolved in DMF (20 mL). HATU (548 mg, 1.44 mmol, 1.5 eq) and N,N-diisopropylethylamine (371 mg, 2.87 mmol, 3.0 eq) were added, and the mixture was stirred at room temperature for 1 hour. After stirring, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a white solid as the crude product of intermediate II (525 mg, 0.890 mmol, yield: 93.0%, m / z (ESI): 591.4 [M+H)). + ).

[0400] Step B: Intermediate II (525 mg, 0.890 mmol, 1.0 eq) was dissolved in dichloromethane (18 mL), and s-trifluoroacetic acid (2 mL) was added to the reaction solution. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the trifluoroacetic acid was removed by vacuum rotary evaporation to obtain a grayish-white solid, which was the trifluoroacetate salt of intermediate III (530 mg, 0.879 mmol, yield: quant., 491.3 [M+H]).+ ).

[0401] Step C: Dissolve the trifluoroacetate of intermediate III (530 mg, 0.879 mmol, 1.0 eq) and intermediate IV (476 mg, 1.23 mmol, 1.4 eq) in methanol (20 mL), add a catalyst amount of acetic acid, and stir at room temperature for 1 hour. Then, add sodium cyanoborohydride (442 mg, 7.03 mmol, 8.0 eq) in several portions while stirring, and continue stirring for 24 hours. After completion, add 30 mL of water, extract the mixture with dichloromethane (3 x 30 mL), combine the organic layers, wash with brine (3 x 30 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the product by silica gel column chromatography to give a yellow solid as intermediate V. (250 mg, 0.290 mmol, yield: 33.0%, m / z (ESI): 862.5 [M+H)) +

[0402] Step D: Intermediate V (250 mg, 0.290 mmol, 1.00 eq) was dissolved in trifluoroacetic acid (3 mL) and stirred at 40 °C for 16 hours. Afterward, excess trifluoroacetic acid was distilled off under reduced pressure to obtain a yellow solid, which was the trifluoroacetate of intermediate VI. (245 mg, 0.290 mmol, yield: quant., m / z (ESI): 728.4 [M+H)) + )

[0403] Step E: The trifluoroacetate of intermediate VI (70 mg, 0.083 mmol, 1.0 eq) and intermediate VII (27 mg, 0.083 mmol, 1.0 eq) were dissolved in DMSO (2 mL). N,N-diisopropylethylamine (54 mg, 0.415 mmol, 5.0 eq) was added by pipette, and the mixture was stirred at room temperature for 10 minutes, followed by stirring at 40 °C for 1.5 hours. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give compound 36 (11 mg, 11.3 μmol, yield: 13.6%). 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.59(s,1H),8.28(s,1H),7.89(d,J=6.9Hz,1H),7.69(dd,J=10.3,6.7Hz,2H),7.44(d,J=7. 3Hz,1H),6.20(d,J=9.3Hz,1H),5.85(m,1H),5.10(dd,J=12.8,5.4Hz,1H),4.41(d,J=12.0Hz,1H),4.15(d,J=12.1Hz,1H),3.92(s ,1H),3.70–3.55(dd,J=27.5,12.1Hz,6H),3.14–2.99(m,5H),2.95–2.80(m,4H),2.70–2.54(m,2H),2.46–2.33(m,4H),2.28–2.11 (m,4H),1.88(dd,J=43.3,11.2Hz,8H),1.71–1.50(m,4H),1.47–1.34(m,4H),1.33–1.19(m,4H),0.98(s,3H).(ESI): 971.5[M+H]+.

[0404] Example 32: Synthesis of Compound 37

[0405]

[0406] Step A: The hydrochloride salt of intermediate I (400 mg, 0.957 mmol, 1.0 eq) and 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (204 mg, 0.957 mmol, 1.0 eq) were dissolved in methanol (20 mL), and a catalyst amount of acetic acid was added. The mixture was stirred at room temperature for 1 hour. Subsequently, sodium cyanoborohydride (360 mg, 5.74 mmol, 6.00 eq) was added in several portions with stirring, and stirring was continued for 24 hours. After the extraction was completed, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a grayish-white solid as the crude product of intermediate II (404 mg, 0.699 mmol, yield: 73.0%, m / z (ESI): 579.5 [M+H)). + ).

[0407] Step B: Intermediate II (404 mg, 0.699 mmol, 1.0 eq) was dissolved in dichloromethane (80 mL), and 4 M dioxane hydrochloride solution (2 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solid precipitate was collected by vacuum filtration. The filter cake was washed with dichloromethane (3 x 10 mL) and dried to obtain a white solid, which was the hydrochloride salt of intermediate III (350 mg, 0.680 mmol, yield: quant., 479.4 [M+H)). + ).

[0408] Step C: The hydrochloride salt of intermediate III (350 mg, 0.680 mmol, 1.0 eq) and 1-tert-butoxycarbonyl-3-azacyclobutanone (233 mg, 1.36 mmol, 2.0 eq) were dissolved in methanol (20 mL), and a catalyst amount of acetic acid was added. The mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (427 mg, 6.80 mmol, 10.0 eq) was added in portions with stirring, and the mixture was stirred for another 24 hours. After the extraction was complete, 30 mL of water was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid as intermediate IV. (185 mg, 0.292 mmol, yield: 43.0%, m / z (ESI): 634.5 [M+H]) + )

[0409] Step D: Intermediate IV (185 mg, 0.292 mmol, 1.0 eq) was dissolved in dichloromethane (9 mL), and s-trifluoroacetic acid (1 mL) was added to the reaction solution. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the trifluoroacetic acid was removed by vacuum rotary evaporation to obtain a grayish-white solid, which was the trifluoroacetate salt of intermediate V (188 mg, 0.290 mmol, yield: quant., 534.5 [M+H)). + ).

[0410] Step E: The trifluoroacetate of intermediate V (188 mg, 0.290 mmol, 1.0 eq) and 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (171 mg, 0.580 mmol, 1.1 eq) were dissolved in dimethyl sulfoxide (10 mL). N,N-diisopropylethylamine (94 mg, 0.725 mmol, 2.5 eq) was added to the reaction mixture, and the mixture was stirred at 60 °C for 6 hours. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give a white solid as intermediate VI. (175 mg, 0.212 mmol, Yield: 75.0%, m / z (ESI): 808.5 [M+H)) + )

[0411] Step F: Intermediate VI (175 mg, 0.212 mmol, 1.00 eq) was dissolved in trifluoroacetic acid (3 mL) and stirred at 40 °C for 14 hours. Afterward, excess trifluoroacetic acid was distilled off under vacuum to obtain a yellow solid, which was the trifluoroacetate of intermediate VII. (164 mg, 0.21 mmol, yield: quant., 674.4 [M+H]) + )

[0412] Step G: The trifluoroacetate of intermediate VII (65 mg, 0.083 mmol, 1.0 eq) and intermediate V (31 mg, 0.083 mmol, 1.0 eq) were dissolved in DMSO (2 mL). N,N-diisopropylethylamine (54 mg, 0.415 mmol, 5.0 eq) was added using a pipette, and the mixture was stirred at room temperature for 10 minutes, followed by stirring at 40 °C for 1 hour. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography to give compound 37 (21 mg, 21.7 μmol, yield: 26.0%). 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.78(m,1H),8.25(d,J=7.3Hz,1H),8.10(s,1H),7.62(d,J=11.1Hz,1 H),7.01–6.90(t,d,J=55.6,7.1Hz,2H),5.85(d,J=9.2Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.44(m,1H),4 .23(s,2H),3.95(m,3H),3.65(m,2H),3.24(t,J=6.2Hz,1H),3.11–2.98(m,3H),2.92–2.79(m,5H),2.69–2. 55(m,3H),2.24–2.07(m,3H),2.06–1.74(m,12H),1.73–1.42(m,8H),1.31–1.21(m,1H),1.16–0.90(m,4H).

[0413] m / z (ESI): 967.5 [M+H] + )

[0414] Example 33: Synthesis of Compound 38

[0415]

[0416] Step A: DIEA (1.75 g, 13.54 mmol, 2.36 mL, 3 eq) was added to a dichloromethane (20 mL) solution of intermediate 1 (1.0 g, 4.51 mmol, 1 eq) and intermediate 2 (1.12 g, 4.51 mmol, 1 eq) at room temperature. The mixture was reacted at room temperature for 3 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was diluted with dichloromethane (50 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate 3 (1.6 g, 3.69 mmol, 81.80% yield) as a white solid. m / z (ESI): 522.3 [M+H] + .

[0417] Step B: Hydrochloric acid gas (10 mL, 4 M, 40 mmol, 10.8 eq) was added dropwise to a dichloromethane solution of intermediate 3 (1.6 g, 3.69 mmol, 1 eq) under ice bath conditions. The reaction mixture was allowed to react at room temperature for 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was evaporated to dryness to give intermediate 4 (1 g, 2.70 mmol, 73.26% yield) as a white solid. m / z (ESI): 422.4 [M+H] + .

[0418] Step C: At room temperature, DIEA (323.26 mg, 2.50 mmol, 435.67 μL, 5 eq) was added to a solution of intermediate 4 (185.00 mg, 500.24 μmol, 1 eq) and 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (147.18 mg, 500.24 μmol, 1 eq) in dimethyl sulfoxide (6 mL). The mixture was reacted at 130 °C for 2 hours. The reaction was monitored to be complete by TLC, and the target compound was obtained by LC-MS. The mixture was diluted with dichloromethane (20 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate 5 (200 mg, 329.18 μmol, 65.80% yield). The product was a yellow solid. m / z (ESI): 678.6 [M+H] + .

[0419] Step D: Ammonium chloride (44.02 mg, 822.96 μmol, 5 eq) was added to a solution of intermediate 5 (100 mg, 164.59 μmol, 1 eq) and iron powder (45.96 mg, 822.96 μmol, 5 eq) in H₂O (0.2 mL) and EtOH (2 mL). The mixture was stirred at 70 °C for 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound. The reaction solution was filtered, and the filter cake was washed twice with ethyl acetate. The filtrate was evaporated to dryness to give intermediate 6 (70 mg, 121.20 μmol, 73.63% yield) as a yellow solid. m / z (ESI): 648.7 [M+H] + .

[0420] Step E: Under nitrogen protection, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (14.03 mg, 24.24 μmol, 0.20 eq) and tris(dibenzylideneacetone)palladium (11.10 mg, 12.12 μmol, 0.1 eq) were added to intermediate 6 (70 mg, 121.20 μmol, 1 eq) and intermediate 7 (39.11 mg, 121.20 μmol, 1 eq) and cesium carbonate (118.46 mg, 363.59 μmol, 3.0 eq) in a 1,4-dioxane (4 mL) solution. The mixture was stirred at 110 °C for 18 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative HPLC to give compound 38 (1.6 mg, yield: 5%). m / z (ESI): 934.6 [M+H] + .

[0421] Example 34: Synthesis of Compound 39

[0422]

[0423] Step A: Accurately weigh starter 1 (1.0 eq, 3 mmol, 660 mg) and starter 2 (1.0 eq, 3.0 mmol, 750 mg) and dissolve them completely in anhydrous DCM. Slowly add DIEA (5.0 eq, 15 mmol, 1.93 g) dropwise to the reaction system. React the system under ice-water bath conditions, then slowly raise the temperature to room temperature. After the reaction is complete as monitored by TLC, extract the reaction system directly with saturated brine (30 mL * 3) to obtain the organic phase. Dry the organic phase directly to obtain crude intermediate 3 (1.2 g, 91% yield). Proceed directly to the next step of the reaction without purification by silica gel column chromatography. m / z (ESI): 440.2 [M+H]+.

[0424] Step B: At room temperature, accurately weigh intermediate 3 (58 mg, 0.1 mmol) and dissolve it in 5 mL of DCM solution. Add TFA (50 mg, 0.4 mmol, 4 eq) to the reaction system and stir slowly for about 2 hours. After the reaction is complete, evaporate the solvent directly to obtain the crude product intermediate 4, a pale yellow solid. The crude product was not purified by silica gel column chromatography and proceeded directly to the next step of the reaction. m / z (ESI): 340.4 [M+H] + .

[0425] Step C: At room temperature, accurately weigh intermediate 4 (340 mg, 1.0 mmol, 1.0 eq) and intermediate 5 (1.1 eq, 0.11 mmol, 370 mg), dissolve the reaction mixture in DMF (20 mL), and completely purge the reaction system under nitrogen protection. Accurately weigh HATU (0.15 mmol, 1.5 eq, 570 mg) and DIEA (0.2 mmol, 2.0 eq, 290 mg) and add them to the reaction system. Stir the reaction overnight at room temperature. Monitor the reaction to ensure complete reaction by TLC. Dilute the mixture with EtOAc (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate 6 (528 mg, 81% yield) as a yellow solid. m / z (ESI): 654.6 [M+H] + .

[0426] Step D: Accurately weigh intermediate 6 (1.0 eq, 0.22 mmol, 150 mg) and dissolve it in a mixed solution of EtOH (10 mL) and H2O (volume ratio 10:1). Add Fe powder (62 mg, 1.1 mmol, 5.0 eq) and NH4Cl (65 mg, 1.1 mmol, 5.0 eq) sequentially. Stir the reaction mixture in an oil bath at 100 °C for 2 hours. TLC showed that the reaction was complete. Filter the reaction mixture with diatomaceous earth, evaporate the organic phase to dryness, dilute with DCM (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate 7 (105 mg, 86% yield), which is a yellow oil. m / z (ESI): 624.2 [M+H] + .

