Protein degradation agent and use thereof

Abstract

Provided are a protein degradation agent and use thereof. The provided tetrahydronaphthyridine compound is a compound represented by formula I or a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a polymorph thereof, a cocrystal thereof, a tautomer thereof, a stereoisomer thereof, or an isotopic compound thereof. The provided compound can be used for degrading BCL-XL protein, thereby selectively eliminating senescent cells. Moreover, the compound has significantly reduced platelet toxicity.

Description

Protein degrading agents and their applications Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a tetrahydronaphthidine compound with BCL-XL protein degradation activity and its application in the prevention or treatment of diseases and / or cancers related to the accumulation of senescent cells. Background Technology

[0002] Aging is a significant risk factor for many human diseases, including cancer, osteoarthritis, osteoporosis, atherosclerosis, neurodegenerative diseases, and diabetes. Increasing evidence suggests a close link between aging and the accumulation of senescent cells. These cells produce reactive oxygen species and various inflammatory mediators, and increased levels of these substances can lead to the degeneration and loss of tissue and organ function. Therefore, selectively eliminating senescent cells may be an innovative strategy for the prevention and treatment of age-related diseases.

[0003] Several small molecule compounds that can selectively kill senescent cells have been reported; these small molecules are also known as "senolytics." Due to the heterogeneity of senescent cells, while these senolytics achieve selective killing of senescent cells to some extent, there is still room for improvement in reducing toxicity and increasing the specificity of killing. Early senolytics mostly targeted important components in the senescent cell anti-apoptotic pathway (SCAP), that is, inducing cell death by blocking anti-apoptotic signals in senescent cells. Compared with normal cells, senescent cells show significantly increased expression of the anti-apoptotic proteins BCL2 / BCL-XL, antagonizing the activity of pro-apoptotic proteins such as Bax, thus enabling senescent cells to resist apoptosis. BCL-XL inhibitors can effectively kill senescent cells as anti-aging drugs. BCL-XL inhibitors induce apoptosis in senescent cells by disrupting the key anti-apoptotic mechanism for maintaining cell survival, achieving the clearance of senescent cells in vitro and in vivo. However, since BCL-XL is crucial for platelet survival, inhibition of BCL-XL causes thrombocytopenia and disrupts coagulation function. Avoiding the platelet toxicity caused by BCL-XL targeting has become a key challenge in drug development. Proteolysis-targeting chimeric molecules (PROTACs) are bifunctional hybrid small molecules that bind E3 ubiquitin ligase ligands and target protein ligands via suitable linker chains. This induces the formation of a ternary complex between the target protein and the E3 ligase, leading to ubiquitination of the target protein. The target protein is then recognized by the ubiquitin / proteasome 26S subunit and ultimately selectively degraded, thereby controlling intracellular target protein levels. Since E3 ligase is poorly expressed in platelets, PROTAC technology can be used to reduce thrombocytopenia caused by BCL-XL targeting. Therefore, BCL-XL PROTACs may represent a more promising treatment for aging. Summary of the Invention

[0004] To address at least one technical problem existing in the prior art, this application provides a novel class of protein-degrading compounds that can selectively remove senescent cells.

[0005] In a first aspect, this application provides a tetrahydronaphthidine compound, which is a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, or isotopic compound of Formula I:

[0006] In formula I,

[0007] X1, X2, and X3 are each independently selected from CR gAnd N, and X1, X2, X3 are not all CR at the same time. g ;

[0008] R a R b R c R d R e R f R g R h R i R j R k They may be the same or different, and are each independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C3-C8 cycloalkyl, halogen-substituted or unsubstituted C2-C8 alkenyl, halogen-substituted or unsubstituted C2-C8 alkynyl, halogen atom, hydroxyl, amino, nitro, cyano, carboxyl, acyl, halogen-substituted or unsubstituted C2-C8 alkoxy;

[0009] Ring A is independently selected from substituted or unsubstituted C6-C20 aromatic rings or substituted or unsubstituted C3-C20 heteroaromatic rings;

[0010] The B ring is absent or is independently selected from the following substituted or unsubstituted groups: C6-C20 aromatic rings, C3-C20 heteroaromatic rings, C3-C8 cycloalkyl rings, C3-C8 heterocycloalkyl rings, C6-C10 spirocyclic rings, C6-C10 heterospirocyclic rings, and C6-C10 heterofused rings;

[0011] When ring A and ring B contain substituents, the substituents are independently selected from the group consisting of: deuterium, halogen, cyano, nitro, amino, amide, ester, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C3-C20 cycloalkyl, C1-C20 heterocyclic, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, and C3-C20 heteroaryl.

[0012] E1 and E2 are either hydrogen or E3 ubiquitin ligands, and E1 and E2 are not both hydrogen at the same time;

[0013] L1 is absent or is a linking group;

[0014] L2 is a linking group;

[0015] V is absent or selected from C1-C6 alkylene, -C1-C6 alkylene-O- or -C1-C3 alkylene-O-C1-C3 alkylene-, wherein the alkylene is optionally substituted with a halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heteroalicycloyl, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl;

[0016] W is selected from C6-C20 aryl, C1-C20 heteroaryl, C6-C20 aryl-C1-C20 heteroaryl, C3-C12 cycloalkyl, C3-C8 heterocycloalkyl, C6-C14 spirocyclic, and C6-C14 fused cycloalkyl; wherein W is optionally substituted with one or more substituents selected from halogen atoms, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C1-C10 alkoxyalkoxy, C1-C10 haloalkyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heterocycloalkyl, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.

[0017] Those skilled in the art will understand that in this application, when L1 is absent, W is directly connected to E1. In this case, Equation I is as shown in Equation I':

[0018] In some implementations, X1 is N. In some implementations, X2 is N. In some implementations, X3 is CR. g .

[0019] In some implementations, X1 is N, and X2 and X3 are CR. g .

[0020] In some implementations, X2 is N, and X1 and X3 are CR. g .

[0021] In some implementations, X3 is N, and X1 and X2 are CR. g .

[0022] In some implementations, R a R b R c R d R e R f R g R h R i R j R kEach is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, halogen-substituted or unsubstituted C2-C6 alkenyl, halogen-substituted or unsubstituted C2-C6 alkynyl, halogen atom, hydroxyl, amino, nitro, cyano, carboxyl, halogen-substituted or unsubstituted C2-C6 alkoxy.

[0023] In some implementations, R a R b R c R d R e R f R g R h R i R j R k Each is independently selected from hydrogen, deuterium, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, halogen atom, halogen-substituted or unsubstituted C2-C6 alkoxy.

[0024] In some implementations, R g It is hydrogen.

[0025] In some implementations, R a R b R c R d R e R f R g R h R i R j R k Both are hydrogen.

[0026] In some embodiments, ring A is selected from the following groups, substituted or unsubstituted: pyridinyl, pyrimidinyl, pyridazinyl, quinolinyl, thiazolyl, imidazolyl, pyrroleyl, pyrazolyl, thiopheneyl, thienofuranyl, thienothiazolyl, carbazolenopyrroleyl, pyridopyrazolyl, pyridopyrroleyl, indoleyl, azaindoleyl, isoquinolinyl, anthraceneyl, phenanthreneyl, benzofuranyl, benzothiopheneyl, indoleyl; when A When the ring contains substituents, the substituents are independently selected from the group consisting of: deuterium, halogen, cyano, nitro, amino, amide, ester, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C1-C8 heterocycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, and C3-C10 heteroaryl.

[0027] In some embodiments, ring A is selected from the following groups, substituted or unsubstituted: thiazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0028] In some preferred embodiments, ring A is pyridinyl.

[0029] In some preferred embodiments, ring A is Where -# indicates the position where ring A connects to the group #-L2-E2, and -* indicates the position where ring A connects to the group The location of the connection.

[0030] In some preferred embodiments, ring A is Where -# indicates the position where ring A connects to the group #-L2-E2, and -* indicates the position where ring A connects to the group The location of the connection.

[0031] In some embodiments, the B ring is selected from the following groups, substituted or unsubstituted: pyrazolyl, pyrroloyl, imidazoyl, pyridyl, pyrimidinyl, indoleyl, indazoleyl, tetrahydropyrroloyl, piperidinyl, aziridine, cubic, pyridazinyl, quinolinyl, thiazoyl, thiophene, thienofuranyl, thienothiazoyl, carbazopyrroloyl, pyridopyrazolyl, pyridopyrroloyl, indoleyl, azinoindoleyl, isoquinolinyl, anthraceneyl, phenanthreneyl, benzene And furanyl, benzothiophene; when the B ring contains substituents, the substituents are independently selected from the group consisting of: deuterium, halogen, cyano, nitro, amino, amide, ester, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C1-C8 heterocycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, C3-C10 heteroaryl.

[0032] In some embodiments, ring B is selected from substituted or unsubstituted pyrazolyl groups or substituted or unsubstituted imidazole groups.

[0033] In some embodiments, when ring B contains a substituent, the substituent is independently selected from the group consisting of: deuterium, fluorine, cyano, nitro, C1-C4 amide, C1-C4 ester, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2F, -CHF2, -CH2CF3, -CF3, -CH2OH, -CH2CH2OH, -NH2, -N(CH3)2.

[0034] In some embodiments, ring B is selected from the following groups:

[0035] In some implementations, ring B is selected from... Where *- indicates the position where ring B connects to ring A. Indicates the B ring and group The location of the connection.

[0036] In some embodiments, the E3 ubiquitin ligand is selected from CRBN ligand, VHL ligand, MDM2 ligand, IAP ligand, DCAF ligand, RNF ligand, and KEAP1 ligand.

[0037] In some implementations, the E3 ubiquitin ligand is selected from CRBN ligands and VHL ligands.

[0038] In some embodiments, the E3 ubiquitin ligase ligand is selected from the group consisting of groups derived from compounds represented by Formulas 1 to 3:

[0039] In Formula 1, R1 is selected from hydrogen atom, deuterium, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, C6-C20 aryl and C3-C20 heteroaryl;

[0040] R2 is selected from hydrogen atom, deuterium, hydroxyl, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, cyano, nitro, C3-C8 cycloalkyl, C3-C8 heterocyclic, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with C1-C8 alkyl.

[0041] R3 is selected from hydrogen atom, deuterium, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkoxyC1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, amino, cyano, C3-C8 cycloalkyl, C3-C8 heterocyclic, C3-C8 cycloalkylC1-C8 alkyl, C3-C8 heterocyclicC1-C8 alkyl, -C1-C8 alkyl-C(=O)NH2, -C1-C8 alkyl-C(=O)NH-C1-C8 alkyl; or R3 is connected to its adjacent benzene ring to form a 5-8 membered heterocycle;

[0042] X4 is -NR a R b 5-6 membered heteroaryl, benzo5-6 membered heterocyclic, R a Selected from hydrogen, deuterium, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, R b Selected from hydrogen, deuterium, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, -C(=O)-R s Rs Selected from hydrogen, unsubstituted, or modified by one or more R 4 The group consisting of the following substituted groups: C1-C8 alkyl, C3-C8 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, R 4 The X4 is selected from deuterium, halogen, C1-C8 alkyl and cyano; optionally, X4 is substituted by one or more substituents selected from deuterium, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C6-C20 aryl, C3-C20 heteroaryl;

[0043] In Formulas 2 and 3, ring C is independently selected from C6-C20 aromatic rings, C3-C20 heteroaromatic rings, and C7-C20 fused alicyclic aromatic rings, R c R5 is independently selected from hydrogen, deuterium, halogen, C1-C8 alkyl, -NH2 and -NH-C1-C8 alkyl; t is 0 or 1.

[0044] In some embodiments, in Formula 1, R1 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C6-C10 aryl, and C3-C10 heteroaryl. In some embodiments, in Formula 1, R1 is selected from hydrogen, deuterium, and C1-C4 alkyl. In some embodiments, in Formula 1, R1 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, or tert-butyl.

[0045] In some embodiments, in Formula 1: R2 is selected from hydrogen atom, deuterium, hydroxyl group, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclic, C3-C10 heteroaryl, and C1-C4 alkyl-substituted C3-C10 heteroaryl. In some embodiments, in Formula 1: R2 is selected from hydrogen atom, deuterium, hydroxyl group, halogen, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkyl-substituted 5-6 membered heteroaryl. In some embodiments, in Formula 1: R2 is selected from hydrogen atom, deuterium, fluorine, hydroxyl group, Methoxy, ethoxy, and propoxy.

[0046] In some embodiments, in Formula 1: R3 is selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, amino, cyano, C3-C6 cycloalkyl, C3-C6 heterocyclic, C 3-6 Cycloalkyl C1-C4 alkyl, C 3-6Heterocyclic C1-C4 alkyl, -C1-C4 alkyl-C(=O)NH2, -C1-C4 alkyl-C(=O)NH-C1-C4 alkyl. In some embodiments, in Formula 1: R3 is selected from hydrogen, deuterium, fluorine, C1-C4 alkyl, C1-C4 haloalkyl, amino, cyano, -C1-C4 alkyl-C(=O)NH2, -C1-C4 alkyl-C(=O)NH-C1-C4 alkyl. In some embodiments, in Formula 1: R3 is selected from hydrogen, deuterium, fluorine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, -CH2-C(=O)NH2, -CH2-C(=O)NH-CH3, -CH2-C(=O)NH-CH2CH3.

[0047] In some embodiments, in Formula 1: R3 is connected to its adjacent benzene ring to form a 5, 6, 7 or 8-membered heterocycle.

[0048] In some implementations, in Equation 1: X4 is -NR a R b 5-6 membered heteroaryl, C3-C6 cycloalkyl substituted 5-6 membered heteroaryl, benzo5-6 membered heterocyclic, R a Selected from hydrogen, deuterium, C1-C4 alkyl, R b Selected from hydrogen, deuterium, C1-C4 alkyl, -C(=O)-R s R s Selected from hydrogen, unsubstituted, or modified by one or more R 4 The group consisting of the following substituted groups: C1-C4 alkyl, C3-C6 cycloalkyl, R 4 The radical is selected from deuterium, fluorine, C1-C4 alkyl, and cyano. In some embodiments, in Formula 1: X4 is -NH2,

[0049] In some embodiments, in Formulas 2 and 3: ring C is independently selected from C6-C10 aromatic rings, C3-C10 heteroaromatic rings, and C7-C12 fused alicyclic aromatic rings. In some embodiments, in Formulas 2 and 3: R c It is independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, -NH2 and -NH-C1-C4 alkyl.

[0050] In some implementations, in Equations 2 and 3: Independently selected from the following groups:

[0051] In some embodiments, in Formula 2, R5 is selected from hydrogen atoms, halogens, and C1-C4 alkyl groups. In some embodiments, in Formula 2, R5 is selected from hydrogen atoms, fluorine, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. In some embodiments, in Formula 2, R5 is a hydrogen atom.

[0052] In some embodiments, the E3 ubiquitin ligase ligand is selected from the group consisting of:

[0053] The definitions of R1 to R5 are the same as those in Equation 1 or Equation 2.

[0054] In some embodiments, either E1 or E2 is hydrogen, and the other is selected from the group consisting of: Or; where the definition of R5 is the same as the definition in Equation 2 above in this invention.

[0055] According to some embodiments of the present invention, L1 is absent, or L1 and L2 are independently selected from any one or more of the following groups to form a structural segment:

[0056] -C(=O)O-, -C(=O)NR6-, -C(=O)NR6O-, -C(=O)NR6SO2-, -C(=O)NR6-C(=O)NR6-, -C(=O)NR6COO-, -CR6R6, -C(=O)-, -O-, -S-, -S(=O-, -S(=O)2-, -NR6-, -CR6=CR6-, -C≡C-, C3-C20 cycloalkyl, C2-C20 heterocycloalkyl, C6-C20 aromatic cycloalkyl, C3-C2 The C3-C20 cycloalkyl, C2-C20 heterocycloalkyl, C6-C20 aromatic cycloalkyl, C3-C20 aromatic heterocycloalkyl, C5-C20 spirocycloalkyl, C5-C20 spirocycloalkyl, C5-C20 bridged cycloalkyl, and C5-C20 bridged heterocycloalkyl groups are optionally substituted with one, two, or three R7 groups; adjacent two or more R7 groups may be linked to form a ring.

[0057] Each R7 is independently selected from halogen, cyano, nitro, C1-C10 alkyl, C1-C10 haloalkyl, -OR6, -NR6R6;

[0058] Each R6 is independently selected from hydrogen, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, -C0-C6 alkylene-(C3-C10 carbocyclic), -C0-C6 alkylene-(3-10 heterocyclic alkyl).

[0059] According to some embodiments of the present invention, L1 is absent, or L1 and L2 are independently selected from any one or more of the following groups to form a structural segment:

[0060] -C(=O)O-, -C(=O)NR6-, -C(=O)NR6O-, -C(=O)NR6SO2-, -C(=O)NR6-C(=O)NR6-, -C(=O)NR6COO-, -CR6R6, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2-, -NR6-, -CR6=CR6-, -C≡C-, C3-C10 cycloalkyl, 3-10 heterocyclic alkyl, C6-C10 aromatic ring, 5-10 aromatic heterocyclic, 5-12 spirocyclic, 5-12 spirocyclic, 5-12 bridged ring and 5-12 bridged heterocyclic; among which C3-C10 cycloalkyl, 3- The 10-membered heterocyclic alkyl, C6-C10 aromatic ring, 5-10-membered aromatic heterocyclic, 5-12-membered spirocyclic, 5-12-membered spirocyclic, 5-12-membered bridged ring and 5-12-membered bridged heterocyclic are optionally substituted by one, two or three R7s; two or more adjacent R7s can be linked to form a ring; each R7 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, OR6, -NR6R6; each R6 is independently selected from hydrogen, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, -C0-C2 alkylene-(C3-C10 carbocyclic), -C0-C2 alkylene-(3-10-membered heterocyclic alkyl).

[0061] In some implementations, in Equation I, when L1 exists, Selected from

[0062] Y3 is selected from hydrogen, deuterium, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl;

[0063] Y1 and Y2 are independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 ynyl, C6-C20 aryl, C1-C20 heteroaryl, and C2-C20 heteroalicyclic groups. Among them, for C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, and C2-C8 ynyl groups, CH2 can be selected from -O-, -S-, -SO2-, -C(=O)-, and -NR. g One or more of the groups are replaced, wherein the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heterocyclocyclic are optionally replaced by one or more of the following groups: halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heterocyclocyclic, C1-C10 alkyl, C2-C8 alkenyl or C2-C8 alkynyl.

[0064] In some embodiments, Y3 is selected from hydrogen, deuterium, C1-C6 alkyl, and C3-C6 cycloalkyl. In some embodiments, Y3 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, Y3 is hydrogen.

[0065] In some embodiments, Y1 and Y2 are independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, and C2-C20 heteroalicyclic groups, wherein the CH2 in the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl groups can be selected from -O-, -S-, -SO2-, -C(=O)-, and -NR. g One or more of the groups are replaced, wherein the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl and C2-C20 heterocyclocyclic are optionally replaced by one or more of the following groups: halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heterocyclocyclic, C1-C10 alkyl, C2-C8 alkenyl or C2-C8 alkynyl.

[0066] In some embodiments, Y1 and Y2 are independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 heteroaryl, and C2-C10 heterocyclocyclic groups, wherein CH2 in the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C2-C10 heterocyclocyclic groups can be selected from -O-, -S-, -SO2-, -C(=O)-, and -NR. g One or more of the groups in the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 heteroaryl, and C2-C10 heterocyclocycloyl groups are optionally replaced by one or more of the following groups: halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, carboxyl group, acyl group, C1-C6 alkoxy group, C6-C10 aryl group, C3-C10 heteroaryl group, C2-C10 heterocyclocycloyl group, C1-C6 alkyl group, C2-C6 alkenyl group, or C2-C6 alkynyl group.

[0067] In some embodiments, Y1 is hydrogen, and Y2 is selected from C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C1-C20 heteroaryl, and C2-C20 heteroalicyclic groups, wherein the CH2 in the C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl groups may be selected from -O-, -S-, -SO2-, -C(=O)-, and -NR. g One or more groups are replaced by a halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, carboxyl group, acyl group, C1-C10 alkoxy group, C6-C20 aryl group, C1-C20 heteroaryl group, C2-C20 heteroalicyclic group, C1-C10 alkyl group, C2-C8 alkenyl group, or C2-C8 alkynyl group, and at least two of the substituents together constitute an alicyclic ring, heteroalicyclic ring, aromatic ring, or heteroaromatic ring.

[0068] In some implementations, both Y1 and Y2 are hydrogen.

[0069] In some embodiments, Y1 and Y2, together with the N atom attached to them, constitute a heterocyclic group. In some embodiments, Y1 and Y2, together with the N atom attached to them, constitute a C2-C20 heterocyclic group, wherein the ring of the C2-C20 heterocyclic group optionally contains one or two additional heteroatoms selected from N or O.

[0070] In some embodiments, the heterocyclic group is selected from halogen atoms, cyano, nitro, C6-C20 aryl, C1-C20 heteroaryl, C1-C10 alkoxy, C1-C10 hydroxyalkyl, C6-C20 aryloxy, C2-C20 heterocyclic, amino, hydroxy, mercapto, etc. -NR Y1 R Y2 One or more substituents are substituted;

[0071] R Y1 and R Y2 The aryl and heteroaryl groups are independently selected from hydrogen, deuterium, C6-C10 aryl, C1-C10 heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the aryl and heteroaryl groups are optionally substituted with a halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, alkoxy, aryl, heteroaryl, heteroalicyclic, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl, wherein the substituents at at least two positions together constitute an alicyclic, heteroalicyclic, aromatic or heteroaromatic ring;

[0072] L Y1 It is selected from C1-C6 alkylene, -C1-C6 alkylene-O- or -C1-C3 alkylene-O-C1-C3 alkylene-, wherein the alkylene is optionally substituted with a halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heterocycloallelate, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl.

[0073] In some implementations, R Y1 and R Y2 The aryl and heteroaryl groups are independently selected from hydrogen, C6-C10 aryl, C1-C10 heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl groups. The aryl and heteroaryl groups are optionally substituted with a halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C8 alkoxy, C6-C10 aryl, C1-C10 heteroaryl, C2-C10 heteroalicyclic, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C8 alkynyl groups. Optionally, the substituents at at least two positions collectively constitute a C3-C10 aliphatic ring, a C2-C10 heteroaliphatic ring, a C6-C10 aromatic ring, or a C1-C10 heteroaryl ring. In some embodiments, R... Y1 and R Y2 It is independently selected from hydrogen and C1-C6 alkyl groups.

[0074] In some embodiments, the C2-C20 heterocyclic group is optionally selected from halogen atoms, hydroxyl groups, mercapto groups, amino groups, nitro groups, cyano groups, C1-C10 alkoxy groups, C1-C10 alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, and C2-C8 alkynyl groups. Substituents of R Y1 and R Y2 It is independently selected from hydrogen and C1-C6 alkyl groups.

[0075] In some embodiments, the C2-C20 heterocyclic group is optionally substituted with one or more substituents selected from halogen, -NH2, -OH, -NO2, carbonyl, -CH2OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.

[0076] In some embodiments, Y1 and Y2, together with the N atom attached to them, constitute a C4-C20 heterocyclic group, which is selected from the following groups:

[0077] R' can independently represent no substituent, a single substituent, or multiple substituents, each substituent being independently selected from deuterium, hydroxyl, halogen, NH2, carboxyl (-COOH). C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl chain, amino-substituted C1-C6 alkyl chain, morpholine-substituted C1-C6 alkyl chain, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, phenyl, benzyl;

[0078] L Y2 It is a C1-C6 alkylene group that is absent or substituted with C1-C6 alkylene, halogen, hydroxyl, or C1-C6 alkoxy, preferably methylene, ethylene, or propylene;

[0079] R Y3 H, deuterium, halogen, hydroxyl, NH2, carboxyl (-COOH), -CONH2, sulfonic acid (-SO3H), -SO2-C1-C6 alkyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, phenyl or benzyl.

[0080] In some implementations, in Formula I, E1 is hydrogen when L1 is present.

[0081] According to some embodiments of the present invention, when L1 is absent, L2 is selected from... L3 is absent or is independently selected from one or more of the following groups:

[0082] R8 is absent or is independently selected from one or more of the following groups:

[0083] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0084] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0085] o can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0086] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0087] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0088] r can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0089] Ring D is independently selected from the group consisting of saturated or unsaturated C2-C20 nitrogen-containing heterocyclic groups; the saturated or unsaturated C2-C20 nitrogen-containing heterocyclic group is optionally substituted by one or more substituents selected from halogen, hydroxyl, carbonyl, carboxyl, cyano, amino, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, C3-C12 cycloalkyl, C1-C10 alkoxy, C2-C10 olefin, C2-C10 alkynyl, C6-C20 aryl, and C3-C20 heteroaryl, and adjacent two or more substituents are optionally linked to form a ring;

[0090] M, Z, and R do not exist or are independently selected from the definitions of CR6R6, NR6, O, or D of the same ring;

[0091] L4 is absent or is independently selected from the group consisting of saturated or unsaturated C2-C20 nitrogen-containing heterocyclic groups and the following groups:

[0092] s can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0093] The saturated or unsaturated C2-20 nitrogen-containing heterocyclic group is optionally substituted by one or more substituents selected from halogen, hydroxyl, carbonyl, carboxyl, cyano, amino, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, C3-C12 cycloalkyl, C1-C10 alkoxy, C2-C10 olefin, C2-C10 alkynyl, C6-C20 aryl, and C3-C20 heteroaryl, and adjacent two or more substituents are optionally linked to form a ring;

[0094] Each R7 involved in L4 is independently selected from halogen, cyano, nitro, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, OR6, -NR6R6; two or more adjacent R7s can be cyclized into 3-10 membered rings;

[0095] The condition is that at least one of L3, R8, and L4 exists;

[0096] Each R6 in L3, R8, and L4 is independently selected from hydrogen, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, -C0-C2 alkylene-(C3-C10 carbocyclic), and -C0-C2 alkylene-(3-10 heterocyclic alkyl); preferably, R6 is independently selected from hydrogen, halogen-substituted or unsubstituted C1-C10 alkyl, -C 1-2Alkylene-substituted or unsubstituted C3-C10 cycloalkyl; more preferably hydrogen.

[0097] In some embodiments, the saturated or unsaturated C2-C20 nitrogen-containing heterocyclic groups involved in rings D and L4 are independently selected from the group consisting of:

[0098] The saturated or unsaturated C2-20 nitrogen-containing heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, CF3, OH, carbonyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C2-C6 olefin, C2-C6 alkynyl, C1-C6 alkyl, COOH, CN, or NH2; a 3-10 membered ring is optionally formed between two or more adjacent substituents.

[0099] In some implementations... Selected from Y3 is independently selected from hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl groups, and L1 is selected from the group consisting of T; in other embodiments, No, L2 is selected from the group consisting of group T; wherein, group T includes one or more of the following structures:

[0100] In some embodiments, V is absent or selected from C1-C6 alkylene groups. In some embodiments, V is absent or selected from methylene, ethylene, propylene, and butylene. In some embodiments, V is absent or is methylene. In some embodiments, V is methylene.

[0101] In some embodiments, W is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, cycloalkyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, indazole, cyclohexyl, cyclopentyl, cycloheptyl, oxaspiro[3.3]heptyl, spiro[2.5]octyl, adamantyl; wherein W is optionally substituted by one or more of fluorine, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C4 alkoxy, C1-C10 alkoxyalkoxy, C1-C4 haloalkyl, C6-C10 aryl, C3-C10 heteroaryl, C2-C6 heterocycloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl.

[0102] In some embodiments, W is selected from the following groups:

[0103] In some embodiments, W is selected from adamantyl and phenyl, and W is optionally substituted by one or more of fluorine, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, trifluoromethyl, methyl, ethyl, isopropyl, tert-butyl, alkoxyalkoxy, methoxy, and ethoxy.

[0104] In some embodiments, W is selected from the following groups:

[0105] In some embodiments, the structure of the compound represented by Formula I is as shown in Formula IA, Formula IB, or Formula IC:

[0106] The definitions of the symbols in the above equations are the same as those in Equation I.

[0107] In some embodiments, the structure of the compound represented by Formula I is as shown in any one of Formulas I-1 to I-9:

[0108] R u and R v Independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, nitro, amino, amide, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C 3-6 Cycloalkyl, C1-C6 heterocycloalkyl, C6-C10 aryl, C3-C10 heteroaryl; preferably, R u and R v All are hydrogen;

[0109] The definitions of other symbols are the same as those in Equation I.

[0110] In some embodiments, the structure of the compound represented by Formula I is as shown in any one of Formula I-10 or I-18:

[0111] The definitions of each symbol in the above formulas are the same as those in Formula I; in Formulas I-16 to I-18, R represents one or more of hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C10 alkoxy, C1-C10 alkoxyalkoxy, C1-C10 haloalkyl, C6-C20 aryl, C1-C20 heteroaryl, C2-C20 heterocycloalkenyl, C1-C10 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl.

[0112] In some embodiments, in formulas I-16 to I-18, R represents one or more of hydrogen, fluorine, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, C1-C4 alkoxy, C1-C4 haloalkyl, C6-C10 aryl, C3-C10 heteroaryl, C2-C6 heterocycloalkyl, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, or C2-C4 alkynyl. In some embodiments, in formulas I-16 to I-18, R represents one or more of hydrogen, fluorine, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, acyl, trifluoromethyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, and ethoxy. In some embodiments, in formulas I-16 to I-18, R represents hydrogen.

[0113] In some embodiments, the compound represented by Formula I is selected from the group consisting of:

[0114] Secondly, this application provides a pharmaceutical composition comprising the tetrahydronaphthidine compound described in the first aspect, and a pharmaceutically acceptable excipient.

[0115] Thirdly, this application provides a method for preventing or treating age-related diseases and / or cancer, comprising administering to a subject in need a therapeutically effective amount of the tetrahydronaphthidine compound of claim 1 or the pharmaceutical composition of claim 2.

[0116] In some embodiments, the age-related diseases are selected from diseases related to the accumulation of senescent cells, preferably from fibrotic diseases.

[0117] In some implementations, the subject is diagnosed with cancer and optionally undergoing cancer treatment selected from chemotherapy and radiation therapy.

[0118] In some embodiments, the diseases associated with the accumulation of senescent cells are selected from fibrotic diseases, ophthalmic diseases, bone and joint diseases, and skin and connective tissue diseases.

[0119] In some implementations, the cancer includes, but is not limited to, hematomas and solid tumors.

[0120] In some embodiments, the fibrotic diseases include, but are not limited to, idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, cutaneous fibrosis, interstitial lung disease, fibrotic pancreatitis, scars, fibrotic scars, superficial or flat scars, cord-like or contracture-like scars, webbed scars, atrophic scars, atrophic scars, bridging scars and vesicular scars, hypertrophic scars, and keloids.

[0121] In some embodiments, the ophthalmic diseases include, but are not limited to, retinopathy, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, and dry age-related macular degeneration.

[0122] In some embodiments, the cancers include, but are not limited to, acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, lymphogranuloma, Kaposi's sarcoma, kidney cancer, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, neuroblastoma, non-lymphoblastic sarcoma, osteosarcoma, ovarian tumor, pancreatic cancer, penile cancer, skin cancer, soft tissue sarcoma, thymic cancer, uterine cancer, vaginal cancer, and prostate cancer.

[0123] Fourthly, this application provides the use of the tetrahydronaphthidine compound described in the first aspect or the pharmaceutical composition described in the second aspect in the preparation of a medicament for the prevention or treatment of aging-related diseases and / or cancer.

[0124] In some implementations, the age-related diseases are selected from diseases related to the accumulation of senescent cells.

[0125] In some embodiments, the diseases associated with the accumulation of senescent cells are selected from fibrotic diseases, ophthalmic diseases, bone and joint diseases, and skin and connective tissue diseases.

[0126] In some implementations, the cancer includes, but is not limited to, hematomas and solid tumors.

[0127] In some embodiments, the fibrotic diseases include, but are not limited to, idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, cutaneous fibrosis, interstitial lung disease, fibrotic pancreatitis, scars, fibrotic scars, superficial or flat scars, cord-like or contracture-like scars, webbed scars, atrophic scars, atrophic scars, bridging scars and vesicular scars, hypertrophic scars, and keloids.

[0128] In some embodiments, the ophthalmic diseases include, but are not limited to, retinopathy, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, and dry age-related macular degeneration.

[0129] In some embodiments, the cancers include, but are not limited to, acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, lymphogranuloma, Kaposi's sarcoma, kidney cancer, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, neuroblastoma, non-lymphoblastic sarcoma, osteosarcoma, ovarian tumor, pancreatic cancer, penile cancer, skin cancer, soft tissue sarcoma, thymic cancer, uterine cancer, vaginal cancer, and prostate cancer.

[0130] Fifthly, this application also provides a method for synthesizing the tetrahydronaphthidine compound as described in the first aspect, comprising:

[0131] The compound of formula Ia is reacted with compound H-E2 to obtain the compound of formula I.

[0132] The definitions of each symbol are the same as in equation I;

[0133] Alternatively, the compound of formula IIa is condensed with intermediate IIb to obtain key intermediate IIc, and intermediate IIc is deprotected to obtain compound IId; compound IId is then reacted with compound H-E2 to obtain the compound of formula I.

[0134] The definitions of each symbol are the same as in equation I;

[0135] Alternatively, the compound shown in formula IIIa can be reacted with the compound of formula H-L1-E1 to obtain the compound of formula I.

[0136] The definitions of each symbol are the same as in equation I;

[0137] Alternatively, the compound of formula IVa can be reacted with the compound of formula H-L5-E2 to obtain the compound of formula I.

[0138] -C(=O)-L5- together represent L2, and the definitions of other symbols are the same as those of I.

[0139] In some embodiments, L1 is absent and E1 is hydrogen, and the method includes: reacting the compound of formula Ia-1 with the H-E2 compound to obtain the compound of formula I.

[0140] The definitions of each symbol are the same as those in the compound described in Formula I.

[0141] In some embodiments, L1 is absent and E1 is hydrogen, and the method includes: condensing the compound of formula IIa-1 with intermediate IIb to obtain the key intermediate IIc-1, deprotecting IIc-1 to obtain IId-1; reacting IId-1 with an H-E2 compound to obtain the compound of formula I:

[0142] The definitions of each symbol are the same as those in the compound described in Formula I.

[0143] In some implementations... Selected from The method includes reacting the compound of formula IIIa-1 with a compound of formula H-L1-E1 to obtain the compound of formula I:

[0144] The definitions of each symbol are the same as those in the compound described in Formula I.

[0145] In some implementations... Selected from The method includes reacting the compound of formula IIIa-2 with a compound of formula H-L1-E1 to obtain the compound of formula I:

[0146] The definitions of each symbol are the same as those in the compound described in Formula I.

[0147] Sixthly, this application also provides intermediate compounds selected from compounds of formula M1, M2, M3, M4, M5, M6 or M7:

[0148] PG represents a protecting group, X represents a protecting group or a halogen, wherein the halogen is preferably chlorine, bromine or iodine, and other symbols are defined as defined above in this invention.

[0149] In a seventh aspect, this application also provides an intermediate compound selected from any one of the following compounds: Attached Figure Description

[0150] Figure 1 shows the platelet toxicity test results of compound RC002 provided by the present invention and control compound A-1331852.

[0151] Figure 2 illustrates the efficacy of the compound RC002 provided by this invention in an animal model of idiopathic pulmonary fibrosis. Figure 2A shows the improvement in white blood cell (WBC) count in the idiopathic pulmonary fibrosis model caused by intratracheal (IT) administration of RC002, and Figure 2B shows the improvement in hydroxyproline (HYP) count in the idiopathic pulmonary fibrosis model caused by intratracheal (IT) administration of RC002.

[0152] Figure 3 shows the efficacy of the compound RC002 provided by this invention against hyperoxia-induced retinopathy. ****p<0.0001 indicates a negative control; one-way ANOVA. Detailed Implementation

[0153] The present invention will be described in detail below with reference to the embodiments: These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation schemes and processes. However, the implementation schemes provided by the present invention are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention. Conditions and methods not specified in the following embodiments are performed according to conventional methods.

[0154] definition

[0155] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight-chain alkyl group. Depending on the structure, an alkyl group can be a monovalent or divalent group (i.e., an alkylene group). In this invention, the alkyl group is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl group" having 1-6 carbon atoms, and even more preferably an alkyl group having 1-4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that "alkyl" as used herein includes all possible configurations and conformations of the alkyl group; for example, "propyl" as used herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl, and tert-butyl, and "pentyl" includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl, etc.