[0427] Step E: At room temperature, accurately weigh intermediate 7 (80 mg, 0.12 mmol, 1.0 eq), intermediate 8 (1.1 eq, 0.13 mmol, 42 mg), the metal catalyst Pd2(dba)3 (0.1 eq, 0.012 mmol, 11 mg), and Cs2CO3 (0.25 mmol, 2.0 eq, 82 mg), and the organophosphorus ligand Xantphos (0.2 eq, 0.025 mmol, 15 mg). Dissolve the reaction mixture in Dioxane (20 mL). The reaction system was fully purged with nitrogen for protection, and then stirred in an oil bath at 110°C for 12 hours. TLC showed that the reaction was complete. The mixture was diluted with EtOAc (10 mL) and washed successively with H2O (10 mL x 3) and saturated NaHCO3 (10 mL x 3). The organic matter was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain the target compound 39 (14 mg, 2% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),10.39(s,1H),8.77(d,J=3.7Hz,1H),8.26(d,J=1.3Hz,1H),8. 07(d,J=8.8Hz,2H),7.76(dd,J=8.6,7.3Hz,1H),7.72–7.64(m,3H),7.44(d,J=7.3Hz,1H),7.28(d,J= 8.7Hz,1H),5.11(d,J=12.8Hz,3H),4.88(d,J=6.9Hz,1H),3.53(s,2H),3.07–2.93(m,3H),2.89(q,J =8.2,6.4Hz,4H),2.67(s,4H),2.13–1.93(m,1H),1.64(d,J=6.9Hz,5H),1.58(d,J=6.2Hz,4H),1.45–

[0428] 1.33(m,3H),1.26(d,J=6.9Hz,3H).m / z(ESI): 910.6[M+H] + .

[0429] Example 35: Synthesis of Compound 40

[0430]

[0431] Step A: Accurately weigh intermediate 1 (254 mg, 1.0 mmol, 1.0 eq) and dissolve it in DMF (10 mL) solution. Add intermediate 2 (276 mg, 1.0 mmol, 1.0 eq) to the reaction system. Heat the reaction mixture in an oil bath at 110 °C and stir for 3 hours. TLC showed that the reaction was complete. Extract the organic phase directly using EA to obtain the product. Concentrate the reaction solution to obtain a colorless oily crude product. Purify the product intermediate 3 by silica gel column chromatography. m / z (ESI): 511.2 [M+H] + .

[0432] Step B: At room temperature, add 2 mL of TFA to a 10 mL solution of intermediate 3 (260 mg, 0.5 mmol, 1.0 eq) in DCM. Stir the reaction mixture at room temperature for 3 hours. TLC showed the reaction was complete. Concentrate the reaction solution to obtain crude intermediate 4, a colorless oil. The crude product was used directly in the next step without purification. m / z (ESI): 411.1 [M+H] + .

[0433] Step C: At room temperature, accurately weigh intermediate 4 (205 mg, 0.5 mmol, 1.0 eq) and intermediate 5 (1.1 eq, 0.55 mmol, 115 mg), dissolve the reaction mixture in DMF (20 mL), and completely purge the reaction system under nitrogen protection. Accurately weigh HATU (0.9 mmol, 1.5 eq, 340 mg) and DIEA (0.9 mmol, 2.0 eq, 117 mg) and add them to the reaction system. Stir the reaction overnight at room temperature. Monitor the reaction to ensure complete reaction by TLC. Dilute the mixture with EtOAc (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate 6 (272 mg, 71% yield) as a yellow solid. m / z (ESI): 594.1 [M+H] + .

[0434] Step D: At room temperature, TFA (3.07 g, 26.92 mmol, 2 mL) was added to a DCM (10 mL) solution of intermediate 6 (200 mg, 0.4 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain crude intermediate 7 (160 mg, 62% yield) as a colorless oil. The crude product was used directly in the next step without purification. m / z (ESI): 494.2 [M+H] + .

[0435] Step E: Accurately weigh intermediate 7 (1.0 eq, 1.0 mmol, 494 mg) and intermediate 8 (1.0 eq, 1.0 mmol, 220 mg) and dissolve them completely in anhydrous DCM. Slowly add DIEA (5.0 eq, 5 mmol, 650 mg) to the reaction system. React the system under ice-water bath conditions, then slowly raise the temperature to room temperature. After the reaction is complete as monitored by TLC, extract the reaction system directly with saturated brine (30 mL * 3) to obtain the organic phase. Dry the organic phase by rotary evaporation to obtain the crude product intermediate 9. Proceed directly to the next reaction without silica gel column chromatography purification. m / z (ESI): 679.2 [M+H] + .

[0436] Step F: Ammonium chloride (44.02 mg, 822.96 μmol, 5 eq) was added to a solution of intermediate 9 (100 mg, 164.59 μmol, 1 eq) and iron powder (45.96 mg, 822.96 μmol, 5 eq) in H₂O (0.2 mL) and EtOH (2 mL). The mixture was stirred at 70 °C for 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound. The reaction solution was filtered, and the filter cake was washed twice with ethyl acetate. The filtrate was evaporated to dryness to give intermediate 10 (70 mg, 121.20 μmol, 73.63% yield) as a yellow solid. m / z (ESI): 649.7 [M+H] + .

[0437] Step G: At room temperature, accurately weigh intermediate 10 (80 mg, 0.12 mmol, 1.0 eq), intermediate 11 (1.1 eq, 0.13 mmol, 42 mg), metal catalyst Pd2(dba)3 (0.1 eq, 0.012 mmol, 11 mg), Cs2CO3 (0.25 mmol, 2.0 eq, 82 mg), organophosphorus ligand Xantphos (0.2 eq, 0.025 mmol, 15 mg), and dissolve the reaction mixture in Dioxane (20 mL). The reaction system was heated in an oil bath at 110°C for 12 hours under nitrogen protection. TLC showed complete reaction. The mixture was diluted with 10 mL of EtOAc and washed successively with 10 mL x 3 H₂O and 10 mL x 3 saturated NaHCO₃. The organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO₂, petroleum ether: ethyl acetate = 0-100%) to give target compound 40 (14 mg, 2% yield) as a yellow solid. m / z (ESI): 936.7 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.42(s,1H),8.77(d,J=3.7Hz,1H),8.25(s,1H),8.11(d,J=8.7Hz,2H),7.75 (d,J=8.6Hz,2H),7.71–7.61(m,2H),7.31(dd,J=7.8,4.7Hz,2H),5.08(dd,J=12.7,5.5Hz,1H),4.86(dd,J=13.5,6.5 Hz,1H),3.88(t,J=8.2Hz,2H),3.76(t,J=7.2Hz,2H),3.53(t,J=7.9Hz,1H),3.21(d,J=6.7Hz,3H),3.15(s,2H),2.9 3–2.79(m,2H),2.65(s,4H),2.12–1.89(m,3H),1.63(d,J=6.8Hz,6H),1.58(t,J=4.8Hz,5H),1.36(d,J=18.6Hz,4H).

[0438] Example 36: Synthesis of Compound 41

[0439]

[0440] Step A: Accurately weigh starter 1 (1.0 eq, 3 mmol, 660 mg) and starter 2 (1.0 eq, 3.0 mmol, 750 mg) and dissolve them completely in anhydrous DCM. Slowly add DIEA (5.0 eq, 15 mmol, 1.93 g) dropwise to the reaction system. React the system under ice-water bath conditions, then slowly raise the temperature to room temperature. After the reaction is complete as monitored by TLC, extract the reaction system directly with saturated brine (30 mL * 3) to obtain the organic phase. Dry the organic phase directly to obtain crude intermediate 3 (1.2 g, 91% yield). Proceed directly to the next step of the reaction without purification by silica gel column chromatography. m / z (ESI): 440.2 [M+H]+.

[0441] Step B: At room temperature, accurately weigh intermediate 3 (580 mg, 0.1 mmol) and dissolve it in 5 mL of DCM solution. Add TFA (2.0 mL) to the reaction system and stir slowly for about 2 hours. After the reaction is complete, evaporate the solvent to dryness to obtain crude intermediate 4, a pale yellow solid. The crude product was not purified by silica gel column chromatography and proceeded directly to the next reaction. m / z (ESI): 340.4 [M+H] + .

[0442] Step C: At room temperature, accurately weigh intermediate 4 (200 mg, 0.6 mmol, 1.0 eq) and intermediate 5 (1.1 eq, 0.66 mmol, 215 mg), dissolve the reaction mixture in DMF (20 mL), and completely purge the reaction system under nitrogen protection. Accurately weigh HATU (0.9 mmol, 1.5 eq, 340 mg) and DIEA (0.9 mmol, 2.0 eq, 117 mg) and add them to the reaction system. Stir the reaction overnight at room temperature. Monitor the reaction for completeness by TLC. Dilute the mixture with EtOAc (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and pass the residue by silica gel column chromatography (SiO2, petroleum ether:

[0443] Purified with ethyl acetate (0-100%), intermediate 6 (272 mg, 71% yield) was given as a yellow solid. m / z (ESI): 639.1 [M+H] + .

[0444] Step D: Accurately weigh intermediate 6 (1.0 eq, 0.33 mmol, 210 mg) at room temperature and dissolve it in a mixed solution of EtOH (10 mL) and water (volume ratio 10:1). Add Fe powder (93 mg, 1.65 mmol, 5.0 eq) and NH4Cl (95 mg, 1.65 mmol, 5.0 eq) sequentially. Stir the reaction mixture in an oil bath at 100 °C for 2 hours. TLC showed that the reaction was complete. Filter the reaction mixture with diatomaceous earth, evaporate the organic phase to dryness, dilute with DCM (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate 7 (395 mg, 86% yield), which is a yellow oil. m / z (ESI): 609.2 [M+H] + .

[0445] Step E: At room temperature, accurately weigh intermediate 7 (61 mg, 0.1 mmol, 1.0 eq), intermediate 8 (1.1 eq, 0.1 mmol, 35 mg), metal catalyst Pd2(dba)3 (0.1 eq, 0.01 mmol, 9.1 mg), Cs2CO3 (0.2 mmol, 2.0 eq, 65 mg), and ligand Xantphos (0.2 eq, 0.02 mmol, 12 mg). Dissolve the reaction mixture in Dioxane (20 mL), and completely purge the reaction system under nitrogen protection. Heat the reaction system in an oil bath at 110 °C and stir for 12 hours. TLC showed complete reaction. Dilute the mixture with EtOAc (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and pass the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-10). Purification was performed to obtain target compound 41 (9.6 mg, 1.5% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.38(s,1H),8.77(d,J=3.7Hz,1H),8.27(d,J=1.3Hz,1H),8.08(d,J=8.8Hz,2H),7.72 (d,J=4.2Hz,1H),7.69(d,J=1.7Hz,2H),7.28(t,J=7.7Hz,1H),6.98(d,J=7.4Hz,1H),6.74(d,J=8.1Hz,1H),5.11(dd,J=13.2 ,5.1Hz,1H),4.88(p,J=7.0Hz,1H),4.46–4.06(m,2H),3.98(d,J=5.2Hz,2H),3.40(s,5H),3.04–2.80(m,6H),2.67(s,3H),2. 37(d,J=18.0Hz,1H),2.12–1.96(m,1H),1.64(d,J=6.9Hz,6H),1.57(s,4H),1.35(s,2H),1.26(s,2H).m / z(ESI): 896.6[M+H] + .

[0446] Example 37: Synthesis of Compound 42

[0447]

[0448] Step A: Accurately weigh starter 1 (1.0 eq, 3 mmol, 660 mg) and starter 2 (1.0 eq, 3.0 mmol, 750 mg) and dissolve them completely in anhydrous DCM. Slowly add DIEA (5.0 eq, 15 mmol, 1.93 g) dropwise to the reaction system. React the system under ice-water bath conditions, then slowly raise the temperature to room temperature. After the reaction is complete as monitored by TLC, extract the reaction system directly with saturated brine (30 mL * 3) to obtain the organic phase. Dry the organic phase directly to obtain crude intermediate 3 (1.2 g, 91% yield). Proceed directly to the next step of the reaction without purification by silica gel column chromatography. m / z (ESI): 440.2 [M+H]+.

[0449] Step B: Accurately weigh intermediate 3 (1.0 eq, 2.0 mmol, 880 mg) at room temperature and dissolve it in a mixed solution of EtOH (10 mL) and water (volume ratio 10:1). Add Fe powder (300 mg, 5 mmol, 2.5 eq) and NH4Cl (300 mg, 5 mmol, 2.5 eq) sequentially. Stir the reaction mixture in an oil bath at 100 °C for 2 hours. TLC showed that the reaction was complete. Filter the reaction mixture with diatomaceous earth, evaporate the organic phase to dryness, dilute with DCM (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate 4 (395 mg, 86% yield), which is a yellow oil. m / z (ESI): 410.2 [M+H] + .

[0450] Step C: Accurately weigh intermediate 4 (1.0 eq, 0.5 mmol, 205 mg) at room temperature and dissolve it in ethyl formate solution (10 mL). Under nitrogen protection, slowly add LiHMDS (6.0 eq, 3.0 mmol) dropwise at 0 °C. After the addition is complete, continue stirring at 0 °C for about 10 mins. Continue adding methyl formate (1.0 eq, 0.5 mmol, 30 mg) dropwise to the reaction system and continue the reaction for about 2 hours. After the reaction is complete, detect the reaction product by TLC. Quench the reaction with saturated brine. Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate 5 (180 mg, 82% yield), which is a yellow oil. m / z (ESI): 438.2 [M+H] + .

[0451] Step D: Accurately weigh intermediate 5 (180 mg, 1.0 eq, 0.4 mmol), place the reaction system in a round-bottom flask, add intermediate 6 (130 mg, 1.0 eq, 0.4 mmol), DMSO solution, and DIEPA (2.0 eq, 0.8 mmol) to the reaction system. Stir the reaction mixture in an oil bath for 3 hours. TLC showed that the reaction was complete. Dissolve the reaction system in EtOAc for extraction to obtain the organic phase. After evaporation to dryness, directly purify the organic phase by silica gel column chromatography to obtain intermediate 7 (242 mg, 78% yield). m / z (ESI): 653.7 [M+H] + .

[0452] Step E: At room temperature, TFA (3.07 g, 26.92 mmol, 2 mL) was added to a DCM (10 mL) solution of intermediate 7 (340 mg, 0.5 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain crude intermediate 8 (168 mg, 60% yield) as a colorless oil. The crude product was used directly in the next step without purification. m / z (ESI): 553.1 [M+H] + .

[0453]

[0454] Step F: At room temperature, accurately weigh intermediate 8 (56 mg, 0.1 mmol, 1.0 eq) and intermediate 9 (1.1 eq, 0.1 mmol, 32 mg), dissolve the reaction mixture in DMF (20 mL), and completely purge the reaction system under nitrogen protection. Accurately weigh HATU (0.15 mmol, 1.5 eq, 58 mg) and DIEA (0.2 mmol, 2.0 eq, 29 mg) and add them to the reaction system. Stir the reaction overnight at room temperature. Monitor the reaction to ensure complete reaction by TLC. Dilute the mixture with EtOAc (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and purify the residue by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain product 42 (5.6 mg, 7.5% yield), as a yellow solid. m / z (ESI): 852.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.54(s,1H),8.91(s,1H),8.00(d,J=8.6Hz,2H),7.73(d,J=8.5Hz ,2H),7.27(t,J=7.6Hz,1H),6.97(d,J=7.5Hz,1H),6.73(d,J=8.1Hz,1H),6.49(d,J=9.3Hz,1H),4.43–4.0 9(m,2H),3.97(s,2H),3.39(s,6H),2.97(s,2H),2.87(d,J=5.7Hz,4H),2.74–2.56(m,2H),2.36(d,J=19. 3Hz,2H),1.99(s,4H),1.80–1.64(m,1H),1.55(d,J=6.2Hz,4H),1.43–1.28(m,3H),1.23(d,J=8.5Hz,6H).

[0455] Example 38: Synthesis of Compound 43

[0456]

[0457] Step F: At room temperature, accurately weigh intermediate 8 (80 mg, 0.14 mmol, 1.0 eq) and intermediate 10 (1.1 eq, 0.15 mmol, 49 mg), dissolve the reaction mixture in DMF (20 mL), and completely purge the reaction system under nitrogen protection. Accurately weigh HATU (0.21 mmol, 1.5 eq, 79 mg) and DIEA (0.28 mmol, 2.0 eq, 36 mg) and add them to the reaction system. Stir the reaction overnight at room temperature. Monitor the reaction for completeness by TLC. Dilute the mixture with EtOAc (10 mL) and wash successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). Dry the organic matter with anhydrous Na2SO4, filter, concentrate under vacuum, and pass the residue by silica gel column chromatography (SiO2, petroleum ether:

[0458] Purified with ethyl acetate (0-100%), the product compound 43 (8.6 mg, 10.2% yield) was given as a yellow solid. m / z (ESI): 866.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.55(s,1H),8.92(s,1H),8.02(d,J=8.5Hz,2H),7.92(d,J= 9.3Hz,1H),7.74(d,J=8.4Hz,2H),7.60(t,J=7.8Hz,1H),7.17–6.98(m,1H),6.50(d,J=9.3Hz,1H),5 .06(dd,J=12.9,5.4Hz,1H),4.84(s,1H),4.12(d,J=4.4Hz,2H),3.01(s,7H),2.74–2.55(m,4H),2.0 2(d,J=12.2Hz,3H),1.70(dd,J=16.1,7.8Hz,4H),1.56(s,4H),1.31(d,J=36.2Hz,5H),1.23(s,3H).

[0459] Example 39: Synthesis of Compound 44

[0460]

[0461] Step A: Accurately weigh intermediate 1 (575 mg, 1.0 eq, 5.0 mmol), place the reaction system in a round-bottom flask, add intermediate 2 (1.38 g, 1.0 eq, 5.0 mmol), DMSO solution, and DIEPA (2.0 eq, 10.0 mmol, 1.29 g) to the reaction system. Stir the reaction mixture in an oil bath for 3 hours. TLC showed that the reaction was complete. Dissolve the reaction system in EtOAc for extraction to obtain the organic phase. After evaporation to dryness, directly purify the organic phase by silica gel column chromatography to obtain intermediate 3 (1.46 g, 78% yield). m / z (ESI): 372.7 [M+H] + .

[0462] Step B: Accurately weigh intermediate 3 (370 mg, 1.0 mmol, 1.0 eq) and dissolve it in DCM (15 mL). Add MCPBA (225 mg, 1.3 mmol, 1.3 eq) to the reaction system. Stir the reaction system at room temperature for about 1 hour. Detect the formation of the reaction product by TLC. After the reaction is complete, monitor the reaction system by LC-MS to obtain the target compound. Quench the reaction system with ice water, evaporate the organic solvent, and extract the reaction system using EA (20 mL × 3). Purify the organic phase by silica gel column chromatography to obtain intermediate 4 (12 mg, 13% yield), m / z (ESI): 370.2 [M + H]. + .

[0463] Step C: Accurately weigh intermediate 5 (48 mg, 0.1 mmol, 1.0 eq) and dissolve it in MeOH (5 mL). Add intermediate 4 (37 mg, 0.1 mmol, 1.05 eq) to the reaction system, add 1 drop of catalytic amount of acetic acid to the reaction system, and heat the reaction system to 40 °C. Stir the reaction system at this temperature for about 1 hour, and continue to add NaBH3CN (30 mg, 4.0 eq) to the reaction system. Place the reaction system in an oil bath and stir for about 12 hours. After the reaction is completed, monitor the reaction system with LC-MS to obtain the target compound. Quench the reaction system with ice water, evaporate the organic solvent, and extract the reaction system with EA (20 mL × 3). Purify the organic phase with preparative HPLC to obtain product 44 (8.5 mg, 10% yield). 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.65(s,1H),8.93(s,1H),8.32(s,2H),8.05(d,J=8.5Hz,2H),7.93(d,J=9.4Hz,1H) ,7.80(d,J=8.4Hz,2H),7.67(t,J=7.6Hz,1H),7.39–7.22(m,2H),6.49(d,J=9.3Hz,1H),5.08(dd,J=12.8,5.7Hz,1H),3.15( t,J=8.4Hz,1H),2.88(dd,J=21.9,11.9Hz,5H),2.59(d,J=18.4Hz,1H),2.15(d,J=7.0Hz,2H),2.00(dt,J=10.6,5.9Hz,3H) ,1.92–1.78(m,3H),1.77–1.59(m,4H),1.51(td,J=13.7,9.7Hz,3H),1.43–1.31(m,4H),1.24(s,7H).m / z(ESI): 837.2[M+H] + .

[0464] Example 40: Synthesis of Compound 45

[0465]

[0466] Step A: At room temperature, TFA (1.14 g, 2.0 eq) was added to a DCM (15 mL) solution of intermediate 1 (1.195 g, 5.0 mmol, 1 eq). The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until it was complete. The target compound was obtained by LC-MS. The crude product was concentrated and the solvent was directly evaporated to obtain intermediate 2 (542 mg, 78% yield), which was a pale yellow liquid.

[0467] Step B: Intermediate 3 (590 mg, 2.0 mmol, 1.0 eq) was added to a 10 mL solution of intermediate 2 (280 mg, 2.0 mmol, 1.0 eq) in DMF at room temperature. The reaction mixture was heated in an oil bath at 110 °C and stirred for 3 hours. TLC showed that the reaction was complete. The organic phase was directly extracted with EA to obtain the product. The reaction solution was concentrated to obtain a colorless oily crude product, which was purified by silica gel column chromatography to obtain intermediate 4. m / z (ESI): 414.2 [M+H] + .

[0468]

[0469] Step C: At room temperature, accurately weigh intermediate 5 (58 mg, 0.1 mmol) and dissolve it in 5 mL of DCM solution. Add TFA (50 mg, 0.4 mmol, 4 eq) to the reaction system and stir slowly for about 10 mins. After the reaction is complete, evaporate the solvent directly to obtain the crude product intermediate 6, a pale yellow solid. The crude product was not purified by silica gel column chromatography and proceeded directly to the next reaction. m / z (ESI): 484.4 [M+H] + .

[0470] Step D: Accurately weigh intermediate 6 (48 mg, 0.1 mmol, 1.0 eq) and dissolve it in MeOH (5 mL). Add intermediate 4 (41 mg, 1.0 mmol, 1.05 eq) to the reaction system, add 1 drop of catalytic amount of acetic acid, and heat the reaction system to 40 °C. Stir the reaction system at this temperature for about 1 hour, then add NaBH3CN (120 mg, 2 mmol). Place the reaction system in an oil bath and stir for about 12 hours. After the reaction is complete, monitor the reaction system by LC-MS to obtain the target compound. Quench the reaction system with ice water, evaporate the organic solvent, and extract the reaction system using EA (20 mL × 3). Purify the organic phase using preparative HPLC to obtain the product (12 mg, 13% yield), m / z (ESI): 881.3 [M+H]. + . 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.61(s,1H),8.94(s,1H),8.06(d,J=8.6Hz,2H),7.82( d,J=8.5Hz,2H),7.59(d,J=11.2Hz,1H),7.20(s,4H),6.88(d,J=7.6Hz,1H),6.52(d,J=9.3Hz,1 H),5.07(dd,J=12.8,5.5Hz,2H),3.90(s,4H),3.83(s,4H),2.99–2.81(m,3H),2.73–2.57(m,3 H),2.02(d,J=7.5Hz,4H),1.90(s,4H),1.79–1.59(m,3H),1.47(d,J=12.3Hz,4H),1.26(s,3H).

[0471] Example 41: Synthesis of Compound 46

[0472]

[0473] Step A: At room temperature, intermediate 2 (860 mg, 3.6 mmol, 1.2 eq) and NaBH3CN (4.5 mmol, 1.5 eq) were added sequentially to a MeOH (10 mL) solution of intermediate 1 (810 mg, 3.0 mmol, 1.0 eq). The reaction mixture was stirred in an oil bath at 40 °C for 12 hours. TLC showed that the reaction was complete. The mixture was diluted with DCM (10 mL) and washed sequentially with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate 3 (840 mg, 57% yield), which was a yellow oil. m / z (ESI): 494.4 [M+H] + .

[0474] Step B: At room temperature, Fe powder (300 mg, 5 mmol, 5 eq) and NH4Cl (300 mg, 5 mmol, 5 eq) were added sequentially to a mixed solution of intermediate 3 (493 mg, 1.0 mmol, 1.0 eq) of EtOH (10 mL) and water (volume ratio 10:1). The reaction mixture was stirred in an oil bath at 100 °C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was filtered through diatomaceous earth, the organic phase was evaporated to dryness, diluted with DCM (10 mL), and washed sequentially with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate 4 (395 mg, 86% yield), a yellow oil. m / z (ESI): 464.2 [M+H] + .

[0475] Step C: At room temperature, accurately weigh intermediate 4 (300 mg, 0.65 mmol, 1.0 eq), intermediate 5 (1.1 eq, 0.7 mmol, 225 mg), metal catalyst Pd2(dba)3 (0.1 eq, 0.065 mmol, 59 mg), Cs2CO3 (1.5 mmol, 2.0 eq, 490 mg), and ligand Xantphos (0.2 eq, 0.13 mmol, 75 mg), and dissolve the reaction mixture in Dioxane (20 mL). The reaction system was fully purged with nitrogen for protection, and then stirred in an oil bath at 110°C for 12 hours. TLC showed that the reaction was complete. The mixture was diluted with EtOAc (10 mL) and washed successively with H2O (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate 6 (350 mg, 76% yield) as a yellow solid. m / z (ESI): 750.6 [M+H] + .

[0476] Step D: At room temperature, TFA (3.07 g, 26.92 mmol, 2 mL) was added to a DCM (10 mL) solution of intermediate 6 (200 mg, 0.4 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain crude intermediate 7 (160 mg, 62% yield) as a colorless oil. The crude product was used directly in the next step without purification. m / z (ESI): 650.1 [M+H] + .

[0477] Step E: Accurately weigh intermediate 7 (65 mg, 1.0 eq, 0.1 mmol), place the reaction system in a round-bottom flask, add intermediate 8 (29 mg, 1.0 eq, 0.1 mmol) to the reaction system, add DMSO solution and DIEPA (5.0 eq, 0.5 mmol, 70 mg) to the reaction system, stir the reaction mixture in an oil bath for 3 hours, and TLC shows that the reaction is complete. Dissolve the reaction system in EtOAc for extraction to obtain the organic phase. After evaporation to dryness, directly purify the product (7 mg, 8% yield) by preparative liquid chromatography. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.42(s,1H),8.76(d,J=3.0Hz,1H),8.24(d,J=17.1Hz,2H),8.0 8(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),7.69(dd,J=11.8,5.7Hz,2H),5.10(dd,J=12.7,5.5Hz,1H),4. 98–4.71(m,1H),3.18(s,3H),3.10(s,3H),2.87(d,J=11.9Hz,4H),2.67(s,3H),2.15–1.99(m,4H),1.88 (d,J=11.7Hz,4H),1.68(s,4H),1.64(d,J=6.9Hz,5H),1.58–1.38(m,3H),1.25(s,2H).m / z(ESI): 924.4

[0478] [M+H] + .

[0479] Example 42: Synthesis of Compound 47

[0480]

[0481] Step A: At room temperature, DIEA (775 mg, 6.00 mmol, 2.60 mL, 3.0 eq) was added to a 10 mL solution of I-1 (443 mg, 2.00 mmol, 1.0 eq) of DCM. Then, II-1 (409 mg, 2.00 mmol, 1.0 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC until complete. LC-MS showed the target compound was obtained. The crude product was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–40%) to give III-1 (720 mg, 1.85 mmol, 92.45% yield), which was a pale yellow solid. m / z (ESI): 390.3 [M+H] + .

[0482] Step B: At room temperature, 4.0 M HCl / dioxane (18.50 mmol, 4.6 mL, 10.0 eq) was added to a 10 mL solution of III-3 (720 mg, 1.85 mmol, 1.0 eq) in DCM. The reaction mixture was stirred at 25 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-1 (520 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 290.3 [M+H] + .

[0483] Step C: At room temperature, K₂CO₃ (497 mg, 3.60 mmol, 2.0 eq) and V₁ (497 mg, 1.80 mmol, 1.0 eq) were added sequentially to a DMF (5 mL) solution of IV-1 (520 mg, 1.80 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 16 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed three times with saturated brine (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0-80%) to give VI-1 (100 mg, 0.18 mmol, 10.18% yield) as a yellow solid. m / z (ESI): 546.4 [M+H] + .

[0484] Step D: At room temperature, iron powder (50 mg, 0.90 mmol, 5.0 eq) and ammonium chloride (50 mg, 0.90 mmol, 5.0 eq) were added sequentially to a solution of VI-1 (100 mg, 0.18 mmol, 1.0 eq) in ethanol / water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0-100%) to give VII-1 (50 mg, 0.10 mmol, 55.56% yield) as a yellow solid. m / z (ESI): 516.4 [M+H] + .