[0156] The term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon chain monovalent or divalent group having carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In this invention, the alkenyl group is preferably an alkenyl group having 2 to 20 carbon atoms, more preferably an alkenyl group having 2 to 10 carbon atoms, even more preferably an alkenyl group having 2 to 8 carbon atoms, and even more preferably an alkenyl group having 2 to 6 carbon atoms. The term is illustrative of groups including, but not limited to, vinyl (i.e., -CH=CH2), 1-propenyl (i.e., -CH=CHCH3), 3-propenyl (or allyl, i.e., -CH2CH=CH2), 2-propenyl (i.e., -C(CH3)=CH2), butadienyl (including 1,2-butadienyl and 1,3-butadienyl), etc.

[0157] The term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon chain monovalent or divalent group having carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds). In this invention, the alkynyl group is preferably an alkynyl group having 2 to 20 carbon atoms, more preferably an alkynyl group having 2 to 10 carbon atoms, even more preferably an alkynyl group having 2 to 8 carbon atoms, and even more preferably an alkynyl group having 2 to 6 carbon atoms. The term is illustratively used to refer to groups including, but not limited to, ethynyl (i.e., -C≡CH), propynyl (i.e., -CH2C≡CH), propynyl (i.e., -C≡CCH3), etc.

[0158] The term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

[0159] The term "alkoxyalkoxy" refers to alkyl-O-alkyl-O-, where the alkyl group is as defined herein. Typical alkoxyalkoxy groups include, but are not limited to, methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.

[0160] The term "cycloalkyl" refers to a monocyclic or polycyclic group (including spirocyclic, bridged, and fused rings) containing only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent or bivalent group (e.g., a cycloalkylene group). In this invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0161] The term "aryl" refers to an aromatic ring in which every atom constituting the ring is a carbon atom. An aryl ring can consist of five, six, seven, eight, nine, or more atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. Depending on the structure, the aryl group can be a monovalent or divalent group (i.e., an arylene).

[0162] The term "heteroaryl" refers to an aryl group that includes one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety means that at least one skeletal atom on the ring of the aryl group is a nitrogen atom. Depending on its structure, a heteroaryl can be a monovalent or bivalent group (i.e., a hypoaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoydinolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc.

[0163] As used herein, the terms "heterocyclic alkyl," "heterocyclic aliphatic," or "heterocyclic" refer to a non-aromatic ring in which one or more of the constituent atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl groups can consist of three, four, five, six, seven, eight, nine, or more than nine atoms. Heterocyclic alkyl groups may be optionally substituted. Examples of heterocyclic groups include, but are not limited to, lactams, lactones, cycloimides, cyclothioimides, cyclocarbamates, tetrahydrothiarans, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxothiacyclohexane, 1,4-oxothiacyclohexadiene, 1,4-oxothiacyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimides, succinimides, barbiturates, and thiobarbiturates. Acids, dioxadiazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolidone, pyrrolidine, imidazoline, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazoline, 1,3-dioxacyclopentene, 1,3-dioxacyclopentene, 1,3-dithiocyclopentene, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline ketone, thiazoline, thiazoline, and 1,3-oxothiocyclopentane. Depending on the structure, the heterocyclic group can be a monovalent or bivalent group (i.e., a heterocyclic alkylene group).

[0164] As used herein, the term "fused alicyclic aromatic ring" refers to a group having one or more aromatic rings fused with a heterocyclic group (i.e., sharing bonds with the heterocyclic ring), for example... wait.

[0165] The term "aromatic heterocyclic" refers to heterocyclic compounds containing aromatic structures, including heteroaromatic rings and fused rings formed by aromatic rings and heterocyclic rings (such as heteroacid rings, heteroaromatic rings, etc.).

[0166] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0167] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0168] The term “optional” means that one or more events described below may or may not occur, and includes both events that occur and events that do not occur.

[0169] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0170] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0171] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0172] The prodrugs and solvates of the compounds in this invention are also included within the scope of this invention. The term "prodrug" here refers to a compound that, in the course of treating a related disease, undergoes a metabolic or chemical transformation to produce the compounds, salts, or solvates of this invention. "Solvate" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming solvates. If the solvent is water, the formed solvate is a hydrate; if the solvent is an alcohol, the formed solvate is an alcohol. The combination of one or more water molecules with one molecule of a substance forms a hydrate, wherein the water retains its molecular state H₂O. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0173] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0174] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0175] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0176] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0177] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0178] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0179] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0180] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0181] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0182] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0183] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0184] Example 1: Synthesis of compound RC001

[0185] The synthesis route is as follows:

[0186] Step 1: Synthesis of compound Int-2

[0187] At 0°C, under nitrogen protection, anhydrous toluene (300 mL), 3-methylpyrazole-4-boronic acid pinacol ester (30 g, 144.18 mmol), and 1-adamantane methanol (33.5 g, 201 mmol) were added to a 500 mL single-necked flask. The reaction mixture was purged with nitrogen three times and stirred at 100°C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Column chromatography purification yielded a white compound, Int-2 (2.5 g, 7.02 mmol, yield 4.87%). MS (ESI) m / z = 357.27 [M + H] +

[0188] Step 2: Synthesis of compound 3A

[0189] To a 100 mL single-necked flask, add 20 mL of 1,4-dioxane, 2.0 mL of water, 1.72 g (5.87 mmol) of tert-butyl 3-bromo-6-chloropyridinecarboxylate, 1.9 g (5.33 mmol) of Int-2, 0.34 g (0.53 mmol) of [1,1′-bis(di-tert-butylphosphine)ferrocene]palladium dichloride, and 5.21 g (16.0 mmol) of cesium carbonate. The reaction mixture was purged with nitrogen three times and stirred at 90 °C for 12 hours. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Column chromatography purification yielded a yellow compound 3A (858 mg, 1.94 mmol, yield 36.4%). MS(ESI)m / z = 442.22[M+H] +

[0190] Step 3: Synthesis of compound SM2

[0191] Acetonitrile (4.0 mL) was added to a 25 mL single-necked flask. While stirring, compound SM1 (200 mg, 0.72 mmol) and CDI (144 mg, 0.89 mmol) were added sequentially. After stirring at room temperature for 0.5 hours, compound DBU (CAS No. 6674-22-2) (172 mg, 1.14 mmol) was added. After stirring at room temperature for another 0.5 hours, 2-aminobenzothiazole (107 mg, 0.72 mmol) was added. The reaction mixture was then purged with nitrogen three times and stirred at 60 °C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by column chromatography to give a white compound SM2 (108 mg, 0.26 mmol, yield 36.6%). MS (ESI) m / z = 411.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.26(s,1H),8.55(d,J=4.8Hz,1H),8.06(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.54(d,J=5.2H z,1H),7.48(t,J=7.2Hz,1H),7.36(t,J=7.2Hz,1H),5.00(s,2H),3.62(t,J=5.6Hz,2H),2.94(t,J=5.6Hz,2H),1.43(s,9H).

[0192] Step 4: Synthesis of compound SM3

[0193] 1,4-Dioxane (3 mL) was added to a 25 mL single-necked flask, followed by the addition of compound SM2 (88 mg, 0.21 mmol) with stirring. Then, 3 mL of 4N hydrogen chloride solution of 1,4-dioxane was added under ice bath conditions. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium carbonate solution (30 mL), extracted with methanol:dichloromethane (1 / 10, 50 mL), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid of the target compound SM3 (60 mg, 0.19 mmol, yield 90.1%). MS (ESI) m / z = 311.0 [M+H] +

[0194] Step 5: Synthesis of compound SM4

[0195] N,N-dimethylformamide (0.4 mL), compound SM3 (20 mg, 0.06 mmol), compound 3A (34.1 mg, 0.08 mmol), cesium carbonate (62.9 mg, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium (4.62 mg, 0.01 mmol) were added to a 10 mL microwave-safe tube. The reaction mixture was microwave-treated at 120 °C for 5 hours under nitrogen protection. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The crude product was purified by column chromatography to give a yellow compound SM4 (23 mg, 0.01 mmol, yield 18.4%). MS (ESI) m / z = 716.4 [M + H] +

[0196] Step 6: Synthesis of Compound 1-1

[0197] At 0°C, dichloromethane (1.0 mL), compound SM4 (79 mg, 0.11 mmol), and trifluoroacetic acid (1.0 mL) were added sequentially to a 25 mL single-necked flask, and the mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the brown target product 1-1 (1.25 mg, 18.9 mol, yield 1.8%) was prepared by reversed-phase HPLC. MS (ESI) m / z = 660.4 [M+H] + .

[0198] Step 7: Synthesis of compounds 1-3

[0199] To a solution of compound 1-1 (100 mg, 0.15 mmol) and compound 1-2 in dichloromethane (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.11 mg, 0.30 mmol) and 4-dimethylaminopyridine (37.03 mg, 0.30 mmol) were added, and the mixture was stirred at 25 °C for 18 hours. The residue was purified by silica gel column chromatography (eluent: 1%–5% methanol / dichloromethane) to give compound 1-3 (140 mg, yield: 93.09%) as a yellow solid. MS (ESI) m / z = 893.2 [M+H] +

[0200] Step 8: Synthesis of compounds 1-4

[0201] Compounds 1-3 (140 mg, 0.15 mmol) were dissolved in a mixed solution of tetrahydrofuran (1 mL), water (0.5 mL), and methanol (0.5 mL), and lithium hydroxide (13.15 mg, 0.31 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. The residue was then concentrated to dryness. The mixture was quenched with hydrochloric acid solution (1.0 mol / L) and filtered to give a yellow solid, compound 1-4 (140 mg, yield: 92.92%). MS (ESI) m / z = 865.2 [M+H] +

[0202] Step 9: Synthesis of compound RC001

[0203] To a solution of compounds 1-5 (46.25 mg, 0.10 mmol) and compounds 1-4 (90 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (59.34 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.03 mL, 0.20 mmol) were added, and the mixture was stirred at 25 °C for 3 hours. The residue was purified by reverse-phase chromatography to give a white solid compound RC001 (18.60 mg, yield: 13.84%). MS (ESI) m / z = 1291.4 [M+H] +

[0204] 1H NMR (400MHz, DMSO-d6): δ12.29(s,1H),11.78(s,1H),8.98(s,1H),8.56(d,J=4.8Hz,1H),8.36(d,J =8.0Hz,1H),8.05(d,J=7.2Hz,1H),7.82(d,J=8.0Hz,1H),7.76(d,J=9.2Hz,1H),7.61–7.58(m,1H), 7.58–7.56(m,1H),7.51–7.46(m,1H),7.45–7.41(m,2H),7.39–7.37(m,2H),7.37–7.35(m,1H),7.2 8(s,1H),7.09(d,J=9.2Hz,1H),5.25(s,2H),5.09(d,J=3.6Hz,1H),4.94–4.88(m,1H),4.51(d,J=9. 2Hz,1H),4.42(t,J=8.0Hz,1H),4.30–4.24(m,1H),4.01–3.96(m,2H),3.71(s,2H),3.65–3.55(m,2 H),3.30–3.30(m,1H),3.10–3.06(m,2H),2.25–2.19(m,1H),2.13(s,3H),2.09–1.97(m,2H),1.94–1 .91(m,3H),1.82–1.75(m,1H),1.68–1.63(m,3H),1.62–1.57(m,4H),1.56–1.51(m,8H),1.48–1.41( m,2H),1.37(d,J=7.2Hz,3H),1.32–1.27(m,2H),1.25–1.22(m,3H),1.22–1.15(m,4H),0.92(s,9H).

[0205] Example 2: Synthesis of compound RC002

[0206] The synthesis route is as follows:

[0207] Step 1: Synthesis of compounds 2-3

[0208] Compound 2-2 (500 mg, 1.82 mmol) was dissolved in DMF (5 mL), and compound 2-1 (1060.79 mg, 2.37 mmol), KHCO3 (273.80 mg, 2.74 mmol), and potassium iodide (30.27 mg, 0.18 mmol) were added. The reaction was then stirred at 40 °C for 24 hours. The reaction was then quenched with brine (20 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give a brown solid compound 2-3 (340 mg, yield: 28%). MS (ESI) m / z = 572.2 [M + H + Na] +

[0209] Step 2: Synthesis of compounds 2-4

[0210] Compound 2-3 (300 mg, 0.55 mmol) was dissolved in a hydrochloric acid solution of dioxane (6 mL, 194.19 mmol), and stirred at 25 °C for 2 hours. The reaction was then concentrated under reduced pressure to give 260 mg of a yellow solid, with a yield of 93%. MS (ESI) m / z = 450.2 [M+H] +

[0211] Step 3: Synthesis of compound RC002

[0212] Compound 2-4 (29.46 mg, 0.06 mmol) was dissolved in DCM (1 mL), and compound 1-1 (40 mg, 0.06 mmol), TEA (0.04 mL, 0.30 mmol), and HATU (24.20 mg, 0.06 mmol) were added. The reaction mixture was then stirred at 25 °C for 15 hours. The mixture was then purified by reverse-phase chromatography to give a grayish-white solid compound RC002 (14.75 mg, yield: 22.30%). MS (ESI) m / z = 1113.4 [M + Na] +

[0213] 1H NMR (400MHz, DMSO-d6): δ12.32(s,1H),11.12(s,1H),8.54(d,J=4.8Hz,1H),8.20(t,J=6.0H z,1H),8.04(d,J=7.6Hz,1H),7.88–7.72(m,2H),7.56(d,J=4.8Hz,1H),7.52(d,J=8.8Hz,1H ),7.48(dd,J=10.4,4.8Hz,2H),7.44(d,J=7.2Hz,1H),7.40–7.32(m,1H),7.28(s,1H),7.04 (d,J=8.8Hz,1H),5.24(s,2H),5.08(dd,J=12.8,5.6Hz,1H),4.36–4.24(m,2H),3.96(t,J=5. 6Hz,2H),3.80–3.72(m,2H),3.68(s,2H),3.60(dd,J=6.0,3.6Hz,2H),3.48(dd,J=6.0,3.6H z,2H),3.44(d,J=2.8Hz,4H),3.40(t,J=6.4Hz,2H),3.24(dd,J=12.0,6.0Hz,2H),3.04(t,J =5.6Hz,2H),2.88(ddd,J=17.2,12.8,5.2Hz,1H),2.56(d,J=17.6Hz,1H),2.52(s,1H),2.07 (s,3H),2.04–1.96(m,1H),1.92(s,3H),1.64(s,1H),1.60(s,2H),1.56(s,2H),1.52(s,7H).

[0214] Example 3: Synthesis of compound RC003

[0215] The synthesis route is as follows:

[0216] Step 1: Synthesis of compound 3-2

[0217] Compound 3-1 (400 mg, 1.54 mmol) was dissolved in DMF (8 mL), and compound 2-1 (894.22 mg, 2.00 mmol), potassium iodide (25.51 mg, 0.15 mmol), and KHCO3 (230.80 mg, 2.31 mmol) were added. The reaction mixture was stirred at 40 °C for 24 hours. The reaction was then quenched with brine (20 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography gave compound 3-2 (113.0 mg, yield: 13.73%) as a brown solid. MS (ESI) m / z = 536.2 [M+H] +

[0218] Step 2: Synthesis of compound 3-3

[0219] Compound 3-2 (100 mg, 0.19 mmol) was dissolved in HCl / dioxane solution and stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to give a yellow solid compound 3-3 (90 mg, yield: 92%). MS (ESI) m / z = 436.2 [M+H] +

[0220] Step 3: Synthesis of compound RC003

[0221] Compound 3-3 (35 mg, 0.07 mmol) was dissolved in DCM (2 mL), and compound 1-1 (48.93 mg, 0.07 mmol), TEA (0.05 mL, 0.37 mmol), and HATU (29.61 mg, 0.08 mmol) were added. The reaction mixture was then stirred at 25 °C for 18 hours. The residue was then purified by reverse-phase chromatography to give a grayish-white solid compound RC003 (42.28 mg, yield: 52.92%). MS (ESI) m / z = 1078.4 [M+H] +

[0222] 1H NMR (400MHz, DMSO-d6): δ12.32(s,1H),10.96(s,1H),8.52(d,J=4.8Hz,1H),8.20(t,J=6.0Hz,1H), 8.04(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.56(d,J=4.8Hz,1H),7.52(d,J=8.8Hz,1H),7.52–7.4 4(m,2H),7.40–7.32(m,1H),7.32(d,J=7.2Hz,1H),7.28(s,1H),7.20(d,J=8.0Hz,1H),7.04(d,J=8 .8Hz,1H),5.24(s,2H),5.12(dd,J=13.2,5.2Hz,1H),4.32(d,J=17.6Hz,1H),4.24(d,J=7.2Hz,1H), 4.20(d,J=5.2Hz,2H),3.96(t,J=5.6Hz,2H),3.76–3.72(m,2H),3.68(s,2H),3.56(dd,J=5.6,3.2H z,2H),3.48(dd,J=6.0,3.6Hz,2H),3.48–3.40(m,4H),3.36(s,2H),3.24(dd,J=12.0,6.0Hz,2H),3. 04(t,J=5.6Hz,2H),2.96–2.84(m,1H),2.56(d,J=18.0Hz,1H),2.44(dd,J=13.2,4.4Hz,1H),2.08(s ,3H),1.96(dd,J=8.8,3.6Hz,1H),1.92(s,3H),1.64(s,1H),1.60(s,2H),1.56(s,2H),1.52(s,7H).

[0223] Example 4: Synthesis of compound RC004

[0224] The synthesis route is as follows:

[0225] Step 1: Synthesis of Compound 4-3

[0226] Compound 4-1 (4.5 g, 20.90 mmol) was dissolved in THF (10 mL), and NaH (1.67 g, 41.80 mmol) was added at 0 °C; the reaction mixture was then stirred at 25 °C for 1 hour. Compound 4-2 (6.98 g, 41.80 mmol) was added to the reaction mixture. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give a colorless oily compound 4-3 (1.0 g, yield: 15.87%). MS (ESI) m / z = 246.2 [M + H- t Bu] +

[0227] Step 2: Synthesis of compound 4-4

[0228] Compound 4-3 (900 mg, 2.99 mmol) was dissolved in 10 mL of HCl and stirred at 25 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure to give compound 4-4 (750 mg), which was used directly in the next step without purification. MS (ESI) m / z = 202.2 [M+H] +

[0229] Step 3: Synthesis of compounds 4-5

[0230] Compound 1-1 (70 mg, 0.11 mmol) was dissolved in DMF (2 mL), and compound 4-4 (27.76 mg, 0.14 mmol), DIEA (0.07 mL, 0.42 mmol), and HATU (48.41 mg, 0.13 mmol) were added. The reaction was then stirred at 25 °C for 18 hours. The reaction was quenched with saturated brine (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give a brown solid compound 4-5 (100 mg, yield: 86%). MS (ESI) m / z = 843.6 [M + H] +

[0231] Step 4: Synthesis of compounds 4-6

[0232] Compounds 4-5 (80 mg, 0.10 mmol) were dissolved in a mixed solvent of THF (1.5 mL), water (0.50 mL), and ethanol (1.50 mL), and then added to LiOH (7.96 mg, 0.19 mmol). The reaction mixture was then stirred at 25 °C for 18 hours. The reaction mixture was concentrated under reduced pressure and water (2 mL) was added. The mixture was adjusted to pH 3 with 1 M HCl and filtered to give a yellow solid product 4-6 (65 mg, yield: 82.63%). MS (ESI) m / z = 829.4 [M+H] +

[0233] Step 4: Synthesis of compound RC004

[0234] Compounds 4-6 (45 mg, 0.05 mmol) were dissolved in DMF (2 mL), and compounds 1-5 (28.96 mg, 0.07 mmol), DIEA (0.03 mL, 0.16 mmol), and HATU (24.77 mg, 0.07 mmol) were added. The reaction mixture was stirred at 25 °C for 18 hours. The residue was then purified by reverse-phase chromatography to give a yellow solid compound RC004 (18.11 mg, yield: 26.57%). MS (ESI) m / z = 628.6 [M / 2+H] +

[0235] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),8.98(d,J=2.8Hz,1H),8.55(d,J=4.8Hz,1H),8.36(dd,J=7.6 ,2.4Hz,1H),8.05(d,J=7.2Hz,1H),7.81(dd,J=8.4,4.4Hz,2H),7.59–7.51(m,2H),7.51–7.46(m,1H) ,7.42(d,J=8.4Hz,2H),7.36(dd,J=8.0,5.2Hz,3H),7.22(s,1H),6.96(d,J=8.8Hz,1H),5.21(q,J=18 .0Hz,2H),4.95–4.83(m,1H),4.51(d,J=9.2Hz,1H),4.41(t,J=8.0Hz,1H),4.29(d,J=16.0Hz,2H),3. 98–3.81(m,2H),3.71(s,2H),3.65–3.53(m,2H),3.43(dd,J=16.8,8.4Hz,4H),3.16(d,J=12.0Hz,1H) ,3.05(d,J=5.6Hz,4H),2.69(dd,J=16.4,7.2Hz,1H),2.52(s,1H),2.46(s,1H),2.45(s,3H),2.24(dd ,J=14.8,10.0Hz,1H),2.15(s,3H),2.06–1.97(m,1H),1.93(s,3H),1.79(ddd,J=12.8,8.4,4.8Hz,1H ),1.66(s,1H),1.62(d,J=12.4Hz,3H),1.56(s,3H),1.52(s,7H),1.35(d,J=6.0Hz,4H),0.90(s,9H).

[0236] Example 5: Synthesis of compound RC005

[0237] The synthesis route is as follows:

[0238] Step 1: Synthesis of Compound 5-4

[0239] Compound 5-2 (3.00 g, 6.69 mmol, 1.00 eq) and compound 5-3 (4.41 g, 12.1 mmol, 1.80 eq) were dissolved in 60 mL of dioxane and 12 mL of water. 1,1-bis(diphenylphosphine)ferrocene palladium chloride (979 mg, 1.34 mmol, 0.2 eq) and cesium carbonate (4.36 g, 13.4 mmol, 2.00 eq) were added. The reaction mixture was stirred at 100 °C under nitrogen protection for 3 hours. The reaction mixture was poured into 40 mL of water and extracted twice with 40 mL of ethyl acetate. The combined organic phases were washed with 40 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily compound 5-4 (3.0 g, yield 64.8%). MS (ESI) m / z = 608.1 [M+H] + .

[0240] Step 2: Synthesis of compound 5-5

[0241] Compound 5-4 (2.20 g, 3.62 mmol, 1.00 eq) was dissolved in 10 mL of methanol, 10 mL of tetrahydrofuran, and 10 mL of water, and lithium hydroxide monohydrate (456 mg, 10.9 mmol, 3.00 eq) was added. The reaction mixture was stirred at 25 °C for 3 hours. The pH of the reaction mixture was adjusted to 6–7 with 1 M hydrochloric acid. The reaction mixture was evaporated to dryness to give a black solid compound 5-5 (2.15 g, crude product). MS (ESI) m / z = 594.0 [M+H] + .

[0242] Step 3: Synthesis of compounds 5-6

[0243] Compound 5-5 (2.15 g, 3.62 mmol, 1.00 eq) and 1,3-benzothiazol-2-amine (544 mg, 3.62 mmol, 1.00 eq) were dissolved in 20 mL of tetrahydrofuran, and N,N-diisopropylethylamine (2.34 g, 18.1 mmol, 5.00 eq) and 2-chloro-1-methylpyridine iodide (4.63 g, 18.1 mmol, 5.00 eq) were added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured into 20 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography to give a brown solid compound 5-6 (2.0 g, yield 65.6%). MS (ESI) m / z = 726.0 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ12.34(s,1H),8.55(d,J=4.9Hz,1H),8.05(d,J=7.5Hz,1H),7.81(d,J=8.0Hz,1H),7.7 0-7.65(m,3H),7.57-7.49(m,3H),7.40-7.35(m,3H),7.04(d,J=8.9Hz,1H),5.44(s,2H),5.21(s,2H),3.93(br t,J=5.8Hz,2H),3.05(br t,J=5.8Hz,2H),2.09(s,3H),1.35(s,9H).

[0244] Step 4: Synthesis of Compound 5-1

[0245] Compound 5-6 (2.0 g, 2.76 mmol, 1.00 eq) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (23.0 g, 202 mmol, 15 mL, 73.3 eq) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was dried under nitrogen to remove dichloromethane and trifluoroacetic acid. The crude product was diluted with 5 mL of dimethylformamide, and the pH was adjusted to 7–8 with N,N-diisopropylethylamine. Further purification by preparative liquid chromatography yielded a white solid, compound 5-1 (318 mg, yield 16.82%). MS (ESI) m / z = 670.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.55(d,J=4.9Hz,1H), 8.05(d,J=7.9Hz,1H), 7.81(d,J=7.9Hz, 1H),7.68-7.63(m,1H),7.61-7.53(m,3H),7.51-7.45(m,3H),7.39-7.33(m,2H),6.91(br d,J=8.8Hz,1H),5.43(s,2H),5.19(s,2H),3.93(br t,J=5.8Hz,2H),3.05-3.02(m,2H),2.14(s,3H).

[0246] Step 5: Synthesis of compound RC005

[0247] Compound 5-1 (60 mg, 0.09 mmol) was dissolved in DMF (2 mL), and compounds 2-4 (46.82 mg, 0.11 mmol), DIEA (0.06 mL, 0.36 mmol), and HATU (44.29 mg, 0.12 mmol) were added. The reaction mixture was stirred at 25 °C for 18 hours. The mixture was then purified by reverse-phase chromatography to give a yellow solid compound RC005 (41.40 mg, yield: 41.96%). MS (ESI) m / z = 1102.4 [M+H] +

[0248] 1 H NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.10(s,1H),8.54(d,J=4.8Hz,1H),8.26(t, J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.76(dd,J=8.4,7.3Hz,1H ),7.64(d,J=7.6Hz,1H),7.58(d,J=7.6Hz,1H),7.54(d,J=5.6Hz,2H),7.53–7.49(m,1 H),7.48(s,1H),7.46(s,1H),7.42(d,J=7.2Hz,1H),7.40–7.33(m,3H),7.04(d,J=8.8 Hz,1H),5.43(s,2H),5.23(s,2H),5.07(dd,J=12.8,5.6Hz,1H),4.33–4.21(m,2H),3 .97(t,J=5.6Hz,2H),3.79–3.72(m,2H),3.57(dd,J=5.6,3.6Hz,2H),3.47(dd,J=5.6, 3.6Hz,2H),3.45–3.37(m,6H),3.28(dd,J=11.6,5.6Hz,2H),3.05(t,J=5.6Hz,2H),2. 87(ddd,J=17.2,14.0,5.3Hz,1H),2.62–2.51(m,2H),2.06(s,3H),2.04–1.96(m,1H).

[0249] Example 6: Synthesis of compound RC006

[0250] The synthesis route is as follows:

[0251] Step 1: Synthesis of Compound 6-2

[0252] Compound 6-1 (500 mg, 1.81 mmol) was dissolved in NMP (4 mL), and compound 2-1 (688.03 mg, 2.35 mmol) and DIEA (0.60 mL, 3.62 mmol) were added. The reaction was stirred at 80 °C for 2 hours. The reaction was then quenched with saturated brine (20 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give a brown solid compound 6-2 (350 mg, yield: 35.25%). MS (ESI) m / z = 549.2 [M+H] +

[0253] Step 2: Synthesis of Compound 6-3

[0254] Compound 6-2 (350 mg, 0.64 mmol) was dissolved in dioxane hydrochloride (7 mL) and stirred at 25 °C for 2 hours. The reaction was then concentrated under reduced pressure to give a brown oily compound 6-3 (300 mg, yield 96.96%). MS (ESI) m / z = 449.3 [M+H] +

[0255] Step 3: Synthesis of compound RC006

[0256] Compound 5-1 (60 mg, 0.09 mmol) was dissolved in DMF (2 mL), and compound 6-3 (46.71 mg, 0.11 mmol), DIEA (0.06 mL, 0.36 mmol), and HATU (44.29 mg, 0.12 mmol) were added. The reaction mixture was stirred at 25 °C for 18 hours. The purified residue was then prepared by reverse-phase chromatography to give a grayish-white solid compound RC006 (44.18 mg, yield: 44.82%). MS (ESI) m / z = 1100.4 [M+H] +

[0257] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),8.98(d,J=2.8Hz,1H),8.55(d,J=4.8Hz,1H),8.36(dd,J=7.6 ,2.4Hz,1H),8.05(d,J=7.2Hz,1H),7.81(dd,J=8.4,4.4Hz,2H),7.59–7.51(m,2H),7.51–7.46(m,1H) ,7.42(d,J=8.4Hz,2H),7.36(dd,J=8.0,5.2Hz,3H),7.22(s,1H),6.96(d,J=8.8Hz,1H),5.21(q,J=18 .0Hz,2H),4.95–4.83(m,1H),4.51(d,J=9.2Hz,1H),4.41(t,J=8.0Hz,1H),4.29(d,J=16.0Hz,2H),3. 98–3.81(m,2H),3.71(s,2H),3.65–3.53(m,2H),3.43(dd,J=16.8,8.4Hz,4H),3.16(d,J=12.0Hz,1H) ,3.05(d,J=5.6Hz,4H),2.69(dd,J=16.4,7.2Hz,1H),2.52(s,1H),2.46(s,1H),2.45(s,3H),2.24(dd ,J=14.8,10.0Hz,1H),2.15(s,3H),2.06–1.97(m,1H),1.93(s,3H),1.79(ddd,J=12.8,8.4,4.8Hz,1H ),1.66(s,1H),1.62(d,J=12.4Hz,3H),1.56(s,3H),1.52(s,7H),1.35(d,J=6.0Hz,4H),0.90(s,9H).

[0258] Example 7 Synthesis of compound RC007

[0259] The synthesis route is as follows:

[0260] Step 1: Synthesis of Compound 7-2

[0261] Sodium sulfite (3.45 g, 27.41 mmol) was added to a mixture of compound 7-1 (5 g, 21.08 mmol) and water (50 mL). The mixture was stirred at 110 °C for 18 hours. The residue was then freeze-dried to give a white solid product 7-2 (8.3 g, yield: 90.75%). MS (ESI) m / z = 239.0 [M+H] +

[0262] Step 2: Synthesis of Compound 7-3

[0263] Compound 7-2 (6 g, 23.05 mmol) was dissolved in a mixed solvent of THF (60 mL) and DMF (3 mL). The mixture was cooled to 0 °C, and thionyl chloride (13.37 mL, 184.41 mmol) was added dropwise to the solution. The solution was then heated to 70 °C and stirred for 1 hour. The solvent was removed under reduced pressure, and the solution was dissolved in acetonitrile (30 mL). The resulting suspension was added to ammonia solution (50 mL, 1298.14 mmol) at 0 °C. After 30 minutes, the reaction mixture was diluted with ethyl acetate and poured into water. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give a yellow oily product 7-3 (3.04 g, yield: 55.57%). MS (ESI) m / z = 238.2 [M+H] +

[0264] Step 3: Synthesis of Compound 7-4

[0265] Compound 5-1 (70 mg, 0.10 mmol) was dissolved in DCM (2 mL), and EDCI (40.08 mg, 0.20 mmol), DMAP (25.54 mg, 0.20 mmol), and compound 7-3 (49.61 mg, 0.20 mmol) were added. The mixture was stirred at 25 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow oil 7-4 (100 mg, yield: 86.10%). MS (ESI) m / z = 889.2 [M+H] +

[0266] Step 4: Synthesis of Compounds 7-5

[0267] Compound 7-4 (90 mg, 0.10 mmol) was dissolved in a mixed solvent of THF (1 mL), H₂O (0.5 mL), and MeOH (0.5 mL), and LiOH (8.48 mg, 0.20 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The residue was then concentrated to dryness. The mixture was quenched with HCl (1.0 mol / L), filtered, and a yellow solid compound 7-5 (50 mg, yield: 55.56%) was given. MS (ESI) m / z = 861.2 [M+H] +

[0268] Step 5: Synthesis of compound RC007

[0269] To a DMF (1 mL) solution of compounds 7-5 (40 mg, 0.04 mmol) and 1-5 (20.66 mg, 0.04 mmol), DIEA (12.01 mg, 0.09 mmol) and HATU (26.50 mg, 0.07 mmol) were added, and the mixture was stirred at 25 °C for 3 hours. The residue was purified by reverse-phase chromatography to give a white solid compound RC007 (30.71 mg, yield: 51.34%). MS (ESI) m / z = 644.4 [M / 2+H] +

[0270] 1 H NMR (400MHz, DMSO-d6): δ12.29(s,1H),11.80(s,1H),8.98(s,1H),8.56(d,J=4.8Hz,1H ),8.35(d,J=8.0Hz,1H),8.07–8.03(m,1H),7.84–7.80(m,1H),7.76(d,J=9.2Hz,1H),7. 67–7.63(m,1H),7.62–7.57(m,2H),7.57–7.54(m,2H),7.51–7.46(m,1H),7.44–7.41(m, 2H),7.39–7.39(m,1H),7.38–7.36(m,2H),7.36–7.32(m,2H),7.11(d,J=9.2Hz,1H),5.4 6(s,2H),5.25(s,2H),5.09(d,J=3.6Hz,1H),4.94–4.87(m,1H),4.50(d,J=9.2Hz,1H),4 .44–4.38(m,1H),4.27(s,1H),4.02–3.97(m,2H),3.63–3.54(m,2H),3.10–3.06(m,2H), 2.45(s,3H),2.23–2.16(m,1H),2.11(s,3H),2.07–1.97(m,2H),1.83–1.74(m,1H),1.64 –1.56(m,2H),1.48–1.39(m,2H),1.36(d,J=7.2Hz,3H),1.30–1.14(m,6H),0.90(s,9H).

[0271] Example 8: Synthesis of compound RC008

[0272] The synthesis route is as follows:

[0273] Step 1: Synthesis of Compound 8-3

[0274] DIPEA (3.19 mL, 19.34 mmol) was added to a DMF (20 mL) solution of compound 8-1 (1.8 g, 6.44 mmol) and compound 8-2 (1.58 g, 9.67 mmol), and the mixture was stirred at 100 °C for 3 hours. The solution was diluted with ethyl acetate and washed with water, 1 mol / L hydrochloric acid solution, sodium bicarbonate solution, and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily compound 8-3 (2.5 g, yield: 85.84%). MS (ESI) m / z = 384.2 [M+H] +

[0275] Step 2: Synthesis of compound 8-4

[0276] Compound 8-3 (2.5 g, 6.91 mmol) was dissolved in THF (20 mL), and hydrazine hydrate (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The resulting reaction mixture was filtered to remove the precipitated phthalohydrazide, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1%–5% methanol / dichloromethane) to give a yellow oil, 8-4 (1.4 g, yield: 87.49%). MS (ESI) m / z = 232.2 [M+H] +

[0277] Step 3: Synthesis of Compound 8-5

[0278] Compound 1-1 (70 mg, 0.10 mmol) was dissolved in DMF (2 mL), and HOBt (28.67 mg, 0.21 mmol) and EDCI (40.68 mg, 0.21 mmol) were added. Then, compound 8-4 (49.09 mg, 0.21 mmol) and TEA (0.04 mL, 0.31 mmol) were added, and the mixture was stirred at 25 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow solid 8-5 (100 mg, yield: 97.16%). MS (ESI) m / z = 437.5 [M / 2+H] +

[0279] Step 4: Synthesis of compounds 8-6

[0280] Compound 8-5 (100 mg, 0.11 mmol) was dissolved in DCM (3 mL), and TFA (1 mL) was added. The mixture was stirred at 25 °C for 3 hours. The residue was purified by reverse-phase chromatography to give a yellow solid compound 8-6 (90 mg, 96.18% yield). MS (ESI) m / z = 409.4 [M / 2+H] +

[0281] Step 5: Synthesis of compound RC008

[0282] Compounds 8-6 (70 mg, 0.08 mmol) and 1-5 (38.09 mg, 0.08 mmol) were dissolved in DMF (2 mL), and DIEA (22.15 mg, 0.17 mmol) and HATU (48.87 mg, 0.12 mmol) were added. The mixture was stirred at 25 °C for 3 hours. The residue was purified by reverse-phase chromatography to give a white solid compound RC008 (22.86 mg, yield: 21.45%). MS (ESI) m / z = 622.6 [M / 2+H] +

[0283] 1 H NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.14(s,1H),8.98(s,1H),8.55(d,J=4.8Hz,1H), 8.36(d,J=7.6Hz,1H),8.06–8.02(m,1H),7.81(d,J=8.0Hz,1H),7.77(d,J=9.2Hz,1H),7. 58–7.55(m,1H),7.54–7.51(m,1H),7.51–7.46(m,1H),7.44–7.41(m,2H),7.39–7.36(m,2 H),7.36–7.33(m,1H),7.28(s,1H),7.03(d,J=8.8Hz,1H),5.24(s,2H),5.08(s,1H),4.94– 4.87(m,1H),4.51(d,J=9.2Hz,1H),4.45–4.39(m,1H),4.27(s,1H),3.98–3.90(m,2H),3. 70(s,2H),3.67–3.57(m,4H),3.08–3.04(m,2H),2.45(s,3H),2.25–2.19(m,1H),2.12(s,3 H),2.09–1.97(m,2H),1.94–1.91(m,3H),1.77(mm,J=12.8Hz,1H),1.68–1.63(m,3H),1.5 8–1.50(m,10H),1.47–1.39(m,3H),1.37(d,J=7.2Hz,3H),1.24–1.16(m,6H),0.93(s,9H).

[0284] Example 9: Synthesis of compound RC009

[0285] The synthetic route of the compound is as follows:

[0286] Step 1: Synthesis of Compound 9-2

[0287] Compound 9-1 (150.00 mg, 0.49 mmol) was dissolved in DMF (3 mL), and compounds 1-5 (262.10 mg, 0.59 mmol), HATU (373.60 mg, 0.98 mmol), and N,N-diisopropylethylamine (0.24 mL, 1.47 mmol) were added. The mixture was stirred at 25 °C for 3 hours. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow oil 9-2 (300.00 mg, yield: 83.48%). MS (ESI) m / z = 732.4 [M+H] +

[0288] Step 2: Synthesis of Compound 9-3

[0289] Compound 9-2 (150.00 mg, 0.21 mmol) was dissolved in tetrahydrofuran (2 mL), and hydrazine hydrate (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The solution was concentrated under reduced pressure, and the residue was prepared by reverse phase resection to give a yellow oil 9-3 (100.00 mg, yield: 81.08%). MS (ESI) m / z = 602.3 [M+H] +

[0290] Step 3: Synthesis of compound RC009

[0291] Compound 5-1 (20.00 mg, 0.03 mmol) was dissolved in DMF (1 mL), and compound 9-3 (21.67 mg, 0.04 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (17.03 mg, 0.05 mmol), and N,N-diisopropylethylamine (0.02 mL, 0.09 mmol) were added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was purified by reverse-phase chromatography to give a white solid compound RC009 (11.59 mg, yield: 30.96%). MS (ESI) m / z = 1253.4 [M+H] +

[0292] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),11.17(s,1H),9.00–8.94(m,1H),8.55(d,J =4.8Hz,1H),8.36(d,J=7.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7. 77(d,J=9.2Hz,1H),7.67–7.63(m,1H),7.59–7.56(m,2H),7.56–7.52(m,2H),7.51 –7.46(m,1H),7.45–7.41(m,2H),7.39–7.37(m,3H),7.37–7.34(m,2H),7.04(d,J=8 .8Hz,1H),5.43(s,2H),5.24(s,2H),4.94–4.86(m,1H),4.51(d,J=9.2Hz,1H),4.4 5–4.38(m,1H),4.30–4.24(m,1H),4.00–3.91(m,2H),3.64–3.55(m,4H),3.07–3.04 (m,2H),2.45(s,3H),2.25–2.18(m,1H),2.11(s,3H),2.08–1.97(m,2H),1.82–1.7 3(m,1H),1.51–1.40(m,2H),1.36(d,J=7.2Hz,5H),1.24–1.08(m,7H),0.92(s,9H).

[0293] Example 10 Synthesis of compound RC010

[0294] The compound structure is as follows:

[0295] Using the same synthesis method as in Example RC008, a white solid RC010 (18.16 mg, yield: 48.02%) was prepared. MS (ESI) m / z = 1247.4 [M+H] +

[0296] 1H NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.30(s,1H),8.98(s,1H),8.55(d,J=4.8Hz, 1H),8.42(d,J=7.6Hz,1H),8.05(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.59–7.55(m ,1H),7.55–7.50(m,1H),7.50–7.46(m,1H),7.44–7.40(m,2H),7.39–7.33(m,4H),7.2 8(s,1H),7.03(d,J=8.8Hz,1H),5.23(s,2H),4.94–4.85(m,1H),4.53(d,J=9.2Hz,1H) ,4.47–4.40(m,1H),4.31–4.24(m,1H),3.99–3.94(m,2H),3.94–3.87(m,2H),3.87–3. 79(m,2H),3.71(s,2H),3.61–3.55(m,3H),3.54–3.48(m,4H),3.08–3.04(m,2H),2.45 (s,3H),2.12(s,3H),2.07–2.00(m,1H),1.95–1.91(m,3H),1.81–1.73(m,1H),1.67–1 .62(m,3H),1.58–1.55(m,2H),1.55–1.45(m,8H),1.36(d,J=7.2Hz,3H),0.93(s,9H).

[0297] Example 11 Synthesis of compound RC011

[0298] The synthetic route of the compound is as follows:

[0299] Step 1: Synthesis of Compound 11-3

[0300] Compound 11-1 (10 g, 53.69 mmol, 1.0 eq) was dissolved in 100 mL of tetrahydrofuran. Compound 11-2 (10.47 g, 53.69 mmol, 1.0 eq) and triethylamine (22.39 mL, 161.07 mmol, 3.0 eq) were added, and the mixture was stirred at 25 °C for 18 hours. The mixture was concentrated to obtain a crude product, which was purified by column chromatography to give a yellow oil, 11-3 (8.92 g, yield: 55%). MS (ESI) m / z = 301.2 [M+H] +

[0301] Step 2: Synthesis of compound 11-4

[0302] Compound 11-3 (1 g, 3.33 mmol, 1.0 eq) was dissolved in 5 mL of dichloromethane, and 5 mL of dioxane hydrochloride solution (4 mol / L) was added. The mixture was stirred at 25 °C for 18 hours. Concentration yielded a white solid, compound 11-4 (0.83 g, yield: 74%). MS (ESI) m / z = 201.2 [M+H] +

[0303] Step 3: Synthesis of Compound 11-5

[0304] Compound 1-1 (50 mg, 0.08 mmol, 1.0 eq) and compound 11-4 (25.60 mg, 0.08 mmol, 1.0 eq) were dissolved in 1 mL of N,N-dimethylformamide. HATU (57.63 mg, 0.15 mmol, 1.9 eq) and DIEA (0.04 mL, 0.23 mmol, 2.9 eq) were added, and the mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to obtain a crude product, which was purified by column chromatography to give a yellow solid compound 11-5 (70 mg, yield: 98%). MS (ESI) m / z = 842.4 [M+H] +

[0305] Step 4: Synthesis of Compound 11-6

[0306] Compound 11-5 (70 mg, 0.08 mmol, 1.0 eq) was dissolved in 0.5 mL of water, 0.5 mL of tetrahydrofuran, and 0.5 mL of methanol. Lithium hydroxide (6.98 mg, 0.17 mmol, 2.0 eq) was added, and the mixture was stirred at 25 °C for 3 hours. The crude product was concentrated, and the pH was adjusted to 3-4 with 2 mL of dilute hydrochloric acid (1 mol / L). The mixture was filtered to give a yellow solid, compound 11-6 (50 mg, yield: 72%). MS (ESI) m / z = 828.4 [M+H] +

[0307] Step 5: Synthesis of compound RC011

[0308] Compound 11-6 (40 mg, 0.05 mmol, 1.0 eq) and intermediate 1-5 (25.77 mg, 0.06 mmol, 1.2 eq) were dissolved in 1 mL of N,N-dimethylformamide. HATU (36.74 mg, 0.10 mmol, 2.0 eq) and DIEA (0.02 mL, 0.15 mmol, 3.0 eq) were added, and the mixture was stirred at 25 °C for 3 hours. The mixture was concentrated to obtain a crude product, which was purified by reverse-phase chromatography to give a yellow solid compound RC011 (35.28 mg, yield: 58%). MS (ESI) m / z = 1254.6 [M+H] +

[0309] 1 H-NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.56(d,J=4.8Hz,1H),8.03(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.59(d,J=8.8Hz,1H),7.56(d,J=5.2Hz, 1H),7.51–7.46(m,1H),7.42–7.39(m,2H),7.38–7.31(m,3H),7.25(s,1H) ,7.04(d,J=8.8Hz,1H),5.23(s,2H),4.92–4.78(m,1H),4.54–4.35(m,3H), 4.27(s,1H),3.89(s,2H),3.73–3.70(m,2H),3.61–3.52(m,4H),3.41–3.1 3(m,3H),3.09–2.97(m,5H),2.88–2.74(m,1H),2.43(s,3H),2.26–2.18(m, 1H),2.13(s,3H),2.07–1.99(m,1H),1.94–1.89(m,3H),1.81–1.74(m,1H), 1.67–1.61(m,3H),1.57–1.40(m,14H),1.34(d,J=7.2Hz,3H),0.89(s,9H).

[0310] Example 12 Synthesis of compound RC012

[0311] The synthetic route of the compound is as follows:

[0312] Step 1: Synthesis of Compound 12-3

[0313] Compound 12-1 (281.14 mg, 0.87 mmol, 1.0 eq), compound 12-2 (500 mg, 1.74 mmol, 2.0 eq), cuprous iodide (33.14 mg, 0.17 mmol, 0.1 eq), bis(acetonitrile)palladium(II) chloride (45.24 mg, 0.17 mmol, 0.1 eq), and triphenylphosphine (1.28 mg, 0.35 mmol, 0.2 eq) were dissolved in 5 mL of N,N-dimethylformamide, and diisopropylamine (704.27 mg, 6.96 mmol, 8.0 eq) was added. The reaction mixture was stirred at 80 °C under nitrogen protection for 2 hours. The reaction mixture was poured into 20 mL of water, extracted twice with 20 mL of ethyl acetate, and the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid hydrochloride of compound 12-3 (300 mg, yield: 32%). MS (ESI) m / z = 552.2 [M + H + Na] +

[0314] 1 H-NMR (400MHz, CDCl3): δ8.13(s,1H),7.82(d,J=7.8Hz,1H),7.58–7.48(m,2H),5.2 3–5.19(m,1H),4.53-4.40(m,1H),4.38-4.15(m,1H),3.82–3.76(m,2H),3.74–3.70( m,2H),3.69–6.58(m,5H),3.55(dd,J=10.8,5.6Hz,3H),3.31(d,J=5.2Hz,2H),2.96 –2.86(m,1H),2.88–2.77(m,1H),2.40–2.35(m,1H),2.25–2.15(m,1H),1.44(s,9H).

[0315] Step 2: Synthesis of Compound 12-4

[0316] Compound 12-3 (400 mg, 0.755 mmol) was dissolved in 5 mL of dioxane hydrochloride, and the reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid hydrochloride of compound 12-4 (500 mg, crude product). MS (ESI) m / z = 430.2 [M+H] + .

[0317] Step 3: Synthesis of compound RC012

[0318] The hydrochloride salt of compound 12-4 (19.53 mg, 0.045 mmol) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (30 mg, 0.045 mmol), N,N-diisopropylethylamine (58.77 mg, 0.455 mmol), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (19.02 mg, 0.050 mmol) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase preparation (formic acid system) to give an off-white solid RC012 (17.35 mg, yield: 35.62%). MS (ESI) m / z = 1071.4 [M+H] +

[0319] 1 H-NMR (400MHz, DMSO-d6): δ12.25(s,1H),10.95(s,1H),8.49(d,J=4.8Hz,1H),8.16(t,J=5.6Hz ,1H),8.00(d,J=7.6Hz,1H),7.76(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),7.62(s,1H),7.50(s,1 H),7.49(d,J=2.8Hz,1H),7.46(d,J=8.8Hz,1H),7.45–7.40(m,1H),7.35–7.28(m,1H),7.23(s, 1H),6.98(d,J=8.8Hz,1H),5.17(s,2H),5.06(dd,J=13.2,5.2Hz,1H),4.39(d,J=17.6Hz,1H),4. 35(s,2H),4.27(d,J=17.6Hz,1H),3.91(t,J=6.0Hz,2H),3.64(s,2H),3.55(dd,J=6.0,3.2Hz,2 H),3.49(dd,J=6.0,3.2Hz,2H),3.42(q,J=7.2Hz,4H),3.36(t,J=6.0Hz,2H),3.23(dd,J=12.0,6 .0Hz,2H),3.01(t,J=5.6Hz,2H),2.92–2.79(m,1H),2.54(d,J=16.0Hz,1H),2.39–2.26(m,1H),2 .03(s,3H),1.98–1.91(m,1H),1.87(s,3H),1.60(s,1H),1.57(s,2H),1.51(s,2H),1.48(s,7H).

[0320] Example 13 Synthesis of compound RC013

[0321] The synthetic route of the compound is as follows:

[0322] Step 1: Synthesis of Compound 13-2

[0323] Compound 13-1 (1 g, 3.0 mmol, 1.0 eq) was dissolved in 15 mL of dimethyl sulfoxide, followed by the addition of compound 12-2 (1 g, 3.0 mmol, 1.0 eq), tetraphenylphosphine (0.34 g, 0.30 mmol, 0.1 eq), cuprous iodide (0.11 g, 0.60 mmol, 0.1 eq), and triethylamine (1.50 g, 14.83 mmol, 4.2 eq). The reaction mixture was stirred at 120 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was diluted with 50 mL of water, extracted twice with 50 mL of ethyl acetate, and the combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid compound 13-2 (330 mg, yield: 20%). MS (ESI) m / z = 444.2 [M+H-Boc] +

[0324] Step 2: Synthesis of Compound 13-3

[0325] Compound 13-2 (300 mg, 0.55 mmol, 1.0 eq) was dissolved in 5 mL of methanol. 5% palladium on carbon (300 mg) was added to the reaction solution, and the reaction mixture was stirred at 30 °C for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to give a yellow solid, compound 13-3 (150 mg, yield: 49%). MS (ESI) m / z = 570.2 [M + H + Na] +

[0326] Step 3: Synthesis of Compound 13-4

[0327] Compound 13-3 (150 mg, 0.27 mmol, 1.0 eq) was dissolved in 5 mL of dioxane hydrochloride, and the reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid hydrochloride of compound 13-4 (130 mg, crude product). MS (ESI) m / z = 448.2 [M+H] +

[0328] Step 3: Synthesis of compound RC013

[0329] Compound 13-4 (29.52 mg, 0.06 mmol, 1.0 eq) was dissolved in 1 mL of N,N-dimethylformamide solution. Compound 1-1 (40 mg, 0.06 mmol, 1.0 eq), N,N-diisopropylethylamine (78.31 mg, 0.61 mmol, 10.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (3.05 mg, 0.06 mmol, 1.0 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was then reverse-phase and purified to obtain a white solid RC013 (11.59 mg, yield: 17%). MS (ESI) m / z = 1089.4 [M+H] +

[0330] 1 H NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.11(s,1H),8.54(d,J=4.8Hz,1H),8.19(t,J =5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.74–7.69(m,2H),7.65(dd ,J=6.0,2.8Hz,1H),7.55(d,J=4.8Hz,1H),7.51(d,J=8.8Hz,1H),7.49–7.45(m,1H),7 .39–7.33(m,1H),7.27(s,1H),7.02(d,J=8.8Hz,1H),5.22(s,2H),5.12(dd,J=12.8,5. 2Hz,1H),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.45(d,J=5.6Hz,6H),3.42(d,J=3.2Hz, 2H),3.39(d,J=6.0Hz,2H),3.35(d,J=6.4Hz,2H),3.28–3.24(m,2H),3.07–3.00(m,4H ),2.92–2.84(m,1H),2.57(t,J=12.8Hz,2H),2.07(s,3H),2.05–2.00(m,1H),1.91(s, 3H),1.80(dd,J=14.4,6.8Hz,2H),1.65(s,1H),1.62(s,2H),1.56(s,2H),1.52(s,7H).

[0331] Example 14 Synthesis of compound RC014

[0332] The compound structure is as follows:

[0333] Synthesis of compound 14-4

[0334] Referring to compound 13-4, starting material compound 13-1 was replaced with compound 3-(4-bromo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (CAS: 2093387-36-9) to synthesize compound 14-4 (3-[4-(3-[2-(2-(2-aminoethoxy)ethoxy)ethoxy]propyl)-1-oxoisoindoline-2-yl]piperidine-2,6-dione); MS (ESI) m / z = 434.2 [M+H] +

[0335] The same synthetic method as that used for RC013 in Example 1 was employed, except that compound 13-4 was replaced with 14-4, to obtain a white solid RC014 (14.97 mg, yield: 23%). MS (ESI) m / z = 1075.4 [M+H] +

[0336] 1H-NMR (400MHz, DMSO-d6): δ12.30(s,1H),10.99(s,1H),8.54(d,J=4.8Hz,1H),8.20(t,J=5. 6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.57–7.52(m,2H),7.51(d,J=8.8Hz,1 H),7.49–7.44(m,1H),7.44–7.42(m,1H),7.42(s,1H),7.38–7.33(m,1H),7.27(s,1H),7.02 (d,J=8.8Hz,1H),5.22(s,2H),5.12(dd,J=13.2,5.2Hz,1H),4.43(d,J=17.2Hz,1H),4.28(d, J=17.2Hz,1H),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.45(ddd,J=10.8,6.0,4.4Hz,6H),3.41 (dd,J=8.0,5.2Hz,4H),3.37(d,J=9.2Hz,2H),3.27(d,J=6.0Hz,2H),3.05(t,J=5.6Hz,2H),2 .95–2.86(m,1H),2.69–2.62(m,2H),2.57(s,1H),2.43–2.32(m,1H),2.07(s,3H),2.02–1.96 (m,1H),1.91(s,3H),1.83–1.75(m,2H),1.65(s,1H),1.62(s,2H),1.56(s,2H),1.52(s,7H).

[0337] Example 15 Synthesis of compound RC015

[0338] The compound structure is as follows:

[0339] Synthesis of Compound 15-4

[0340] Referring to compound 12-4, starting material compound 12-1 was replaced with compound 3-(4-bromo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (CAS: 2093387-36-9) to synthesize compound 15-4 (3-[4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindoline-2-yl]piperidine-2,6-dione), MS (ESI) m / z = 430.2 [M+H] +

[0341] The same synthetic method as that used for RC012 in Example 1 was employed, except that compound 12-4 was replaced with 15-4, to obtain a white solid RC015 (13.78 mg, yield: 28.89%). MS (ESI) m / z = 1071.4 [M+H] +

[0342] 1 H-NMR (400MHz, DMSO-d6): δ12.30 (s, 1H), 11.00 (s, 1H), 8.54 (d, J = 4.8Hz, 1H), 8.20 (t,J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.75(d,J=7.6Hz,1H ),7.70–7.65(m,1H),7.56–7.45(m,4H),7.39–7.33(m,1H),7.27(s,1H),7.02(d,J= 8.8Hz,1H),5.22(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.49–4.27(m,4H),3.96(t,J =5.6Hz,2H),3.68(s,2H),3.62–3.56(m,2H),3.54(dt,J=6.4,3.2Hz,2H),3.49–3.4 2(m,4H),3.38(d,J=6.0Hz,2H),3.26(dd,J=12.0,6.0Hz,2H),3.05(t,J=5.6Hz,2H) ,2.98–2.82(m,1H),2.56(dd,J=15.6,8.0Hz,1H),2.47–2.37(m,1H),2.07(s,3H),2 .04–1.95(m,1H),1.91(s,3H),1.64(s,1H),1.61(s,2H),1.55(s,2H),1.52(s,7H).

[0343] Example 16 Synthesis of compound RC016

[0344] The compound structure is as follows:

[0345] Synthesis of compound 16-4

[0346] Referring to compounds 2-4, starting material compound 2-1 was replaced with compound N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]tert-butyl carbamate, and starting material compound 2-2 was replaced with compound 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindoline-1,3-dione (CAS: 835616-60-9) to synthesize compound 16-4 (4-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione), MS (ESI) m / z = 449.2 [M+H] +

[0347] The same synthetic method as that used for RC002 in Example 1 was employed, except that compound 2-4 was replaced with 16-4, to obtain a white solid RC016 (13 mg, yield: 38.20%). MS (ESI) m / z = 1090.4 [M+H] +

[0348] 1 H NMR (400MHz, DMSO-d6): δ12.30 (s, 1H), 11.09 (s, 1H), 8.54 (d, J = 4.8Hz, 1H), 8.19(t,J=5.2Hz,1H),8.04(d,J=7.4Hz,1H),7.81(d,J=8.0Hz,1H),7.57–7.5 3(m,2H),7.51(d,J=8.8Hz,1H),7.49–7.45(m,1H),7.39–7.33(m,1H),7.27( s,1H),7.09(d,J=8.6Hz,1H),7.02(dd,J=7.8,6.0Hz,2H),6.57(t,J=5.6Hz,1 H),5.22(s,2H),5.04(dd,J=12.8,5.2Hz,1H),3.96(t,J=5.6Hz,2H),3.68(s ,2H),3.57(t,J=5.4Hz,2H),3.52–3.47(m,4H),3.45–3.40(m,6H),3.38–3.36 (m,2H),3.29–3.23(m,2H),3.05(t,J=5.6Hz,2H),2.90–2.82(m,1H),2.65–2 .50(m,2H),2.07(s,3H),2.04–1.96(m,1H),1.91(s,3H),1.64–1.50(m,12H).

[0349] Example 17 Synthesis of compound RC017

[0350] The synthetic route of the compound is as follows:

[0351] Step 1: Synthesis of Compound 17-3

[0352] Compound 17-1 (400 mg, 1.183 mmol, 1.0 eq) was dissolved in 10 mL of N,N-dimethylformamide, followed by the sequential addition of compound 12-2 (509 mg, 1.774 mmol, 1.5 eq), triphenylphosphine (62.05 mg, 0.237 mmol, 0.2 eq), cuprous iodide (22.53 mg, 0.118 mmol, 0.1 eq), palladium(II) bis(acetonitrile) chloride (30.69 mg, 0.118 mmol, 0.1 eq), and diisopropylamine (478.78 mg, 4.731 mmol, 4.0 eq). The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 17-3 (200 mg, yield: 31.05%). MS (ESI) m / z = 445.2 [M+H-Boc] +

[0353] Step 2: Synthesis of Compound 17-4

[0354] Compound 17-3 (200 mg, 0.38 mmol, 1.0 eq) was dissolved in 2 mL of dioxane hydrochloride. The reaction solution was stirred at 25 °C for 3 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 17-4 (170 mg, yield: 96%). MS (ESI) m / z = 445.2 [M+H] +

[0355] Step 3: Synthesis of compound RC017

[0356] Compound 17-4 (33.68 mg, 0.076 mmol, 1.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution, and compound 1-1 (50 mg, 0.076 mmol, 1.0 eq), N,N-diisopropylethylamine (49.63 mg, 0.38 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (35.06 mg, 0.091 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC017 (9.72 mg, yield: 12%). MS (ESI) m / z = 1086.4 [M+H]+

[0357] 1 H-NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.12(s,1H),8.53(d,J=4.8Hz,1H),8.21 (t,J=5.6Hz,1H),8.04(d,J=7.2Hz,1H),7.80(d,J=8.0Hz,1H),7.54(d,J=4.8Hz,1H ),7.52–7.45(m,2H),7.38–7.33(m,1H),7.28(s,1H),7.15(d,J=7.6Hz,1H),7.08(d d,J=8.0,1.0Hz,1H),7.00(t,J=8.0Hz,2H),5.39(dd,J=12.4,5.6Hz,1H),5.21(s,2 H),4.42(s,2H),3.96(t,J=5.6Hz,2H),3.68(s,2H),3.61(d,J=4.0Hz,2H),3.59(s, 3H),3.55–3.52(m,2H),3.49–3.43(m,4H),3.40(t,J=6.0Hz,2H),3.27(d,J=6.0Hz, 1H),3.05(t,J=5.6Hz,2H),2.86(d,J=16.4Hz,2H),2.73–2.59(m,2H),2.07(s,3H), 2.05–1.98(m,1H),1.91(s,3H),1.65(s,1H),1.62(s,2H),1.56(s,2H),1.52(s,7H).

[0358] Example 18 Synthesis of compound RC018

[0359] The synthetic route of the compound is as follows:

[0360] Step 1: Synthesis of Compound 18-3

[0361] Compound 18-1 (4 g, 30.26 mmol, 2.0 eq) was dissolved in 50 mL of tetrahydrofuran, followed by the addition of compound 18-2 (4.89 g, 15.13 mmol, 1.0 eq), tri-tert-butylphosphine (0.61 g, 3.02 mmol, 0.2 eq), N-methyldicyclohexylamine (5.91 g, 30.266 mmol, 2.0 eq), and tris(dibenzylacetone)palladium (1.39 g, 1.51 mmol, 0.1 eq). The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 18-3 (1.5 g, yield: 26.48%). MS(ESI)m / z = 389.2[M+H] +

[0362] Step 2: Synthesis of compound 18-4

[0363] Compound 18-3 (1 g, 2.58 mmol, 1.0 eq) was dissolved in 20 mL of methanol, and 10% palladium on carbon (1 g) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a yellow solid compound 18-4 (0.5 g, yield: 50%).

[0364] Step 3: Synthesis of Compound 18-5

[0365] Compound 18-4 (500 mg, 1.28 mmol, 1.0 eq) was dissolved in 10 mL of tetrahydrofuran, followed by the addition of methanesulfonyl chloride (220 mg, 1.92 mmol, 1.5 eq) and triethylamine (259 mg, 2.56 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL), the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily compound 18-5 (480 mg, yield: 80%). MS (ESI) m / z = 469.0 [M+H] +

[0366] Step 4: Synthesis of Compound 18-6

[0367] Compound 18-5 (480 mg, 1.02 mmol, 1.0 eq) was dissolved in 10 mL of N,N-dimethylformamide (10 mL), and sodium azide (100 mg, 1.53 mmol, 1.5 eq) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a white solid, compound 18-6 (260 mg, yield: 61%). MS (ESI) m / z = 438.2 [M + H + Na] +

[0368] Step 5: Synthesis of compound 18-7

[0369] Compound 18-6 (260 mg, 0.62 mmol, 1.0 eq) was dissolved in 5 mL of ethyl acetate, and palladium on carbon (200 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a yellow solid compound 18-7 (60 mg, yield: 25%). MS (ESI) m / z = 390.2 [M + Na] +

[0370] Step 6: Synthesis of compound RC018

[0371] Compound 18-7 (25.82 mg, 0.06 mmol, 1.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution, and compound 1-1 (40 mg, 0.06 mmol, 1.0 eq), N,N-diisopropylethylamine (39.18 mg, 0.30 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (27.66 mg, 0.07 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC018 (8.39 mg, yield: 13%). MS (ESI) m / z = 1031.4 [M+H] +

[0372] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),11.11(s,1H),8.54(d,J=4.8Hz,1H),8.19(t,J= 5.6Hz,1H),8.03(d,J=7.2Hz,1H),7.80(d,J=8.2Hz,1H),7.78(d,J=6.4Hz,1H),7.76(s ,1H),7.69(d,J=8.8Hz,1H),7.54(d,J=4.8Hz,1H),7.51(d,J=8.8Hz,1H),7.46(d,J=8. 2Hz,1H),7.35(t,J=7.6Hz,1H),7.28(s,1H),7.02(d,J=8.8Hz,1H),5.22(s,2H),5.12(d d,J=12.8,5.6Hz,1H),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.62(t,J=6.4Hz,2H),3.44( d,J=5.2Hz,4H),3.39(t,J=6.0Hz,2H),3.26(d,J=5.6Hz,2H),3.04(d,J=5.2Hz,2H),2.9 5(t,J=6.4Hz,2H),2.87(d,J=13.6Hz,1H),2.56(dd,J=22.4,12.0Hz,2H),2.07(s,3H), 2.03(d,J=5.2Hz,1H),1.91(s,3H),1.65(s,1H),1.62(s,2H),1.56(s,2H),1.52(s,7H).

[0373] Example 19 Synthesis of compound RC019

[0374] The synthetic route of the compound is as follows:

[0375] Step 1: Synthesis of Compound 19-2

[0376] Compound 12-1 (250 mg, 0.77 mmol, 1.0 eq) was dissolved in 5 mL of N,N-dimethylformamide, followed by the sequential addition of compound 19-1 (213.02 mg, 0.77 mmol, 1.0 eq), tris(dibenzylindeneacetone)dipalladium(0) (70.84 mg, 0.08 mmol, 0.1 eq), tri-tert-butylphosphine (156.52 mg, 0.774 mmol, 1.0 eq), and N-methyldicyclohexylamine (453.39 mg, 2.32 mmol, 3.0 eq). The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a red oily compound 19-2 (263 mg, yield: 66%). MS (ESI) m / z = 418.2 [M+H-Boc] +

[0377] Step 2: Synthesis of Compound 19-3

[0378] Compound 19-2 (263 mg, 0.508 mmol, 1.0 eq) was dissolved in 3 mL of methanol, and 10% palladium on carbon (54.08 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a yellow solid compound 19-3 (160 mg, yield: 61%). MS (ESI) [M+H-Boc] + =420.2

[0379] Step 3: Synthesis of Compound 19-4

[0380] Compound 19-3 (100 mg, 0.19 mmol, 1.0 eq) was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a yellow solid compound 19-4 (150 mg, crude product). MS (ESI) [M+H) + =420.2

[0381] Step 4: Synthesis of compound RC019

[0382] Compound 1-1 (20 mg, 0.03 mmol, 1.0 eq) was dissolved in 1 mL of N,N-dimethylformamide solution, and compound 19-4 (15.26 mg, 0.036 mmol, 1.2 eq), N,N-diisopropylethylamine (0.025 mL, 0.15 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (13.83 mg, 0.036 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give a white solid RC019 (7.92 mg, yield: 25%). MS (ESI), m / z = 1061.4 [M+H] +

[0383] 1 H-NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.97(s,1H),8.55(d,J=4.8Hz,1H),8 .20(t,J=5.7Hz,1H),8.04(d,J=7.4Hz,1H),7.81(d,J=8.0Hz,1H),7.60(d,J=7.8 Hz,1H),7.55(d,J=4.9Hz,1H),7.53–7.45(m,2H),7.42(s,1H),7.36(ddd,J=8.7, 6.1,2.0Hz,2H),7.28(s,1H),7.03(d,J=8.8Hz,1H),5.23(s,2H),5.09(dd,J=13. 3,5.1Hz,1H),4.32(dd,J=49.8,17.2Hz,2H),3.96(t,J=5.8Hz,2H),3.68(s,2H), 3.60(t,J=6.8Hz,2H),3.48–3.37(m,10H),3.30–3.23(m,2H),3.05(t,J=5.6Hz,2 H),2.88(t,J=6.8Hz,3H),2.57(d,J=16.8Hz,1H),2.42–2.31(m,1H),2.07(s,3H) ,2.03–1.95(m,1H),1.92(s,3H),1.64(d,J=12.0Hz,3H),1.54(d,J=14.6Hz,9H).

[0384] Example 20 Synthesis of compound RCO20

[0385] The compound structure is as follows:

[0386] Synthesis of compound 20-7

[0387] Referring to compound 18-7, starting material compound 18-2 was replaced with compound 5-bromolenalidomide (CAS: 1010100-26-1) to synthesize compound 20-7 (3-[5-(2-{2-[2-aminoethoxy]ethoxy}ethyl)-1-oxoisoindoline-2-yl]piperidine-2,6-dione), MS (ESI) m / z = 376.2 [M+H] +

[0388] The same synthetic method as in Example RC018 was used, except that compound 18-7 was replaced with 20-7, to prepare a white solid RC020 (12.66 mg, yield: 20%). MS m / z = 1017.4 [M+H] +

[0389] 1 H-NMR (400MHz, DMSO-d6): δ12.30(s,1H),10.97(s,1H),8.54(s,1H),8.20(t,J=5.6Hz,1H),8.03(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.57–7.4 2(m,4H),7.40(s,1H),7.34(dd,J=15.6,8.0Hz,2H),7.28(s,1H),7.03(d, J=8.8Hz,1H),5.23(s,2H),5.09(dd,J=13.2,5.2Hz,1H),4.37–4.26(m,2H ),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.59(t,J=6.8Hz,2H),3.44(s,3H), 3.39(t,J=6.0Hz,2H),3.28–3.23(m,2H),3.04(t,J=5.6Hz,2H),2.95–2.8 1(m,3H),2.65–2.54(m,1H),2.36(dd,J=13.2,4.4Hz,1H),2.07(s,3H),2. 01–1.95(m,1H),1.91(s,3H),1.63(d,J=11.2Hz,3H),1.58-1.45(m,10H).

[0390] Example 21 Synthesis of compound RC021

[0391] The compound structure is as follows:

[0392] Synthesis of Compound 21-7

[0393] Referring to compound 18-7, starting material compound 18-1 was replaced with compound 2-[2-[2-(ethoxy)ethoxy]ethoxy]ethane-1-ol to synthesize compound 21-7 (5-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione), MS (ESI) m / z = 434.2 [M+H]+

[0394] The same synthetic method as in Example RC018 was used, except that compound 18-7 was replaced with 21-7, to prepare a white solid RC0201 (11.78 mg, yield: 18.07%). MS (ESI) m / z = 1075.4 [M+H] +

[0395] 1 H-NMR (400MHz, DMSO-d6): δ12.26(s,1H),11.11(s,1H),8.54(d,J=4.8Hz,1H),8.19 (t,J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=5.2Hz,1H),7.78(s,2H),7.70(d ,J=8.8Hz,1H),7.55(d,J=4.8Hz,1H),7.51(d,J=8.8Hz,1H),7.47(d,J=8.0Hz,1H), 7.36(t,J=7.6Hz,1H),7.27(s,1H),7.03(d,J=8.8Hz,1H),5.22(s,2H),5.13(dd,J=1 2.8,5.6Hz,1H),3.96(t,J=5.6Hz,2H),3.68(s,2H),3.63(t,J=6.4Hz,2H),3.45(s, 4H), 3.42 (s, 4H), 3.39 (t, J = 6.0Hz, 2H), 3.26 (dd, J = 11.6, 6.0Hz, 2H), 3.05 (t, J = 5. 6Hz,2H),2.97(t,J=6.4Hz,2H),2.90–2.82(m,1H),2.63–2.52(m,2H),2.07(s,3H), 2.06–2.00(m,1H),1.91(s,3H),1.65(s,1H),1.62(s,2H),1.56(s,2H),1.52(s,7H).

[0396] Example 22 Synthesis of compound RCO22

[0397] The synthetic route of the compound is as follows:

[0398] Step 1: Synthesis of compound 22-2

[0399] Compound 22-1 (20 g, 80.22 mmol, 1.0 eq) was dissolved in 220 mL of dichloromethane, and p-toluenesulfonyl chloride (23 g, 120.33 mmol, 1.5 eq), 4-dimethylaminopyridine (2 g, 16.04 mmol, 0.2 eq), and N,N-diisopropylethylamine (31 g, 240.66 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (200 mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a colorless oily compound 22-2 (15 g, yield: 46%). MS (ESI) m / z = 426.2 [M+H+Na] +

[0400] Step 2: Synthesis of compound 22-4

[0401] Compound 22-2 (15 g, 37.17 mmol, 1.0 eq) was dissolved in 200 mL of acetonitrile, followed by the sequential addition of compound 22-3 (12 g, 55.76 mmol, 1.5 eq), potassium iodide (0.62 g, 3.718 mmol, 0.1 eq), and cesium carbonate (18 g, 55.76 mmol, 1.5 eq). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to give a colorless oily compound 22-4 (11 g, yield: 65.53%). MS (ESI) m / z = 452.2 [M+H] +

[0402] Step 3: Synthesis of compound 22-5

[0403] Compound 22-4 (11 g, 24.36 mmol, 1.0 eq) was dissolved in 150 mL of methanol, and palladium on carbon (8 g) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a colorless oily compound 22-5 (6 g, yield: 77%). MS (ESI) m / z = 318.2 [M+H] +

[0404] Step 4: Synthesis of Compound 22-7

[0405] Compound 22-5 (300 mg, 0.94 mmol, 1.0 eq) was dissolved in 5 mL of N-methylpyrrolidone, and compound 22-6 (278.06 mg, 0.94 mmol, 1.0 eq) and N,N-diisopropylethylamine (244 mg, 1.88 mmol, 2.0 eq) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give compound 22-7 (100 mg, yield: 17%) as a white solid. MS (ESI) m / z = 592.4 [M+H] +

[0406] Step 5: Synthesis of Compound 22-8

[0407] Compound 22-7 (100 mg, 0.17 mmol, 1.0 eq) was dissolved in 2 mL of dioxane hydrochloride. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to give a white solid compound 22-8 (100 mg, crude product). MS (ESI) m / z = 492.2 [M+H] +

[0408] Step 6: Synthesis of compound RC022

[0409] The hydrochloride salt of compound 22-8 (32.01 mg, 0.06 mmol, 1.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (40 mg, 0.06 mmol, 1.0 eq), N,N-diisopropylethylamine (39.18 mg, 0.30 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (27.66 mg, 0.07 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RCO22 (4.54 mg, yield: 6.61%). MS (ESI) m / z = 1133.4 [M+H] +

[0410] 1H-NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.10(s,1H),8.55(d,J=4.8Hz,1H),8.1 8(t,J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.68(d,J=11.6Hz, 1H),7.55(d,J=4.8Hz,1H),7.49(dd,J=14.4,8.4Hz,2H),7.36(t,J=7.6Hz,2H),7. 27(s,1H),7.02(d,J=8.8Hz,1H),5.23(s,2H),5.10(dd,J=12.8,5.6Hz,1H),3.95(t ,J=5.6Hz,2H),3.69(s,2H),3.50–3.47(m,2H),3.45(s,4H),3.41(d,J=6.0Hz,2H) ,3.28(d,J=6.0Hz,4H),3.16(s,4H),3.06(d,J=5.6Hz,2H),2.86(d,J=12.0Hz,1H), 2.62–2.56(m,1H),2.52(s,2H),2.44(d,J=5.6Hz,2H),2.07(s,3H),2.05–1.98(m, 1H),1.92(s,3H),1.66(s,1H),1.63(s,2H),1.57(s,2H),1.53(s,7H),1.24(s,1H).