[0485] Step E: At room temperature, tris(dibenzylacetone)palladium (9 mg, 0.01 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (12 mg, 0.02 mmol, 0.2 eq), cesium carbonate (65 mg, 0.20 mmol, 2.0 eq), and VIII-1 (32 mg, 0.10 mmol, 1.0 eq) were added sequentially to a solution of VII-1 (50 mg, 0.10 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 47 (15 mg, 0.019 mmol, 18.71% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.25(s,1H),8.73(d,J=3.6Hz,1H),8.25(d,J=1.6Hz,1H),7.99(d,J=8.8Hz,2H),7.74( d,J=8.8Hz,2H),7.69(d,J=12.0Hz,1H),7.60-7.50(m,2H),7.10(d,J=8.4Hz,1H),7.01(d,J=7.2Hz,1H),6.56(t,J=5.6Hz,1H) ,5.05(dd,J=12.8,5.6Hz,1H),4.87(p,J=6.8Hz,1H),3.54(t,J=5.6Hz,2H),3.48-3.38(m,4H),2.94(q,J=6.0Hz,2H),2.90–2. 81(m,1H),2.66(s,3H),2.64–2.55(m,1H),2.51-2.44(m,1H),2.06–1.89(m,1H),1.64(d,J=6.8Hz,6H).m / z(ESI): 802.8[M+H] + .

[0486] Example 43: Synthesis of Compound 48

[0487]

[0488] Step A: At room temperature, DIEA (581 mg, 4.50 mmol, 3.0 eq) was added to a 10 mL solution of DCM containing I-2 (332 mg, 1.50 mmol, 1.0 eq). Then, II-2 (439 mg, 1.50 mmol, 1.0 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC until complete. LC-MS showed the target compound was obtained. The crude product was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–50%) to obtain III-2 (700 mg, 1.47 mmol, 97.74% yield), which was a pale yellow solid. m / z (ESI): 478.5 [M+H] + .

[0489] Step B: At room temperature, 4.0 M HCl / dioxane (14.70 mmol, 3.7 mL, 10.0 eq) was added to a DCM (10 mL) solution of III-2 (700 mg, 1.47 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-2 (550 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 378.2 [M+H] + .

[0490] Step C: At room temperature, K₂CO₃ (403 mg, 2.92 mmol, 2.0 eq) and V₂ (403 mg, 1.46 mmol, 1.0 eq) were added sequentially to a DMF (5 mL) solution of IV-2 (550 mg, 1.46 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 16 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed three times with saturated brine (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0-90%) to give VI-2 (120 mg, 0.19 mmol, 12.97% yield) as a yellow solid. m / z (ESI): 634.2 [M+H] + .

[0491] Step D: At room temperature, iron powder (53 mg, 0.95 mmol, 5.0 eq) and ammonium chloride (52 mg, 0.95 mmol, 5.0 eq) were added sequentially to a solution of VI-2 (120 mg, 0.19 mmol, 1.0 eq) in ethanol / water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0-100%) to give VII-2 (60 mg, 0.095 mmol, 49.86% yield) as a yellow solid. m / z (ESI): 603.2 [M+H] + .

[0492] Step E: At room temperature, tris(dibenzylacetone)palladium (9 mg, 0.01 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (12 mg, 0.02 mmol, 0.2 eq), cesium carbonate (62 mg, 0.19 mmol, 2.0 eq), and VIII-2 (31 mg, 0.095 mmol, 1 mL) were added sequentially to a solution of VII-2 (60 mg, 0.095 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 48 (25 mg, 0.028 mmol, 29.59% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.27(s,1H),8.74(d,J=3.6Hz,1H),8.25(s,1H),8.00(d,J=8.8Hz,2H),7.74(d,J =8.8Hz,2H),7.69(d,J=12.0Hz,1H),7.61–7.45(m,2H),7.12(d,J=8.8Hz,1H),7.03(d,J=7.2Hz,1H),6.59(t,J=5.6Hz,1 H),5.06(dd,J=12.8,5.6Hz,1H),4.87(p,J=6.8Hz,1H),3.60(t,J=5.6Hz,2H),3.57–3.42(m,10H),3.39(t,J=6.0Hz,2H) ,2.89(p,J=6.0Hz,3H),2.67(s,3H),2.63–2.54(m,2H),2.13–1.97(m,1H),1.65(d,J=6.8Hz,6H).m / z(ESI): 890.2[M+H] + .

[0493] Example 44: Synthesis of Compound 49

[0494]

[0495] Step A: At room temperature, DIEA (1.29 g, 9.96 mmol, 2.0 eq) was added to a 20 mL solution of I-3 (1.1 g, 4.98 mmol, 1.0 eq) in DCM. Then, II-3 (1.24 g, 4.98 mmol, 1.0 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC until complete. LC-MS showed the target compound was obtained. The crude product was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–60%) to give III-3 (2.1 g, 4.85 mmol, 97.35% yield), which was a pale yellow solid. m / z (ESI): 434.1 [M+H] + .

[0496] Step B: At room temperature, 4.0 M HCl / dioxane (48.50 mmol, 12.1 mL, 10.0 eq) was added to a 20 mL solution of III-3 (2.1 g, 4.85 mmol, 1.0 eq) in DCM. The reaction mixture was stirred at 25 °C for 5 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-3 (1.6 g, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 334.1 [M+H] + .

[0497] Step C: At room temperature, K₂CO₃ (662 mg, 4.80 mmol, 2.0 eq) and V-3 (663 mg, 2.40 mmol, 1.0 eq) were added sequentially to a DMF (10 mL) solution of IV-3 (800 mg, 2.40 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 16 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0-90%) to give VI-3 (290 mg, 0.49 mmol, 20.51% yield) as a yellow solid. m / z (ESI): 590.1 [M+H] + .

[0498] Step D: At room temperature, iron powder (138 mg, 2.45 mmol, 5.0 eq) and ammonium chloride (133 mg, 2.45 mmol, 5.0 eq) were added sequentially to a solution of VI-3 (290 mg, 0.49 mmol, 1.0 eq) in ethanol / water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give VII-3 (230 mg, 0.41 mmol, 83.95% yield) as a yellow solid. m / z (ESI): 560.0 [M+H] + .

[0499] Step E: At room temperature, tris(dibenzylacetone)palladium (17 mg, 0.018 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (21 mg, 0.036 mmol, 0.2 eq), cesium carbonate (117 mg, 0.36 mmol, 2.0 eq) and VIII-3 (58 mg, 0.18 mmol, 1.0 eq) were added sequentially to a solution of VII-3 (100 mg, 0.18 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 49 (15 mg, 0.018 mmol, 10.00% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.27(s,1H),8.73(d,J=3.7Hz,1H),8.25(s,1H),8.00(d,J=8.5Hz,2H),7.73(d,J= 8.5Hz,2H),7.69(d,J=11.9Hz,1H),7.54(q,J=6.8,5.6Hz,2H),7.10(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.58(t,J=5. 8Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.87(p,J=6.9Hz,1H),3.58(t,J=5.5Hz,2H),3.54–3.49(m,2H),3.50–3.38(m,6H) ,2.99–2.80(m,3H),2.66(s,3H),2.59(d,J=17.7Hz,2H),2.10–1.95(m,1H),1.64(d,J=6.8Hz,6H).m / z(ESI): 846.6[M+H] + .

[0500] Example 45: Synthesis of Compound 50

[0501]

[0502] Step A: At room temperature, DIEA (1.75 g, 13.58 mmol, 2.0 eq) was added to a 20 mL solution of I-4 (1.5 g, 6.79 mmol, 1.0 eq) in DCM. Then, II-4 (0.67 g, 6.79 mmol, 1.0 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC until complete. LC-MS showed the target compound was obtained. The crude product was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–30%) to give III-4 (1.8 g, 6.34 mmol, 93.36% yield), a white solid. m / z (ESI): 285.2 [M+H] + .

[0503] Step B: At room temperature, copper sulfate pentahydrate (8 mg, 0.03 mmol, 0.05 eq), IV-4 (258 mg, 0.60 mmol, 1.0 eq), and sodium vitamin C (12 mg, 0.06 mmol, 0.10 eq) were added sequentially to a DMF (5 mL) solution of III-4 (170 mg, 0.60 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (20 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0-90%) to give V-4 (290 mg, 0.41 mmol, 67.69% yield) as a yellow solid. m / z (ESI): 715.6 [M+H] + .

[0504] Step C: At room temperature, iron powder (115 mg, 2.05 mmol, 5.0 eq) and ammonium chloride (111 mg, 2.05 mmol, 5.0 eq) were added sequentially to a solution of V-4 (290 mg, 0.41 mmol, 1.0 eq) in ethanol / water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give VI-4 (240 mg, 0.35 mmol, 85.49% yield) as a yellow solid. m / z (ESI): 685.6 [M+H] + .

[0505] Step D: At room temperature, tris(dibenzylacetone)palladium (14 mg, 0.015 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (17 mg, 0.030 mmol, 0.2 eq), cesium carbonate (98 mg, 0.30 mmol, 2.0 eq) and VII-4 (48 mg, 0.15 mmol, 1.0 eq) were added sequentially to a solution of VI-4 (100 mg, 0.15 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 4 (18 mg, 0.019 mmol, 12.36% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.73(d,J=3.7Hz,1H),8.25(d,J=1.3Hz,1H),8.08–

[0506] 7.91(m,3H),7.73(d,J=8.9Hz,2H),7.69(d,J=12.0Hz,1H),7.57(dd,J=8.6,7.1Hz,1H),7.11(d,J=8.6Hz,1H) ,7.04(d,J=7.0Hz,1H),6.58(t,J=5.7Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.87(p,J=6.9Hz,1H),4.49(t,J=5 .2Hz,2H),4.45(s,2H),3.81(t,J=5.2Hz,2H),3.57(t,J=5.4Hz,2H),3.53(s,4H),3.44(t,J=5.9Hz,4H),3.12 –2.79(m,3H),2.66(s,3H),2.63–2.55(m,2H),2.09–1.95(m,1H),1.64(d,J=6.9Hz,6H).m / z(ESI): 971.6[M+H] + .

[0507] Example 46: Synthesis of Compound 51

[0508]

[0509] Step A: At room temperature, a hydrobromic acid solution (1 mL, 33%) in acetic acid was slowly added dropwise to a solution of I-5 (200 mg, 0.26 mmol, 1.0 eq) in acetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed the target compound. The crude product II-5 (160 mg, 0.25 mmol, 95.56% yield) was concentrated and directly proceeded to the next step. The product was a pale yellow solid. m / z (ESI): 285.2 [M+H] + .

[0510] Step B: At room temperature, tris(dibenzylacetone)palladium (9 mg, 0.010 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (11 mg, 0.020 mmol, 0.2 eq), cesium carbonate (65 mg, 0.20 mmol, 2.0 eq), and III-5 (33 mg, 0.10 mmol, 1.0 eq) were added sequentially to a solution of II-5 (64 mg, 0.10 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 51 (3.4 mg, 0.0036 mmol, 3.64% yield) as a yellow solid. m / z (ESI): 934.7 [M+H] + .

[0511] Example 47: Synthesis of Compound 52

[0512]

[0513] Step A: DIEA (5.84 g, 45.24 mmol, 2.0 eq) and II-8 (4.21 g, 22.62 mmol, 1.0 eq) were added to a DCM (80 mL) solution of I-8 (5.0 g, 22.62 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored to completion by TLC, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (150 mL) and washed three times with saturated brine (150 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–80%) to give III-8 (8.0 g, 21.56 mmol, 95.33% yield) as a white solid. m / z (ESI): 372.2 [M+H] +.

[0514] Step B: At room temperature, 4.0 M dioxane chloride solution (215.63 mmol, 54.0 mL, 10.0 eq) was added to a DCM (100 mL) solution of III-8 (8.0 g, 21.56 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-7 (5.5 g, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 272.2 [M+H] + .

[0515] Step C: At room temperature, 2 drops of acetic acid and V-8 (279 mg, 1.63 mmol, 1.0 eq) were added to a methanol (10 mL) solution of IV-8 (500 mg, 1.63 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours, and then sodium cyanoborohydride (205 mg, 3.26 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–100%) to give VI-8 (600 mg, 1.41 mmol, 86.41% yield) as a pale yellow solid. m / z (ESI): 427.1 [M+H] + .

[0516] Step D: At room temperature, 4.0 M dioxane chloride solution (14.10 mmol, 3.5 mL, 10.0 eq) was added to a DCM (10 mL) solution of VI-8 (600 mg, 1.41 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product VII-8 (500 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 327.1 [M+H] + .

[0517] Step E: At room temperature, 2 drops of acetic acid and VIII-8 (275 mg, 1.38 mmol, 1.0 eq) were added to a methanol (10 mL) solution of VII-8 (500 mg, 1.38 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours, and then sodium cyanoborohydride (173 mg, 2.76 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give IX-8 (300 mg, 0.59 mmol, 42.71% yield) as a pale yellow solid. m / z (ESI): 510.2 [M+H] + .

[0518] Step F: At room temperature, 4.0 M dioxane chloride solution (5.90 mmol, 1.5 mL, 10.0 eq) was added to a DCM (5 mL) solution of IX-8 (300 mg, 0.59 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product X-8 (200 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 410.1 [M+H] + .

[0519] Step G: At room temperature, DIEA (115 mg, 0.89 mmol, 2.0 eq) and XI-8 (122 mg, 0.44 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of X-7 (200 mg, 0.44 mmol, 1.0 eq). The reaction mixture was stirred at 130 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give XII-8 (240 mg, 0.36 mmol, 82.02% yield) as a yellow solid. m / z (ESI): 666.2 [M+H] + .

[0520] Step H: Iron powder (101 mg, 1.80 mmol, 5.0 eq) and ammonium chloride (97 mg, 1.80 mmol, 5.0 eq) were added sequentially to an ethanol / water (5 mL / 1 mL) solution of XII-8 (240 mg, 0.36 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (40 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give XIII-8 (160 mg, 0.25 mmol, 70.00% yield) as a yellow solid. m / z (ESI): 636.2 [M+H] + .