[0411] Example 23 Synthesis of compound RCO23

[0412] The synthetic route of the compound is as follows:

[0413] Step 1: Synthesis of compound 23-2

[0414] Compound 23-1 (550 mg, 2.36 mmol, 1.0 eq.) was dissolved in 6 mL of N,N-dimethylformamide, followed by the sequential addition of compound 12-2 (1.36 mg, 4.72 mmol, 2.0 eq.), triphenylphosphine (123.81 mg, 0.47 mmol, 0.2 eq.), N-methyldicyclohexylamine (955.28 mg, 9.44 mmol, 4.0 eq.), cuprous iodide (44.95 mg, 0.24 mmol, 0.1 eq.), and bis(acetonitrile)palladium(II) chloride (61.36 mg, 0.24 mmol, 0.1 eq.). The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 23-2 (620 mg, yield: 60%). MS (ESI) m / z = 462.2 [M + H + Na] +

[0415] Step 2: Synthesis of compound 23-3

[0416] Compound 23-2 (200 mg, 0.455 mmol, 1.0 eq) was dissolved in 0.3 mL methanol, 1 mL water, and 1 mL tetrahydrofuran, and lithium hydroxide (57.29 mg, 1.365 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove methanol and diluted with 5 mL water. The pH of the reaction mixture was adjusted to 6 with dilute hydrochloric acid (2 M). Extraction was performed with ethyl acetate (20 mL), and the organic layer was concentrated to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 23-3 (130 mg, yield: 67%). MS (ESI) m / z = 426.2 [M+H] +

[0417] Step 3: Synthesis of Compound 23-5

[0418] Compound 23-3 (130 mg, 0.31 mmol, 1.0 eq) was dissolved in 1 mL of N,N-dimethylformamide solution, and compound 23-4 (50.29 mg, 0.31 mmol, 1.0 eq), N,N-diisopropylethylamine (0.152 mL, 0.92 mmol, 3.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (127.80 mg, 0.34 mmol, 1.1 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (20 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 23-5 (130 mg, yield: 79%). MS(ESI)m / z = 558.2[M+H+Na] +

[0419] Step 4: Synthesis of Compounds 23-6

[0420] Compound 23-5 (130 mg, 0.24 mmol, 1.0 eq) was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid compound 23-6 (110 mg, yield: 82%). MS (ESI) m / z = 436.2 [M + H + Na] +

[0421] Step 5: Synthesis of compound RC023

[0422] Compound 1-1 (30 mg, 0.05 mmol, 1.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 23-6 (26.68 mg, 0.05 mmol, 1.0 eq), N,N-diisopropylethylamine (0.023 mL, 0.14 mmol, 3.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (19.02 mg, 0.05 mmol, 1.0 eq) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RCO23 (29.08 mg, yield: 54%). MS (ESI) m / z = 1077.4 [M+H] +

[0423] 1H-NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.87(s,1H),8.64(dd,J=8.0,2.4Hz,1H ),8.55(d,J=4.8Hz,1H),8.22(t,J=5.6Hz,1H),8.05(d,J=8.0Hz,1H),7.81(d,J=8. 0Hz,1H),7.64(t,J=7.6Hz,1H),7.55(d,J=4.8Hz,1H),7.53–7.44(m,2H),7.43–7.3 2(m,3H),7.29(s,1H),7.03(d,J=8.8Hz,1H),5.23(s,2H),4.82–4.72(m,2H),4.39( s,2H),3.96(t,J=5.6Hz,2H),3.69(s,2H),3.59(dd,J=5.6,3.2Hz,2H),3.53(dd,J =6.0,3.2Hz,2H),3.46(d,J=2.4Hz,4H),3.40(t,J=6.0Hz,2H),3.28(t,J=6.0Hz,2H ),3.06(t,J=5.2Hz,2H),2.76(d,J=12.8Hz,1H),2.54(d,J=3.2Hz,1H),2.08(s,3H) ,2.03–1.96(m,1H),1.92(s,3H),1.64(d,J=12.4Hz,3H),1.57(s,2H),1.53(s,7H).

[0424] Example 24 Synthesis of compound RC024

[0425] The compound structure is as follows:

[0426] Synthesis of Compound 24-6

[0427] Referring to compound 23-6, starting material compound 23-1 was replaced with compound methyl 4-bromo-3-fluorobenzoate (CAS: 849758-12-9), and 23-4 was replaced with (S)-3-aminopiperidin-2,6-dione hydrochloride (CAS: 25181-50-4) to synthesize compound 24-6 ((S)-4-[3-(2-{2-[2-aminoethoxy]ethoxy}ethoxy)prop-1-yn-1-yl]-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide), MS (ESI) m / z = 436.4 [M+H] +

[0428] The same synthetic method as that used for RC023 in Example 1 was employed, except that compound 23-6 was replaced with 24-6, to obtain white solid RC024 (28.99 mg, yield: 30%). MS (ESI) m / z = 1077.4 [M+H] +

[0429] 1 H-NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.89(s,1H),8.93(d,J=8.4Hz,1H),8.5 5(d,J=4.8Hz,1H),8.22(t,J=5.6Hz,1H),8.05(d,J=7.2Hz,1H),7.81(d,J=8.0Hz, 1H),7.75–7.69(m,2H),7.67–7.61(m,1H),7.55(d,J=4.8Hz,1H),7.53–7.44(m,2H ),7.39-7.33(m,1H),7.29(s,1H),7.03(d,J=8.8Hz,1H),5.22(s,2H),4.82–4.74(m ,2H),4.43(s,2H),3.96(t,J=5.6Hz,2H),3.69(s,2H),3.60(dd,J=5.8,3.2Hz,2H) ,3.53(dd,J=5.6,3.2Hz,2H),3.47(t,J=5.2Hz,4H),3.40(t,J=6.0Hz,2H),3.28(t ,J=6.0Hz,2H),3.06(t,J=5.6Hz,2H),2.85–2.71(m,1H),2.56(s,1H),2.08(s,3H) ,2.02–1.96(m,1H),1.92(s,3H),1.64(d,J=12.0Hz,3H),1.56(s,2H),1.53(s,7H).

[0430] Example 25 Synthesis of compound RC025

[0431] The synthetic route of the compound is as follows:

[0432] Step 1: Synthesis of Compound 25-1

[0433] Compound 23-1 (1 g, 4.29 mmol, 1.0 eq) was dissolved in 10 mL of toluene, followed by the sequential addition of compound 22-5 (1.77 g, 5.578 mmol, 1.3 eq), palladium acetate (0.10 g, 0.429 mmol, 0.1 eq), cesium carbonate (2.10 g, 6.43 mmol, 1.5 eq), and 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (0.53 g, 0.858 mmol, 0.2 eq). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a red oily compound 25-1 (800 mg, yield: 39%). MS(ESI)m / z = 470.2[M+H] +

[0434] Step 2: Synthesis of compound 25-2

[0435] Compound 25-1 (300 mg, 0.639 mmol, 1.0 eq) was dissolved in 3 mL of methanol and 3 mL of water, and lithium hydroxide (107 mg, 2.556 mmol, 4.0 eq) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, and the pH of the solution was adjusted to 7 with dilute hydrochloric acid (1 M). The solution was extracted with ethyl acetate (5 mL), and the organic layer was concentrated to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 25-2 (250 mg, yield: 86%). MS (ESI) m / z = 456.2 [M+H] +

[0436] Step 3: Synthesis of Compound 25-3

[0437] Compound 25-2 (200 mg, 0.43 mmol, 1.0 eq) was dissolved in 3 mL of N,N-dimethylformamide, followed by the sequential addition of compound 23-4 (72.26 mg, 0.43 mmol, 1.0 eq), N,N-diisopropylethylamine (170 mg, 1.31 mmol, 3.0 eq), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (217 mg, 0.57 mmol, 1.3 eq). The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a red oily compound 25-3 (100 mg, yield: 40%). MS(ESI)m / z = 566.2[M+H]+

[0438] Step 4: Synthesis of compound 25-4

[0439] Compound 25-3 (100 mg, 0.177 mmol, 1.0 eq) was dissolved in 5 mL of dioxane hydrochloride. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 25-4 (80 mg, crude product). MS (ESI) m / z = 466.3 [M+H] +

[0440] Step 5: Synthesis of compound RC025

[0441] Compound 25-4 (42.33 mg, 0.091 mmol, 2.0 eq) was dissolved in 5 mL of N,N-dimethylformamide solution, and compound 1-1 (30 mg, 0.045 mmol, 1.0 eq), N,N-diisopropylethylamine (36.17 mg, 0.227 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (20.75 mg, 0.055 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC025 (29.57 mg, yield: 58%). MS (ESI) m / z = 1107.4 [M+H] +

[0442] 1H-NMR (400MHz, DMSO-d6): δ12.34(s,1H),10.85(s,1H),9.76(s,1H),8.56(d,J=4.8Hz, 1H),8.27(t,J=5.8Hz,1H),8.15–8.09(m,1H),8.05(d,J=7.5Hz,1H),7.82(d,J=8.0Hz,1 H),7.65(t,J=9.1Hz,1H),7.57–7.53(m,1H),7.52–7.47(m,1H),7.40–7.35(m,1H),7.2 9(s,1H),7.05(d,J=8.8Hz,1H),6.88(d,J=9.7Hz,1H),6.85(s,1H),5.24(s,2H),4.78–4 .67(m,2H),3.96(t,J=5.8Hz,4H),3.74(d,J=5.0Hz,2H),3.69(s,2H),3.62–3.47(m,6H ),3.41(t,J=6.4Hz,2H),3.37–3.25(m,4H),3.14(d,J=8.0Hz,4H),3.06(t,J=5.7Hz,2H) ,2.83–2.72(m,1H),2.52(dd,J=9.4,2.3Hz,2H),2.14(dd,J=12.8,8.7Hz,1H),2.09(s,3 H),2.04–1.96(m,1H),1.92(s,3H),1.66(s,1H),1.63(s,2H),1.56(s,2H),1.53(s,7H).

[0443] Example 26 Synthesis of compound RC026

[0444] The compound structure is as follows:

[0445] Synthesis of compound 26-4

[0446] Referring to compound 25-4, starting material compound 23-1 was replaced with methyl 4-bromo-3-fluorobenzoate (CAS: 849758-12-9), and 23-4 was replaced with (S)-3-aminopiperidin-2,6-dione hydrochloride (CAS: 25181-50-4) to synthesize compound 26-4 ((S)-4-[4-[2-(2-(2-aminoethoxy)ethoxy)ethyl]piperazin-1-yl]-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide), MS (ESI) m / z = 466.2 [M+H] +

[0447] The same synthetic method as that used for RC025 in Example 1 was employed, except that compound 25-4 was replaced with 26-4, to obtain a white solid RC026 (26.04 mg, yield: 51%). MS (ESI) m / z = 1107.4 [M+H] +

[0448] 1 H-NMR (400MHz, DMSO-d6): δ12.34(s,1H),10.87(s,1H),9.66(s,1H),8.70(d,J=8.4Hz,1H), 8.56(d,J=4.8Hz,1H),8.25(t,J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.82(d,J=8.0Hz,1H),7. 66(dd,J=10.0,5.2Hz,2H),7.56(d,J=4.8Hz,1H),7.53–7.47(m,2H),7.41–7.34(m,1H),7.2 8(s,1H),7.15(t,J=8.8Hz,1H),7.04(d,J=8.8Hz,1H),5.24(s,2H),4.80–4.71(m,1H),3.95( t,J=5.6Hz,2H),3.74(d,J=4.8Hz,4H),3.56–3.53(m,5H),3.52–3.49(m,3H),3.40(d,J=6.0 Hz,2H),3.36(s,2H),3.29(d,J=6.0Hz,2H),3.25(d,J=12.8Hz,2H),3.13(d,J=12.4Hz,2H),3 .05(t,J=5.6Hz,2H),2.83–2.74(m,1H),2.58–2.52(m,1H),2.15–2.09(m,1H),2.08(d,J=3.6 Hz,3H),1.99–1.94(m,1H),1.92(s,3H),1.66(s,1H),1.63(s,2H),1.56(s,2H),1.52(s,7H).

[0449] Example 27 Synthesis of compound RC027

[0450] The synthetic route of the compound is as follows:

[0451] Step 1: Synthesis of Compound 27-2

[0452] Compound 27-1 (10 g, 60.20 mmol, 1.0 eq) was dissolved in 100 mL of concentrated sulfuric acid, and N-bromosuccinimide (21.43 g, 120.40 mmol, 2.0 eq) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (200 mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 27-2 (8 g, yield: 51%). MS (ESI) m / z = 263.0 [M+H] +

[0453] Step 2: Synthesis of compound 27-4

[0454] Compound 27-2 (500 mg, 1.90 mmol, 1.0 eq) was dissolved in 6 mL of N,N-dimethylformamide, and compound 27-3 (312.88 mg, 1.90 mmol, 1.0 eq) and N,N′-carbonyldiimidazole (308.25 mg, 1.90 mmol, 1.0 eq) were added. The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 27-4 (250 mg, yield: 37%). MS (ESI) m / z = 355.0 [M+H] +

[0455] Step 3: Synthesis of compound 27-5

[0456] Compound 12-2 (404.60 mg, 1.41 mmol, 2.0 eq) was dissolved in 5 mL of N,N-dimethylformamide, followed by the addition of compound 27-4 (250 mg, 0.70 mmol, 1.0 eq), cuprous iodide (13.41 mg, 0.07 mmol, 0.1 eq), triphenylphosphine (36.93 mg, 0.14 mmol, 0.2 eq), diisopropylamine (284.95 mg, 2.82 mmol, 4.0 eq), and palladium dichloride diacetonitrile (18.30 mg, 0.07 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 27-5 (200 mg, yield: 51%). MS (ESI) m / z = 584.2 [M + H + Na] +

[0457] Step 4: Synthesis of compound 27-6

[0458] Compound 27-5 (200 mg, 0.36 mmol, 1.0 eq) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid compound 27-6 (180 mg, yield: 88%). MS (ESI) m / z = 462.2 [M+H] +

[0459] Step 5: Synthesis of compound RC027

[0460] Compound 1-1 (40 mg, 0.06 mmol, 1.0 eq) was dissolved in 1 mL of N,N-dimethylformamide solution, and compound 27-6 (27.97 mg, 0.06 mmol, 1.0 eq), N,N-diisopropylethylamine (0.027 mL, 0.13 mmol, 3.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (25.15 mg, 0.07 mmol, 1.1 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC027 (7.28 mg, yield: 13%). MS (ESI) m / z = 1103.4 [M+H] +

[0461] 1H-NMR (400MHz, DMSO-d6): δ8.51(d,J=4.8Hz,1H),7.93(d,J=7.6Hz,1H),7.80–7.70(m,3H),7.52(d,J=2.8Hz,1H),7.5 0(d,J=5.2Hz,1H),7.48–7.44(m,2H),7.39(s,1H),7.35(t,J=7.6Hz,2H),7.07(d,J=8.8Hz,1H),5.34(d,J=6.0Hz,3H), 5.10–5.04(m,1H),4.58(s,3H),4.35(s,2H),4.03(t,J=6.0Hz,2H),3.76(s,2H),3.63(s,4H),3.62(s,4H),2.83–2.76 (m,2H),2.73–2.68(m,2H),2.19(s,1H),2.14(s,3H),2.02(s,1H),1.98(s,3H),1.73(s,3H),1.68(s,2H),1.63(s,7H).

[0462] Example 28 Synthesis of compound RC028

[0463] The synthetic route of the compound is as follows:

[0464] Step 1: Synthesis of compound 28-2

[0465] Compound 28-1 (1 g, 4.62 mmol, 1.0 eq) was dissolved in 10 mL of toluene, followed by the sequential addition of compound 22-5 (1.91 g, 6.01 mmol, 1.3 eq), palladium acetate (0.10 g, 0.46 mmol, 0.1 eq), cesium carbonate (2.26 g, 6.94 mmol, 1.5 eq), and 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (0.29 g, 0.46 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a red oily compound 28-2 (700 mg, yield: 33%). MS(ESI)m / z = 453.2[M+H] +

[0466] Step 2: Synthesis of compound 28-3

[0467] Compound 28-2 (400 mg, 0.88 mmol, 1.0 eq) was dissolved in 5 mL of methanol and 5 mL of water, and lithium hydroxide (148 mg, 3.53 mmol, 4.0 eq) was added. The reaction mixture was stirred at 25 °C for 16 hours. The pH of the solution was adjusted to 7 with dilute hydrochloric acid (1 M), and the mixture was extracted with ethyl acetate (5 mL). The organic layer was concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 28-3 (300 mg, yield: 62%). MS (ESI) m / z = 439.2 [M+H] +

[0468] Step 3: Synthesis of compound 28-5

[0469] Compound 28-3 (200 mg, 0.45 mmol, 1.0 eq) was dissolved in 5 mL of N,N-dimethylformamide, followed by the sequential addition of compound 28-4 (75 mg, 0.45 mmol, 1.0 eq), N,N-diisopropylethylamine (176 mg, 1.36 mmol, 3.0 eq), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (225 mg, 0.59 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 28-5 (100 mg, yield: 40%). MS(ESI)m / z = 549.5 [M+H] +

[0470] Step 4: Synthesis of compound 28-6

[0471] Compound 28-5 (100 mg, 0.18 mmol, 1.0 eq) was dissolved in 5 mL of dioxane hydrochloride. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 28-6 (80 mg, crude). This was used directly in the next reaction without further purification. MS (ESI) m / z = 449.4 [M+H] +

[0472] Step 5: Synthesis of compound RC028

[0473] The hydrochloride salt of compound 28-6 (35.57 mg, 0.079 mmol, 1.3 eq) was dissolved in 5 mL of N,N-dimethylformamide solution. Compound 1-1 (40 mg, 0.061 mmol, 1.0 eq), N,N-diisopropylethylamine (39.17 mg, 0.303 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (27.66 mg, 0.073 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give a white solid RC028 (5.24 mg, yield: 8%). MS (ESI) m / z = 1090.4 [M+H] +

[0474] 1 H NMR (400MHz, DMSO-d6): δ12.27(s,1H),10.85(s,1H),8.71(d,J=8.2Hz,1H),8. 54(s,1H),8.27(d,J=2.8Hz,1H),8.20(t,J=5.6Hz,1H),8.05(d,J=7.6Hz,1H), 7.82(t,J=7.2Hz,2H),7.55(d,J=4.4Hz,1H),7.52(d,J=8.8Hz,1H),7.48(d,J= 7.2Hz,1H),7.40-7.36(m,2H),7.29(s,1H),7.04(d,J=8.8Hz,1H),5.24(s,2H) ,4.79-4.68(m,1H),3.96(t,J=5.6Hz,2H),3.69(s,2H),3.49(t,J=5.8Hz,2H), 3.46-3.40(m,6H),3.27(d,J=6.0Hz,7H),3.06(t,J=5.6Hz,2H),2.84-2.74(m, 1H),2.52(s,4H),2.46(t,J=5.6Hz,2H),2.20-2.14(m,1H),2.08(s,3H),2.05- 1.98(m,1H),1.93(s,3H),1.66(s,1H),1.63(s,2H),1.57(s,2H),1.53(s,7H).

[0475] Example 29 Synthesis of compound RC029

[0476] The synthetic route of the compound is as follows:

[0477] Step 1: Synthesis of Compound 29-3

[0478] Compound 29-2 (1.94 g, 9.65 mmol, 1.0 eq) was dissolved in 20 mL of tetrahydrofuran. Sodium hydroxide (0.77 g, 19.317 mmol, 2.0 eq) was added at 0 °C, and the mixture was stirred for 1 hour. Then, compound 29-1 (2 g, 9.659 mmol, 1.0 eq) was added. The reaction mixture was stirred at 25 °C for 15 hours under a nitrogen atmosphere. The reaction mixture was poured into saturated ammonium chloride water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a colorless oily compound 29-3 (300 mg, yield: 9%), MS (ESI) m / z = 272.2 [M+H-56]. +

[0479] Step 2: Synthesis of compound 29-4

[0480] Compound 29-3 (233.09 mg, 0.71 mmol, 1.2 eq) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of compound 13-1 (200 mg, 0.59 mmol, 1.0 eq), cuprous iodide (11.30 mg, 0.06 mmol, 0.1 eq), triphenylphosphine (31.11 mg, 0.12 mmol, 0.2 eq), palladium dichloride diacetonitrile (15.39 mg, 0.06 mmol, 0.1 eq), and diisopropylamine (240.12 mg, 2.37 mmol, 4.0 eq). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 29-4 (700 mg, yield: 33%). MS (ESI) m / z = 484.4 [M + H - 100] +

[0481] Step 3: Synthesis of Compound 29-5

[0482] Compound 29-4 (100 mg, 0.17 mmol, 1.0 eq) was dissolved in 5 mL of methanol, and palladium on carbon (80 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours under hydrogen protection. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with 10 mL of methanol. The filtrate was concentrated under reduced pressure to give a yellow solid compound 29-5 (80 mg, yield: 79%). MS (ESI) m / z = 488.2 [M + H - 100] +

[0483] Step 4: Synthesis of Compound 29-6

[0484] Compound 29-5 (90 mg, 0.15 mmol, 1.0 eq) was dissolved in 3 mL of dichloromethane, followed by the addition of 1 mL of trifluoroacetic acid. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid compound 29-6 (80 mg, crude product). MS (ESI) m / z = 488.2 [M+H] +

[0485] Step 5: Synthesis of compound RC029

[0486] The trifluoroacetate of compound 29-6 (63.53 mg, 0.121 mmol, 2.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (40 mg, 0.061 mmol, 1.0 eq), N,N-diisopropylethylamine (39.17 mg, 0.303 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (25.36 mg, 0.067 mmol, 1.1 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC029 (11.01 mg, yield: 16%). MS (ESI) m / z = 1129.4 [M+H] +

[0487] 1H NMR (400MHz, DMSO-d6): δ12.38(s,1H),11.18(s,1H),8.61(d,J=4.8Hz,1H),8. 11(d,J=7.2Hz,1H),7.87(d,J=8.0Hz,1H),7.81-7.76(m,2H),7.73(dd,J=8.0,4 .4Hz,1H),7.64-7.58(m,2H),7.57-7.51(m,1H),7.45-7.39(m,1H),7.28(s,1H) ,7.02(d,J=8.8Hz,1H),5.32-5.20(m,2H),5.19-5.14(m,1H),4.00-3.91(m,2H) ,3.76(s,2H),3.71(d,J=8.4Hz,1H),3.55-3.49(m,4H),3.48-3.42(m,6H),3.37 -3.31(m,2H),3.29-3.23(m,1H),3.17-3.07(m,5H),2.96-2.82(m,2H),2.69-2. 58(m,2H),2.20(s,3H),2.14-2.06(m,1H),1.97(s,3H),1.92-1.83(m,2H),1.70 (s,1H),1.67(s,2H),1.61(s,2H),1.59-1.52(m,7H),1.47(s,1H),1.15(s,1H).

[0488] Example 30 Synthesis of compounds RC030 and RC031

[0489] The synthetic route of the compound is as follows:

[0490] Step 1: Synthesis of Compound 30-1

[0491] Compound 18-1 (10 g, 75.666 mmol, 1.0 eq) was dissolved in 120 mL of dichloromethane, and p-toluenesulfonyl chloride (17.31 g, 90.799 mmol, 1.5 eq) and triethylamine (15.31 g, 151.332 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (200 mL) and extracted three times with ethyl acetate (200 mL × 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a colorless oily compound 30-1 (13 g, yield: 60%). MS (ESI) m / z = 309.2 [M + Na] +

[0492] Step 2: Synthesis of compound 30-2

[0493] Compound 30-1 (10 g, 34.924 mmol, 1.0 eq) was dissolved in 130 mL of acetonitrile, followed by the sequential addition of compound 11-1 (6.5 g, 34.924 mmol, 1.0 eq), potassium carbonate (9.65 g, 69.847 mmol, 2.0 eq), and potassium iodide (1.16 g, 6.985 mmol, 0.2 eq). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into water (200 mL) and extracted three times with ethyl acetate (200 mL × 3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow oily compound 30-2 (3 g, yield: 28%). MS (ESI) m / z = 301.2 [M + H - 100] +

[0494] Step 3: Synthesis of compounds 30-3 and 30-4

[0495] Compound 30-2 (2.5 g, 8.322 mmol, 1.5 eq) was dissolved in 40 mL of N,N-dimethylformamide, followed by the sequential addition of compound 12-1 (1.79 g, 5.548 mmol, 1.0 eq), N-methyldicyclohexylamine (3.25 g, 16.644 mmol, 3.0 eq), tris(dibenzylacetone)dipalladium (0.51 g, 0.555 mmol, 0.1 eq), and tri-tert-butylphosphine (2.25 g, 1.110 mmol, 0.2 eq). The reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection. The reaction mixture was poured into water (50 mL) and extracted three times with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a mixture of yellow solid compounds 30-3 and 30-4 (800 mg, yield: 26%). MS (ESI) m / z = 543.2 [M + H-100] +

[0496] Step 4: Synthesis of compounds 30-5 and 30-6

[0497] A mixture of compounds 30-3 and 30-4 (500 mg, 0.921 mmol, 1.0 eq) was dissolved in 10 mL of methanol, and palladium on carbon (400 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated to give a yellow solid mixture of compounds 30-5 and 30-6 (350 mg). MS (ESI) m / z = 545.2 [M+H] +

[0498] Step 5: Synthesis of compounds 30-7 and 30-8

[0499] A mixture of compounds 30-5 and 30-6 (350 mg, 0.643 mmol, 1.0 eq) was dissolved in 10 mL of dioxane hydrochloride, and the reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated to give a yellow solid mixture of compounds 30-7 and 30-8 (200 mg) (crude product). MS (ESI) m / z = 445.2 [M+H] +

[0500] Step 6: Synthesis of compounds RC030 and RC031

[0501] The hydrochloride salts of mixtures 30-7 and 30-8 (41.11 mg, 0.076 mmol, 1.0 eq) were dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (50 mg, 0.076 mmol, 1.0 eq), N,N-diisopropylethylamine (48.97 mg, 0.379 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (34.58 mg, 0.091 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase reaction to give off-white solid RC030 (11.39 mg, yield: 13%) and off-white solid RC031 (4.63 mg, yield: 5%).

[0502] RC030: MS(ESI)m / z=1086.4[M+H] +

[0503] 1H NMR(400MHz,DMSO-d6):δ12.30(s,1H),10.98(s,1H),8.55(d,J=4.0Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.61(d,J=7.6Hz,1H),7.57-7.53(m,2H),7.50-7.45(m,1H),7.43(s,1H),7.37-7.31(m,2H),7.22(s,1H),6.97(d,J=8.8Hz,1H),5.21(s,2H),5.09(dd,J=13.2,5.2Hz,1H),4.33(dd,J=50.0,17.2Hz,2H),3.90(t,J=5.6Hz,2H),3.71(s,2H),3.61(t,J=6.8Hz,2H),3.48–3.43(m,2H),3.42–3.37(m,4H),3.37-3.34(m,2H),3.05(t,J=5.6Hz,2H),2.93(s,2H),2.90-2.87(m,2H),2.60(s,1H),2.40-2.34(m,1H),2.29(t,J=6.0Hz,2H),2.25(s,2H),2.15(s,3H),2.09-2.03(m,2H),2.00-1.94(m,2H),1.92(s,3H),1.65(s,1H),1.62(s,2H),1.57(s,2H),1.52(s,7H).

[0504] RC031:MS(ESI)m / z=1086.4[M+H] +

[0505] 1H NMR (400MHz, DMSO-d6): δ12.29(s,1H),10.98(s,1H),8.55(d,J=4.8Hz,1H),8.03(d,J =8.0Hz,1H),7.80(d,J=8.0Hz,1H),7.67(d,J=7.6Hz,1H),7.56(s,1H),7.54(d,J=3.6H z,1H),7.52(s,1H),7.47(t,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),7.34(t,J=7.6Hz,1H) ,7.22(s,1H),6.97(d,J=8.8Hz,1H),5.21(s,2H),5.10(dd,J=13.6,4.4Hz,1H),4.59–4 .52(m,1H),4.47–4.38(m,1H),4.30(d,J=16.8Hz,1H),3.90(t,J=5.6Hz,2H),3.71(s, 2H),3.45–3.35(m,8H),3.05(t,J=5.6Hz,2H),2.93(s,2H),2.62–2.54(m,1H),2.38(dd ,J=13.2,4.8Hz,1H),2.34–2.24(m,4H),2.14(s,3H),2.07(s,2H),2.10–2.00(m,2H),1 .91(s,3H),1.64(s,1H),1.61(s,2H),1.56(s,2H),1.52(s,7H),1.32(d,J=6.4Hz,3H).

[0506] Example 31 Synthesis of compound RCO32

[0507] The synthetic route of the compound is as follows:

[0508] Step 1: Synthesis of compound 32-3

[0509] Compound 32-1 (2.0 g, 8.05 mmol, 1.0 eq) was dissolved in chloroform (20 mL), and N,N-diisopropylethylamine (2.1 mL, 12.0 mmol, 1.5 eq) and compound 32-2 (0.91 g, 7.65 mmol, 0.95 eq) were added sequentially. The reaction mixture was stirred at 50 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with an aqueous sodium hydroxide solution (0.2 M, 20 mL) and extracted three times with dichloromethane (3 × 20 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give a colorless oily compound 32-3 (370 mg, yield: 16%).

[0510] 1 H NMR (400MHz, CDCl3): δ5.14(s,1H),3.64-3.58(m,6H),3.53(t,J=5.2Hz,2H),3.45(d,J=2.4H z,2H),3.37-3.26(m,2H),2.92-2.83(m,2H),2.21(t,J=2.4Hz,1H),1.70(s,1H),1.44(s,9H).

[0511] Step 2: Synthesis of compound 32-5

[0512] Compounds 32-4 (350 mg, 1.08 mmol, 1.0 eq) and 32-3 (341 mg, 1.19 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of diisopropylamine (438 mg, 4.33 mmol, 4.0 eq), cuprous iodide (41.2 mg, 0.217 mmol, 0.2 eq), triphenylphosphine (28.4 mg, 0.108 mmol, 0.1 eq), and bis(acetonitrile)palladium(II) dichloride (28.1 mg, 0.108 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography to give the yellow solid product compound 32-5 (350 mg, yield: 61%).

[0513] 1 H NMR (400MHz, DMSO-d6): δ11.01(s,1H),7.75(d,J=7.6Hz,1H),7.68(d,J=6.8Hz,1H),7.55(t,J=7 .6Hz,1H),6.80-6.68(m,1H),5.16(dd,J=13.6,5.2Hz,1H),4.48(d,J=17.6Hz,1H),4.33(d,J=17 .6Hz,1H),3.75(s,1H),3.58-3.45(m,6H),3.37(t,J=6.2Hz,2H),3.31-3.28(m,2H),3.12-3.00( m,2H),2.95-2.84(m,2H),2.73-2.56(m,1H),2.47-2.35(m,2H),2.10-1.98(m,1H),1.36(s,9H).

[0514] Step 3: Synthesis of compound 32-6

[0515] Compound 32-5 (330 mg, 0.624 mmol, 1.0 eq) was dissolved in methanol (10 mL), and palladium on carbon (66 mg, 10%, 0.1 eq) was added. The reaction mixture was purged with a hydrogen balloon, and stirred at 25 °C for 5 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure to give a yellow solid compound 32-6 (75 mg, yield: 22%). MS (ESI) m / z = 533.4 [M+H] +

[0516] Step 4: Synthesis of Compound 32-7

[0517] Compound 32-6 (100 mg, 0.17 mmol, 1.0 eq) was dissolved in dioxane (3 mL), followed by the addition of a dioxane solution in hydrochloric acid (2 mL, 4 M). The reaction mixture was stirred at 25 °C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid compound 32-7 (50 mg, yield: 87%). MS (ESI) m / z = 433.2 [M+H] +

[0518] Step 5: Synthesis of compound RC032

[0519] Compound 1-1 (25.0 mg, 0.038 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 32-7 (35.4 mg, 0.076 mmol, 2.0 eq), N-methylimidazole (135 mg, 0.189 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid RCO32 (15.56 mg, yield: 28%). MS (ESI) m / z = 538.0 [M / 2+H] +

[0520] 1H NMR (400MHz, DMSO-d6): δ10.99(s,1H),8.64-8.43(m,1H),8.31-8.13(m,1H),8.03(d,J=7.6Hz,1H),7.80(d,J=7.6Hz,1H),7. 58-7.39(m,6H),7.35(t,J=7.5Hz,1H),7.27(s,1H),7.03(d,J=8.8Hz,1H),5.23(s,2H),5.12(dd,J=12.8,4.8Hz,1H),4.43(d, J=16.8Hz,1H),4.28(d,J=17.2Hz,1H),3.95(s,2H),3.68(s,2H),3.42-3.27(m,11H),3.08-2.97(m,3H),2.97-2.83(m,2H),2 .71-2.55(m,7H),2.43-2.29(m,1H),2.07(s,3H),2.00-1.87(m,3H),1.79-1.71(m,2H),1.67-1.60(m,3H),1.57-1.48(m,8H).

[0521] Example 32 Synthesis of compound RCO33

[0522] The synthetic route of the compound is as follows:

[0523] Step 1: Synthesis of compound 33-2

[0524] Compound 33-1 (2.0 g, 11.4 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL) under ice bath conditions, and sodium hydride (0.55 g, 13.6 mmol, 60%, 1.2 eq) was added. The reaction mixture was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. Then, compound 33-2 (2.55 g, 17.1 mmol, 1.5 eq) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 1.5 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give a yellow oily compound 33-2 (1.55 g, yield: 64%).

[0525] 1H NMR (400MHz, CDCl3): δ4.15 (d, J = 2.4Hz, 2H), 3.75-3.58 (m, 2H), 3.51-3.34 (m, 2H), 2.91 (s, 3H), 2.42 (s, 1H), 1.45 (s, 9H).

[0526] Step 2: Synthesis of compound 33-3

[0527] Compound 33-2 (1.55 g, 7.26 mmol, 1.0 eq) was dissolved in dioxane (10 mL), followed by the addition of a dioxane solution in hydrochloric acid (5 mL, 20.0 mmol, 4 M). The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid, compound 33-3 (1.05 g, yield: 96%).

[0528] 1 H NMR (400MHz, D2O): δ4.47-4.17(m,2H),3.98-3.79(m,2H),3.44-3.17(m,2H),2.76(s,3H).

[0529] Step 3: Synthesis of compound 33-5

[0530] Compounds 33-3 (1.05 g, 7.04 mmol, 1.0 eq) and 33-4 (3.78 g, 14.1 mmol, 2.0 eq) were dissolved in acetonitrile (30 mL), and potassium carbonate (2.92 g, 21.1 mmol, 3.0 eq) was added. The reaction mixture was stirred at 70 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched with water (30 mL) and extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give a yellow oily compound 33-5 (1.50 g, yield: 71%).

[0531] 1 H NMR (400MHz, CDCl3): δ5.24(s,1H),4.17(d,J=2.4Hz,2H),3.65(t,J=5.6Hz,2H),3.56(t,J=5.6Hz,2H),3.50(t,J=5.2H z,2H),3.36-3.26(m,2H),2.68(t,J=5.6Hz,2H),2.64(t,J=5.6Hz,2H),2.42(t,J=2.4Hz,1H),2.33(s,3H),1.44(s,9H).

[0532] Step 4: Synthesis of compound 33-6

[0533] Compounds 32-4 (300 mg, 0.928 mmol, 1.0 eq) and 33-5 (334 mg, 1.11 mmol, 1.2 eq) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of diisopropylamine (375 mg, 3.71 mmol, 4.0 eq), cuprous iodide (35.3 mg, 0.186 mmol, 0.2 eq), triphenylphosphine (24.3 mg, 0.09 mmol, 0.1 eq), and bis(acetonitrile)palladium(II) dichloride (24.1 mg, 0.09 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 18 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid, compound 33-6 (120 mg, yield: 24%). MS (ESI) m / z = 543.0 [M+H] +

[0534] Step 5: Synthesis of Compound 33-7

[0535] Compound 33-6 (100 mg, 0.189 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and palladium on carbon (20.1 mg, 0.019 mmol, 10%, 0.1 eq) was added. The reaction mixture was purged with a hydrogen balloon, and stirred at 25 °C for 12 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (20 mL). The filtrate was concentrated under reduced pressure to give a yellow solid compound 33-7 (95 mg, yield: 94%).

[0536] 1 H NMR (400MHz, CDCl3): δ8.22(s,1H),7.74(dd,J=7.2,1.2Hz,1H),7.48-7.34(m,2H),5.44-5.20(m,2H),4.45(d,J=16.0Hz,1H),4.31(d,J=1 6.0Hz,1H),3.60-3.38(m,8H),3.34-3.24(m,2H),2.97-2.78(m,2H), 2.78-2.59(m,5H),2.46-2.17(m,5H),1.99-1.85(m,2H),1.44(s,9H).

[0537] Step 6: Synthesis of Compound 33-8

[0538] Compound 33-7 (90 mg, 0.165 mmol, 1.0 eq) was dissolved in dioxane (5 mL), followed by the addition of a dioxane solution in hydrochloric acid (3 mL, 4 M). The reaction mixture was stirred at 25 °C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid compound 33-8 (75 mg, yield: 94%). MS (ESI) m / z = 447.4 [M+H] +

[0539] Step 7: Synthesis of compound RC033

[0540] Compound 1-1 (25.0 mg, 0.038 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 33-8 (21.9 mg, 0.045 mmol, 2.0 eq), N-methylimidazole (135 mg, 0.189 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid RC033 (11.81 mg, yield: 10%). MS (ESI) m / z = 545.0 [M / 2+H] +

[0541] 1 H NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.99(s,1H),8.54(s,1H),8.22(s,1H),8.14(s,0.5H),8.04(d,J=7.4Hz,1H),7. 81(d,J=7.6Hz,1H),7.62-7.33(m,7H),7.28(s,1H),7.03(d,J=8.4Hz,1H),5.23(s,2H),5.13(d,J=8.4Hz,1H),4.42(d,J= 17.2Hz,1H),4.27(d,J=17.2Hz,1H),3.95(s,2H),3.68(s,3H),3.49-3.29(m,11H),3.05(s,2H),2.99-2.81(m,1H),2.71- 2.57(m,6H),2.44-2.22(m,4H),2.10-1.96(m,4H),1.91(s,3H),1.85-1.72(m,2H),1.68-1.59(m,3H),1.54-1.45(m,9H).

[0542] Example 33 Synthesis of compound RC034

[0543] The compound structure is as follows:

[0544] Synthesis of Compound 34-8

[0545] Referring to compound 33-8, reaction intermediate 33-5 was replaced with compound N-{2-[4-(2-{[prop-2-yn-1-yl]oxy}ethyl)piperazin-1-yl]ethyl}carbamate tert-butyl ester to synthesize compound 34-8 (3-(4-(3-(2-(4-(2-aminoethyl)piperazin-1-yl)ethoxy)propyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione), MS (ESI) m / z = 458.2 [M+H] +

[0546] The same synthetic method as that used for RC033 in Example 1 was employed, except that compound 33-8 was replaced with 34-8, to obtain a white solid compound RC034 (20.8 mg, yield: 50%). MS (ESI) m / z = 550.4 [M / 2+H] +

[0547] 1 H NMR (400MHz, DMSO-d6): δ12.34(s,1H),11.00(s,1H),8.55(d,J=4.8Hz,1H),8 .32(s,1H),8.16–8.09(m,1H),8.05(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7 .60-7.49(m,3H),7.49-7.40(m,2H),7.39-7.32(m,1H),7.29(s,1H),7.04(d, J=8.8Hz,1H),5.24(s,2H),5.14(dd,J=13.2,5.2Hz,1H),4.44(d,J=17.2Hz,1 H),4.29(d,J=17.2Hz,1H),3.96(t,J=5.6Hz,2H),3.68(s,2H),3.44(t,J=6.0 Hz,4H),3.27-3.14(m,3H),3.06(t,J=5.6Hz,2H),2.99-2.84(m,1H),2.67(t, J=7.6Hz,2H),2.63-2.55(m,1H),2.47-2.29(m,12H),2.07(s,3H),2.04-1.97 (m,1H),1.91(s,3H),1.88-1.76(m,2H),1.68-1.60(m,3H),1.58-1.50(m,9H).

[0548] Example 34 Synthesis of compound RC035

[0549] The compound structure is as follows:

[0550] Synthesis of Compound 35-8

[0551] Referring to compound 33-8, reaction intermediate 33-5 was replaced with compound tert-butyl(2-(4-(propynyl)piperazin-1-yl)ethyl)carbamate to synthesize compound 35-8 (3-[4-(3-[4-(2-aminoethyl)piperazin-1-yl]propyl)-1-oxoisoindoline-2-yl]piperidine-2,6-dione), MS (ESI) m / z = 414.2 [M+H] +

[0552] The same synthetic method as that used for RC033 in Example 1 was employed, except that compound 33-8 was replaced with 35-8, to obtain a white solid compound RC035 (15.05 mg, yield: 38%). MS (ESI) m / z = 528.5 [M / 2+H] +

[0553] 1 H NMR (400MHz, DMSO-d6): δ12.31(s,1H),11.00(s,1H),8.55(d,J=4.4Hz,1H),8.31(s,1H),8.18–8.09(m,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8. 0Hz,1H),7.60–7.49(m,3H),7.49-7.42(m,2H),7.38-7.31(m,1H),7.30 (s,1H),7.04(d,J=8.8Hz,1H),5.24(s,2H),5.14(dd,J=13.2,5.2Hz,1H) ,4.46(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.96(t,J=5.6Hz,2H), 3.69(s,2H),3.26-3.15(m,3H),3.11-3.00(m,2H),3.01-2.83(m,1H),2. 69-2.55(m,3H),2.43-2.22(m,12H),2.07(s,3H),2.03-1.96(m,1H),1.9 5-1.87(m,3H),1.81-1.72(m,2H),1.68-1.61(m,3H),1.59-1.47(m,9H).

[0554] Example 35 Synthesis of compound RC036

[0555] The compound structure is as follows:

[0556] Synthesis of compound 36-4

[0557] Referring to compound 13-4, starting material 13-1 was replaced with compound 12-1, and compound 12-2 was replaced with tert-butyl 2-(2-(propoxy)ethoxy)ethylcarbamate, to synthesize compound 36-4 (3-[5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-1-oxoisoindoline-2-yl]piperidin-2,6-dione), MS (ESI) m / z = 390.2 [M+H] +

[0558] The same synthetic method as in Example RC013 was used, except that compound 13-4 was replaced with 36-4, to obtain a white solid compound RC036 (9.38 mg, yield: 16%). MS (ESI) m / z = 1031.4 [M+H] +

[0559] 1 H NMR (400MHz, DMSO-d6): δ12.29(s,1H),10.97(s,1H),8.54(d,J=4.8Hz,1H),8.31(s ,1H),8.20(t,J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.58(d,J= 7.6Hz,1H),7.54-7.52(m,1H),7.49-7.45(m,1H),7.38-7.31(m,2H),7.30-7.25(m, 2H),7.02(d,J=8.8Hz,1H),5.22(s,2H),5.09(dd,J=13.2,5.2Hz,1H),4.37(d,J=17. 2Hz,1H),4.25(d,J=17.2Hz,1H),3.94(t,J=5.6Hz,2H),3.68(s,2H),3.47-3.40(m, 6H),3.35-3.32(m,2H),3.29(s,2H),3.04(t,J=5.6Hz,2H),2.94-2.85(m,1H),2.68- 2.64(m,2H),2.61-2.55(m,1H),2.39-2.33(m,1H),2.07(s,3H),1.99-1.94(m,1H), 1.91(s,3H),1.78-1.71(m,2H),1.65(s,1H),1.62(s,2H),1.55(s,2H),1.52(s,7H).

[0560] Example 36 Synthesis of compound RC037

[0561] The compound structure is as follows:

[0562] Synthesis of Compound 37-8

[0563] Referring to compound 22-8, starting material 22-1 was replaced with compound 2-(2-(3-hydroxypropoxy)ethoxy)ethylcarbamate tert-butyl ester to synthesize compound 37-8 (5-[4-(3-(2-(2-aminoethoxy)ethoxy)propyl)piperazin-1-yl]-6-fluoro-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione), MS (ESI) m / z = 506.2 [M+H] +

[0564] The same synthetic method as in Example RC022 was used, except that compound 22-8 was replaced with 37-8, to prepare the yellow solid compound RC037 (7.57 mg, yield: 11%). MS (ESI) m / z = 574.4 [M / 2+H] +

[0565] 1 H NMR (400MHz, DMSO-d6): δ12.31(s,1H),11.16-11.06(m,1H),8.55(d,J=4.8Hz,1H),8.24-8.17(m,1H),8.04(d,J=7.6Hz,1H),7.82(d,J =8.0Hz,1H),7.75-7.65(m,1H),7.56(d,J=5.2Hz,1H),7.53-7.46(m,2H),7.40-7.33(m,2H),7.28(s,1H),7.04(d,J=8.8Hz,1H),5.24(s ,2H),5.15-5.03(m,1H),4.15-4.01(m,1H),3.97-3.94(m,2H),3.69(s,2H),3.47-3.36(m,8H),3.30-3.25(m,2H),3.17(d,J=5.2Hz,6H) ,3.12-3.03(m,2H),2.92-2.81(m,1H),2.36-2.24(m,2H),2.13-1.97(m,5H),1.96-1.88(m,4H),1.70-1.60(m,4H),1.57-1.50(m,10H).

[0566] Example 37 Synthesis of compound RC038

[0567] The synthetic route of the compound is as follows:

[0568] Step 1: Synthesis of compound 38-3

[0569] Compound 38-1 (320 mg, 1.31 mmol) was dissolved in DMF (5 mL) at 0 °C, and NaH (78.6 mg, 1.96 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. Then, compound 38-2 (505 mg, 1.44 mmol) was added to the reaction mixture at 25 °C, and the mixture was stirred at 25 °C for 3 h. Saturated NH4Cl (20 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The colorless oily compound 38-3 (330 mg, yield: 60%) was purified by rapid silica gel chromatography.

[0570] 1 H NMR (400MHz, DMSO-d6) δ7.39-7.26(m,5H),4.50(s,2H),3.60-3.55(m,4H),3.54-3.51(m,2H),3.50-3. 46(m,2H),3.41(t,J=6.4Hz,2H),3.31-3.25(m,4H),2.33-2.24(m,6H),1.68-1.60(m,2H),1.40(s,9H).

[0571] Step 2: Synthesis of compound 38-4

[0572] Compound 38-3 (230 mg, 0.544 mmol) was dissolved in methanol (5 mL) at 25 °C, and 5% Pd / C (57.92 mg, 0.54 mmol, 5% wt, 55% in water) was added. The mixture was purged three times with hydrogen, and stirred at 50 °C for 2 hours under hydrogen protection. The reaction mixture was filtered and concentrated to give compound 38-4 (200 mg, crude product). MS (ESI) m / z = 333.6 [M+H] +

[0573] Step 3: Synthesis of compound 38-5

[0574] Compound 38-4 (200 mg, 0.602 mmol) was dissolved in tetrahydrofuran (2 mL) at 25 °C, and compound 2-2 (181.48 mg, 0.662 mmol), benzyl [(1E)-[(benzyloxy)carbonyl]diazenin]formate (356 mg, 1.20 mmol), and triphenylphosphine (316 mg, 1.20 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was quenched with water (20 mL) and then extracted three times with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give a yellow oily product, compound 38-5 (150 mg, yield: 42.4%). MS (ESI) m / z = 587.4.1 [MH] +

[0575] Step 4: Synthesis of compound 38-6

[0576] Compound 38-5 (150 mg, 0.255 mmol) was dissolved in 1,4-dioxane hydrochloride (3 mL, 4 M) at 25 °C and stirred for 10 minutes. The reaction mixture was concentrated to give compound 38-6 (150 mg, crude product). MS (ESI) m / z = 489.3 [M+H] +

[0577] Step 5: Compound RC038

[0578] Compound 38-6 (24.43 mg, 0.050 mmol) was dissolved in DMF (1 mL) at 25 °C. HATU (25.93 mg, 0.068 mmol), N,N-diisopropylethylamine (0.008 mL, 0.045 mmol), and compound 1-1 (30 mg, 0.045 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give a yellow solid compound RC038 (4.09 mg, yield: 8.00%). MS (ESI) m / z = 1131.3 [M+H] +

[0579] 1H NMR (400MHz, DMSO-d6): δ12.37-12.20(m,1H),11.11(s,1H),8.54(s,1H),8.04(s,1H),7.82-7.77(m,2H),7.57-7.55(m,1H),7. 54-7.52(m,1H),7.51-7.44(m,3H),7.38-7.33(m,1H),7.22(s,1H),6.97(d,J=8.8Hz,1H),5.21(s,2H),5.11-5.05(m,1H),4.35- 4.31(m,2H),3.93-3.89(m,2H),3.79-3.76(m,2H),3.73-3.70(m,2H),3.62-3.57(m,2H),3.28-3.27(m,1H),3.09-3.03(m,4H), 2.93-2.87(m,4H),2.14-2.08(m,3H),2.11(s,3H),2.04-1.94(m,6H),1.94-1.89(m,4H),1.68-1.61(m,4H),1.59-1.51(m,11H).

[0580] Example 38 Synthesis of compound RC039

[0581] The compound structure is as follows:

[0582] Synthesis of Compound 39-7

[0583] Referring to compound 30-7, starting material 22-1 was replaced with compound 2-(2-(3-hydroxypropoxy)ethoxy)ethylcarbamate tert-butyl ester to synthesize compound 39-7 (3-[1-oxo-5-(2-(2-(2-(piperidin-4-oxy)ethoxy)ethoxy)ethyl)isoindoline-2-yl]piperidin-2,6-dione), MS (ESI) m / z = 460.7 [M+H] +

[0584] The same synthetic method as that used for RC030 in Example 1 was employed, except that compound 30-7 was replaced with 39-7, to prepare a yellow solid compound RC039 (3.01 mg, yield: 18%). MS (ESI) m / z = 1102.4 [M+H] +

[0585] 1H NMR (400MHz, DMSO-d6): δ12.37-11.62(m,1H),10.98(s,1H),8.51(s,1H),8.04-7.96(m,1H),7.80-7.72(m,1H),7.63-7.59(m,1H),7. 55-7.48(m,2H),7.46-7.41(m,2H),7.38-7.30(m,2H),7.22(s,1H),6.96-6.90(m,1H),5.22-5.14(m,1H),5.13-5.05(m,2H),4.42-4. 36(m,1H),4.31-4.23(m,1H),3.93-3.83(m,2H),3.69(s,2H),3.66-3.59(m,3H),3.50-3.44(m,4H),3.41-3.38(m,2H),3.30-3.29(m, 1H),3.11-3.00(m,5H),2.92-2.78(m,5H),2.14(s,3H),2.01-1.95(m,3H),1.94-1.88(m,4H),1.66-1.59(m,4H),1.57-1.48(m,11H).

[0586] Example 39 Synthesis of compound RC040

[0587] The compound structure is as follows:

[0588] Synthesis of compound 40-4

[0589] Referring to compound 13-4, starting material 13-1 was replaced with compound 3-(4-bromo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (CAS: 2093387-36-9), and compound 12-2 was replaced with tert-butyl 2-(2-(prop-2-yn-1-yloxy)ethoxy)ethylcarbamate to synthesize compound 40-4 (3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione), MS (ESI) m / z = 390.3 [M+H] +

[0590] The same synthetic method as in Example RC013 was used, except that compound 13-4 was replaced with 40-4, to prepare the yellow solid compound RC040 (11.02 mg, yield: 23.5%). MS (ESI) m / z = 516.4 [M / 2+H] +

[0591] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.98(s,1H),8.54(d,J=4.8Hz,1H),8.23-8.15(m,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8 .0Hz,1H),7.56-7.49(m,3H),7.48-7.43(m,1H),7.43-7.33(m,3H),7.28(s,1H),7.03(d,J=8.8Hz,1H),5.22(s,2H),5.15-5.06(m, 1H),4.47-4.36(m,1H),4.32-4.21(m,1H),4.01-3.91(m,2H),3.68(s,2H),3.06-3.02(m,2H),2.95-2.85(m,2H),2.72-2.53(m,6H ),2.45-2.30(m,5H),2.07(s,3H),2.03-1.94(m,2H),1.93-1.89(m,3H),1.80-1.72(m,2H),1.65-1.59(m,3H),1.58-1.46(m,10H).

[0592] Example 40 Synthesis of compound RC041

[0593] The compound structure is as follows:

[0594] Synthesis of Compound 41-6

[0595] Referring to compound 28-6, starting material 22-5 was replaced with compound 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethylcarbamate tert-butyl ester to synthesize compound 41-6 ((S)-5-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)prop-1-yn-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridinecarboxamide), MS (ESI) m / z = 419.5 [M+H] +

[0596] The same synthetic method as in Example RC028 was used, except that compound 28-6 was replaced with 41-6, to prepare the yellow solid compound RC041 (7.55 mg, yield: 11%). MS (ESI) m / z = 530.8 [M / 2+H] +

[0597] 1H NMR (400MHz, DMSO-d6): δ12.28(s,1H),10.87(s,1H),9.11(d,J=8.4Hz,1H),8.72(s,1H),8.58-8.51(m,1H),8.26-8.18(s,1H),8.11-8.00( m,3H),7.81(d,J=8.0Hz,1H),7.59-7.44(m,3H),7.40-7.32(m,1H),7. 28(s,1H),7.05-6.99(m,1H),5.22(s,2H),4.86-4.74(m,1H),4.43(s, 2H),3.99-3.93(m,2H),3.69(s,2H),3.64-3.58(m,2H),3.56-3.51(m ,2H),3.49-3.44(m,4H),3.42-3.37(m,3H),3.29-3.23(m,1H),3.09-3 .01(m,2H),2.86-2.72(m,1H),2.28-2.13(m,1H),2.08(s,3H),2.05-1 .96(m,1H),1.95-1.88(m,3H),1.69-1.60(m,3H),1.57-1.50(m,10H).

[0598] Example 41 Synthesis of compound RCO42

[0599] Synthesis of Compound 42-8

[0600] Referring to compound 33-8, reaction intermediate 33-5 was replaced with compound 2-(prop-2-yn-1-yloxy)ethylcarbamate tert-butyl ester to synthesize compound 42-8 (3-(4-(3-(2-aminoethoxy)propyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione), MS (ESI) m / z = 346.2 [M+H] +

[0601] The same synthetic method as that used for RC033 in Example 1 was employed, except that compound 33-8 was replaced with 42-8, to obtain a white solid compound RC042 (5.2 mg, yield: 11%). MS (ESI) m / z = 987.4 [M+H] +

[0602] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.99(s,1H),8.54(d,J=4.8Hz,1H),8.23( t,J=5.6Hz,1H),8.03(d,J=7.2Hz,1H),7.81(d,J=8.0Hz,1H),7.56-7.53(m,1H),7 .54-7.50(m,2H),7.50-7.46(m,1H),7.39(t,J=7.2Hz,2H),7.37-7.32(m,1H),7.3 0(s,1H),7.04(d,J=8.8Hz,1H),5.23(s,2H),5.16-5.08(m,1H),4.45-4.37(m,1H), 4.30-4.23(m,1H),4.00-3.89(m,2H),3.68(s,2H),3.39-3.35(m,2H),3.33-3.26( m,4H),3.04-2.98(m,2H),2.96-2.86(m,1H),2.66-2.60(m,2H),2.60-2.54(m,1H), 2.40-2.30(m,1H),2.08(s,3H),2.00-1.94(m,1H),1.93-1.88(m,3H),1.82-1.73( m,2H),1.67-1.64(m,1H),1.63-1.60(m,2H),1.58-1.54(m,2H),1.53-1.49(m,7H).

[0603] Example 42 Synthesis of compounds RC043 and RC044

[0604] The compound structure is as follows:

[0605] Synthesis of compounds 43-7 and 43-8

[0606] Referring to compounds 30-7 and 30-8, reaction intermediate 30-2 was replaced with compound tert-butyl 2-(ethoxy)ethylcarbamate to synthesize compounds 43-7 (3-(5-(2-(2-aminoethoxy)ethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione) and 43-8 (3-(5-(1-(2-aminoethoxy)ethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione), MS (ESI) m / z = 332.2 [M+H] +

[0607] Using the same synthesis method as in Examples RC030 and RC031, except that compound 30-7 was replaced with 43-7 and compound 30-8 was replaced with 43-8, the off-white solid compounds RC043 and RC044 were obtained.

[0608] RC043 (8.92 mg, yield: 5.06%), MS (ESI) m / z = 487.5 [M / 2+H] +

[0609] 1 H NMR (400MHz, DMSO-d6): δ12.24(s,1H),10.98(s,1H),8.65-8.49(m,1H),8.22(t,J=5.6Hz,1H),8.02(d,J=7.6Hz,1H),7.81(d,J=8.0Hz, 1H),7.58-7.45(m,4H),7.40-7.28(m,4H),7.05(d,J=8.8Hz,1H),5.23(s,2H),5.12-5.03(m,1H),4.32(d,J=17.2Hz,1H),4.21(d,J=17.2 Hz,1H),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.57(t,J=6.4Hz,2H),3.41(t,J=6.0Hz,2H),3.30-3.25(m,2H),3.08-3.00(m,2H),2.96-2.8 2(m,3H),2.64-2.56(m,1H),2.39-2.28(m,1H),2.07(s,3H),2.01-1.95(m,1H),1.93-1.88(m,3H),1.66-1.59(m,3H),1.58-1.49(m,9H).

[0610] RC044 (3.41 mg, yield: 2.1%), MS (ESI) m / z = 487.5 [M / 2+H] +

[0611] 1H NMR (400MHz, DMSO-d6): δ12.24(s,1H),10.98(s,1H),8.65-8.49(m,1H),8.22(t,J=5.6Hz,1H),8.02(d,J=7.6Hz,1H),7.81(d,J=8.0Hz, 1H),7.58-7.45(m,4H),7.40-7.28(m,4H),7.05(d,J=8.8Hz,1H),5.23(s,2H),5.12-5.03(m,1H),4.32(d,J=17.2Hz,1H),4.21(d,J=17.2 Hz,1H),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.57(t,J=6.4Hz,2H),3.41(t,J=6.0Hz,2H),3.30-3.25(m,2H),3.08-3.00(m,2H),2.96-2.8 2(m,3H),2.64-2.56(m,1H),2.39-2.28(m,1H),2.07(s,3H),2.01-1.95(m,1H),1.93-1.88(m,3H),1.66-1.59(m,3H),1.58-1.49(m,9H).

[0612] Example 43 Synthesis of compound RC045

[0613] Synthesis of Compound 45-8

[0614] Referring to compound 33-8, reaction intermediate 33-5 was replaced with compound benzyl(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)(2-(prop-2-yn-1-yloxy)ethyl)carbamate to synthesize compound 45-8(3-(4-(3-(2-((2-(2-(2-aminoethoxy)ethyl)amino)ethoxy)propyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione), MS (ESI) m / z = 433.2 [M+H] +

[0615] The same synthetic method as that used for RC033 in Example 1 was employed, except that compound 33-8 was replaced with 45-8, to obtain the white solid compound RC045 (8.46 mg, yield: 21%). MS (ESI) m / z = 538.0 [M / 2+H] + .

[0616] 1H NMR (400MHz, DMSO-d6): δ10.98(s,1H),8.55(d,J=4.8Hz,1H),8.31(s,1H),8.29-8.21(m,1H),8.04(d,J=8.0Hz,1H),7.81(d ,J=8.0Hz,1H),7.59-7.34(m,6H),7.28(s,1H),7.04(d,J=8.8Hz,1H),5.23(s,2H),5.17-5.10(m,1H),4.43(d,J=17.2Hz,1H ),4.28(d,J=17.2Hz,1H),4.00-3.90(m,2H),3.69(s,2H),3.54-3.48(m,5H),3.07-3.03(m,2H),2.96-2.87(m,6H),2.70-2. 53(m,5H),2.46-2.29(m,3H),2.11-1.97(m,5H),1.94-1.90(m,3H),1.85-1.79(m,2H),1.67-1.61(m,3H),1.57-1.50(m,9H).

[0617] Example 44 Synthesis of compound RC046

[0618] The synthetic route of the compound is as follows:

[0619] Step 1: Synthesis of Compound 46-2

[0620] Under ice bath conditions, triphenylphosphine (9.60 g, 36.6 mmol, 1.5 eq) and imidazole (500 mg, 7.30 mmol, 0.3 eq) were added to a dichloromethane (80 mL) solution of compound 46-1 (7.5 mL, 24.3 mmol, 1.0 eq). The reaction mixture was stirred for 0.5 h, and then iodine (8.00 g, 31.5 mmol) was added in portions to the reaction mixture. The reaction was slowly brought to room temperature and stirred for 12 h. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted twice with dichloromethane (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give a colorless oily compound 46-2 (4.00 g, yield: 52%).

[0621] 1H NMR (400MHz, CDCl3): δ4.92 (s, 1H), 3.71 (t, J = 6.4Hz, 2H), 3.55 (t, J = 5.2Hz, 2H), 3.36-3.30 (m, 2H), 3.25 (t, J = 6.4Hz, 2H), 1.45 (s, 9H).

[0622] Step 2: Synthesis of compound 46-4

[0623] Compound 22-3 (1.70 g, 7.71 mmol, 1.2 eq), potassium carbonate (2.20 g, 15.9 mmol, 2.5 eq), and sodium iodide (100 mg, 0.635 mmol, 0.1 eq) were added to a solution of compound 46-2 (2.00 g, 6.34 mmol, 1.0 eq) in acetonitrile (30 mL). The reaction mixture was stirred at 70 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched with water (30 mL) and extracted twice with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give a colorless oily compound 46-4 (2.00 g, yield: 77%). MS (ESI) m / z = 408.4 [M+H] +

[0624] Step 3: Synthesis of compound 46-5

[0625] Compound 46-4 (1.00 g, 2.45 mmol, 1.0 eq) and acetic acid (200 mg, 3.39 mmol) were dissolved in methanol (20 mL), and palladium on carbon (200 mg, 0.094 mmol, 0.04 eq, 5%) was added. The reaction mixture was purged with hydrogen gas at 40 psi using a hydrogen cylinder, and stirred at 50 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a colorless oily compound 46-5 (600 mg, yield: 89%). MS (ESI) m / z = 274.5 [M+H] +

[0626] Step 4: Synthesis of compound 46-6

[0627] Potassium carbonate (278 mg, 2.01 mmol, 1.1 eq) and compound 32-2 (217 mg, 1.46 mmol, 0.8 eq) were added to a 20 mL acetonitrile solution of compound 46-5 (500 mg, 1.83 mmol, 1.0 eq). The reaction mixture was stirred at -15 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give a yellow oily compound 46-6 (355 mg, yield: 62%).

[0628] 1 H NMR (400MHz, CDCl3): δ5.16(s,1H),3.64(t,J=5.2Hz,2H),3.51(t,J=5.2Hz,2 H),3.38–3.19(m,4H),2.86–2.49(m,10H),2.25(t,J=2.4Hz,1H),1.44(s,9H).

[0629] Step 5: Synthesis of compounds 46-7

[0630] Compounds 32-4 (371 mg, 1.14 mmol, 1.1 eq) and 46-6 (325 mg, 1.04 mmol, 1.0 eq) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of diisopropylamine (422 mg, 4.17 mmol, 4.0 eq), cuprous iodide (39.7 mg, 0.209 mmol, 0.2 eq), triphenylphosphine (27.3 mg, 0.104 mmol, 0.1 eq), and bis(acetonitrile)palladium(II) dichloride (27.1 mg, 0.104 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography to give the yellow solid product compound 46-7 (200 mg, yield: 35%).

[0631] 1H NMR (400MHz, CDCl3): δ8.31(s,1H),7.83(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.45(t,J=7.6Hz,1H),5.28-5.13(m,2H),4.64-4.52(m,1H),4. 51-4.37(m,1H),3.74-3.56(m,4H),3.56-3.46(m,2H),3.37-3.20(m,2H ),3.05-2.75(m,7H),2.58-2.41(m,2H),2.36-2.13(m,5H),1.42(s,9H).

[0632] Step 6: Synthesis of Compound 46-8

[0633] Compound 46-7 (200 mg, 0.361 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL) and acetic acid (3 mL), and palladium on carbon (76.8 mg, 0.072 mmol, 0.2 eq) and palladium hydroxide (101 mg, 0.072 mmol, 0.2 eq) were added. The reaction mixture was purged with hydrogen gas at 50 psi using a hydrogen cylinder, and stirred at 40 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a yellow solid compound 46-8 (150 mg, yield: 74%). MS (ESI) m / z = 558.4 [M+H] +

[0634] Step 7: Synthesis of Compounds 46-9

[0635] A solution of dioxane in hydrochloric acid (5 mL, 4 M) was added to a 5 mL solution of dioxane in compound 46-8 (140 mg, 0.251 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid compound 46-9 (124 mg, crude product).

[0636] MS(ESI)m / z = 458.5[M+H] +

[0637] Step 8: Synthesis of compound RC046

[0638] Compound 1-1 (25.0 mg, 0.038 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 46-9 (37.4 mg, 0.076 mmol, 2.0 eq), N-methylimidazole (135 mg, 0.189 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid compound RC046 (10.9 mg, yield: 26%). MS (ESI) m / z = 550.4 [M / 2+H] +

[0639] 1 H NMR (400MHz, DMSO-d6): δ12.34(s,1H),11.00(s,1H),8.55(d,J=4.8Hz,1H),8.31(s,1H),8.25-8.14(m,1H),8.05(d,J=7.2Hz,1H),7.81(d, J=7.6Hz,1H),7.60-7.49(m,3H),7.49-7.42(m,2H),7.40-7.32(m,1H),7.27(s,1H),7.03(d,J=8.8Hz,1H),5.24(s,2H),5.18-5.09(m,1H), 4.50-4.39(m,1H),4.34-4.26(m,1H),3.95(t,J=5.6Hz,2H),3.69(s, 2H),3.50-3.35(m,11H),3.08-3.01(m,2H),2.99-2.84(m,2H),2.72-2 .53(m,4H),2.47-2.21(m,5H),2.08(s,3H),2.03-1.96(m,2H),1.95- 1.89(m,3H),1.81-1.70(m,2H),1.68-1.59(m,3H),1.59-1.48(m,9H).

[0640] Example 45 Synthesis of compound RC047

[0641] The synthetic route of the compound is as follows:

[0642] Step 1: Synthesis of Compound 47-3

[0643] Pd2(dba)3 (61.4 mg, 0.0670 mmol) and tri-tert-butylphosphine (27.1 mg, 0.134 mmol) were added to a DMF (3 mL) solution of compound 47-1 (100 mg, 0.670 mmol), compound 47-2 (340 mg, 1.01 mmol), and dicyclohexyl(methyl)amine (262 mg, 1.34 mmol). The mixture was stirred at 80 °C for 12 hours under nitrogen protection. Water (20 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel chromatography to give compound 47-3 as a pale yellow solid.

[0644] 1 H NMR (400MHz, DMSO-d6): δ11.17-11.15(m,1H),7.38-7.36(m,1H),7.12-7.10(m,2H),6.85-6.82(m,2H),6.54-6.49(m,1H),6.37-6.30(m, 1H),4.46-4.38(m,1H),3.42-3.41(m,3H),2.80-2.74(m,2H),2.71-2 .65(m,2H),2.39-2.35(m,2H),2.13-2.06(m,2H),1.97-1.91(m,2H).

[0645] Step 2: Synthesis of compound 47-4

[0646] At 25°C, Pd / C (15.7 mg, 0.148 mmol, 10% wt, 55% aqueous solution) was added to a MeOH (3 mL) solution of compound 47-3 (120 mg, 0.295 mmol). The mixture was stirred at 50°C for 16 hours under H2 (hydrogen balloon) protection. After the reaction was complete, the reactants were filtered through diatomaceous earth, the filter cake was washed with MeOH (10 mL), and concentrated under reduced pressure to give a yellow oily compound 47-4 (50.0 mg, yield: 33%). MS (ESI) m / z = 409.2 [M+H] +

[0647] Step 3: Synthesis of compound RC047

[0648] Compound 47-4 (50 mg, 0.12 mmol) was dissolved in DCM (2 mL) at 25 °C. Compound 1-1 (40 mg, 0.061 mmol), EDCI (23.2 mg, 0.121 mol), and DMAP (14.8 mg, 0.121 mmol) were added, and the mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered and purified by preparative HPLC to give a yellow solid compound RC047 (4.45 mg, yield: 7%). MS (ESI) m / z = 1050.4 [M+H] +

[0649] 1 H NMR (400MHz, DMSO-d6): δ12.29(s,1H),11.84-11.76(m,1H),11.08(s,1H),8.58-8.54(m,1H),8.07-8.02(m,1H),7.85- 7.80(m,1H),7.61-7.47(m,3H),7.40-7.35(m,1H),7.31-7.24(m,1H),7.15-7.06(m,1H),7.01-6.93(m,2H),6.85-6.78 (m,1H),5.37-5.30(m,1H),5.30-5.19(m,2H),4.01-3.91(m,2H),3.72-3.65(m,2H),3.28-3.28(m,2H),3.11-3.01(m,3 H),2.96-2.84(m,2H),2.72-2.55(m,6H),2.16-2.10(m,3H),2.04-1.88(m,5H),1.71-1.61(m,5H),1.58-1.50(m,11H).

[0650] Example 46 Synthesis of compound RC048

[0651] The synthetic route of the compound is as follows:

[0652] Step 1: Synthesis of Compound 48-2

[0653] NaH (79.5 mg, 2.00 mmol) was added to a THF (5 mL) solution of compound 29-2 (200 mg, 0.994 mmol) at 0 °C, and the mixture was stirred at 25 °C for 30 min. Compound 48-1 (392 mg, 0.994 mmol) was added to the reactants, and the mixture was stirred at 25 °C for 2 h. Saturated NH4Cl (50 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to rapid silica gel column chromatography to give a pale yellow oily compound 48-2 (300 mg, yield: 71%). MS (ESI) m / z = 324.5 [M-100+H] +

[0654] Step 2: Synthesis of Compound 48-3

[0655] Pd / C (75.4 mg, 0.708 mmol, 10% wt, 55% in water) was added to a methanol (10 mL) solution of compound 48-2 (300 mg, 0.708 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 hours under H2 (hydrogen balloon) protection. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH (10 mL). The mother liquor was concentrated under reduced pressure to give a pale yellow oily compound 48-3 (180 mg, yield: 76%). MS (ESI) m / z = 278.1 [M-56+H] +

[0656] Step 3: Synthesis of compound 48-4

[0657] At 0 °C, DBAD (233 mg, 0.780 mmol) was added to a THF (3 mL) solution of compound 48-3 (130 mg, 0.390 mmol), compound 2-2 (118 mg, 0.429 mmol), and PPh3 (205 mg, 0.780 mmol). The mixture was stirred at 25 °C for 1 hour. Water (5 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (5 mL x 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to rapid silica gel column chromatography to give a colorless oily compound 48-4 (100 mg, yield: 38%). MS (ESI) m / z = 490.2 [M-100+H] + ,

[0658] Step 4: Synthesis of compound 48-5

[0659] Compound 48-4 (100 mg, 0.170 mmol) was dissolved in DCM (3 mL), and TFA (2 mL) was added to the solution. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give a colorless solid compound 48-5 (150 mg, crude yield: 98%), which could be used in the next step without further purification. MS (ESI) m / z = 489.7 [M+H] +

[0660] Step 5: Synthesis of compound RC048

[0661] HATU (34.6 mg, 0.0910 mmol) was added to a DMF (3 mL) solution of compound 48-5 (40 mg, 0.082 mmol), compound 1-1, and DIEA (0.03 mL, 0.182 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction solution was filtered and purified by preparative HPLC to give a yellow solid compound RC048 (11.18 mg, yield: 17%). MS (ESI) m / z = 1131.4 [M+H] +

[0662] 1 H NMR (400MHz, DMSO-d6): δ12.30(s,1H),11.10(s,1H),8.56-8.52(m,1H),8.06-8.01(m,1H),7.83-7.75(m,2H),7.56-7.42 (m,5H),7.38-7.32(m,1H),7.21(s,1H),6.98-6.93(m,1H),5.26-5.11(m,2H),5.10-5.04(m,1H),4.35-4.28(m,2H),3.96 -3.83(m,2H),3.80-3.75(m,2H),3.72-3.66(m,2H),3.62-3.59(m,2H),3.51-3.46(m,2H),3.43-3.35(m,4H),3.30-3.24( m,4H),3.22-3.10(m,2H),3.08-3.02(m,3H),2.89-2.76(m,2H),2.16-2.12(m,3H),2.08-1.83(m,5H),1.67-1.45(m,14H).