[0521] Step I: At room temperature, tris(dibenzylacetone)palladium (15 mg, 0.016 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (19 mg, 0.032 mmol, 0.2 eq), cesium carbonate (104 mg, 0.32 mmol, 2.0 eq) and XIV-8 (52 mg, 0.16 mmol, 1.0 eq) were added sequentially to a dioxane (5 mL) solution of XIII-8 (100 mg, 0.16 mmol, 1.0 eq). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 52 (46 mg, 0.050 mmol, 31.25% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.33(s,1H),8.69(d,J=4.0Hz,1H),8.18–

[0522] 7.99(m,2H),7.67(dd,J=8.4,6.0Hz,3H),7.46(s,1H),7.32(dd,J=7.6,3.2Hz,2H),7.24–

[0523] 7.16(m,1H),5.09(dd,J=12.8,5.2Hz,1H),4.50–4.27(m,2H),4.18(p,J=6.4Hz, 1H),3.54(d,J=11.2Hz,1H),3.34-3.28(m,4H),2.98-2.78(m,8H),2.74-2.65(m ,2H),2.65–2.54(m,2H),2.38-2.26(s,4H),2.13(s,1H),2.07–1.96(m,1H),1.7 7-1.67(m,2H),1.38-1.28(m,2H),1.21(d,J=6.4Hz,6H).m / z(ESI):925.7[M+H] + .

[0524] Example 48: Synthesis of Compound 53

[0525]

[0526] Step A: At room temperature, DIEA (716 mg, 5.55 mmol, 3.0 eq), II-6 (424 mg, 1.85 mmol, 1.0 eq), and HATU (775 mg, 2.04 mmol, 1.1 eq) were added to a DMF (10 mL) solution of I-6 (500 mg, 1.85 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–70%) to give III-6 (800 mg, 1.66 mmol, 89.72% yield) as a pale yellow solid. m / z (ESI): 483.5 [M+H] + .

[0527] Step B: At room temperature, 4.0 M dioxane chloride solution (16.60 mmol, 4.2 mL, 10.0 eq) was added to a DCM (10 mL) solution of III-6 (800 mg, 1.66 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-6 (660 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 383.4 [M+H] + .

[0528] Step C: At room temperature, DIEA (129 mg, 1.00 mmol, 2.0 eq) and V-6 (138 mg, 0.50 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of IV-6 (190 mg, 0.50 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–90%) to give VI-6 (300 mg, 0.47 mmol, 94.04% yield) as a yellow solid. m / z (ESI): 639.6 [M+H] + .

[0529] Step D: At room temperature, iron powder (132 mg, 2.35 mmol, 5.0 eq) and ammonium chloride (127 mg, 2.35 mmol, 5.0 eq) were added sequentially to a solution of VI-6 (300 mg, 0.47 mmol, 1.0 eq) in ethanol / water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give VII-6 (200 mg, 0.33 mmol, 70.21% yield) as a yellow solid. m / z (ESI): 609.6 [M+H] + .

[0530] Step E: At room temperature, tris(dibenzylacetone)palladium (30 mg, 0.033 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (38 mg, 0.066 mmol, 0.2 eq), cesium carbonate (215 mg, 0.66 mmol, 2.0 eq) and VIII-6 (107 mg, 0.33 mmol, 1.0 eq) were added sequentially to a solution of VII-6 (200 mg, 0.33 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 53 (50 mg, 0.056 mmol, 16.89% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.33(s,1H),8.69(d,J=4.0Hz,1H),8.05(d,J=8.8Hz,2H),7.74– 7.57(m,3H),7.45(s,1H),7.32(dd,J=7.8,3.2Hz,2H),7.24–7.15(m,1H),5.08(dd,J=12.8,5.2Hz,1H), 4.33(t,J=4.4Hz,2H),4.18(p,J=6.8Hz,1H),3.85–3.50(m,6H),3.33(s,2H),3.05–2.71(m,8H),2.58(d ,J=16.0Hz,2H),2.12–1.93(m,1H),1.71(d,J=19.6Hz,4H),1.22(d,J=6.4Hz,6H).m / z(ESI): 898.6[M+H] + .

[0531] Example 49: Synthesis of Compound 54

[0532]

[0533] Step A: Potassium carbonate (1.02 g, 7.38 mmol, 2.0 eq) and II-7 (1.03 g, 3.69 mmol, 1.0 eq) were added to a DMF (10 mL) solution of I-7 (1.0 g, 3.69 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (60 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0–80%) to give III-7 (0.25 g, 0.53 mmol, 14.48% yield) as a pale yellow solid. m / z (ESI): 469.5 [M+H] + .

[0534] Step B: At room temperature, 4.0 M dioxane chloride solution (5.30 mmol, 1.3 mL, 10.0 eq) was added to a DCM (10 mL) solution of III-7 (250 mg, 0.53 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-7 (220 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 369.5 [M+H] + .

[0535] Step C: At room temperature, DIEA (232 mg, 1.80 mmol, 3.0 eq) and V-7 (166 mg, 0.60 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of IV-7 (220 mg, 0.60 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 3 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give VI-7 (340 mg, 0.54 mmol, 90.81% yield) as a yellow solid. m / z (ESI): 625.6 [M+H] + .

[0536] Step D: At room temperature, iron powder (151 mg, 2.70 mmol, 5.0 eq) and ammonium chloride (146 mg, 2.70 mmol, 5.0 eq) were added sequentially to an ethanol / water (5 mL / 1 mL) solution of VI-7 (340 mg, 0.54 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (40 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give VII-7 (300 mg, 0.51 mmol, 93.53% yield) as a yellow solid. m / z (ESI): 595.6 [M+H] + .

[0537] Step E: At room temperature, tris(dibenzylacetone)palladium (16 mg, 0.017 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (20 mg, 0.034 mmol, 0.2 eq), cesium carbonate (110 mg, 0.34 mmol, 2.0 eq) and VIII-7 (55 mg, 0.17 mmol, 1.0 eq) were added sequentially to a solution of VII-7 (100 mg, 0.17 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 54 (30 mg, 0.034 mmol, 20.00% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.31(s,1H),8.68(d,J=3.8Hz,1H),8.04(d,J=8.5Hz,2H),7.65(d,J=8.2H z,3H),7.45(s,1H),7.28(t,J=7.4Hz,2H),7.19(d,J=11.5Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.31(t,J=4.3Hz ,2H),4.17(q,J=6.5Hz,1H),3.62(d,J=11.7Hz,2H),3.31(s,4H),3.01–2.72(m,7H),2.56(d,J=17.4Hz,2H),2.44 (s,4H),2.18(d,J=6.7Hz,2H),2.04–1.90(m,1H),1.80–1.56(m,3H),1.20(d,J=6.5Hz,6H).m / z(ESI): 884.3[M+H] + .

[0538] Example 50: Synthesis of Compound 55

[0539]

[0540] Step A: At room temperature, 2 drops of acetic acid and II-9 (0.73 g, 3.69 mmol, 1.0 eq) were added to a methanol (20 mL) solution of I-9 (1.0 g, 3.69 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours, and then sodium cyanoborohydride (0.46 g, 7.38 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (60 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–80%) to give III-9 (0.50 g, 1.10 mmol, 29.85% yield) as a pale yellow solid. m / z (ESI): 455.4 [M+H] + .

[0541] Step B: At room temperature, 4.0 M dioxane chloride solution (11.00 mmol, 2.75 mL, 10.0 eq) was added to a DCM (10 mL) solution of III-9 (500 mg, 1.10 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-9 (360 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 355.4 [M+H] + .

[0542] Step C: At room temperature, 2 drops of acetic acid and V-9 (188 mg, 1.1 mmol, 1.0 eq) were added to a methanol (10 mL) solution of IV-9 (500 mg, 1.10 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 hours, and then sodium cyanoborohydride (138 mg, 2.20 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give VI-9 (500 mg, 0.98 mmol, 89.30% yield) as a pale yellow solid. m / z (ESI): 510.5 [M+H] + .

[0543] Step D: At room temperature, 4.0 M dioxane chloride solution (9.80 mmol, 2.45 mL, 10.0 eq) was added to a DCM (10 mL) solution of VI-9 (500 mg, 0.98 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-9 (380 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 410.4 [M+H] + .

[0544] Step E: At room temperature, DIEA (360 mg, 2.79 mmol, 3.0 eq) and VIII-9 (257 mg, 0.93 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-9 (380 mg, 0.93 mmol, 1.0 eq). The reaction mixture was stirred at 130 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (60 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give IX-9 (260 mg, 0.39 mmol, 42.00% yield) as a yellow solid. m / z (ESI): 666.6 [M+H] + .

[0545] Step F: At room temperature, iron powder (109 mg, 1.95 mmol, 5.0 eq) and ammonium chloride (105 mg, 1.95 mmol, 5.0 eq) were added sequentially to an ethanol / water (5 mL / 1 mL) solution of IX-9 (260 mg, 0.39 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (40 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give X-9 (200 mg, 0.31 mmol, 80.76% yield) as a yellow solid. m / z (ESI): 636.7 [M+H] + .

[0546] Step G: At room temperature, tris(dibenzylacetone)palladium (15 mg, 0.016 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (18 mg, 0.032 mmol, 0.2 eq), cesium carbonate (104 mg, 0.32 mmol, 2.0 eq) and XI-9 (52 mg, 0.16 mmol, 1.0 eq) were added sequentially to a dioxane (5 mL) solution of X-9 (100 mg, 0.16 mmol, 1.0 eq). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 55 (68 mg, 0.074 mmol, 45.95% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.32(s,1H),8.69(d,J=3.6Hz,1H),8.03(d,J=8.4Hz,2H),7.64(d,J=8.8Hz,2H),7.57(dd,J=8.4,7.2H z,1H),7.46(s,1H),7.20(d,J=11.6Hz,1H),7.13(d,J=7.2Hz,1H),6.78(d,J=8.4Hz,1H),5.05(dd,J=12.8,5.6Hz,1H),4.32(t,J=4.4Hz,2H), 4.29–4.12(m,3H),3.90(s,2H),3.33(t,J=4.4Hz,2H),3.14(t,J=6.3H z,1H),2.95-2.75(m,7H),2.66–2.54(m,4H),2.51–2.44(m,1H),2.25-2 .15(m,1H),2.07–1.94(m,1H),1.79(t,J=11.2Hz,2H),1.68(d,J=12.0H z,2H),1.47–1.23(m,3H),1.21(d,J=6.4Hz,6H).m / z(ESI):925.6[M+H] + .

[0547] Example 51: Synthesis of Compound 56

[0548]

[0549] Step A: At room temperature, tris(dibenzylacetone)palladium (9 mg, 0.010 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (12 mg, 0.020 mmol, 0.2 eq), cesium carbonate (65 mg, 0.20 mmol, 2.0 eq) and II-11 (32 mg, 0.10 mmol, 1.0 eq) were added sequentially to a solution of I-11 (64 mg, 0.10 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (30 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 56 (25 mg, 0.027 mmol, 27.11% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.38(s,1H),8.76(d,J=3.6Hz,1H),8.26(d,J=1.2Hz,1H),8.12–8.03(m,2H),7.74–7.64(m,3H ),7.57(dd,J=8.4,7.2Hz,1H),7.13(d,J=7.2Hz,1H),6.79(d,J=8.4Hz,1H),5.05(dd,J=12.8,5.6Hz,1H),4.87(p,J=6.8Hz,1H),4.32- 4.18(m,2H),3.96-3.85(m,1H),3.16(q,J=6.4Hz,1H),2.94-2.74(m,8H),2.67(s,3H),2.64–2.55(m,4H),2.51–2.45(m,1H),2.19(d,J =11.2Hz,1H),2.09–1.95(m,1H),1.87–1.73(m,2H),1.69(s,2H),1.64(d,J=6.9Hz,6H),1.36(t,J=12.0Hz,2H).m / z(ESI): 922.9[M+H] + .

[0550] Example 52: Synthesis of Compound 57

[0551]

[0552] Step A: At room temperature, add tris(dibenzylacetone)palladium (9 mg, 0.010 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (12 mg, 0.020 mmol, 0.2 eq), cesium carbonate (65 mg, 0.20 mmol, 2.0 eq), and II-10 (32 mg, 0.10 mmol, 1.0 eq) sequentially to a solution of I-10 (60 mg, 0.10 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 57 (15 mg, 0.017 mmol, 17.05% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.39(s,1H),8.77(d,J=3.6Hz,1H),8.27(s,1H),8.08(d,J=8.4Hz, 2H),7.78–7.59(m,4H),7.29(t,J=7.2Hz,2H),5.06(dd,J=12.8,5.2Hz,1H),4.88(p,J=6.8Hz,1H),3.63(d, J=11.6Hz,2H),3.00-2.75(m,7H),2.67(s,3H),2.58(d,J=17.6Hz,1H),2.46(s,4H),2.20(d,J=6.8Hz,2H), 2.09–1.94(m,1H),1.72(d,J=13.2Hz,2H),1.64(d,J=6.8Hz,6H),1.32-1.15(m,2H).m / z(ESI): 881.7[M+H] + .

[0553] Example 53: Synthesis of Compound 58

[0554]

[0555] Step A: DIEA (1.3 g, 10.00 mmol, 2.0 eq) and II-12 (1.3 g, 5.00 mmol, 1.0 eq) were added to a DCM (20 mL) solution of I-12 (1.1 g, 5.00 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until complete, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–70%) to give III-12 (2.0 g, 4.56 mmol, 91.12% yield) as a pale yellow solid. m / z (ESI): 440.2 [M+H] + .

[0556] Step B: At room temperature, 45.60 mmol (11.4 mL, 10.0 eq) of 4.0 M dioxane hydrochloride solution was added to a 15 mL DCM solution of III-12 (2.0 g, 4.56 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-12 (1.5 g, crude hydrochloride) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 340.2 [M+H] + .

[0557] Step C: At room temperature, 2 drops of acetic acid and V-12 (182 mg, 1.07 mmol, 1.0 eq) were added to a methanol (10 mL) solution of IV-12 (400 mg, 1.07 mmol, 1.0 eq). The reaction mixture was stirred at 50 °C for 16 hours, and then sodium cyanoborohydride (135 mg, 2.14 mmol, 2.0 eq) was added. The reaction mixture was stirred at 40 °C for another 5 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–80%) to give VI-12 (450 mg, 0.91 mmol, 85.13% yield) as a pale yellow solid. m / z (ESI): 495.2 [M+H] + .