[0663] Example 47 Synthesis of compound RC049

[0664] The compound structure is as follows:

[0665] Synthesis of Compound 49-6

[0666] Referring to compound 29-6, reaction intermediate 13-1 was replaced with compound 3-(4-bromo-1-oxoisoindoline-2-yl)piperidin-2,6-dione (CAS: 2093387-36-9) to synthesize compound 49-6 (3-[1-oxo-4-[3-[2-[2-(piperidin-4-yloxy)ethoxy]ethoxy]propyl]isoindoline-2-yl]piperidin-2,6-dione), MS (ESI) m / z = 474.6 [M+H] +

[0667] The same synthetic method as that used for RC029 in Example 1 was employed, except that compound 29-6 was replaced with 49-6, to obtain a white solid compound RC049 (8.75 mg, yield: 12.38%). MS (ESI) m / z = 1115.6 [M+H] +

[0668] 1 H NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.99(s,1H),8.54(d,J=4.8Hz,1H),8.04(d,J= 7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.56-7.51(m,3H),7.50-7.44(m,1H),7.43(d,J=4.0H z,2H),7.38-7.33(m,1H),7.22(s,1H),6.96(d,J=8.8Hz,1H),5.26-5.09(m,3H),4.47- 4.40(m,1H),4.31-4.24(m,1H),3.94-3.83(m,2H),3.69(s,2H),3.67-3.58(m,1H),3.50 -3.46(m,2H),3.45-3.40(m,4H),3.39-3.34(m,5H),3.28-3.17(m,2H),3.10-3.00(m,3 H),2.96-2.87(m,1H),2.85-2.76(m,1H),2.68-2.63(m,2H),2.62-2.55(m,1H),2.43-2. 34(m,1H),2.14(s,3H),2.02-1.96(m,1H),1.93-1.88(m,3H),1.84-1.76(m,2H),1.67-1 .57(m,4H),1.56-1.54(m,2H),1.53-1.47(m,7H),1.44–1.37(m,1H),1.12-1.01(m,1H).

[0669] Example 48 Synthesis of compound RC050

[0670] The synthetic route of the compound is as follows:

[0671] Step 1: Synthesis of Compound 50-3

[0672] Compound 50-2 (1.76 g, 7.24 mmol, 2.0 eq) and N,N-diisopropylethylamine (2.40 mL, 14.4 mmol, 4.0 eq) were added to a solution of compound 50-1 (1.00 g, 3.62 mmol, 1.0 eq) in N-methylpyrrolidone (15 mL). The reaction mixture was stirred at 90 °C for 18 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched with water (30 mL) and extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give a yellow oily compound 50-3 (1.70 g, yield: 94%). MS (ESI) m / z = 500.4 [M+H] +

[0673] Step 2: Synthesis of Compound 50-4

[0674] A solution of dioxane in hydrochloric acid (5 mL, 4 M) was added to a 10 mL solution of compound 50-3 (800 mg, 1.60 mmol, 1.0 eq) containing dioxane. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid compound 50-4 (800 mg, crude product).

[0675] Step 3: Synthesis of compound RC050

[0676] Compound 1-1 (25 mg, 0.038 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 50-4 (41.2 mg, 0.076 mmol, 2.0 eq), N-methylimidazole (135 mg, 0.189 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid compound RC050 (20.62 mg, yield: 52%). MS (ESI) m / z = 521.2 [M / 2+H] +

[0677] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),11.08(s,1H),8.61-8.48(m,1H),8.18(t,J=5.6Hz,1H),8.07-7.98(m,1H),7.85-7.75(m,1H),7. 65(d,J=8.4Hz,1H),7.56-7.43(m,3H),7.38-7.22(m,1H),7.30-7.22(m,2H),7.20-7.13(m,1H),7.03(d,J=8.8Hz,1H),5.25(s,2H),5.1 2-5.02(m,1H),3.99-9.87(m,2H),3.69(s,2H),3.47-3.38(m,4H),3.18-3.11(m,2H),3.05-3.01(m,2H),2.93-2.85(m,1H),2.64-2.54( m,2H),2.44-2.32(m,4H),2.28-2.19(m,2H),2.09(s,3H),2.05-1.99(m,1H),1.95-1.89(m,3H),1.67-1.61(m,3H),1.59-1.50(m,11H).

[0678] Example 49 Synthesis of compound RC051

[0679] Step 1: Synthesis of Compound 51-2

[0680] Dimethyl sulfoxide (17.3 mL, 243 mmol) was added dropwise to a solution of oxalyl chloride (9.48 mL, 112 mmol) in dichloromethane (200 mL) under dry ice-ethanol bath conditions. The reaction mixture was stirred at -78 °C for 0.5 h. Then, compound 51-1 (10.0 g, 48.7 mmol) and triethylamine (60.8 mL, 438 mmol) were added sequentially to the reaction mixture. After stirring at low temperature for 0.5 hours, the temperature was gradually increased to 25 °C and stirred for 17 hours. After the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted twice with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give a yellow oily compound 51-2 (9.00 g, yield: 91%).

[0681] 1 H NMR (400MHz, CDCl3): δ5.38(s,1H),3.99-3.84(m,2H),3.59-3.49(m,2H),3.45-3.23(m,2H),1.47(s,9H).

[0682] Step 2: Synthesis of compound 51-3

[0683] Compound 11-1 (1.35 g, 7.24 mmol) and N,N-diisopropylethylamine (2.40 mL, 14.4 mmol) were added to a solution of compound 50-1 (1.00 g, 3.62 mmol) in N-methylpyrrolidone (15 mL). The reaction mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched with water (30 mL) and extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give a yellow solid compound 51-3 (1.30 g, yield: 81%).

[0684] 1 H NMR (400MHz, CDCl3): δ7.98 (s, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.06 (dd, J = 8.4, 2.4Hz, 1H), 4.94 (dd,J=12.4,5.2Hz,1H),3.65-3.58(m,4H),3.44-3.39(m,4H),2.92-2.74(m,3H),2.18-2.08(m,1H),1.49(s,9H).

[0685] Step 3: Synthesis of compound 51-4

[0686] Compound 51-3 (1.30 g, 2.93 mmol) was dissolved in dioxane (5 mL), followed by the addition of a dioxane solution in hydrochloric acid (5 mL, 4 M). The reaction mixture was stirred at 25 °C for 0.5 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid, compound 51-4 (1.11 g, crude product). MS (ESI) m / z = 343.2 [M+H] +

[0687] Step 4: Synthesis of Compound 51-5

[0688] Compound 51-4 (500 mg, 1.32 mmol) was dissolved in a mixed solution of dichloromethane (45 mL) and N,N-dimethylformamide (10 mL), followed by the addition of triethylamine (0.55 mL, 3.96 mmol) and stirring for 5 min. Acetic acid (317 mg, 5.28 mmol) was then added, and the reaction mixture was stirred at 0 °C for 0.5 hours. Compound 51-2 (1.34 g, 6.61 mmol) and sodium borohydride acetate (1.12 g, 5.29 mmol) were then added. Under nitrogen protection, the reaction mixture was stirred at 25 °C for 11.5 hours. After the reaction was complete, water (30 mL) and saturated sodium bicarbonate solution (10 mL) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a yellow solid product, compound 51-5 (300 mg, 43%).

[0689] 1 H NMR (400MHz, CDCl3): δ8.04(s,1H),7.70(d,J=8.4Hz,1H),7.30-7.27(m,1H),7.09-7.02(m,1H),5.18(s,1H),4.97-4.91(m,1H) ,3.70-3.60(s,2H),3.57-3.52(m,2H),3.51-3.40(m,4H),3.35-3.28(m,2H),2.98-2.64(m,9H),2.17-2.11(m,1H),1.44(s,9H).

[0690] Step 5: Synthesis of compounds 51-6

[0691] Compound 51-5 (300 mg, 0.566 mmol) was dissolved in dioxane (5 mL), and then a dioxane solution in hydrochloric acid (5 mL, 4 M) was added. Under nitrogen protection, the reaction mixture was stirred at 25 °C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid compound 51-6 (325 mg, crude product).

[0692] 1H NMR (400MHz, DMSO-d6): δ11.09(s,1H),10.95(s,1H),8.25(s,3H),7.76(d,J=8 .4Hz,1H),7.52-7.45(m,1H),7.40-7.31(m,1H),5.15-5.03(m,1H),4.24-4.11( m,2H),3.85-3.78(m,4H),3.71-3.61(m,6H),3.42-3.35(m,2H),3.25-3.14(m,2 H),3.06-2.98(m,2H),2.93-2.84(m,1H),2.64–2.51(m,2H),2.08-1.98(m,1H).

[0693] Step 6: Synthesis of compound RC051

[0694] Compound 1-1 (25.0 mg, 0.038 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 51-6 (43.5 mg, 0.076 mmol), N-methylimidazole (135 mg, 0.189 mmol), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol) were added. The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a yellow solid compound RC051 (15.78 mg, yield: 39%). MS (ESI) m / z = 536.2 [M / 2+H] +

[0695] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),11.08(s,1H),8.54(d,J=4.8Hz,1H),8.34-8.19(m,1H),8.06(d,J=7.6Hz,1H),7 .82(d,J=7.6Hz,1H),7.68(d,J=8.4Hz,1H),7.57-7.47(m,3H),7.41-7.34(m,1H),7.32-7.24(m,2H),7.22-7.15(m,1H), 7.05(d,J=8.8Hz,1H),5.22(s,2H),5.12-5.04(m,1H),3.98-3.90(m,2H),3.73-3.34(m,10H),3.29-3.14(m,4H),3.07-2 .72(m,7H),2.62-2.52(m,2H),2.09(s,3H),2.05-2.00(m,1H),1.94-1.89(m,3H),1.67-1.61(m,3H),1.58-1.50(m,9H).

[0696] Example 50 Synthesis of compound RC052

[0697] The synthetic route of the compound is as follows:

[0698] Step 1: Synthesis of Compound 52-2

[0699] 25 mL of liquid bromine was added to a round-bottom flask at 0 °C. Iron powder (8.04 g, 144.03 mmol, 2 eq) was then added in portions, and the mixture was stirred at 0–5 °C for 1 hour. (1r,3R,5S,7S)-3,5-dimethyladamantane-1-carboxylic acid (15 g, 72.01 mmol, 1 eq) was added in portions at 0–10 °C. The mixture was allowed to warm naturally to 25 °C and then stirred for 72 hours. The reaction mixture was diluted with 100 mL of ethyl acetate at 0–5 °C, and then carefully quenched dropwise with 150 mL of saturated sodium thiosulfate solution at 0–5 °C. After stirring at room temperature for 30 min, the mixture was filtered through diatomaceous earth and washed with 200 mL of ethyl acetate. The separated organic phase was washed with 300 mL of saturated sodium thiosulfate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a yellow solid compound 52-2 (20.8 g, crude).

[0700] 1H NMR (400MHz, DMSO-d6): δ12.21(br s,1H),2.22(s,1H),2.05-1.87(m,4H),1.74-1.34(m,5H),1.28-1.05(m,2H),0.94-0.82(m,6H).

[0701] Step 2: Synthesis of compound 52-3

[0702] Boranetetrahydrofuran (1M, 217.28 mL, 3 eq) was added dropwise to a 250 mL tetrahydrofuran solution of compound 52-2 (20.8 g, 72.43 mmol, 1 eq) at 0–5 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was then quenched by adding 250 mL methanol dropwise to the reaction mixture at 0–5 °C under a nitrogen atmosphere. The quenched reaction mixture was stirred at room temperature for 1 hour and then concentrated to give the crude product. The crude product was purified by column chromatography to give a white solid compound 52-3 (9.28 g, yield: 46.90%).

[0703] 1 H NMR (400MHz, DMSO-d6): δ4.50 (s, 1H), 3.05 (d, J = 5.6Hz, 2H), 1.91 (s, 6H), 1.24-1.13 (m, 3H), 1.12-1.01 (m, 3H), 0.85 (s, 6H).

[0704] Step 3: Synthesis of compound 52-4

[0705] Sodium methoxide (7.91 g, 146.41 mmol, 4 eq) was added to 150 mL of a methanol solution of compound 52-3 (10 g, 36.60 mmol, 1 eq), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily compound 52-4 (2.43 g, 10.83 mmol, yield 29.59%).

[0706] 1 H NMR (400MHz, CDCl3): δ3.33(s,2H),3.24(s,3H),1.38(d,J=7.3Hz,6H),1.18-1.07(m,6H),0.92(s,6H)

[0707] Step 4: Synthesis of Compounds 52-6

[0708] Compound 52-5 (3.73 g, 17.95 mmol, 1.1 eq) and tributyl cyanimide (11.81 g, 48.94 mmol, 3 eq) were added to 50 mL of acetonitrile solution containing compound 52-4 (3.66 g, 16.31 mmol, 1 eq). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography and preparative liquid chromatography to obtain a crude product (~1.2 g). The crude product was further purified by chiral separation to obtain a white solid compound 52-6 (0.90 g, yield: 12.88%). MS (ESI) m / z = 415.3 [M+H] +

[0709] Step 5: Synthesis of compound SM-6

[0710] Compound SM3 (1.01 g, 3.25 mmol, 1 eq) was dissolved in 15 mL of dimethyl sulfoxide, and cesium carbonate (4.24 g, 13.02 mmol, 4 eq) and compound SM5 (2.86 g, 9.76 mmol, 3 eq) were added. The reaction mixture was stirred at 95 °C for 16 hours. The reaction mixture was poured into 30 mL of water, and the pH was adjusted to 7 with 1 N hydrochloric acid. The mixture was then filtered, and the filtrate was extracted twice with 30 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid compound SM-6 (1.02 g, yield 55.33%).

[0711] Step 6: Synthesis of Compounds 52-7

[0712] Compound SM6 (1 g, 1.77 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and triethylamine (357.26 mg, 3.53 mmol, 491.42 μL, 2 eq) and 2-(trimethylsilyl)ethoxymethyl chloride (441.47 mg, 2.65 mmol, 468.66 μL, 1.5 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into 50 mL of water and extracted twice with 50 mL of dichloromethane. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow oily compound 52-7 (0.97 g, yield 78.86%).

[0713] Step 7: Synthesis of Compounds 52-8

[0714] Compound 52-6 (0.90 g, 2.10 mmol, 2 eq), potassium carbonate (435.66 mg, 3.15 mmol, 3 eq), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (115.33 mg, 157.61 μmol, 0.15 eq) were added to a mixed solution of 10 mL of dioxane and 1 mL of water. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was poured into 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily compound 52-8 (411 mg, yield: 36.98%). MS (ESI) m / z = 904.7 [M+H] +

[0715] Step 8: Synthesis of compounds 52-9

[0716] Trifluoroacetic acid (6.14 g, 53.85 mmol, 4 mL, 142.38 eq) was added to a 2 mL solution of compound 52-8 (0.4 g, 378.22 μmol, 1 eq) in dichloromethane. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to obtain a residue, which was dissolved in 3 mL of methanol. N,N-diisopropylethylamine was added to adjust the pH to 9, followed by preparative liquid chromatography to obtain a white solid compound 52-9 (157.19 mg, yield: 57.22%). MS (ESI) m / z = 718.5 [M+H]+

[0717] Step 9: Synthesis of Compounds 52-10

[0718] Compound 32-4 (1.00 g, 3.10 mmol, 1.0 eq) was dissolved in 15 mL of dimethyl sulfoxide, followed by the sequential addition of compound 12-2 (1.78 g, 6.19 mmol, 2.0 eq), tetraphenylphosphine (0.36 g, 0.31 mmol, 0.1 eq), cuprous iodide (0.06 g, 0.31 mmol, 0.1 eq), and triethylamine (1.25 g, 12.38 mmol, 4.0 eq). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with 50 mL of water, extracted twice with 50 mL of ethyl acetate, and the combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid compound 52-10 (300 mg, yield: 18%). MS (ESI) m / z = 430.2 [M+H-Boc] +

[0719] Step 10: Synthesis of Compounds 52-11

[0720] Compound 52-10 (300 mg, 0.566 mmol, 1.0 eq) was dissolved in 20 mL of methanol. 5% palladium on carbon (300 mg) was added to the reaction solution, and the reaction mixture was stirred at 30 °C for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to give a yellow solid compound 52-11 (150 mg, yield: 49%). MS (ESI) m / z = 534.2 [M+H] +

[0721] Step 11: Synthesis of Compounds 52-12

[0722] Compound 52-11 (150 mg, 0.281 mmol, 1.0 eq) was dissolved in 10 mL of dioxane hydrochloride, and the reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 52-12 (150 mg, crude product). MS (ESI) m / z = 434.2 [M+H] +

[0723] Step 12: Synthesis of compound RC052

[0724] Compound 52-12 (24 mg, 0.056 mmol, 2.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution, and compound 52-9 (20 mg, 0.028 mmol, 1.0 eq), N,N-diisopropylethylamine (18.0 mg, 0.139 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (12.71 mg, 0.033 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC052 (2.24 mg, yield: 7%). MS (ESI) m / z = 567.2 [M / 2+H] +

[0725] 1H NMR (400MHz, DMSO-d6): δ12.38(s,1H),11.05(s,1H),8.61(d,J=4.8Hz,1H),8.27 (t,J=5.6Hz,1H),8.11(d,J=7.2Hz,1H),7.88(d,J=8.0Hz,1H),7.63-7.59(m,2H), 7.59-7.52(m,2H),7.52-7.46(m,2H),7.45-7.40(m,1H),7.35(s,1H),7.10(d,J= 8.8Hz,1H),5.29(s,2H),5.23-5.13(m,1H),4.49(d,J=17.2Hz,1H),4.34(d,J=17. 2Hz,1H),4.02(t,J=6.0Hz,2H),3.86(s,2H),3.55-3.48(m,7H),3.35-3.31(m,4H ),3.14(s,3H),3.12-3.09(m,2H),3.03-2.92(m,2H),2.73-2.68(m,2H),2.67-2.6 1(m,1H),2.49-2.43(m,1H),2.11(s,3H),2.08-2.03(m,1H),1.90-1.82(m,2H),1 .40(s,2H),1.35-1.24(m,6H),1.22-1.11(m,4H),1.09-1.00(m,2H),0.91(s,6H).

[0726] Example 51 Synthesis of compound RC053

[0727] The synthetic route of the compound is as follows:

[0728] Step 1: Synthesis of compound RC053

[0729] Compound 28-6 (37.5 mg, 0.084 mmol, 2.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution, and compound 52-9 (20 mg, 0.028 mmol, 1.0 eq), N,N-diisopropylethylamine (18.0 mg, 0.139 mmol, 5.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (12.7 mg, 0.033 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give an off-white solid RC053 (2.61 mg, yield: 8%). MS (ESI) m / z = 1148.2 [M+H] +

[0730] 1 H NMR (400MHz, DMSO-d6): δ12.26(s,1H),10.85(s,1H),8.71(d,J=8.0Hz,1H),8.54(d, J=4.8Hz,1H),8.28-8.24(m,1H),8.22(t,J=6.0Hz,1H),8.03(d,J=7.6Hz,1H),7.81( t,J=8.0Hz,2H),7.55-7.50(m,2H),7.50-7.45(m,1H),7.39-7.31(m,2H),7.30(s,1H) ),7.04(d,J=8.8Hz,1H),5.23(s,2H),4.77-4.69(m,1H),3.96(t,J=6.0Hz,2H),3.81( s,2H),3.49(t,J=6.0Hz,2H),3.46-3.44(m,3H),3.44-3.40(m,3H),3.30-3.29(m,2H ),3.29-3.25(m,6H),3.08(s,3H),3.07-3.02(m,2H),2.84-2.74(m,1H),2.55-2.52( m,2H),2.45(t,J=5.6Hz,2H),2.22-2.12(m,1H),2.06(s,3H),2.04-1.97(m,1H),1.3 8-1.31(m,2H),1.27-1.16(m,5H),1.16-1.05(m,4H),1.05-0.95(m,2H),0.84(s,6H).

[0731] Example 52 Synthesis of compound RC054

[0732] The compound structure is as follows:

[0733] Synthesis of Compound 54-8

[0734] Referring to compound 33-8, reaction intermediate 33-5 was replaced with compound tert-butyl(2-(methyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)amino)ethyl)carbamate to synthesize compound 54-8 (3-[4-(3-{2-[2-((2-aminoethyl)(methyl)amino)ethoxy]ethoxy}propyl)-1-oxoisoindoline-2-yl]piperidine-2,6-dione), MS (ESI) m / z = 447.5 [M+H] +

[0735] The same synthetic method as that used for RC033 in Example 1 was employed, except that compound 33-8 was replaced with 54-8, to obtain a white solid compound RC054 (15.27 mg, yield: 23%). MS (ESI) m / z = 545.0 [M / 2+H] +

[0736] 1 H NMR (400MHz, DMSO-d6): δ12.24(s,1H),10.99(s,1H),8.54(d,J=4.4Hz,1H),8.08(t ,J=5.6Hz,1H),8.03(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.57-7.53(m,2H),7.51 -7.45(m,2H),7.43-7.39(m,2H),7.38-7.33(m,1H),7.28(s,1H),7.03(d,J=8.8Hz, 1H),5.23(s,2H),5.15-5.07(m,1H),4.42(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H), 3.95(t,J=5.6Hz,2H),3.68(s,2H),3.46-3.37(m,8H),3.22-3.15(m,2H),3.05(t,J =5.6Hz,2H),2.95-2.86(m,1H),2.66-2.56(m,3H),2.45(t,J=6.0Hz,2H),2.43-2.31 (m,3H),2.15(s,3H),2.06(s,3H),2.02-1.96(m,1H),1.94-1.89(m,3H),1.82-1.74 (m,2H),1.67-1.63(m,1H),1.63-1.59(m,2H),1.58-1.54(s,2H),1.54-1.49(m,7H).

[0737] Example 53 Synthesis of compound RC055

[0738] The synthetic route of the compound is as follows:

[0739] Step 1: Synthesis of Compound 55-3

[0740] Compound 55-1 (7.83 g, 34.9 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (100 mL), followed by the sequential addition of compound 55-2 (10 g, 70 mmol, 2.0 eq) and triethylamine (3.53 g, 34.9 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 16 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography to give the yellow oily product compound 55-3 (4.1 g, yield: 41%). MS (ESI) m / z = 287.6 [M+H] + .

[0741] Step 2: Synthesis of compound 55-4

[0742] Compound 55-3 (1.00 g, 3.49 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.90 g, 7.0 mmol, 2.0 eq) and benzyl chloroformate (1.19 g, 6.98 mmol, 2.0 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography to give the yellow oily product compound 55-4 (1 g, yield: 68%).

[0743] 1 H NMR (400MHz, CDCl3): δ7.38-7.28(m,5H),5.31-5.17(m,1H),5.13(s,2H),4.25-4.12(m,2H),3.71-3.6 1(m,4H),3.60-3.55(m,2H),3.51-3.40(m,4H),3.34-3.23(m,2H),2.42(t,J=2.4Hz,1H),1.42(s,9H).

[0744] Step 3: Synthesis of compound 55-5

[0745] Compounds 32-4 (400 mg, 1.23 mmol, 1.0 eq) and 55-4 (624 mg, 1.48 mmol, 1.2 eq) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of diisopropylamine (501 mg, 4.95 mmol, 4.0 eq), cuprous iodide (47.1 mg, 0.248 mmol, 0.2 eq), triphenylphosphine (32.4 mg, 0.124 mmol, 0.1 eq), and bis(acetonitrile)palladium(II) dichloride (32.1 mg, 0.124 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 18 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid compound 55-5 (300 mg, yield: 36%).

[0746] 1 H NMR (400MHz, CDCl3): δ7.89-7.82(m,1H),7.66-7.60(m,1H),7.49-7.44(m,1H),7.36-7.31(m,6H),5.28-5.18(m,2H),5.15-5.08(m, 3H),4.58-4.34(m,4H),3.75-3.51(m,9H),2.97-2.92(m,1H),2.91-2.83(m,2H),2.48-2.34(m,1H),2.28-2.15(m,1H),1.41(s,9H).

[0747] Step 4: Synthesis of compound 55-6

[0748] Compound 55-5 (250 mg, 0.377 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL) and acetic acid (3 mL), and palladium on carbon (80.2 mg, 0.075 mmol, 0.2 eq) and palladium hydroxide (105 mg, 0.075 mmol, 0.2 eq) were added. The reaction mixture was purged with hydrogen gas at 50 psi using a hydrogen cylinder, and stirred at 40 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure to give a yellow solid compound 55-6 (200 mg, yield: 79%). MS (ESI) m / z = 567.0 [M-100+H] +

[0749] Step 5: Synthesis of compound 55-7

[0750] A solution of dioxane in hydrochloric acid (5 mL, 4 M) was added to a 5 mL solution of dioxane in compound 55-6 (200 mg, 0.300 mmol, 1.0 eq). The reaction mixture was stirred at 60 °C for 18 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid compound 55-7 (140 mg, crude product).

[0751] MS(ESI)m / z = 433.2[M+H] +

[0752] Step 6: Synthesis of compound RC055

[0753] Compound 1-1 (25 mg, 0.038 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 55-7 (35.5 mg, 0.076 mmol, 2.0 eq), N-methylimidazole (135 mg, 0.189 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid compound RC055 (8.05 mg, yield: 20%). MS (ESI) m / z = 538.0 [M / 2+H] +

[0754] 1 H NMR (400MHz, DMSO-d6): δ8.58-8.52(m,1H),8.30-8.22(m,1H),8.04(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.58-7. 36(m,7H),7.28(s,1H),7.04(d,J=8.8Hz,1H),5.23(s,2H),5.16-5.10(m,1H),4.43(d,J=17.2Hz,1H),4.28(d,J=17.2 Hz,1H),4.04-3.87(m,2H),3.68(s,2H),3.54-3.39(m,8H),3.06(d,J=5.6Hz,2H),2.97-2.85(m,2H),2.77-2.60(m,6 H),2.42-2.32(m,3H),2.10-1.95(m,5H),1.94-1.90(m,3H),1.84-1.77(m,2H),1.66-1.61(m,3H),1.57-1.51(m,9H).

[0755] Example 54 Synthesis of compound RC056

[0756] Step 1: Synthesis of Compound 56-1

[0757] Compound 29-2 (2.01 g, 9.99 mmol, 1.0 eq) was dissolved in 20 mL of N,N-dimethylformamide. NaH (600 mg, 15.0 mmol, 1.5 eq) was added at 0 °C under nitrogen protection and the mixture was stirred for 0.5 h. Compound 38-2 (3.5 g, 10 mmol, 1.0 eq) was added to the reaction mixture, and the mixture was stirred at 25 °C for 15.5 h. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (20 mL) and extracted three times with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow oil compound 56-1 (2.0 g, yield: 53%).

[0758] 1 H NMR (400MHz, DMSO-d6): δ7.38-7.24(m,5H),4.48(s,2H),3.64-3.58(m,2H),3.58-3.54(m,4H),3.54- 3.50(m,4H),3.49-3.42(m,1H),3.03-2.91(m,2H),1.80-1.72(m,2H),1.38(s,9H),1.35-1.25(m,2H).

[0759] Step 2: Synthesis of Compound 56-2

[0760] Compound 56-1 (1.8 g, 4.7 mmol, 1.0 eq) was dissolved in 30 mL of methanol, and wet palladium on carbon (900 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere (hydrogen balloon). The reaction mixture was filtered through diatomaceous earth and washed with methanol (30 mL). The solution was concentrated under reduced pressure to give yellow oil compound 56-2 (1.1 g, yield: 80%).

[0761] 1 H NMR (400MHz, DMSO-d6): δ4.57-4.53(m,1H),3.66-3.58(m,2H),3.55-3.50(m,4H),3.50-3.45(m ,2H),3.44-3.39(m,2H),3.03-2.90(m,2H),1.82-1.72(m,2H),1.39(s,9H),1.35-1.24(m,2H).

[0762] Step 3: Synthesis of Compound 56-3

[0763] Compound 56-2 (3 g, 10.367 mmol, 1.0 eq) was dissolved in 45 mL of dichloromethane, and triethylamine (3.2 g, 31.102 mmol, 3.0 eq) and p-toluenesulfonyl chloride (2.9 g, 15.551 mmol, 1.5 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow oily compound 56-3 (1.5 g, yield: 32%).

[0764] 1 H NMR (400MHz, CDCl3): δ7.79(d,J=8.4Hz,2H),7.33(d,J=8.4Hz,2H),4.17-4.11(m,2H),3.78-3.71(m,2H),3.71-3.67(m,2H ),3.59-3.53(m,4H),3.47-3.40(m,1H),3.08-2.99(m,2H),2.44(s,3H),1.83-1.75(m,2H),1.52-1.46(m,2H),1.44(s,9H).

[0765] Step 4: Synthesis of compound 56-5

[0766] Compound 12-1 (3.0 g, 9.3 mmol, 1.0 eq) was dissolved in 30 mL of dioxane, followed by the addition of compound (tributyltin) in methanol (3.58 g, 11.1 mmol, 1.2 eq) and tetra(triphenylphosphine)palladium (1.07 g, 0.928 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into a saturated potassium fluoride aqueous solution (20 mL) and extracted three times with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 56-5 (300 mg, yield: 12%). MS (ESI) m / z = 297.2 [M + Na] +

[0767] Step 5: Synthesis of compound 56-6

[0768] Compound 56-5 (300 mg, 1.094 mmol, 1.0 eq) was dissolved in 3 mL of N,N-dimethylformamide. NaH (87.5 mg, 2.19 mmol, 2.0 eq) was added at 0 °C under nitrogen protection and the mixture was stirred for 0.5 h. Compound 56-3 (728 mg, 1.64 mmol, 1.5 eq) was added to the reaction mixture, and the mixture was stirred at 25 °C for 15.5 h. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (20 mL) and extracted three times with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 56-6 (100 mg, yield: 16%). MS (ESI) m / z = 446.2 [M + H - 100] +

[0769] Step 6: Synthesis of compounds 56-7

[0770] Compound 56-6 (100 mg, 0.183 mmol, 1.0 eq) was dissolved in 3 mL of dioxane hydrochloride. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 56-7 (60 mg, crude product), which was used directly in the next reaction. MS (ESI) m / z = 445.5 [M+H] +

[0771] Step 7: Synthesis of compound RC056

[0772] The hydrochloride salt of compound 56-7 (50 mg, 0.10 mmol, 1.7 eq) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (40 mg, 0.061 mmol, 1.0 eq), N,N-diisopropylethylamine (47 mg, 0.36 mmol, 6.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (25 mg, 0.067 mmol, 1.1 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give a white solid compound RC056 (12.23 mg, yield: 18%). MS (ESI) m / z = 1087.2 [M+H] + ,

[0773] 1H NMR (400MHz, DMSO-d6): δ12.31(s,1H),10.98(s,1H),8.54(d,J=4.8Hz,1H),8.04(d,J=7.6Hz ,1H),7.81(d,J=7.6Hz,1H),7.67(d,J=7.6Hz,1H),7.56-7.50(m,3H),7.50-7.45(m,1H),7.4 2(d,J=7.6Hz,1H),7.39-7.33(m,1H),7.22(s,1H),6.96(d,J=8.8Hz,1H),5.27-5.06(m,3H), 4.59(s,2H),4.43(d,J=17.6Hz,1H),4.30(d,J=17.6Hz,1H),3.93-3.86(m,2H),3.69(s,2H),3 .66-3.59(m,1H),3.58-3.51(m,4H),3.47-3.37(m,4H),3.31-3.25(m,2H),3.23-3.15(m,1H) ,3.12-3.00(m,3H),2.95-2.85(m,1H),2.84-2.77(m,1H),2.63-2.55(m,1H),2.41-2.32(m,1H ),2.14(s,3H),2.02-1.95(m,1H),1.93-1.85(m,3H),1.64-1.62(m,1H),1.62-1.59(m,2H),1 .57-1.53(m,2H),1.53-1.46(m,7H),1.45-1.35(m,1H),1.30-1.23(m,1H),1.13-1.01(m,1H).

[0774] Example 55 Synthesis of compound RC057

[0775] Step 1: Synthesis of Compound 57-2

[0776] Compounds 32-4 (1.00 g, 3.09 mmol, 1.0 eq) and 57-1 (1.56 g, 10.8 mmol, 3.5 eq) were dissolved in N,N-dimethylformamide (20 mL), followed by the addition of diisopropylamine (1.25 g, 12.3 mmol, 4.0 eq), cuprous iodide (58.9 mg, 0.309 mmol, 0.2 eq), triphenylphosphine (162 mg, 0.619 mmol, 0.1 eq), and bis(acetonitrile)palladium(II) dichloride (80.2 mg, 0.309 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product compound 57-2 (1.2 g, crude product). MS (ESI) m / z = 387.2, [M+H] +

[0777] Step 2: Synthesis of Compound 57-3

[0778] Compound 57-2 (500 mg, 1.55 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and 4-dimethylaminopyridine (75.8 mg, 0.621 mmol, 0.2 eq), triethylamine (0.861 mL, 6.21 mmol, 2.0 eq), and p-toluenesulfonyl chloride (888 mg, 4.65 mmol, 1.5 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography to give the yellow solid compound 57-3 (550 mg, yield: 33%).

[0779] 1H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.86 (d, J = 7.6Hz, 1H), 7.79 (d, J = 8.4Hz, 2H), 7.6 4-7.61(m,1H),7.49-7.46(m,1H),7.33(d,J=8.0Hz,2H),5.27-5.13(m,1H),4.54(d ,J=16.8Hz,1H),4.44(s,2H),4.40(d,J=16.8Hz,1H),4.20-4.14(m,2H),3.75-3.69 (m,2H),3.68-3.64(m,2H),2.97-2.78(m,2H),2.49-2.38(m,4H),2.27-2.16(m,1H).

[0780] Step 3: Synthesis of compound 57-5

[0781] Compound 57-3 (550 mg, 1.017 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), followed by the sequential addition of compound 57-4 (210 mg, 1.22 mmol, 1.2 eq), potassium iodide (202 mg, 1.22 mmol, 1.2 eq), and potassium carbonate (281 mg, 2.03 mmol, 2.0 eq). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give the yellow solid compound 57-5 (250 mg, yield: 45%). MS (ESI) m / z = 541.3, [M+H] + .

[0782] Step 4: Synthesis of compound 57-6

[0783] Compound 57-5 (200 mg, 0.370 mmol, 1.0 eq) was dissolved in tetrahydrofuran (15 mL) and acetic acid (3 mL), and palladium on carbon (78.4 mg, 0.074 mmol, 0.2 eq) and palladium hydroxide (103 mg, 0.074 mmol, 0.2 eq) were added. The reaction mixture was purged with hydrogen gas at 50 psi using a hydrogen cylinder, and stirred at 40 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give a yellow solid compound 57-6 (180 mg, yield: 89%). MS (ESI) m / z = 544.6 [M+H] + .

[0784] Step 5: Synthesis of compound 57-7

[0785] Compound 57-6 (180 mg, 0.330 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (2 mL). The reaction mixture was stirred at 25 °C for 0.5 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure to give a yellow solid, compound 57-7 (184 mg, crude product). MS (ESI) m / z = 444.6 [M+H] + .

[0786] Step 6: Synthesis of compound RC057

[0787] Compound 1-1 (25.0 mg, 0.038 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 57-7 (42.3 mg, 0.076 mmol, 2.0 eq), N-methylimidazole (135 mg, 0.189 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (12.7 mg, 0.045 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid RC057 (18.65 mg, yield: 45%). MS (ESI) m / z = 544.0 [M / 2+H] + .

[0788] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.54(d,J=4.4Hz,1H),8.47(d,J=7.6Hz,1H),8.03(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.57-7.42(m,6H),7 .39-7.31(m,1H),7.25(s,1H),7.04(d,J=8.8Hz,1H),5.25(s,2H),5.12(d d,J=13.2,5.2Hz,1H),4.44(d,J=17.2Hz,1H),4.32-4.23(m,2H),3.92(t,J =5.6Hz,2H),3.67(s,2H),3.48-3.44(m,8H),3.21(t,J=5.6Hz,2H),3.07- 3.02(m,2H),2.96-2.86(m,1H),2.81(t,J=7.2Hz,2H),2.66(t,J=7.6Hz,2H ),2.62-2.56(m,1H),2.40-2.35(m,2H),2.06(s,3H),2.03-1.96(m,1H),1. 94-1.88(m,3H),1.85-1.76(m,2H),1.66-1.60(m,3H),1.60-1.42(m,10H).

[0789] Example 56 Synthesis of compound RC058

[0790] Step 1: Synthesis of Compound 58-2

[0791] Compound 30-1 (3.30 g, 11.5 mmol), compound 58-1 (2.77 g, 13.8 mmol), and cesium carbonate (9.39 g, 28.8 mmol) were placed in 50 mL of acetonitrile, and potassium iodide (1.91 g, 11.5 mmol) was added. The reaction mixture was stirred at 70 °C for 12 hours. After the reaction was complete, water (30 mL) was added to quench the reaction solution, and the mixture was extracted twice with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. Purification by reversed-phase column chromatography yielded a yellow oily compound 58-2 (1.4 g, yield: 39%).

[0792] 1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),6.57-6.46(m,1H),4.22-4.17(m,1H),4.00-3.96(m,1H),3.93-3.83(m,2H ),3.82-3.76(m,2H),3.66-3.53(m,4H),2.90-2.66(m,5H),1.90-1.82(m,2H),1.39(s,9H),1.28-1.16(m,2H).

[0793] Step 2: Synthesis of Compound 58-3

[0794] Compound 58-2 (1.20 g, 3.82 mmol), compound 12-1 (823 mg, 2.55 mmol), and N-methyldicyclohexylamine (995 mg, 5.09 mmol) were dissolved in 10 mL of LMF at 25 °C. T-Bu3P (51.5 mg, 0.255 mmol) and Pd2(dba)3 (466 mg, 0.509 mmol) were then added to the solution. ， The mixture was then stirred at 100°C for 16 hours. The reaction solution was quenched with water (30 mL), extracted twice with ethyl acetate (30 mL x 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. Purification by rapid silica gel chromatography yielded a yellow solid compound 58-3 (560 mg, yield: 40%), MS (ESI) m / z = 557.6 [M+H]. + .

[0795] Step 3: Synthesis of Compound 58-4

[0796] Compound 58-3 (260 mg, 0.467 mmol) was dissolved in 3 mL of tetrahydrofuran at 25 °C, and palladium / carbon (49.7 mg, 0.467 mmol, 10% wt, 55% in water) was added. The reaction was stirred at 25 °C for 16 hours under hydrogen balloon conditions. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with 10 mL of tetrahydrofuran, and the filtrate was concentrated to give a yellow solid compound 58-4 (250 mg, yield: 96%), MS (ESI) m / z = 559.4 [M+H]. + .

[0797] Step 4: Synthesis of compound 58-5

[0798] Compound 58-4 (250 mg, 0.447 mmol) was dissolved in dichloromethane at 25 °C, and trifluoroacetic acid (102 mg, 0.895 mmol) was added. The mixture was stirred for 10 minutes. The reaction solution was concentrated to give a yellow oily crude compound 58-5 (400 mg, crude), which was used directly in the next reaction without purification. MS (ESI) m / z = 459.4 [M+H] + .

[0799] Step 5: Synthesis of compound RC058

[0800] Compound 58-5 (41.7 mg, 0.0910 mmol), DIEA (0.0300 mL, 0.182 mmol), and HATU (46.1 mg, 0.121 mmol) were dissolved in 2 mL of LDMF at 25 °C. Compound 1-1 (40.0 mg, 0.0610 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was filtered, and the filtrate was used to prepare a yellow solid compound RC058 (6.48 mg, yield: 9.71%). MS (ESI) m / z = 551.0 [M / 2+H] + .

[0801] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.50(s,1H),8.02(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.64-7.40 (m,5H),7.39-7.31(m,2H),7.20(s,1H),7.08-6.99(m,1H),5.35-5.18(m,1H),5.13-5.06(m,1H),4.49-4.1 3(m,2H),4.12-3.59(m,5H),3.59-3.48(m,5H),3.30-3.30(m,2H),3.07-2.83(m,9H),2.68-2.66(m,1H),2. 63-2.58(m,1H),2.43-2.29(m,4H),2.14(s,3H),2.04-1.87(m,6H),1.71-1.59(m,4H),1.58-1.43(m,11H).

[0802] Example 57 Synthesis of compound RC059

[0803] The compound structure is as follows:

[0804] Synthesis of compound 59-5

[0805] Referring to compound 58-5, reaction intermediate 58-2 was replaced with compound 4-[N-methyl-N-(2-(2-ethyleneoxyethoxy)ethyl)amino]piperidine-1-carboxylic acid tert-butyl ester to synthesize compound 59-5 (3-{5-[2-(2-{2-[methyl(piperidin-4-yl)amino]ethoxy}ethoxy)ethyl]-1-oxoisoindoline-2-yl}piperidine-2,6-dione), MS (ESI) m / z = 473.2 [M+H] +

[0806] The same synthetic method as that used for RC058 in Example 1 was employed, except that compound 58-5 was replaced with 59-5, to prepare the yellow solid compound RC059 (6.03 mg, yield: 9%). MS (ESI) m / z = 558.0 [M / 2+H] + .

[0807] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.98(s,1H),8.55(d,J=4.8Hz,1H),8.05(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.64-7.52(m,3H ),7.51-7.42(m,2H),7.40-7.34(m,2H),7.24(s,1H),6.96(d,J=9.2Hz,1H),5.20(s,2H),5.14-5.06(m,1H),4.44-4.24(m,3H),3.96-3.84 (m,2H),3.77-3.59(m,4H),3.52-3.43(m,4H),3.41-3.36(m,2H),3.30-3.28(m,2H),3.19-3.13(m,1H),3.07-3.03(m,2H),2.96-2.86(m,3 H),2.76-2.68(m,1H),2.62-2.55(m,1H),2.42-2.35(m,2H),2.19-2.06(m,6H),2.03-1.88(m,5H),1.68-1.60(m,4H),1.58-1.35(m,12H).

[0808] Example 58 Synthesis of compound RC060

[0809] Step 1: Synthesis of Compound 60-2

[0810] Potassium carbonate (11.1 g, 80.5 mmol, 3.0 eq) and compound 60-1 (6.69 g, 53.7 mmol, 2.0 eq) were added to a solution of compound 11-1 (5.00 g, 26.8 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL). The mixture was stirred at 110 °C for 5 hours under nitrogen. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated NaCl solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to give a yellow oily compound 60-2 (3.0 g, yield: 40%).

[0811] 1 H NMR (400MHz, CDCl3) δ4.03(s,1H),3.72-3.63(m,4H),3.63-3.57(m,2H),3.48-3.38(m,4H),2.64-2.54(m,2H),2.51-2.40(m,4H),1.44(s,9H).

[0812] Step 2: Synthesis of Compound 60-3

[0813] Compound 56-5 (400 mg, 1.45 mmol, 1.0 eq) was dissolved in 10 mL of dichloromethane / dimethyl sulfoxide (9 / 1, v / v), and triethylamine (293 mg, 2.90 mmol, 2.0 eq) and methanesulfonyl chloride (249 mg, 2.17 mmol, 1.5 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was used directly in the next step.

[0814] Step 3: Synthesis of Compound 60-4

[0815] Compound 60-2 (300 mg, 1.09 mmol, 1.0 eq) was dissolved in 10 mL of N,N-dimethylformamide. Sodium hydroxide (87 mg, 2.2 mmol, 2.0 eq) was added at 0 °C and the mixture was stirred for 0.5 h. The reaction solution of compound 60-3 was added to the mixture. The mixture was stirred at 25 °C for 15.5 h under a nitrogen atmosphere. The reaction solution was poured into a saturated ammonium chloride aqueous solution (20 mL) and extracted three times with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 60-4 (80 mg, yield: 13%).

[0816] MS(ESI)m / z = 531.2[M+H] + .

[0817] Step 4: Synthesis of Compound 60-5

[0818] Compound 60-4 (80 mg, 0.15 mmol, 1.0 eq) was dissolved in 3 mL of dioxane hydrochloride. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a yellow oil compound 60-5 (50 mg, crude product). MS (ESI) m / z = 431.2 [M+H] + .

[0819] Step 5: Synthesis of compound RC060

[0820] The hydrochloride salt of compound 60-5 (42 mg, 0.09 mmol, 2.0 eq) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (30 mg, 0.045 mmol, 1.0 eq), N,N-diisopropylethylamine (41 mg, 0.31 mmol, 7.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (22 mg, 0.06 mmol, 1.3 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give a white solid RC060 (1.99 mg, yield: 4%). MS (ESI) m / z = 537.7 [M / 2+H] + .

[0821] 1H NMR (400MHz, DMSO-d6) δ12.34(s,1H),10.96(d,J=6.4Hz,1H),8.57(d,J=4.4Hz,1H),8.04(d,J=7.6Hz,1H),7.82(d,J=8.0Hz,1H),7.63-7.56(m,3H ),7.48(d,J=7.6Hz,1H),7.41-7.35(m,3H),7.25(s,1H),7.08-7.01(m,1 H),6.00-5.91(m,1H),5.26-5.19(m,2H),4.85-4.71(m,1H),4.52-4.37(m ,1H),3.95-3.87(m,2H),3.72(s,2H),3.68-3.58(s,2H),3.57-3.42(m,6 H),3.10-3.00(m,4H),3.00-2.88(m,2H),2.82-2.73(m,1H),2.64-2.53(m ,2H),2.41(s,4H),2.15(s,3H),2.09-1.98(m,2H),1.97-1.88(m,4H),1. 69-1.65(s,1H),1.65-1.62(m,2H),1.59-1.56(m,2H),1.55-1.47(m,7H).

[0822] Example 59 Synthesis of compound RC061

[0823] Step 1: Synthesis of Compound 61-3

[0824] To a solution of compound 61-1 (100 mg, 0.339 mmol, 1.0 eq) and compound 61-2 (125 mg, 0.406 mmol, 1.2 eq) in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (0.168 mL, 1.01 mmol, 3.0 eq) and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (193 mg, 0.508 mmol, 1.5 eq) were added. The reaction mixture was stirred at 25 °C for 0.5 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted three times with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give a yellow solid compound 61-3 (60.0 mg, yield: 30%). MS (ESI) m / z = 607.0 [M + Na] + .

[0825] Step 2: Synthesis of compound 61-4

[0826] Compound 61-3 (60.0 mg, 0.103 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 0.5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a yellow solid compound 61-4 (60.0 mg, crude product). MS (ESI) m / z = 484.5 [M+H] + .

[0827] Step 3: Synthesis of compound RC061

[0828] Compound 1-1 (35 mg, 0.053 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (3 mL), and compound 61-4 (63.5 mg, 0.106 mmol, 2.0 eq), N-methylimidazole (21.2 mg, 0.265 mmol, 5.0 eq), and N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (17.8 mg, 0.064 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen protection. The reaction mixture was purified by reverse-phase chromatography to give a white solid compound RC061 (30.84 mg, yield: 51%). MS (ESI) m / z = 564.0 [M / 2+H] + .

[0829] 1H NMR (400MHz, DMSO-d6) δ12.30(s,1H),10.96(s,1H),10.10(s,1H),8.54(d,J= 4.8Hz,1H),8.22(t,J=5.8Hz,1H),8.04(d,J=7.2Hz,1H),7.93(s,1H),7.81(d, J=8.4Hz,2H),7.77-7.72(m,1H),7.56-7.45(m,3H),7.39-7.33(m,1H),7.28( s,1H),7.02(d,J=8.8Hz,1H),5.22(s,2H),4.86-4.78(m,1H),4.58-4.51(m,1H ),4.46-4.36(m,1H),4.10(s,2H),4.02-3.88(m,2H),3.68(s,2H),3.65-3.60 (m,2H),3.59-3.54(m,2H),3.52-3.44(m,4H),3.43-3.38(m,2H),3.30-3.26(m ,2H),3.05(t,J=5.6Hz,2H),2.93-2.82(m,1H),2.61-2.54(m,1H),2.41-2.30 (m,1H),2.10-2.01(m,4H),1.92(s,3H),1.68-1.60(m,3H),1.58-1.49(m,9H).

[0830] Example 60 Synthesis of compound RC062

[0831] Step 1: Synthesis of Compound 62-3

[0832] Compound 62-1 (10.0 g, 62.0 mmol, 1.0 eq) was dissolved in 120 mL of N,N-dimethylformamide. NaH (6.20 g, 155 mmol, 2.5 eq, 60%) was added under nitrogen protection at 0 °C and stirred for 0.5 h. Compound 62-2 (13.5 g, 58.9 mmol, 0.95 eq) was added to the reaction mixture, and the mixture was stirred at 25 °C for 15.5 h under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted three times with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow oil compound 62-3 (6 g, yield: 31%). MS (ESI) m / z = 210.2 [M+H-100] + .

[0833] Step 2: Synthesis of compound 62-4

[0834] Compound 62-3 (5.0 g, 16 mmol, 1.0 eq) was dissolved in 60 mL of methanol, and 2 g of wet palladium on carbon was added. The reaction mixture was stirred at 50 °C for 16 hours under a hydrogen atmosphere (hydrogen balloon). The reaction mixture was filtered through diatomaceous earth and washed with methanol (50 mL). The solution was concentrated under reduced pressure to give a yellow oil compound 62-4 (3 g, yield: 84%), MS (ESI) m / z = 242.2 [M + Na]. + .

[0835] Step 3: Synthesis of Compound 62-5

[0836] Compound 62-4 (2.7 g, 12 mmol, 1.0 eq) was dissolved in 40 mL of dichloromethane, and triethylamine (1.87 g, 18.5 mmol, 1.5 eq), p-toluenesulfonyl chloride (3.52 g, 18.4 mmol, 1.5 eq), and 4-dimethylaminopyridine (0.30 g, 2.46 mmol, 0.2 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow oily compound 62-5 (1 g, yield: 22%).

[0837] 1 H NMR (400MHz, CDCl3) δ7.82-7.77(m,2H),7.35(d,J=8.0Hz,2H),4.13(t,J=6.0Hz,2H),3.45(t,J=6 .0Hz,2H),3.38(t,J=5.2Hz,2H),3.26-3.19(m,2H),2.45(s,3H),1.93-1.85(m,2H),1.44(s,9H).

[0838] Step 4: Synthesis of Compounds 62-7

[0839] Compound 12-1 (10 g, 31 mmol, 1.0 eq) was dissolved in 100 mL of dioxane, followed by the addition of bis(triphenylphosphine)phosphine dichloride (2.41 g, 3.10 mmol, 0.1 eq), triethylamine (9.39 g, 92.8 mmol, 3.0 eq), and compound 62-6 (16.76 g, 46.42 mmol, 1.5 eq). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 62-7 (3.2 g, yield: 32.90%). MS (ESI) m / z = 315.2 [M+H] + .

[0840] Step 5: Synthesis of Compound 62-8

[0841] Compound 62-7 (3.00 g, 9.544 mmol, 1.0 eq) was dissolved in 40 mL of 3N HCl. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid, compound 62-8 (2.3 g, yield: 84.18%). MS (ESI) m / z = 287.4 [M+H] + .

[0842] Step 6: Synthesis of Compounds 62-9

[0843] Compound 62-8 (1.1 g, 3.8 mmol, 1.0 eq) was dissolved in 10 mL of isopropanol, and formic acid (0.71 g, 15.4 mmol, 4.0 eq), triethylamine (0.78 g, 7.69 mmol, 2.0 eq), and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) chloride (1.22 g, 1.92 mmol, 0.5 eq) were added sequentially. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 62-9 (500 mg, yield: 45.14%). MS(ESI)m / z = 289.2[M+H] + .

[0844] Step 7: Synthesis of Compound 62-10

[0845] Compound 62-9 (200 mg, 0.69 mmol, 1.0 eq) was dissolved in 3 mL of acetonitrile and 1 mL of tetrahydrofuran. Potassium iodide (115 mg, 0.69 mmol, 1.0 eq), cesium carbonate (565 mg, 1.73 mmol, 1.0 eq), and compound 62-5 (518 mg, 1.38 mmol, 2.0 eq) were added sequentially. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give a yellow solid compound 62-10 (100 mg, yield: 29%). MS (ESI) m / z = 490.3 [M+H] + .

[0846] Step 8: Synthesis of Compound 62-11

[0847] Compound 62-10 (100 mg, 0.204 mmol, 1.0 eq) was dissolved in 3 mL of dioxane hydrochloride (4 N). The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow solid compound 62-11 (50 mg, crude product), which was directly used in the next reaction. MS (ESI) m / z = 390.2 [M+H] + .

[0848] Step 9: Synthesis of compound RC062

[0849] The hydrochloride salt of compound 62-11 (38 mg, 0.091 mmol, 1.5 eq) was dissolved in 2 mL of N,N-dimethylformamide solution. Compound 1-1 (40 mg, 0.061 mmol, 1.0 eq), N,N-diisopropylethylamine (47 mg, 0.36 mmol, 6.0 eq), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (25 mg, 0.067 mmol, 1.1 eq) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by reverse-phase chromatography to give a white solid RC062 (19.05 mg, yield: 30%). MS (ESI) m / z = 516.4 [M / 2+H] + .

[0850] 1H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.53(d,J=4.8Hz,1H),8.19(t,J=5.6Hz,1 H),8.04(d,J=7.6Hz,1H),7.81(d,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),7.54-7.5 1(m,2H),7.52-7.49(m,1H),7.49-7.44(m,2H),7.38-7.32(m,1H),7.26(s,1H), 7.02(d,J=8.8Hz,1H),5.21(s,2H),5.18-5.12(m,1H),4.86-4.79(m,1H),4.45-4 .38(m,1H),4.28-4.21(m,1H),3.95(t,J=6.0Hz,2H),3.73-3.62(m,4H),3.33-3 .23(m,6H),3.04(t,J=5.6Hz,2H),2.99-2.92(m,1H),2.76-2.68(m,1H),2.36-2. 27(m,1H),2.06(s,3H),2.02-1.95(m,1H),1.93-1.88(m,3H),1.69-1.63(m,2H) ,1.63-1.59(m,3H),1.57-1.53(s,2H),1.53-1.49(s,7H),1.34(d,J=6.4Hz,3H).

[0851] Example 61 Synthesis of compound RC063

[0852] Step 1: Synthesis of Compound 63-2

[0853] Diisopropylamine (1.25 g, 12.3 mmol, 4.0 eq) was added to a DMF (20 mL) solution of compound 32-4 (1.0 g, 3.0 mmol, 1.0 eq) and compound 63-1 (929 mg, 9.28 mmol, 3.0 eq). Then, Ph3P (162.3 mg, 0.619 mmol, 0.1 eq), CuI (58.9 mg, 0.309 mmol, 0.2 eq), and bis(acetonitrile)dichloropalladium(II) (80.2 mg, 0.309 mmol, 0.1 eq) were added. The mixture was stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the solution was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give compound 63-2 (450 mg, yield: 42%) as a white solid.

[0854] 1H NMR (400MHz, DMSO-d6) δ11.00 (s, 1H), 7.77 (d, J = 7.6Hz, 1H), 7.79-7.75 (m, 1 H),7.74-7.70(m,1H),5.19-5.10(m,1H),4.74-4.64(m,1H),4.53-4.44(m,3H ),4.38-4.31(m,1H),3.68-3.56(m,1H),3.55-3.54(m,1H),3.50-3.39(m,1H) ,2.98-2.84(m,1H),2.64-2.55(m,1H),2.48-2.40(m,1H),2.06-1.96(m,1H).

[0855] Step 2: Synthesis of compound 63-4

[0856] Compound 63-3 (471 mg, 1.53 mmol, 1.5 eq), Cs₂CO₃ (832 mg, 2.55 mmol, 3.0 eq), and KI (169 mg, 1.02 mmol, 1.0 eq) were added to a solution of compound 63-2 (350 mg, 1.02 mmol, 1.0 eq) in CH₃CN (15 mL) and THF (5 mL). The mixture was stirred at 55 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to give a yellow solid compound 63-4 (250 mg, yield: 43%). MS (ESI) m / z = 569.2 [M+H] + .

[0857] Step 3: Synthesis of Compound 63-5

[0858] To a tetrahydrofuran (20 mL) solution of compound 63-4 (350 mg, 0.615 mmol, 1.0 eq), 10% Pd / C (132 mg, 0.123 mmol, 0.2 eq) and Pd(OH)₂ (172 mg, 0.123 mmol, 0.2 eq) were added. Hydrogen gas was then displaced using a hydrogen balloon. Under hydrogen balloon conditions, the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the mixture was filtered through a diatomaceous earth mat, washed with tetrahydrofuran (20 mL), and the filtrate was concentrated under reduced pressure to give the target product compound 63-5 (200 mg, yield: 57%) as a yellow solid. MS (ESI) m / z = 572.4 [M+H] + .

[0859] Step 4: Synthesis of compound 63-6

[0860] Hydrochloric acid / 1,4-dioxane (4 mL, 4 M) was added to a 3 mL solution of compound 63-5 (200 mg, 0.349 mmol, 1.0 eq) in 1,4-dioxane, and the mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid compound 63-6 (177 mg, crude product). MS (ESI) m / z = 472.5 [M+H] + .

[0861] Step 5: Synthesis of compound RC063

[0862] Compounds 63-6 (46.2 mg, 0.091 mmol, 2.0 eq), NMI (18.1 mg, 0.227 mmol, 5.0 eq), and TCFH (15.2 mg, 0.055 mmol, 1.2 eq) were added to a DMF (3 mL) solution of compound 1-1 (30.0 mg, 0.045 mmol, 1.0 eq). The mixture was stirred at 25 °C for 0.5 h under nitrogen atmosphere. The reaction solution was purified by reverse-phase reaction to give a white solid compound RC063 (19.03 mg, yield: 37%). MS (ESI) m / z = 557.9 [M / 2+H] + .

[0863] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.58-8.49(m,1H),8.03(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.59-7.51(m,3H),7.50-7.42(m ,3H),7.39-7.30(m,1H),7.22(s,1H),6.97(d,J=8.8Hz,1H),5.28-5.19(m,2H),5.18-5.12(m,1H),4.65-4.53(m,1H),4.49-4.42(m,1H ),4.30-4.24(m,1H),3.93-3.86(m,2H),3.73-3.68(m,2H),3.65-3.42(m,9H),3.10-2.90(m,5H),2.77-2.66(m,3H),2.54-2.51(m,1H) ,2.43-2.33(m,1H),2.31-2.06(m,7H),2.04-1.98(m,2H),1.92-1.87(m,3H),1.87-1.79(m,2H),1.65-1.59(m,3H),1.57-1.44(m,11H).

[0864] Example 62 Synthesis of compound RC064

[0865] Step 1: Synthesis of Compound 64-2

[0866] NaH (0.24 g, 9.84 mmol, 1.5 eq, 60%) was added to a THF (20 mL) solution of compound 56-2 (1.90 g, 6.56 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h under nitrogen. Then KI (1.31 g, 7.87 mmol, 1.2 eq) and compound 64-1 (2.19 g, 13.1 mmol, 2.0 eq) were added. The mixture was stirred at 25 °C for 2.5 h under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to give a yellow oily compound 64-2 (1.50 g, yield: 61%).

[0867] 1 H NMR (400MHz, CDCl3) δ4.21 (q, J = 7.2Hz, 2H), 4.15 (s, 2H), 3.84-3.68 (m, 6H), 3.68-3.59 (m, 4H), 3.51-3. 43(m,1H),3.11-3.00(m,2H),1.88-1.78(m,2H),1.55-1.47(m,2H),1.45(s,9H),1.28(t,J=7.2Hz,3H).

[0868] Step 2: Synthesis of Compound 64-3

[0869] At 25 °C, NaOH (47.9 mg, 1.19 mmol, 1.5 eq) was added to a solution of compound 64-2 (300 mg, 0.799 mmol, 1.0 eq) in THF (2 mL), H₂O (2 mL), and MeOH (2 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give a yellow, oily crude product 64-3 (250 mg, yield: 85%). MS (ESI) m / z = 348.0 [M+H] + .

[0870] Step 3: Synthesis of compound 64-4

[0871] At 25 °C, DIEA (0.42 mL, 2.54 mmol, 5.0 eq) and HATU (386 mg, 1.01 mmol, 2.0 eq) were added to a DMF (5 mL) solution of compound 61-1 (150 mg, 0.508 mmol, 1.0 eq) and compound 64-3 (352 mg, 1.01 mmol, 2.0 eq). The mixture was stirred at 25 °C for 1 hour under nitrogen. Water (20 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was subjected to rapid silica gel column chromatography to give a yellow solid compound 64-4 (100 mg, yield: 31%). MS (ESI) m / z = 525.6 [M-100+H] + .

[0872] Step 4: Synthesis of Compound 64-5

[0873] TFA (1 mL) was added to a DCM (3 mL) solution of compound 64-4 (100 mg, 0.160 mmol, 1.0 eq). The mixture was stirred at 25 °C for 1 hour under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 64-5 (100 mg, yield: 97%). MS (ESI) m / z = 525.2 [M+H] + .

[0874] Step 5: Synthesis of compound RC064

[0875] Compounds 64-5 (55.6 mg, 0.106 mmol, 2.0 eq), NMI (21.2 mg, 0.265 mmol, 5.0 eq), and TCFH (17.8 mg, 0.064 mmol, 1.2 eq) were added to a DMF (3 mL) solution of compound 1-1 (35.0 mg, 0.053 mmol, 1.0 eq). The mixture was stirred at 25 °C for 1 hour under nitrogen atmosphere. After the reaction was complete, the solution was purified using a reversed-phase preparative column to give a white solid compound RC064 (30.14 mg, yield: 49%). MS (ESI) m / z = 584.0 [M / 2+H] + .

[0876] 1H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.96(s,1H),10.11(s,1H),8.54(d,J=4 .8Hz,1H),8.04(d,J=7.6Hz,1H),7.94(s,1H),7.81(d,J=8.4Hz,2H),7.78-7.7 2(m,1H),7.57-7.51(m,2H),7.51-7.45(m,1H),7.39-7.33(m,1H),7.22(s,1H) ,6.95(d,J=8.8Hz,1H),5.28-5.09(m,2H),4.89-4.76(m,1H),4.61-4.49(m,1H ),4.46-4.35(m,1H),4.12(s,2H),3.97-3.80(m,2H),3.72-3.61(m,5H),3.59- 3.54(m,2H),3.51-3.33(m,5H),3.32-3.24(m,4H),3.22-3.15(m,1H),3.12-3. 01(m,3H),2.94-2.78(m,2H),2.61-2.54(m,1H),2.41-2.31(m,1H),2.14(s,3H ),2.09-2.02(m,1H),1.95-1.88(m,3H),1.65-1.60(m,3H),1.57-1.47(m,9H).

[0877] Example 63 Synthesis of compound RC065

[0878] Step 1: Synthesis of Compound 65-2

[0879] Under nitrogen protection, compound 65-1 (10.0 g, 38.6 mmol) was dissolved in acetonitrile at 0 °C. Diboron (9.79 g, 38.6 mmol) and 2-methyl-2-(nitrosooxy)propane (5.97 g, 57.9 mmol) were added, and the reaction mixture was stirred overnight at 25 °C. The reaction mixture was quenched with water (200 mL) and then extracted twice with ethyl acetate (200 mL × 2). The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give compound 65-2 (800 mg, yield: 11%) as a yellow solid, MS (ESI) m / z = 371.2 [M + H]. + .

[0880] Step 2: Synthesis of Compound 65-4

[0881] Compound 65-2 (500 mg, 1.35 mmol) was dissolved in tetrahydrofuran (8 mL) at 25 °C. Compound 65-3 (277 mg, 2.03 mmol), potassium carbonate (373 mg, 2.70 mmol), and S-Phos Pd G3 (100 mg, 0.270 mmol) were added. The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was quenched with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give a yellow solid compound 65-4 (200 mg, yield: 49%), MS (ESI) m / z = 301.2 [M + H]. + .

[0882] Step 3: Synthesis of Compound 65-5

[0883] Compound 65-4 was dissolved in tetrahydrofuran (2 mL) at 25 °C, and 10% palladium / carbon (100 mg, 0.940 mmol) was added. The mixture was stirred overnight at 25 °C under hydrogen balloon protection. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 20 mL of methanol. The filtrate was concentrated to give crude compound 65-5 (200 mg, yield: 99%), a pale yellow solid. MS (ESI) m / z = 303.2 [M+H] + .

[0884] Step 4: Synthesis of Compound 65-6

[0885] Under nitrogen protection, compound 65-5 (150 mg, 0.496 mmol) was dissolved in tetrahydrofuran (4 mL) at 0 °C, and sodium hydrogen (39.7 mg, 0.992 mmol, 60% purity) was added. The mixture was stirred at room temperature for 1.5 hours. Then, compound 22-2 (300 mg, 0.744 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 60 °C. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and then extracted twice with ethyl acetate (5 mL × 2). The combined organic phases were washed with brine (4 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give a yellow solid compound 65-6 (100 mg, yield: 38%), MS (ESI) m / z = 434.2 [M-100+H]. + .

[0886] Step 5: Synthesis of Compound 65-7

[0887] Compound 65-6 (100 mg, 0.187 mmol) was dissolved in dichloromethane (2 mL) at 25 °C, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 25 °C for 10 minutes. The reaction solution was concentrated to give a yellow oily compound 65-7 (150 mg, crude product), MS (ESI) m / z = 434.2 [M+H]. + .

[0888] Step 6: Synthesis of compound RC065

[0889] Compound 65-7 (29.6 mg, 0.0680 mmol) was dissolved in DMF (2 mL) at 25 °C. HATU (25.9 mg, 0.0680 mmol), DIEA (0.015 mL, 0.091 mmol), and compound 1-1 (30.0 mg, 0.0450 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give a white solid compound RC065 (3.2 mg, yield: 7%). MS (ESI) m / z = 1075.3 [M+H] + .

[0890] 1 H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.11(s,1H),8.60-8.50(m,1H),8.23-8.15(m,1H),8.06-8.01(m,1H),7.82-7.77(m,3H ),7.72-7.68(m,1H),7.55-7.46(m,3H),7.38-7.32(m,1H),7.27(s,1H),7.05-7.01(m,1H),5.22(s,2H),5.16-5.08(m,1H),4. 01-3.93(m,2H),3.70-3.67(m,2H),3.66-3.61(m,2H),3.45(s,4H),3.42(s,4H),3.39-3.37(m,3H),3.28-3.26(m,2H),3.07-3 .03(m,2H),2.98-2.95(m,2H),2.09-1.97(m,6H),1.93-1.89(m,3H),1.66-1.61(m,3H),1.58-1.50(m,10H),1.24-1.23(m,3H).

[0891] Example 64 Synthesis of compound RC066

[0892] Step 1: Synthesis of Compound 66-2

[0893] To a DMF (20 mL) solution of compound 66-1 (10.0 g, 47.2 mmol, 1.0 eq), PMBCl (9.60 g, 61.3 mmol, 1.3 eq) and KOH (5.29 g, 94.3 mmol, 2.0 eq) were added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give a yellow solid, compound 66-2 (10.0 g, yield: 64%). MS (ESI) m / z = 334.0 [M+H] + .

[0894] Step 2: Synthesis of Compound 66-4

[0895] Compound 66-3 (1.23 mL, 18.0 mmol, 3.0 eq) and tetrabutylammonium bromide (190 mg, 0.602 mmol, 0.1 eq) were added to a mixed solution of compound 66-2 (2.00 g, 6.02 mmol, 1.0 eq) in HCl / H₂O (40 mL, 2 M) and CH₃CN (20 mL). The mixture was stirred at 105 °C for 12 hours under nitrogen. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove acetonitrile, and then saturated NaHCO₃ (100 mL) and CH₃COOH were added to adjust the pH to 5. The mixture was extracted with EtOAc (100 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to give a yellow oily compound 66-4 (1.50 g, yield: 61%).

[0896] 1 H NMR (400MHz, DMSO-d6) δ12.16 (s, 1H), 7.76-7.69 (m, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.16 (d, J = 8.8Hz, 2H), 7.06-6. 98(m,1H),6.85-6.80(m,2H),6.30(s,1H),5.27(s,2H),3.69(s,3H),3.49-3.41(m,2H),2.59(t,J=6.8Hz,2H).

[0897] Step 3: Synthesis of Compound 66-5

[0898] Urea (2.70 g, 11.1 mmol, 3.0 eq) was added to a solution of compound 66-4 (1.50 g, 3.71 mmol, 1.0 eq) in acetic acid (5 mL). The mixture was stirred at 120 °C for 12 hours under nitrogen. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was extracted with EtOAc (30 mL × 3) by adding saturated NaHCO3 (30 mL) aqueous solution. The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid column chromatography to give a yellow solid compound 66-5 (500 mg, yield: 31%), MS (ESI) m / z = 429.2 [M+H). + .

[0899] Step 4: Synthesis of Compound 66-6

[0900] To a 1,4-dioxane (5 mL) solution of compound 66-5 (300 mg, 0.699 mmol, 1.0 eq), sodium tert-butoxide (201 mg, 2.09 mmol, 3.0 eq), Pd-peppsi-iheptCl (50.9 mg, 0.070 mmol, 0.1 eq), and compound 22-5 (1.11 g, 3.49 mmol, 5.0 eq) were added. The mixture was stirred at 120 °C for 5 hours under nitrogen. After the reaction was complete, the reactants were concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to give a yellow solid compound 66-6 (150 mg, yield: 32%).

[0901] 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.57(d,J=9.2Hz,1H),7.14(d,J=8.8Hz,2H),6.92–6.77(m,5H),5.36(s,2H),4.11(t,J=6.7Hz, 2H),3.77(s,3H),3.66–3.62(m,4H),3.54(t,J=5.2Hz,4H),3.34–3.27(m,8H),2.88–2.84(m,4H),2.34–2.32(m,2H),1.43(s,9H).

[0902] Step 5: Synthesis of Compound 66-7

[0903] Compound 66-6 (150 mg, 0.225 mmol, 1.0 eq) was dissolved in TFA (5 mL) and stirred at 80 °C for 12 hours under nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a yellow solid compound 66-7 (126 mg, crude product). MS (ESI) m / z = 445.5 [M+H] + .

[0904] Step 6: Synthesis of compound RC066

[0905] Compounds 66-7 (126 mg, 0.225 mmol, 5.1 eq), NMI (18.1 mg, 0.225 mmol, 5.0 eq), and TCFH (25.4 mg, 0.091 mmol, 2.0 eq) were added to a DMF (3 mL) solution of compound 1-1 (30.0 mg, 0.045 mmol, 1.0 eq). The mixture was stirred at 25 °C for 0.5 h under nitrogen atmosphere. The reaction solution was purified by reverse-phase preparative column chromatography to give a white solid compound RC066 (4.20 mg, yield: 8%). MS (ESI) m / z = 1087.3 [M+H] + .

[0906] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),10.49(s,1H),8.59-8.47(m,1H),8.20(t,J=5.6Hz,1H),8.01(d,J=7.6Hz,1H),7 .78(d,J=8.0Hz,1H),7.54-7.40(m,4H),7.33(t,J=7.6Hz,1H),7.27(s,1H),7.02(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1 H),6.63(s,1H),5.20(s,2H),3.95(t,J=5.2Hz,2H),3.90(t,J=6.4Hz,2H),3.68(s,2H),3.51-3.39(m,14H),3.12-3.0 0(m,7H),2.73(t,J=6.4Hz,2H),2.45(t,J=5.6Hz,2H),2.07(s,3H),1.92(s,3H),1.69-1.61(m,3H),1.58-1.51(m,9H).

[0907] Example 65 Synthesis of compound RC067

[0908] The compound structure is as follows:

[0909] Synthesis of Compounds 67-9

[0910] Referring to compound 46-9, reaction intermediate 46-6 was replaced with compound tert-butyl{2-[4-(prop-2-yn-1-yl)piperazin-1-yl]ethyl}carbamate, and intermediate 32-4 was replaced with 3-(5-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione to synthesize compound 67-9 (3-[5-[3-[4-(2-aminoethyl)piperazin-1-yl]propyl]-1-oxoisoindololin-2-yl]piperidin-2,6-dione), MS(ESI) m / z = 413.6 [M+H] +

[0911] The same synthetic method as that used for RC046 in Example 1 was employed, except that compound 46-9 was replaced with 67-9, to obtain a white solid compound RC067 (16.1 mg, yield: 25%). MS (ESI) m / z = 1055.2 [M+H] + .