[0558] Step D: At room temperature, 4.0 M dioxane hydrochloride solution (9.10 mmol, 2.3 mL, 10.0 eq) was added to a DCM (10 mL) solution of VI-12 (450 mg, 0.91 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-12 (350 mg, crude hydrochloride) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 395.1 [M+H] + .

[0559] Step E: Trifluoroacetic anhydride (186 mg, 0.89 mmol, 1.0 eq) was added to a DCM (10 mL) solution of VII-12 (350 mg, 0.89 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until complete, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–70%) to give VIII-12 (400 mg, 0.82 mmol, 92.13% yield) as a pale yellow solid. m / z (ESI): 491.2 [M+H] + .

[0560] Step F: Tetrahydroxydiboron (220 mg, 2.46 mmol, 3.0 eq) and 2,2-bipyridine (13 mg, 0.08 mmol, 0.1 eq) were added to a DMF (5 mL) solution of VIII-12 (400 mg, 0.82 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. LC-MS showed the target compound. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0–100%) to give IX-12 (350 mg, 0.76 mmol, 92.78% yield) as a pale yellow solid. m / z (ESI): 461.2 [M+H] + .

[0561] Step G: LiHMDS (3.8 mL, 3.80 mmol, 1 M, 5.0 eq) was added to a solution of IX-12 (350 mg, 0.76 mmol, 1.0 eq) in ethyl formate (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (30 mL). The organic phase was washed three times with saturated brine (30 mL) and dried over anhydrous Na2SO4. The mixture was filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0–60%) to give X-12 (300 mg, 0.61 mmol, 80.89% yield) as a pale yellow solid. m / z (ESI): 489.1 [M+H] + .

[0562] Step H: Sodium hydride (16 mg, 0.40 mmol, 60%, 2.0 eq) and XI-12 (65 mg, 0.20 mmol, 1.0 eq) were added sequentially to a DMF / THF (4 mL / 1 mL) solution of X-12 (100 mg, 0.20 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was subjected to column chromatography (SiO₂, petroleum ether:

[0563] Purified with ethyl acetate (0–100%), XII-12 (60 mg, 0.085 mmol, 42.67% yield) was given as a pale yellow solid. m / z (ESI): 704.2 [M+H] + .

[0564] Step I: Potassium carbonate (24 mg, 0.17 mmol, 2.0 eq) was added to a methanol (5 mL) solution of XII-12 (60 mg, 0.085 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was concentrated to obtain crude product VIII-12 (50 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 608.2 [M+H] + .

[0565] Step J: At room temperature, DIEA (32 mg, 0.25 mmol, 3.0 eq) and XIV-12 (24 mg, 0.082 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of XIII-12 (50 mg, 0.082 mmol, 1.0 eq). The reaction mixture was stirred at 130 °C for 1 hour. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 58 (5 mg, 0.0057 mmol, 6.92% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.55(s,1H),8.88(s,1H),8.35(s,1H),8.17(d,J=8.6Hz,2H),7.86(d,J=9.4Hz,1H),7.67(d,J=8. 8Hz,2H),7.59(d,J=11.2Hz,1H),6.90(d,J=7.6Hz,1H),6.41(d,J=9.2Hz,1H),5.89(t,J=8.2Hz,1H),5.06(dd,J=12.8,5.6Hz,1H),4.19(t ,J=7.8Hz,2H),3.91(t,J=6.0Hz,2H),3.30-3.20(m,2H),2.95-2.85(m,4H),2.63–2.55(m,2H),2.46-2.40(m,1H),2.25-2.15(m,4H),2.10 –1.96(m,2H),1.93-1.83(m,2H),1.73(d,J=11.6Hz,1H),1.50(t,J=5.6Hz,4H),1.35-1.28(m,4H),1.06(s,3H).m / z(ESI): 441.8[1 / 2M+H] + .

[0566] Example 54: Synthesis of Compound 59

[0567]

[0568] Step A: Potassium carbonate (2.76 g, 20.00 mmol, 2.0 eq) and II-13 (3.33 g, 10.00 mmol, 1.0 eq) were added to a DMF (20 mL) solution of I-13 (1.55 g, 10.00 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 60 °C for 20 hours. The reaction was monitored by TLC until complete. LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–50%) to give III-13 (3.2 g, 9.47 mmol, 94.67% yield) as a pale yellow solid. m / z (ESI): 239.1 [M⁻¹⁰⁰ + H] + .

[0569] Step B: At room temperature, m-CPBA (3.27 g, 18.94 mmol, 2.0 eq) was added to a DCM (40 mL) solution of III-13 (3.2 g, 9.47 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored to completion by TLC, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–60%) to give IV-13 (3.4 g, 9.19 mmol, 97.03% yield) as a pale yellow solid. m / z (ESI): 271.1 [M⁻¹⁰⁰⁺H] + .

[0570] Step C: At room temperature, 4.0 M dioxane hydrochloride solution (91.90 mmol, 23.0 mL, 10.0 eq) was added to a DCM (50 mL) solution of IV-13 (3.4 g, 9.19 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product V-13 (2.5 g, crude hydrochloride) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 271.1 [M+H] + .

[0571] Step D: At room temperature, 2 drops of acetic acid and 1-Boc-3-azacyclobutanone (279 mg, 1.63 mmol, 1.0 eq) were added to a methanol (10 mL) solution of V-13 (500 mg, 1.63 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (205 mg, 3.26 mmol, 2.0 eq) was added. The mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–90%) to give VI-13 (600 mg, 1.41 mmol, 86.61% yield) as a pale yellow solid. m / z (ESI): 426.2 [M+H] + .

[0572] Step E: At room temperature, 4.0 M dioxane hydrochloride solution (14.10 mmol, 3.5 mL, 10.0 eq) was added to a DCM (10 mL) solution of VI-13 (600 mg, 1.41 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-13 (500 mg, crude hydrochloride) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 326.1 [M+H] + .

[0573] Step F: At room temperature, 2 drops of acetic acid and N-tert-butoxycarbonyl-4-piperidinone (123 mg, 0.62 mmol, 1.0 eq) were added to a methanol (10 mL) solution of VII-13 (200 mg, 0.62 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (78 mg, 1.24 mmol, 2.0 eq) was added to the reaction mixture. The mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–90%) to give VIII-13 (260 mg, 0.51 mmol, 82.55% yield) as a pale yellow solid. m / z (ESI): 509.2 [M+H] + .

[0574] Step G: At room temperature, 4.0 M dioxane hydrochloride solution (5.10 mmol, 1.3 mL, 10.0 eq) was added to a DCM (5 mL) solution of VIII-13 (260 mg, 0.51 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IX-13 (200 mg, crude hydrochloride) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 409.1 [M+H] + .

[0575] Step H: Trifluoroacetic anhydride (103 mg, 0.49 mmol, 1.0 eq) was added to a DCM (10 mL) solution of IX-13 (200 mg, 0.49 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was monitored by TLC until complete, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give X-13 (220 mg, 0.44 mmol, 89.80% yield) as a pale yellow solid. m / z (ESI): 505.2 [M+H] + .

[0576] Step I: Tetrahydroxydiboron (116 mg, 1.30 mmol, 3.0 eq) and 2,2-bipyridine (6 mg, 0.04 mmol, 0.1 eq) were added to a DMF (5 mL) solution of X-13 (220 mg, 0.44 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. LC-MS showed the target compound. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give XI-13 (200 mg, 0.42 mmol, 95.45% yield) as a pale yellow solid. m / z (ESI): 475.1 [M+H] + .

[0577] Step J: LiHMDS (2.1 mL, 2.10 mmol, 1 M, 5.0 eq) was added to a solution of XI-13 (200 mg, 0.42 mmol, 1.0 eq) in ethyl formate (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (30 mL). The organic phase was washed three times with saturated brine (30 mL) and dried over anhydrous Na₂SO₄. The mixture was filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–60%) to give XII-13 (200 mg, 0.40 mmol, 95.24% yield) as a pale yellow solid. m / z (ESI): 503.1 [M+H] + .

[0578] Step K: Sodium hydride (32 mg, 0.80 mmol, 60%, 2.0 eq) and XIII-13 (130 mg, 0.40 mmol, 1.0 eq) were added sequentially to a DMF / THF (4 mL / 1 mL) solution of XII-13 (200 mg, 0.40 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine (30 mL), and the organic layer was dried over anhydrous Na2SO4. The mixture was filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO2, methanol:dichloromethane = 0–10%) to give XIV-13 (180 mg, 0.25 mmol, 62.76% yield) as a pale yellow solid. m / z (ESI): 718.2 [M+H] + .

[0579] Step L: Potassium carbonate (69 mg, 0.50 mmol, 2.0 eq) was added to a methanol (5 mL) solution of XIV-13 (180 mg, 0.25 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 40 °C for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was concentrated to obtain crude product XV-13 (150 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 622.2 [M+H] + .

[0580] Step M: At room temperature, DIEA (39 mg, 0.30 mmol, 3.0 eq) and XVI-13 (30 mg, 0.10 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of XV-13 (62 mg, 0.10 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 59 (45 mg, 0.050 mmol, 50.00% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),10.64(s,1H),8.91(s,1H),8.24(d,J=8.8Hz,2H),7.88(d,J=9.2Hz,1H),7.77(d,J=8.8Hz,2H),7.72 (d,J=11.2Hz,1H),7.45(d,J=7.6Hz,1H),6.44(d,J=9.2Hz,1H),5.92(t,J=8.0Hz,1H),5.12(dd,J=12.8,5.6Hz,1H),4.69(s,1H),3.50(d,J =10.4Hz,2H),3.44–3.33(m,2H),3.23–3.10(m,1H),3.02-2.90(m,3H ),2.84-2.72(m,5H),2.69–2.56(m,2H),2.49-2.43(m,1H),2.32–2.14 (m,2H),2.11–1.97(m,2H),1.95–1.83(m,4H),1.82-1.70(m,5H),1.54-1.42(m,2H),1.39–1.23(m,2H),1.08(s,3H).m / z(ESI): 896.6[M+H] + .

[0581] Example 55: Synthesis of Compound 60

[0582]

[0583] Step A: DIEA (0.90 g, 7.00 mmol, 2.0 eq) and II-19 (1.00 g, 3.50 mmol, 1.0 eq) were added to a DCM (20 mL) solution of I-19 (0.82 g, 3.50 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored to completion by TLC, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–80%) to give III-19 (1.60 g, 3.32 mmol, 94.84% yield) as a white solid. m / z (ESI): 483.2 [M+H] + .

[0584] Step B: At room temperature, 4.0 M ethyl hydrochloride solution (33.20 mmol, 8.3 mL, 10.0 eq) was added to a 10 mL solution of ethyl acetate (1.60 g, 3.32 mmol, 1.0 eq) containing III-19. The reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-19 (1.3 g, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 383.1 [M+H] + .

[0585] Step C: At room temperature, 2 drops of acetic acid and V-19 (111 mg, 0.52 mmol, 1.0 eq) were added to a methanol (10 mL) solution of IV-19 (200 mg, 0.52 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (95 mg, 1.56 mmol, 3.0 eq) was added. The reaction mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give VI-19 (250 mg, 0.43 mmol, 83.03% yield) as a pale yellow solid. m / z (ESI): 580.2 [M+H] + .

[0586] Step D: At room temperature, a 4.0 M ethyl hydrochloride solution (4.30 mmol, 1.1 mL, 10.0 eq) was added to a 5 mL solution of ethyl acetate (250 mg, 0.43 mmol, 1.0 eq) of VI-19. The reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-19 (210 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 480.2 [M+H] + .

[0587] Step E: At room temperature, DIEA (170 mg, 1.32 mmol, 3.0 eq) and VIII-19 (129 mg, 0.44 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-19 (210 mg, 0.44 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 1 hour. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give IX-19 (140 mg, 0.19 mmol, 42.26% yield) as a yellow solid. m / z (ESI): 754.3 [M+H] + .

[0588] Step F: At room temperature, a hydrobromic acid-acetic acid solution (1 mL) was slowly added dropwise to a 2 mL solution of IX-19 (38 mg, 0.05 mmol, 1.0 eq) in acetic acid. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product X-19 (30 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 620.2 [M+H] + .

[0589] Step F: At room temperature, DIEA (26 mg, 0.20 mmol, 4.0 eq) and XI-19 (16 mg, 0.05 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of X-19 (30 mg, 0.05 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 60 (7 mg, 0.008 mmol, 16.24% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.60(s,1H),7.99–7.59(m,3H),7.46(d,J=7.4Hz,1H),6.22(d,J=9.2Hz,1H),5.87 (t,J=8.4Hz,1H),5.12(dd,J=12.8,5.2Hz,1H),4.33(d,J=23.2Hz,1H),4.15–3.84(m,1H),3.63(d,J=12.4Hz,4H),3.17( d,J=5.2Hz,4H),2.99(d,J=10.8Hz,2H),2.91(t,J=12.4Hz,3H),2.73–2.55(m,2H),2.45(s,4H),2.35–2.13(m,4H),2.09 –1.99(m,1H),1.97–1.80(m,6H),1.78–1.55(m,3H),1.46(s,1H),1.34–1.28(m,3H),0.99(s,3H).m / z(ESI): 861.3[M+H] - .

[0590] Example 56: Synthesis of Compound 61

[0591]

[0592] Step A: At room temperature, 2 drops of acetic acid and II-20 (105 mg, 0.52 mmol, 1.0 eq) were added to a methanol (10 mL) solution of I-20 (200 mg, 0.52 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (95 mg, 1.56 mmol, 3.0 eq) was added. The reaction mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give III-20 (270 mg, 0.48 mmol, 91.90% yield) as a pale yellow solid. m / z (ESI): 566.2 [M+H] + .

[0593] Step B: At room temperature, a 4.0 M ethyl hydrochloride solution (4.80 mmol, 1.2 mL, 10.0 eq) was added to a 5 mL solution of ethyl acetate (270 mg, 0.48 mmol, 1.0 eq) of III-20. The reaction mixture was stirred at 40 °C for 3 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-20 (230 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 466.2 [M+H] + .

[0594] Step C: At room temperature, DIEA (190 mg, 1.47 mmol, 3.0 eq) and V-20 (144 mg, 0.49 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of IV-20 (230 mg, 0.49 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 1 hour. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give VI-20 (70 mg, 0.095 mmol, 19.33% yield) as a yellow solid. m / z (ESI): 740.2 [M+H] + .

[0595] Step D: At room temperature, slowly add 1 mL of hydrobromic acid-acetic acid solution to a 2 mL solution of VI-20 (70 mg, 0.095 mmol, 1.0 eq) in acetic acid. Stir the reaction mixture at room temperature for 2 hours. LC-MS showed the target compound. Concentrate the reaction solution to obtain crude product VII-20 (60 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 606.2 [M+H] + .

[0596] Step E: At room temperature, DIEA (52 mg, 0.40 mmol, 4.0 eq) and VIII-20 (29 mg, 0.10 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-20 (60 mg, 0.10 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 4 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 61 (13 mg, 0.015 mmol, 15.33% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.62(d,J=10.0Hz,1H),8.05–7.49(m,3H),7.07(d,J=7.6Hz,1H),6.22( d,J=9.2Hz,1H),5.87(t,J=8.0Hz,1H),5.09(dd,J=12.8,5.2Hz,1H),4.34(d,J=22.8Hz,1H),3.99(d,J=56.0Hz ,1H),3.78–3.52(m,5H),3.19(s,4H),3.09–2.82(m,3H),2.77–2.57(m,2H),2.48–2.35(m,2H),2.32–1.99(m, 4H),1.98–1.80(m,4H),1.75-1.55(m,3H),1.47(s,1H),1.38–1.27(m,6H),1.00(s,3H).m / z(ESI): 849.4[M+H] + .

[0597] Example 57: Synthesis of Compound 62

[0598]

[0599] Step A: At room temperature, DIEA (201 mg, 1.56 mmol, 3.0 eq), II-18 (126 mg, 0.52 mmol, 1.0 eq), and HATU (217 mg, 0.57 mmol, 1.1 eq) were added to a DMF (5 mL) solution of I-18 (200 mg, 0.52 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored to completion by TLC, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–70%) to give III-18 (300 mg, 0.50 mmol, 94.66% yield) as a pale yellow solid. m / z (ESI): 607.2 [M+H] + .

[0600] Step B: At room temperature, a 4.0 M ethyl hydrochloride solution (5.0 mmol, 1.3 mL, 10.0 eq) was added to a 5 mL solution of ethyl acetate (300 mg, 0.50 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-18 (240 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 507.1 [M+H] + .

[0601] Step C: At room temperature, DIEA (243 mg, 1.88 mmol, 4.0 eq) and V-18 (138 mg, 0.47 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of IV-18 (240 mg, 0.47 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 1 hour. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–90%) to give VI-18 (240 mg, 0.31 mmol, 65.47% yield) as a yellow solid. m / z (ESI): 781.2 [M+H] + .

[0602] Step D: At room temperature, slowly add 1 mL of hydrobromic acid-acetic acid solution to a 2 mL solution of VI-18 (78 mg, 0.10 mmol, 1.0 eq) in acetic acid. Stir the reaction mixture at room temperature for 1 hour. LC-MS showed the target compound. Concentrate the reaction solution to obtain crude product VII-18 (60 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 647.1 [M+H] + .

[0603] Step E: At room temperature, DIEA (48 mg, 0.37 mmol, 4.0 eq) and VIII-18 (30 mg, 0.093 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-18 (60 mg, 0.093 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 62 (5 mg, 0.0056 mmol, 6.05% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.59(d,J=12.4Hz,1H),7.94–7.55(m,3H),7.44(dd,J=7.6,3.2Hz,1H),6.19(d,J=9.2Hz,1H ),5.84(d,J=8.8Hz,1H),5.10(dd,J=12.8,5.2Hz,1H),4.53(d,J=13.2Hz,1H),4.31(d,J=18.8Hz,1H),4.14–3.84(m,2H),3.70–3. 54(m,4H),3.53-3.40(m,1H),3.07(t,J=12.8Hz,3H),2.98–2.80(m,3H),2.64–2.55(m,2H),2.35(d,J=7.2Hz,2H),2.23-2.13(m,1 H),2.08–1.73(m,11H),1.71–1.45(m,3H),1.44–1.28(m,5H),1.26(d,J=3.6Hz,1H),0.97(d,J=8.4Hz,3H).m / z(ESI): 890.6[M+H] + .

[0604] Example 58: Synthesis of Compound 63

[0605]

[0606] Step A: At room temperature, DIEA (201 mg, 1.56 mmol, 3.0 eq), II-21 (126 mg, 0.52 mmol, 1.0 eq), and HATU (217 mg, 0.57 mmol, 1.1 eq) were added to a DMF (5 mL) solution of I-21 (200 mg, 0.52 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored to be complete by TLC, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–70%) to give III-21 (300 mg, 0.50 mmol, 94.48% yield) as a pale yellow solid. m / z (ESI): 607.3 [M+H] + .

[0607] Step B: At room temperature, a 4.0 M ethyl hydrochloride solution (5.0 mmol, 1.3 mL, 10.0 eq) was added to a 10 mL solution of ethyl acetate (300 mg, 0.50 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-21 (250 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 507.2 [M+H] + .

[0608] Step C: At room temperature, DIEA (129 mg, 1.00 mmol, 2.0 eq) and V-21 (147 mg, 0.50 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of IV-21 (250 mg, 0.50 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 1 hour. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–90%) to give VI-21 (240 mg, 0.31 mmol, 61.54% yield) as a yellow solid. m / z (ESI): 781.3 [M+H] + .

[0609] Step D: At room temperature, a hydrobromic acid-acetic acid solution (1 mL) was slowly added dropwise to a 2 mL solution of VI-21 (78 mg, 0.10 mmol, 1.0 eq) in acetic acid. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-21 (66 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 647.2 [M+H] + .

[0610] Step E: At room temperature, DIEA (52 mg, 0.40 mmol, 4.0 eq) and VIII-21 (33 mg, 0.10 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-21 (66 mg, 0.10 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 63 (5 mg, 0.056 mmol, 5.62% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.59(s,1H),7.96–7.57(m,3H),7.45(d,J=6.8Hz,1H),6.19(d,J=9.2Hz,1H),5.84(t,J= 8.0Hz,1H),5.11(dd,J=12.8,5.2Hz,1H),4.47(d,J=12.8Hz,1H),4.31(d,J=14.0Hz,1H),4.17(d,J=13.2Hz,1H),3.99(d,J=59 .2Hz,1H),3.67(s,2H),3.50(d,J=16.4Hz,2H),3.26(s,5H),3.06(d,J=12.8Hz,3H),2.96–2.80(m,1H),2.60(q,J=8.8,6.8Hz, 7H),2.18(s,1H),2.09–1.77(m,8H),1.65(d,J=12.4Hz,3H),1.41(d,J=12.4Hz,2H),1.03–0.77(m,3H).m / z(ESI): 889.3[M+H] - .

[0611] Example 59: Synthesis of Compound 64

[0612]

[0613] Step A: At room temperature, 2 drops of acetic acid and II-16 (148 mg, 0.74 mmol, 1.0 eq) were added to a methanol (10 mL) solution of I-16 (200 mg, 0.74 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (140 mg, 2.22 mmol, 3.0 eq) was added. The reaction mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–80%) to give III-16 (260 mg, 0.57 mmol, 77.56% yield) as a pale yellow solid. m / z (ESI): 454.1 [M+H] + .

[0614] Step B: At room temperature, 4.0 M dioxane chloride solution (5.7 mmol, 1.5 mL, 10.0 eq) was added to a DCM (5 mL) solution of III-16 (260 mg, 0.57 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-16 (200 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 354.1 [M+H] + .

[0615] Step C: At room temperature, 2 drops of acetic acid and V-16 (97 mg, 0.57 mmol, 1.0 eq) were added to a methanol (10 mL) solution of IV-16 (200 mg, 0.57 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (107 mg, 1.71 mmol, 3.0 eq) was added. The reaction mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give VI-16 (130 mg, 0.26 mmol, 45.61% yield) as a pale yellow solid. m / z (ESI): 509.2 [M+H] + .

[0616] Step D: At room temperature, 4.0 M dioxane chloride solution (2.60 mmol, 0.70 mL, 10.0 eq) was added to a DCM (4 mL) solution of VI-16 (130 mg, 0.26 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-16 (105 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 409.2 [M+H] + .

[0617] Step E: At room temperature, DIEA (101 mg, 0.78 mmol, 3.0 eq) and VIII-16 (76 mg, 0.26 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-16 (105 mg, 0.26 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give IX-16 (116 mg, 0.17 mmol, 65.38% yield) as a yellow solid. m / z (ESI): 683.2 [M+H] + .

[0618] Step F: Tetrahydroxydiboron (46 mg, 0.51 mmol, 3.0 eq) and 4,4-bipyridine (3 mg, 0.017 mmol, 0.1 eq) were added sequentially to a DMF (5 mL) solution of IX-16 (116 mg, 0.17 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 20 °C for 10 min. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (40 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give X-16 (90 mg, 0.14 mmol, 82.35% yield) as a yellow solid. m / z (ESI): 653.2 [M+H] + .

[0619] Step G: At room temperature, tris(dibenzylacetone)palladium (6 mg, 0.007 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (8 mg, 0.014 mmol, 0.2 eq), cesium carbonate (46 mg, 0.14 mmol, 2.0 eq), and XI-16 (23 mg, 0.07 mmol, 1.0 eq) were added sequentially to a dioxane (5 mL) solution of X-16 (45 mg, 0.07 mmol, 1.0 eq). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 64 (5.0 mg, 0.005 mmol, 7.14% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.45(s,1H),8.77(d,J=3.6Hz,1H),8.24(s,1H),8.10(d,J=8.4Hz,2 H),7.77(d,J=8.4Hz,2H),7.69(d,J=12.0Hz,1H),7.61(d,J=11.2Hz,1H),6.91(d,J=7.6Hz,1H),5.07(dd,J= 12.8,5.6Hz,1H),4.86(q,J=6.8Hz,1H),4.23(s,2H),3.97(s,2H),3.08(q,J=7.2Hz,16H),2.90(d,J=18.0H z,2H),2.66(s,3H),2.59(d,J=18.4Hz,2H),2.12–1.95(m,4H),1.63(d,J=6.8Hz,6H).m / z(ESI): 939.5[M+H] + .

[0620] Example 60: Synthesis of Compound 65

[0621]

[0622] Step A: At room temperature, 2 drops of acetic acid and II-15 (158 mg, 0.74 mmol, 1.0 eq) were added to a methanol (10 mL) solution of I-15 (200 mg, 0.74 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (140 mg, 2.22 mmol, 3.0 eq) was added. The mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–80%) to give III-15 (320 mg, 0.69 mmol, 93.24% yield) as a pale yellow solid. m / z (ESI): 468.2 [M+H] + .

[0623] Step B: At room temperature, 4.0 M dioxane chloride solution (6.90 mmol, 1.73 mL, 10.0 eq) was added to a DCM (5 mL) solution of III-15 (320 mg, 0.69 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-15 (250 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 368.2 [M+H] + .

[0624] Step C: At room temperature, 2 drops of acetic acid and V-15 (116 mg, 0.68 mmol, 1.0 eq) were added to a methanol (10 mL) solution of IV-15 (250 mg, 0.68 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (128 mg, 2.04 mmol, 3.0 eq) was added. The reaction mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give VI-15 (330 mg, 0.63 mmol, 92.97% yield) as a pale yellow solid. m / z (ESI): 523.2 [M+H] + .

[0625] Step D: At room temperature, 4.0 M dioxane chloride solution (6.30 mmol, 1.6 mL, 10.0 eq) was added to a DCM (5 mL) solution of VI-15 (330 mg, 0.63 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product IV-15 (250 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 423.1 [M+H] + .

[0626] Step E: At room temperature, DIEA (228 mg, 1.77 mmol, 3.0 eq) and VIII-15 (173 mg, 0.59 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-15 (250 mg, 0.59 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 2 hours. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (50 mL) and washed three times with saturated brine (60 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give IX-15 (180 mg, 0.26 mmol, 43.83% yield) as a yellow solid. m / z (ESI): 697.2 [M+H] + .

[0627] Step F: Tetrahydroxydiboron (70 mg, 0.78 mmol, 3.0 eq) and 4,4-bipyridine (4 mg, 0.026 mmol, 0.1 eq) were added sequentially to a DMF (5 mL) solution of IX-15 (180 mg, 0.26 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 10 min. TLC showed complete reaction, and LC-MS showed the target compound. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–100%) to give X-15 (150 mg, 0.23 mmol, 86.63% yield) as a yellow solid. m / z (ESI): 667.2 [M+H] + .

[0628] Step G: At room temperature, tris(dibenzylacetone)palladium (8 mg, 0.009 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (10 mg, 0.018 mmol, 0.2 eq), cesium carbonate (59 mg, 0.18 mmol, 2.0 eq), and XI-15 (29 mg, 0.09 mmol, 1.0 eq) were added sequentially to a solution of X-15 (60 mg, 0.09 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 6 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0-10%) to give compound 65 (11 mg, 0.012 mmol, 12.84% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.42(s,1H),8.76(d,J=3.6Hz,1H),8.26(s,2H),8.08(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),7. 70(d,J=12.0Hz,1H),7.59(d,J=11.2Hz,1H),6.91(d,J=7.6Hz,1H),5.07(dd,J=12.8,5.6Hz,1H),4.88(p,J=7.2Hz,1H),4.21(t,J=7.6H z,2H),3.93(t,J=7.2Hz,2H),3.27–3.17(m,1H),3.11(t,J=12.4Hz,1H),2.87(d,J=11.6Hz,3H),2.76(d,J=10.4Hz,2H),2.67(s,3H),2. 62(s,1H),2.17-2.00(m,3H),1.90-1.75(m,6H),1.64(d,J=6.8Hz,9H),1.55–1.37(m,4H),1.06(t,J=12.4Hz,2H).m / z(ESI): 953.6[M+H] + .

[0629] Example 61: Synthesis of Compound 66

[0630]

[0631] Step A: At room temperature, 2 drops of acetic acid and II-14 (230 mg, 0.62 mmol, 1.0 eq) were added to a methanol (10 mL) solution of I-14 (200 mg, 0.62 mmol, 1.0 eq). The reaction mixture was stirred at 40 °C for 16 hours, and then sodium cyanoborohydride (77 mg, 1.24 mmol, 2.0 eq) was added. The reaction mixture was stirred at 40 °C for another 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 0–100%) to give III-14 (150 mg, 0.22 mmol, 35.48% yield) as a pale yellow solid. m / z (ESI): 683.2 [M+H] + .

[0632] Step B: Tetrahydroxydiboron (59 mg, 0.66 mmol, 3.0 eq) and 2,2-bipyridine (3 mg, 0.02 mmol, 0.1 eq) were added to a DMF (5 mL) solution of III-14 (150 mg, 0.22 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 10 min. LC-MS showed the target compound. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0–100%) to give IV-14 (70 mg, 0.11 mmol, 50.00% yield) as a pale yellow solid. m / z (ESI): 653.2 [M+H] + .

[0633] Step C: At room temperature, tris(dibenzylacetone)palladium (10 mg, 0.011 mmol, 0.1 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (13 mg, 0.022 mmol, 0.2 eq), cesium carbonate (72 mg, 0.22 mmol, 2.0 eq), and V-14 (35 mg, 0.11 mmol, 1 mL) were added sequentially to a solution of IV-14 (70 mg, 0.11 mmol, 1.0 eq) in dioxane (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried with anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 66 (5 mg, 0.005 mmol, 4.85% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.43(s,1H),8.77(d,J=3.6Hz,1H),8.26(s,1H),8.09(d,J=8.4Hz,2H),7.76( d,J=8.4Hz,2H),7.70(d,J=11.6Hz,2H),7.43(d,J=7.2Hz,1H),5.33(s,1H),5.11(dd,J=12.8,5.6Hz,1H),4.88(p,J= 7.2Hz,1H),3.20-3.06(m,1H),2.98-2.86(m,2H),2.84-2.70(m,6H),2.67(s,4H),2.63-2.55(m,1H),2.19(s,1H),2. 04(s,1H),1.87(d,J=12.0Hz,2H),1.82–1.70(m,5H),1.65(d,J=6.8Hz,9H),1.55-1.35(m,3H).m / z(ESI): 939.6[M+H] + .

[0634] Example 62: Synthesis of Compound 67

[0635]

[0636] Step A: At room temperature, DIEA (201 mg, 1.56 mmol, 3.0 eq), II-21 (119 mg, 0.52 mmol, 1.0 eq), and HATU (217 mg, 0.57 mmol, 1.1 eq) were added to a 5 mL solution of DMF containing I-17 (200 mg, 0.52 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (40 mL) and washed three times with saturated brine (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–70%) to give III-21 (280 mg, 0.47 mmol, 90.26% yield) as a pale yellow solid. m / z (ESI): 593.2 [M+H] + .

[0637] Step B: At room temperature, 4.0 M ethyl hydrochloride solution (4.7 mmol, 1.2 mL, 10.0 eq) was added to a 10 mL solution of ethyl acetate (280 mg, 0.47 mmol, 1.0 eq) of III-17. The reaction mixture was stirred at 40 °C for 2 hours. LC-MS showed that the target compound was obtained. The reaction solution was concentrated to obtain crude product IV-21 (230 mg, crude product) as a white solid. The crude product was used directly in the next step without purification. m / z (ESI): 493.2 [M+H] + .

[0638] Step C: At room temperature, DIEA (121 mg, 0.94 mmol, 2.0 eq) and V-17 (138 mg, 0.47 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of IV-17 (230 mg, 0.47 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 1 hour. TLC showed complete reaction, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 0–90%) to give VI-17 (330 mg, 0.43 mmol, 91.66% yield) as a yellow solid. m / z (ESI): 767.2 [M+H] + .

[0639] Step D: At room temperature, a hydrobromic acid-acetic acid solution (1 mL) was slowly added dropwise to a 2 mL solution of VI-17 (77 mg, 0.10 mmol, 1.0 eq) in acetic acid. The reaction mixture was stirred at room temperature for 1 hour. LC-MS showed the target compound. The reaction solution was concentrated to obtain crude product VII-17 (63 mg, crude product) as a pale yellow solid. The crude product was used directly in the next step without purification. m / z (ESI): 633.2 [M+H] + .

[0640] Step E: At room temperature, DIEA (52 mg, 0.40 mmol, 4.0 eq) and VIII-17 (33 mg, 0.10 mmol, 1.0 eq) were added sequentially to a DMSO (5 mL) solution of VII-17 (63 mg, 0.10 mmol, 1.0 eq). The reaction mixture was stirred at 90 °C for 2 hours. TLC showed that the reaction was complete, and LC-MS showed that the target compound was obtained. The mixture was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by preparative TLC (methanol:dichloromethane = 0–10%) to give compound 67 (5.0 mg, 0.059 mmol, 5.94% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.61(s,1H),8.00–7.58(m,3H),7.47(d,J=7.2Hz,1H),6.22(d,J=9.2Hz,1H),5. 87(t,J=8.0Hz,1H),5.12(dd,J=12.8,5.4Hz,1H),4.54(d,J=12.8Hz,1H),4.34(d,J=17.6Hz,1H),4.22–3.83(m,2H),3. 80-3.60(m,4H),3.55-3.41(m,1H),3.24–2.98(m,5H),2.95-2.80(m,2H),2.72–2.60(m,3H),2.22(d,J=10.8Hz,1H),2. 10-2.00(m,3H),2.01-1.82(m,4H),1.80-1.52(m,8H),1.50–1.33(m,2H),1.00(d,J=7.6Hz,3H).m / z(ESI): 876.4[M+H] + .

[0641] Example 63: Synthesis of Compound 68

[0642]

[0643] Step A: DIEA (2.08 g, 16.11 mmol, 2.81 mL, 3 eq) was added to a 20 mL solution of II-1 (1 g, 5.37 mmol, 1 eq) in DCM at room temperature. Then, I-1 (1.19 g, 5.37 mmol, 1 eq) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. LC-MS showed the target compound was obtained. The crude product was concentrated and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to obtain intermediate III-1 (1.5 g, 4.04 mmol, 75.22% yield), a pale yellow solid. m / z (ESI): 372.2 [M+H] + .

[0644] Step B: Ammonium chloride (360.05 mg, 6.73 mmol, 5 eq) was added to a solution of III-1 (500 mg, 1.35 mmol, 1 eq) and iron powder (375.90 mg, 6.73 mmol, 5 eq) in H2O (1 mL) and EtOH (10 mL). The mixture was stirred at 70 °C for 2 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound. The reaction solution was filtered, and the filter cake was washed twice with ethyl acetate. The filtrate was evaporated to dryness to give intermediate IV-1 (365 mg, 1.07 mmol, 79.41% yield) as a white solid. m / z (ESI): 342.2 [M+H] + .

[0645] Step C: Under nitrogen protection, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (84.74 mg, 146.45 μmol, 0.2 eq) and tris(dibenzylideneacetone)palladium (67.05 mg, 73.22 μmol, 0.1 eq) were added to a solution of V (236.32 mg, 732.23 μmol, 1 eq), IV-1 (300 mg, 878.67 μmol, 1.2 eq) and cesium carbonate (715.72 mg, 2.20 mmol, 3 eq) in 1,4-dioxane (5 mL). The mixture was stirred at 110 °C for 8 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was diluted with ethyl acetate (20 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0-100%) to give intermediate VI-1 (350 mg, 557.59 μmol, 76.15% yield). The product was a white solid. m / z (ESI): 628.8 [M+H] + .

[0646] Step D: Hydrochloric acid gas (0.5 mL, 4 M, 2 mmol, 25 eq) was added dropwise to a solution of VI-1 (50 mg, 79.66 μmol, 1 eq) in dichloromethane (3 mL). The reaction mixture was allowed to react at room temperature for 3 hours. The reaction was monitored by TLC until complete, and LC-MS showed the presence of the target compound. The mixture was evaporated to dryness to give intermediate VII-1 (30 mg, 54.54 μmol, 68.47% yield) as a white solid. m / z (ESI): 528.8 [M+H] + .

[0647] Step E: Hydrochloric acid gas (10 mL, 4 M, 40 mmol, 8.5 eq) was added dropwise to a solution of VIII-1 (1 g, 4.69 mmol, 1 eq) in dichloromethane (6 mL). The reaction mixture was allowed to react at room temperature for 3 hours. The reaction was monitored by TLC until complete, and LC-MS showed the presence of the target compound. The mixture was evaporated to dryness to give intermediate IX-1 (600 mg, 4.01 mmol, 85.53% yield) as a white solid. m / z (ESI): 114.2 [M+H] + .

[0648] Step F: Potassium carbonate (691.00 mg, 5.00 mmol, 5 eq) was added to a DMF (6 mL) solution of IX-1 (149.61 mg, 999.93 μmol, 1 eq) and X-1 (276.2 mg, 999.93 μmol, 1 eq). The mixture was stirred at 90 °C for 8 hours. The reaction was monitored by TLC until complete. LC-MS showed that the target compound was obtained. The mixture was diluted with dichloromethane (20 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate XI-1 (20 mg, 54.15 μmol, 5.42% yield) as a yellow solid. m / z (ESI): 370.4 [M+H] + .

[0649] Step G: Sodium cyanoborohydride (5.10 mg, 81.22 μmol, 1.5 eq) was added to a methanol (3 mL) solution of XI-1 (20 mg, 54.15 μmol, 1 eq) and VII-1 (30.49 mg, 54.15 μmol, 1 eq) at room temperature. The mixture was reacted overnight at room temperature. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The crude product was concentrated and purified by preparative HPLC to obtain compound 68 (15.5 mg, yield: 30.95%, purity: 95.25%). m / z (ESI): 881.6 [M+H]+. 1 H NMR (400MHz, Chloroform-d) δ8.44(d,J=3.7Hz,1H),8.37(s,1H),8.18(d,J=1.4Hz,1H),7.91–7.86(m,2H),7.79(d,J=11. 6Hz,1H),7.73(d,J=8.6Hz,2H),7.68–7.60(m,2H),7.22(d,J=2.3Hz,1H),6.99(dd,J=8.6,2.4Hz,1H),4.92(dd,J=12.1,5 .3Hz,1H),4.74(p,J=7.0Hz,1H),3.89(d,J=13.0Hz,2H),3.04(s,4H),2.96–2.84(m,4H),2.79(dd,J=16.2,12.4Hz,2H),2 .70(s,3H),2.51(s,4H),2.21(d,J=6.7Hz,2H),2.11(dd,J=8.5,6.1Hz,1H),1.79(d,J=13.3Hz,2H),1.71(d,J=6.9Hz,6H).

[0650] Example 64: Synthesis of Compound 69

[0651]

[0652] Step A: DIEA (1.75 g, 13.54 mmol, 2.36 mL, 3 eq) was added to a solution of I-2 (1.0 g, 4.51 mmol, 1 eq) and II-2 (1.12 g, 4.51 mmol, 1 eq) in dichloromethane (20 mL) at room temperature. The mixture was reacted at room temperature for 3 hours. The reaction was monitored by TLC until complete, and LC-MS showed the target compound was obtained. The mixture was diluted with dichloromethane (50 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate III-2 (1.6 g, 3.69 mmol, 81.80% yield) as a white solid. m / z (ESI): 334.3 [M-100+H] + .

[0653] Step B: Hydrochloric acid gas (10 mL, 4 M, 40 mmol, 10.8 eq) was added dropwise to a dichloromethane solution of III-2 (1.6 g, 3.69 mmol, 1 eq) under ice bath conditions. The reaction mixture was allowed to react at room temperature for 4 hours. The reaction was monitored by TLC until complete, and LC-MS showed the presence of the target compound. The mixture was evaporated to dryness to give intermediate IV-2 (1 g, 2.70 mmol, 73.26% yield) as a white solid. m / z (ESI): 334.3 [M+H] + .

[0654] Step C: At room temperature, add DIEA (323.26 mg, 2.50 mmol, 435.67 μL, 5 eq) to a solution of IV-2 (185.00 mg, 500.24 μmol, 1 eq) and 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (147.18 mg, 500.24 μmol, 1 eq) in dimethyl sulfoxide (6 mL). The mixture was reacted at 130 °C for 2 hours. The reaction was monitored to be complete by TLC, and the target compound was obtained by LC-MS. The mixture was diluted with dichloromethane (20 mL) and washed successively with water (10 mL x 2) and saturated NaHCO3 (10 mL x 2). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0-100%) to give intermediate V-2 (200 mg, 329.18 μmol, 65.80% yield). The product was a yellow solid. m / z (ESI): 608.6 [M+H] + .

[0655] Step D: Ammonium chloride (44.02 mg, 822.96 μmol, 5 eq) was added to a solution of V-2 (100 mg, 164.59 μmol, 1 eq) and iron powder (45.96 mg, 822.96 μmol, 5 eq) in H2O (0.2 mL) and EtOH (2 mL). The mixture was stirred at 70 °C for 2 hours. The reaction was monitored by ...

Claims

1. Selected from the following compounds or their pharmaceutically acceptable salts: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A pharmaceutical composition, said composition comprising: The compound of claim 1 or a pharmaceutically acceptable salt thereof; Optional: at least one pharmaceutically acceptable excipient, carrier, or diluent.

3. The pharmaceutical composition according to claim 2, wherein, The pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and flow aids; The pharmaceutically acceptable carriers include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

4. The pharmaceutical composition according to any one of claims 2 to 3, characterized in that, The composition is suitable for oral or injectable administration.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 2 to 4, in the preparation of a treatment or prevention of CDK-related conditions. in, The CDK-related diseases are proliferative disorders and their associated malignancies or cancers, including tumors with amplified or overexpressed Cyclin D or CCNE1 / 2.

6. The use according to claim 5, wherein, The malignant tumors or cancers mentioned are selected from: bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, skin cancer, lymphatic hematopoietic tumors, myeloid hematopoietic tumors, tumors originating from stromal cells, tumors of the central or peripheral nervous system, gliomas, seminomas, teratomas, osteosarcomas, keratospinomas, or Kaposi's sarcoma.

7. The use according to claim 5, wherein, The malignant tumor or cancer is selected from epidermal carcinoma, melanoma, leukemia, or thyroid follicular carcinoma.

8. Use of a kit in the preparation of a medicament for treating, inhibiting, or preventing CDK-related diseases, wherein, The kit comprises the compound according to claim 1 or a pharmaceutically acceptable salt or the pharmaceutical composition according to any one of claims 2 to 4.

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