[0912] 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),10.98(s,1H),8.55(s,1H),8.19(s,1H),8.05(d,J=7.6Hz,1H),7.82(d,J=8.0Hz,1H),7.66(d,J=7.6Hz,1H) ,7.57-7.53(m,2H),7.50-7.44(m,2H),7.40-7.33(m,3H),7.04(d,J=8.4 Hz,1H),5.24(s,2H),5.14-5.06(m,1H),4.42(d,J=17.2Hz,1H),4.29(d,J =17.2Hz,1H),3.96(t,J=5.6Hz,2H),3.69(s,2H),3.31-3.22(m,6H),3.1 1-3.00(m,3H),2.98-2.84(m,3H),2.77-2.69(m,3H),2.63-2.55(m,2H), 2.47-2.30(m,4H),2.10(s,3H),2.02-1.96(m,1H),1.95-1.82(m,5H),1. 68-1.65(m,1H),1.64-1.61(m,2H),1.58-1.55(m,2H),1.54-1.50(m,7H).

[0913] Example 66 Synthesis of compound RC068

[0914] Step 1: Synthesis of Compound 68-3

[0915] Under nitrogen protection, Pd(PPh3)4 (182 mg, 0.156 mmol, 0.1 eq) was added to a solution of compound 12-1 (500 mg, 1.55 mmol, 1.0 eq) and compound 68-2 (1.0 g, 3.0 mmol, 2.0 eq) in N,N-dimethylformamide (20 mL). The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, saturated potassium fluoride (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to a yellow solid compound 68-3 (400 mg, yield: 91%). MS (ESI) m / z = 285.2 [M+H] + .

[0916] Step 2: Synthesis of Compound 68-4

[0917] At 0 °C, potassium osmium dihydrate (52 mg, 0.14 mmol, 0.1 eq) and sodium periodate (900 mg, 4.208 mmol) were added to a solution of 1,4-dioxane (10 mL) and water (5 mL) of compound 68-3 (400 mg, 1.41 mmol, 1.0 eq). The mixture was stirred at room temperature for 12 hours under nitrogen. After the reaction was complete, saturated ammonium chloride (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to a yellow solid compound 68-4 (200 mg, crude product), which was used directly in the next reaction.

[0918] 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),10.15(s,1H),8.15(s,1H),8.06(d,J=8.8Hz,1H),7.95(s,1H),5.21- 5.14(m,1H),4.62-4.52(m,1H),4.48-4.41(m,1H),3.59-3.49(m,2H),2.64-2.55(m,1H),2.45-2.37(m,1H).

[0919] Step 3: Synthesis of Compound 68-6

[0920] Compound 68-5 (303 mg, 1.322 mmol, 2.0 eq) and acetic acid (3.97 mg, 0.066 mmol, 1.0 eq) were added to a solution of compound 68-4 (180 mg, 0.661 mmol, 1.0 eq) in DCE (6 mL) and MeOH (2 mL). The mixture was stirred at 25 °C for 0.5 h under nitrogen. Sodium cyanoborate (85.9 mg, 1.32 mmol) was added. The mixture was stirred at 25 °C for 2.5 h under nitrogen. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to a yellow solid compound 68-6 (300 mg, yield: 93%). MS(ESI)m / z = 486.4 [M+H] + .

[0921] Step 4: Synthesis of Compound 68-7

[0922] To a solution of compound 68-6 (300 mg, 0.618 mmol, 1.0 eq) in 1,4-dioxane (3 mL), dioxane hydrochloride (5 mL, 4 M) was added, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give a yellow solid compound 68-7 (250 mg, crude product). MS (ESI) m / z = 386.3 [M+H] + .

[0923] Step 5: Synthesis of compound RC068

[0924] NMI (18.1 mg, 0.227 mmol, 1.0 eq) and TCFH (19.1 mg, 0.068 mmol, 1.2 eq) were added to a solution of compound 1-1 (30 mg, 0.045 mmol, 1.0 eq) in DMF (3 mL). The mixture was stirred at 25 °C for 0.5 h under nitrogen atmosphere. The reaction solution was purified by reverse-phase preparative column chromatography to give solid compound RC068 (7.84 mg, yield: 16%), MS (ESI) m / z = 514.4 [M / 2+H]. + .

[0925] 1H NMR (400MHz, DMSO-d6) δ12.21 (s, 1H), 10.98 (s, 1H), 8.55 (d, J = 4.8Hz, 1H), 8.12(t,J=5.6Hz,1H),8.01(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.67(d ,J=8.0Hz,1H),7.55(d,J=4.8Hz,1H),7.52-7.48(m,2H),7.48-7.39(m,2H) ,7.32(t,J=7.6Hz,1H),7.28(s,1H),7.04(d,J=8.8Hz,1H),5.24(s,2H),5. 15-5.05(m,1H),4.44(d,J=17.2Hz,1H),4.31(d,J=17.2Hz,1H),3.95(t,J= 5.6Hz,2H),3.68(s,2H),3.53(s,2H),3.22-3.18(m,2H),3.05(t,J=5.6Hz, 2H),2.98-2.84(m,2H),2.62-2.57(m,1H),2.38-2.28(m,9H),2.06(s,3H), 2.02-1.97(m,2H),1.94-1.89(m,3H),1.67-1.61(m,3H),1.58-1.51(m,9H).

[0926] Example 67 Synthesis of compound RC069

[0927] Step 1: Synthesis of Compound 69-3

[0928] To a solution of compound 12-1 (1.00 g, 3.09 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL), K3PO4 (790 mg, 3.71 mmol, 1.2 eq), Pd(dppf)Cl2 (230 mg, 0.309 mmol, 0.1 eq), and compound 69-2 (640 mg, 3.25 mmol, 1.05 eq) were added. The reaction mixture was stirred at 120 °C for 3 hours under nitrogen. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to a yellow solid, compound 69-3 (600 mg, yield: 62%).

[0929] 1H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 7.57 (d, J = 8.0Hz, 1H), 7.49 (s, 1H), 7.45-7.37(m,2H),5.95(d,J=12.8Hz,1H),5.15-5.02(m,1H),4.43-4.34( m,1H),4.30-4.21(m,1H),3.94(q,J=7.2Hz,2H),2.96-2.86(m,1H),2.64- 2.54(m,1H),2.45-2.33(m,1H),2.02-1.95(m,1H),1.27(t,J=7.2Hz,3H).

[0930] Step 2: Synthesis of Compound 69-4

[0931] Compound 69-3 (600 mg, 1.91 mmol, 1.0 eq) was dissolved in 5 mL of HCOOH. The mixture was stirred at 25 °C for 0.5 h under nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a yellow solid crude product, compound 69-4 (630 mg, crude product). MS (ESI) m / z = 287.2 [M+H] + .

[0932] Step 3: Synthesis of Compound 69-5

[0933] Compound 69-7 (961 mg, 4.19 mmol, 2.0 eq) and sodium cyanoborohydride (413 mg, 6.28 mmol, 3.0 eq) were added to a mixed solution of compound 69-4 (600 mg, 2.09 mmol, 1.0 eq) in DCE (6 mL) and MeOH (2 mL). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by rapid silica gel chromatography to a yellow solid, compound 69-5 (300 mg, yield: 28%).

[0934] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.40(s,1H),7.73-7.64(m,1H),7.50(s,1H),7.41(d,J=7.6Hz,1H),5.24-5.02(m,1 H),4.43(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),3.13-2.94(m,11H),2.64-2.53(m,5H),2.43-2.32(m,4H),1.37(s,9H).

[0935] Step 4: Synthesis of compound 69-6

[0936] A solution of dioxane in hydrochloric acid (4 mL, 4 M) was added to a 2 mL solution of 1,4-dioxane containing compound 69-5 (300 mg, 0.600 mmol, 1.0 eq), and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a yellow solid compound 69-6 (250 mg, crude product). MS (ESI) m / z = 400.3 [M+H] + .

[0937] Step 5: Synthesis of compound RC069

[0938] NMI (18.1 mg, 0.227 mmol, 5.0 eq) and TCFH (19.1 mg, 0.068 mmol, 1.2 eq) were added to a DMF (3 mL) solution of compound 1-1 (30 mg, 0.045 mmol, 1.0 eq) and compound 69-6 (36.3 mg, 0.091 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 0.5 h under nitrogen atmosphere. The reaction mixture was purified by reverse-phase preparation to obtain the corresponding compounds. The product was prepared by concentrating the solution under reduced pressure to remove acetonitrile, then adding saturated NaHCO3 (20 mL) and extracting with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by HPLC to give a yellow solid compound RC069 (1.12 mg, yield: 13%), MS (ESI) m / z = 521.4 [M / 2 + H). + .

[0939] 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.99(s,1H),8.56(d,J=4.8Hz,1H),8.53(s,1H),8.09(d,J=7.6Hz,1H),7.90-7.79(m,1H ),7.70(d,J=8.0Hz,1H),7.59-7.33(m,7H),7.11-7.03(m,1H),5.23(s,2H),5.14-5.06(m,1H),4.43(d,J=17.2Hz,1H),4.31(d,J =17.6Hz,1H),4.06-3.97(m,2H),3.70(s,2H),3.62-3.58(m,5H),3.17-3.12(m,4H),3.09-3.06(m,2H),2.98-2.85(m,3H),2.68 -2.55(m,3H),2.43-2.32(m,2H),2.14-2.06(m,3H),2.03-1.86(m,5H),1.77-1.74(m,2H),1.68-1.61(m,3H),1.58-1.49(m,9H).

[0940] Example 68 Synthesis of compound RC070

[0941] The compound structure is as follows:

[0942] Synthesis of Compound 70-6

[0943] Referring to compound 69-6, reaction intermediate 69-7 was replaced with compound benzyl[2-(2,6-diazaspiro[3.3]heptane-2-yl)ethyl]carbamate to synthesize compound 70-6 (3-[5-[2-[6-(2-aminoethyl)-2,6-diazaspiro[3.3]heptane-2-yl]ethyl]-1-oxoisoindoline-2-yl]piperidine-2,6-dione), MS(ESI) m / z = 412.4 [M+H] +

[0944] The same synthetic method as that used for RC069 in Example 1 was employed, except that compound 69-6 was replaced with 70-6 to obtain the white solid compound RC070 (3.00 mg, yield: 6%). MS (ESI) m / z = 527.5 [M / 2+H] + .

[0945] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.54(d,J=4.8Hz,1H),8.26(s,1H),8.07-8.03(m,1H),7.81(d,J=7.6Hz,1H ),7.60(d,J=7.6Hz,1H),7.55-7.46(m,3H),7.42-7.31(m,3H),7.27(s,1H),7.03(d,J=8.8Hz,1H),5.24(s,2H),5. 13-5.03(m,1H),4.39(d,J=17.2Hz,1H),4.27(d,J=17.2Hz,1H),3.95(t,J=6.0Hz,2H),3.69(s,2H),3.08-3.03(m, 10H),2.66-2.54(m,6H),2.38-2.30(m,4H),2.06(s,3H),2.00-1.90(m,5H),1.67-1.62(m,3H),1.58-1.51(m,9H).

[0946] Example 69 Synthesis of compound RC071

[0947] The compound structure is as follows:

[0948] Synthesis of Compound 71-6

[0949] Referring to compound 69-6, reaction intermediate 69-7 was replaced with compound benzyl[2-(3,9-diazaspiro[5.5]undecane-3-yl)ethyl]carbamate to synthesize compound 71-6 (3-[5-[2-[9-(2-aminoethyl)-3,9-diazaspiro[5.5]undecane-3-yl]ethyl]-1-oxoisoindoline-2-yl]piperidine-2,6-dione), MS(ESI) m / z = 468.4 [M+H] +

[0950] The same synthetic method as that used for RC069 in Example 1 was employed, except that compound 69-6 was replaced with 71-6, to obtain the white solid compound RC071 (29.13 mg, yield: 55%). MS (ESI) m / z = 555.4 [M / 2+H] + .

[0951] 1H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.98(s,1H),8.56(d,J=4.8Hz,1H),8.18(s,1H),8.14(s,1H),8.04(d,J=7.6Hz,1H),7.82(d,J=8 .0Hz,1H),7.67(d,J=7.6Hz,1H),7.58-7.45(m,4H),7.41-7.34(m,2H),7.30(s,1H),7.05(d,J=8.8Hz,1H),5.26(s,2H),5.14-5.08(m,1 H),4.43(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),3.97(t,J=5.6Hz,2H),3.69(s,2H),3.09-3.04(m,2H),2.99-2.86(m,4H),2.86-2.75 (m,2H),2.69-2.55(m,5H),2.46-2.32(m,6H),2.08(s,3H),2.05-1.88(m,5H),1.68-1.62(m,3H),1.60-1.50(m,10H),1.48-1.32(m,8H).

[0952] Example 70 Synthesis of compound RC072

[0953] Step 1: Synthesis of Compound 72-3

[0954] Compound 72-1 (170 mg, 0.566 mmol) was dissolved in 1,2,-dichloroethane (6 mL) at 25 °C. Compound 72-2 (311 mg, 1.13 mmol) and acetic acid (3.0 μL, 0.057 mmol) were added, and the mixture was stirred for 0.5 h. Then, sodium triacetoxyborohydride (597 mg, 2.83 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), and then extracted twice with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was subjected to column chromatography to give a yellow solid compound 72-3 (100 mg, yield: 32%), MS (ESI) m / z = 561.2 [M + H]. + .

[0955] Step 2: Synthesis of compound 72-4

[0956] Compound 72-3 (80.0 mg, 0.143 mmol) was dissolved in tetrahydrofuran (3 mL) at 25 °C, and 10% palladium / carbon (40.0 mg, 0.376 mmol) was added. The mixture was stirred for 16 hours at 25 °C under a hydrogen balloon (15 psi). The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated to give crude compound 72-4 (60 mg, yield: 99%) as a yellow oil. MS (ESI) m / z = 426.4 [M+H] + .

[0957] Step 3: Synthesis of compound RC072

[0958] Compound 72-4 (14.2 mg, 0.0330 mmol) was dissolved in DMF (2 mL) at 25 °C. DIEA (0.015 mL, 0.091 mmol) and HATU (23.1 mg, 0.0610 mmol) were added, and the mixture was stirred for 0.5 h. Then, compound 1-1 (20.0 mg, 0.0300 mmol) was added, and the mixture was stirred at 25 °C for 1.5 h. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give a white solid compound RC072 (2.32 mg, yield: 7%). MS (ESI) m / z = 533.4 [M / 2+H] + .

[0959] 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),10.98(s,1H),8.55-8.54(m,1H),8.06-8.03(m,1H),7.82-7.79(m,1H),7.62-7.59( m,1H),7.56-7.55(m,1H),7.54-7.53(m,1H),7.50-7.46(m,1H),7.44-7.43(m,1H),7.37-7.34(m,2H),7.23-7.18(m,2H), 6.97-6.94(m,1H),5.34-5.32(m,1H),5.27-5.06(m,4H),4.46-4.21(m,3H),3.71-3.69(m,2H),3.65-3.59(m,4H),3.07-3 .03(m,4H),2.92-2.87(m,4H),2.15(s,3H),2.03-1.96(m,6H),1.93-1.89(m,4H),1.65-1.60(m,4H),1.57-1.49(m,12H).

[0960] Example 71 Synthesis of compound RC073

[0961] The compound structure is as follows:

[0962] Synthesis of Compound 73-4

[0963] Referring to compound 72-4, by replacing reaction intermediate 72-2 with compound benzyl[2-(3,9-diazaspiro[5.5]undecane-3-yl)ethyl]carbamate, compound 73-4 (3-[4-[3-[9-(2-aminoethyl)-3,9-diazaspiro[5.5]undecane-3-yl]propyl]-1-oxoisoindoline-2-yl]piperidin-2,6-dione) was synthesized, with MS (ESI) m / z = 482.3 [M+H] +

[0964] The same synthetic method as that used for RC072 in Example 1 was employed, except that compound 72-4 was replaced with 73-4, to obtain the white solid compound RC073 (4.32 mg, yield: 10%). MS (ESI) m / z = 584.2 [M / 2 + Na] + .

[0965] 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),10.97(s,1H),8.55-8.53(m,1H),8.04(d,J=8.0Hz,1H),7.81(d,J=7.6Hz,1H),7.61(d,J=7.6Hz, 1H),7.56-7.54(m,1H),7.54-7.53(m,1H),7.49-7.45(m,1H),7.44-7.43(m,1H),7.37-7.34(m,2H),7.24-7.17(m,2H),6.97-6.94(m,1H ),5.33-5.31(m,1H),5.27-5.06(m,4H),4.44-4.23(m,3H),3.91-3.86(m,2H),3.70-3.69(m,2H),3.65-3.59(m,4H),3.48-3.45(m,6H) ,3.07-3.02(m,4H),2.92-2.87(m,4H),2.15-2.14(m,3H),2.03-1.96(m,6H),1.93-1.89(m,4H),1.66-1.60(m,4H),1.57-1.49(m,12H).

[0966] Example 72 Synthesis of compound RC074

[0967] Step 1: Synthesis of Compound 74-2

[0968] N,N-dimethylformamide (3.0 mL) was added to a 25 mL single-necked flask. While stirring, compound 74-1 (300 mg, 1.08 mmol), N,N-diisopropylethylamine (0.54 mL, 3.23 mmol), and HATU (614 mg, 1.62 mmol) were added sequentially. After stirring at room temperature for 0.5 hours, 2-aminobenzothiazole (194 mg, 1.29 mmol) was added. The reaction mixture was purged with nitrogen three times and stirred at 40 °C for 5 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by slurrying with ethyl acetate (15 mL) to obtain a white compound 74-2 (350 mg, yield: 79.1%). MS (ESI) m / z = 411.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.09(s,1H),8.78(s,1H),8.57(s,1H),8.05(d,J=7.6Hz,1H),7.80(d,J=7.6Hz,1H ),7.49(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),4.78(s,2H),3.62(s,2H),2.89(t,J=4.0Hz,2H),1.41(s,9H).

[0969] Step 2: Synthesis of compound 74-3

[0970] 1,4-Dioxane (5 mL) was added to a 25 mL single-necked flask, followed by the addition of compound 74-2 (260 mg, 0.63 mmol) with stirring. Then, 10 mL of 4N hydrogen chloride solution of 1,4-dioxane was added under ice bath conditions. The reaction mixture was stirred at room temperature for 3 hours, quenched with saturated sodium carbonate solution (10 mL), and extracted with n-butanol (20 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid containing the target compound 74-3 (130 mg, yield: 66.1%). MS (ESI) m / z = 311.0 [M + H] + . 1H NMR (400MHz, DMSO-d6): δ13.09(s,1H),8.78(s,1H),8.57(s,1H),8.05(d,J=7.6Hz,1H),7.80(d,J=7.6 Hz,1H),7.49(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),4.78(s,2H),3.62(s,2H),2.89(t,J=4.0Hz,2H).

[0971] Step 3: Synthesis of compound 74-4

[0972] N,N-dimethylformamide (3.0 mL), compound 74-3 (84.2 mg, 0.27 mmol), 3A (80 mg, 0.18 mmol), cesium carbonate (206 mg, 0.63 mmol), and bis(tri-tert-butylphosphine)palladium (18.5 mg, 0.04 mmol) were added to a 10 mL microwave-safe tube. The reaction mixture was microwaved at 120 °C for 2 hours under nitrogen protection. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. Purification yielded a yellow compound 74-4 (106 mg, yield: 69.5%). MS (ESI) m / z = 716.3 [M+H] +

[0973] Step 4: Synthesis of compound 74-5

[0974] At 0°C, dichloromethane (2.0 mL), compound 74-4 (79 mg, 0.11 mmol), and trifluoroacetic acid (2.0 mL) were added sequentially to a 25 mL single-necked flask, and the mixture was stirred at 25°C for 4 hours. The reaction solution was concentrated, and the white target product 74-5 (6.35 mg, yield: 8.72%) was obtained by reverse reaction. MS (ESI) m / z = 660.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ13.09(br,1H),12.83(br,1H),8.80(s,1H),8.60(s,1H),8.05(d,J =7.6Hz,1H),7.81(d,J=8.4Hz,1H),7.54(d,J=8.8Hz,1H),7.49(t,J=7.9Hz,1H),7.37(t,J= 7.2Hz,1H),7.28(s,1H),7.03(d,J=8.8Hz,1H),5.02(s,2H),3.94(t,J=5.6Hz,2H),3.71(s, 2H),3.01(t,J=5.6Hz,2H),2.11(s,3H),1.93(s,3H),1.68-1.61(m,3H),1.60-1.50(m,9H).

[0975] Step 5: Synthesis of compound RC074

[0976] Compound 38-6 (29.6 mg, 0.0610 mmol) was dissolved in DMF (2 mL) at 25 °C, and HATU (23.1 mg, 0.0610 mmol), DIEA (0.030 mL, 0.182 mmol), and compound 1-1 (20 mg, 0.030 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give a white solid compound RC074 (9.08 mg, yield: 27%). MS (ESI) m / z = 565.8 [M / 2+H] + .

[0977] 1H NMR (400MHz, DMSO-d6) δ13.10(s,1H),11.10(s,1H),8.79(s,1H),8.59(s,1H),8.03(d,J=8.0Hz,1H),7.82-7.78(m,2H),7 .53-7.49(m,2H),7.49-7.44(m,2H),7.38-7.34(m,1H),7.20(s,1H),7.00-6.91(m,1H),5.10-5.04(m,1H),5.00(s,2H),4 .34-4.31(m,2H),3.91-3.86(m,2H),3.79-3.76(m,2H),3.70(s,2H),3.62-3.59(m,2H),3.44-3.42(m,2H),3.04-3.00(m, 2H),2.95-2.80(m,4H),2.61-2.55(m,2H),2.16-1.97(m,10H),1.95-1.88(m,5H),1.68-1.59(m,4H),1.57-1.49(m,11H).

[0978] Example 73 Synthesis of compound RC075

[0979] The compound structure is as follows:

[0980] The same synthetic method as that used for RC074 in Example 1 was employed, except that compound 38-6 was replaced with 14-4, to obtain the white solid compound RC075 (1.51 mg, yield: 3%). MS (ESI) m / z = 1076.4 [M+H] + .

[0981] 1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),10.99(s,1H),8.59(s,1H),8.22-8.17(m,1H),8.07-8.01(m,1H),7.8 3-7.77(m,1H),7.57-7.45(m,4H),7.44-7.42(m,2H),7.38-7.34(m,1H),7.26(s,1H),7.05-7.01(m,1H),5.3 5-5.28(m,2H),5.15-5.10(m,1H),4.46-4.41(m,1H),4.31-4.25(m,1H),3.97-3.92(m,2H),3.67(s,2H),3. 03-2.98(m,4H),2.66-2.57(m,4H),2.05(s,3H),2.03-1.88(m,13H),1.68-1.59(m,5H),1.58-1.50(m,13H).

[0982] Example 74 Synthesis of compound RC076

[0983] The compound structure is as follows:

[0984] The same synthetic method as that used for RC074 in Example 1 was employed, except that compound 38-6 was replaced with 2-4, to obtain the white solid compound RC076 (12.94 mg, yield: 26%). MS (ESI) m / z = 546.4 [M / 2+H] + .

[0985] 1H NMR (400MHz, DMSO-d6) δ13.05(s,1H),11.10(s,1H),8.78(s,1H),8.58(s,1H),8.19(t,J=5.6Hz,1H),8.03(d,J=7.6Hz,1H),7.82-7 .73(m,2H),7.50-7.41(m,4H),7.39-7.34(m,1H),7.26(s,1H),7.02(d,J=8.8Hz,1H),5.12-4.99(m,3H),4.34-4.26(m,2H),3.95(t ,J=5.6Hz,2H),3.78-3.74(m,2H),3.67(s,2H),3.61-3.57(m,2H),3.50-3.46(m,2H),3.45-3.39(m,5H),3.26-3.22(m,2H),3.00(t ,J=5.6Hz,2H),2.90-2.83(m,1H),2.61-2.51(m,2H),2.07-1.98(m,4H),1.93-1.88(m,3H),1.66-1.60(m,3H),1.58-1.47(m,10H).

[0986] Example 75 Synthesis of compound RC077

[0987] Step 1: Synthesis of Compound 77-2

[0988] At 0 °C, concentrated sulfuric acid (4.1 mL, 77.1 mmol, 0.5 eq) was added to a methanol (250 mL) solution of compound 77-1 (25.0 g, 154 mmol, 1.0 eq). Under nitrogen protection, the reaction mixture was stirred at 25 °C for 1 hour, and then stirred at 80 °C for another 11 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. Ethyl acetate (100 mL) and water (200 mL) were added to the crude product, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated NaCl solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to obtain the colorless oily product compound 77-2 (30.0 g, yield: 93%).

[0989] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.0Hz,1H),7.46(s,1H),7.32(d,J=8.0Hz,1H),3.89(s,3H),3.88(s,3H),2.40(s,3H).

[0990] Step 2: Synthesis of compound 77-3

[0991] To a carbon tetrachloride (150 mL) solution of compound 77-2 (10.0 g, 48.0 mmol, 1.0 eq), N-succinimide bromide (8.72 g, 48.9 mmol, 1.0 eq) and azobisisobutyronitrile (2.37 g, 14.4 mmol, 0.3 eq) were added. The mixture was stirred at 80 °C for 12 hours under nitrogen. After the reaction was complete, dichloromethane (100 mL) was added to the reaction solution, followed by washing with saturated NaCl solution (50 mL x 3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to obtain a yellow oily compound 77-3 (9.00 g, yield: 65%). MS (ESI) m / z = 289.0 [M+H] + .

[0992] Step 3: Synthesis of compound 77-5

[0993] NaH (3.13 g, 78.3 mmol, 1.5 eq) was added to a tetrahydrofuran (100 mL) solution of compound 77-4 (23.5 g, 156 mmol, 3.0 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere, followed by the addition of compound 77-3 (15.0 g, 52.2 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 3 h. After the reaction was complete, MeOH (100 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to give a yellow oily compound 77-5 (2.90 g, yield: 15%).

[0994] 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 8.0Hz, 1H), 7.69-7.63 (m, 1H), 7.55-7.48 (m, 1H) ),4.62(s,2H),3.90(s,3H),3.89(s,2H),3.73-3.64(m,10H),3.63-3.59(m,2H).

[0995] Step 4: Synthesis of compound 77-6

[0996] TsCl (3.09 g, 16.2 mmol, 2.0 eq) was added to a DCM (15 mL) solution of compound 5 (2.90 g, 8.13 mmol, 1.0 eq), DMAP (0.50 g, 4.06 mmol, 0.5 eq), and Et3N (1.1 mL, 8.13 mmol, 1.0 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hours under nitrogen. After the reaction was complete, DCM (100 mL) was added to the reaction solution, and the mixture was washed with saturated NaCl solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to obtain a yellow oily compound 77-6 (4.00 g, 96%). MS (ESI) m / z = 511.2 [M+H] + .

[0997] Step 5: Synthesis of compound 77-7

[0998] At 0 °C, Ph3P (4.11 g, 15.6 mmol, 2.0 eq) was added to a solution of compound 77-6 (4.00 g, 7.83 mmol, 1.0 eq) and CBr4 (3.25 g, 9.79 mmol, 1.25 eq) in acetone (30 mL). The mixture was stirred at 25 °C for 2 hours under nitrogen atmosphere. After the reaction was complete, DCM (100 mL) was added to the reaction solution, followed by washing with saturated NaCl solution (50 mL x 3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to obtain a yellow oily compound 77-7 (2.50 g, yield: 76%). MS (ESI) m / z = 419.2 [M+H] + .

[0999] Step 6: Synthesis of compounds 77-8

[1000] At 25°C, compound 77-7 (2.50 g, 5.96 mmol, 1.0 eq) was subjected to... i Na₂SO₃ (1.50 g, 11.9 mmol, 2.0 eq) was added to a solution of PrOH (15 mL) and H₂O (15 mL). The mixture was stirred at 85 °C for 2 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give a yellow solid compound 77-8 (2.60 g, crude product). MS (ESI) m / z = 421.2 [M-Na+2H] + .

[1001] Step 7: Synthesis of compounds 77-9

[1002] At 25 °C, SOCl2 (2.13 mL, 29.3 mmol, 5.0 eq) was added to a solution of compound 77-8 (2.60 g, 5.87 mmol, 1.0 eq) in THF (50 mL) and DMF (0.045 mL, 0.588 mmol, 0.1 eq). The mixture was stirred at 85 °C for 2 hours under nitrogen. The reaction solution was then cooled to -20 °C, and NH3·H2O (2.2 mL, 58.7 mmol, 10 eq) was added dropwise, followed by stirring under nitrogen for 2 hours. H2O (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel column chromatography to give a yellow oily compound 77-9 (2.00 g, yield: 81%).

[1003] 1 H NMR (400MHz, CDCl3) δ7.74 (d, J = 7.6Hz, 1H), 7.70-7.66 (m, 1H), 7.54-7.49 (m, 1H), 5.19 (s, 2H) ,4.61(s,2H),4.02-3.94(m,2H),3.91(d,J=4.4Hz,6H),3.71-3.62(m,8H),3.36-3.27(m,2H).

[1004] Step 8: Synthesis of compounds 77-10

[1005] To a 20 mL ethanol solution of compound 77-9 (2.00 g, 4.76 mmol, 1.0 eq), 7.94 mL of NaOH / H₂O (3 M) was added. The mixture was stirred at 80 °C for 4 hours under nitrogen atmosphere. After the reaction was complete, 25 mL of HCl (1 M) was added to the reaction solution, and the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to give a yellow oily compound 77-10 (1.50 g, yield: 80%). MS (ESI) m / z = 392.2 [M+H] + .

[1006] Step 9: Synthesis of compounds 77-12

[1007] To a CH3CN (21 mL) solution of compounds 77-10 (400 mg, 1.02 mmol, 1.0 eq) and 77-11 (502 mg, 3.06 mmol, 3.0 eq), 1,1-carbonyldiimidazole (413 mg, 2.55 mmol, 2.5 eq) and DIEA (0.60 mL, 3.75 mmol, 3.7 eq) were added. The mixture was stirred at 25 °C for 12 hours under nitrogen. H2O (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated NaCl solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel column chromatography to give a white solid compound 77-12 (150 mg, yield: 30%).

[1008] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.91(d,J=7.6Hz,1H),7.86(s,1H),7.83(d,J=7.6Hz,1H),6.73(s,2H),5.22-5.09(m,1H),4.70(s,2 H),3.77(t,J=6.4Hz,2H),3.64-3.59(m,4H),3.56(s,4H),3.25(t,J=6.4Hz,2H),2.96-2.83(m,1H),2.65-2.51(m,2H),2.12-2.02(m,1H).

[1009] Step 10: Synthesis of compound RC077

[1010] Compounds 77-12 (22.0 mg, 0.045 mmol, 1.0 eq), NMI (18.1 mg, 0.227 mmol, 5.0 eq), and TCFH (25.4 mg, 0.091 mmol, 2.0 eq) were added to a DMF (3 mL) solution of compound 1-1 (30.0 mg, 0.045 mmol, 1.0 eq). The reaction mixture was then stirred at 25 °C for 0.5 h. The reaction solution was purified by reverse-phase chromatography to give a white solid compound (1.00 mg, yield: 2%). MS (ESI) m / z = 563.5 [M / 2+H] + .

[1011] 1H NMR (400MHz, DMSO-d6) δ12.27(s,1H),11.76(s,1H),11.12(s,1H),8.55(d,J=4.8Hz,1H),8.04(d,J=7.2Hz,1H),7.85(d,J=7.6Hz, 1H),7.81(d,J=7.6Hz,2H),7.77(d,J=7.6Hz,1H),7.60-7.54(m,2H),7.51-7.45(m,1H),7.38-7.34(m,1H),7.29(s,1H),7.11(d,J =8.8Hz,1H),5.24(s,2H),5.17-5.11(m,1H),4.64(s,2H),4.03-3.95(m,2H),3.77(t,J=6.4Hz,2H),3.70(s,2H),3.63-3.45(m,10 H),3.08-3.05(m,2H),2.64-2.55(m,2H),2.11(s,3H),2.03-2.01(m,2H),1.92-1.89(m,3H),1.65-1.60(m,3H),1.58-1.51(m,9H).

[1012] Example 75 Synthesis of compound RC078

[1013] The compound structure is as follows:

[1014] The same synthetic method as in Example RC002 was used, except that compounds 2-4 were replaced with 6-3, to prepare a white solid compound RC078 (23.1 mg, yield: 28%). MS (ESI) m / z = 1090.2 [M+H] + .

[1015] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),11.09(s,1H),8.54(d,J=4.8Hz,1H),8.19(t,J=5.6Hz,1H),8.04(d,J=7.6Hz,1H),7.81(d,J=8. 0Hz,1H),7.56-7.45(m,4H),7.38-7.33(m,1H),7.27(s,1H),7.09(d,J=8.8Hz,1H),7.04-6.99(m,2H),6.60-6.53(m,1H),5.22(s,2H) ,5.07-5.01(m,1H),3.95(t,J=5.6Hz,2H),3.68(s,2H),3.57(t,J=5.6Hz,2H),3.52-3.47(m,4H),3.46-3.39(m,7H),3.27-3.24(m,2H ),3.05(t,J=5.6Hz,2H),2.91-2.82(m,1H),2.61-2.54(m,1H),2.07(s,3H),2.04-1.87(m,5H),1.66-1.60(m,3H),1.59-1.48(m,10H).

[1016] Example 76 Synthesis of compound RC079

[1017] Step 1: Synthesis of Compound 79-1

[1018] A solution of compound 52-3 (1 g, 3.66 mmol, 1 eq) and N,N-diisopropylethylamine (2.37 g, 18.30 mmol, 3.19 mL, 5 eq) in 2-methoxyethanol (11.14 g, 146.41 mmol, 40 eq) was stirred at 120 °C for 16 hours. The reaction mixture was poured into 20 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic layers were washed with 30 mL of saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography to give an orange oil, compound 79-1 (685 mg, yield 69.73%). 1 H NMR (400MHz, CDCl3): δ3.62-3.53(m,2H),3.52-3.45(m,2H),3.38(s,3H),3.31(s,2H),1.44-1.40(m,6H),1.18-1.06(m,6H),0.91(s,6H).

[1019] Step 2: Synthesis of compound 79-3

[1020] Compound 79-2 (594.08 mg, 3.06 mmol, 1.2 eq) and tributyl cyanimide (2.46 g, 10.21 mmol, 4 eq) were added to 7 mL of an acetonitrile solution of compound 79-1 (685 mg, 2.55 mmol, 1 eq). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated to give a crude product. The crude product was subjected to column chromatography to give a yellow oily compound 79-3 (1.08 g, yield 95.23%). MS (ESI) m / z = 444.9 [M+H] +

[1021] Step 3: Synthesis of compound 79-4

[1022] To a 15 mL tetrahydrofuran solution of diisopropylamine (491.89 mg, 4.86 mmol, 687.00 μL, 2 eq), n-butyllithium (2.5 M, 1.94 mL, 2 eq) was added dropwise at -65 °C, followed by stirring under a nitrogen atmosphere at -65 °C for 0.5 h. Then, a 5 mL tetrahydrofuran solution of compound 79-3 (1.08 g, 2.43 mmol, 1 eq) was added dropwise to the mixture at -65 °C, followed by stirring under a nitrogen atmosphere at -65 °C for 1 h. Next, iodomethane (517.48 mg, 3.65 mmol, 226.96 μL, 1.5 eq) was added dropwise at -65 °C, and the reaction mixture was stirred under a nitrogen atmosphere at -65 °C for 1 h. The reaction was quenched with 30 mL of saturated ammonium chloride aqueous solution and extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 30 mL of saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily compound 79-4 (0.69 g, yield 61.93%). MS (ESI) m / z = 459.1 [M+H] +

[1023] Step 4: Synthesis of compound 79-6

[1024] To an 8 mL tetrahydrofuran solution of compound 79-4 (0.69 g, 1.51 mmol, 1 eq), n-butyllithium (2.5 M, 1.20 mL, 2 eq) was added dropwise at -65 °C, and the mixture was stirred at -65 °C under a nitrogen atmosphere for 0.5 h. Then, to the above mixture, compound 79-5 (560.15 mg, 3.01 mmol, 614.19 μL, 2 eq) was added dropwise at -65 °C, and the mixture was stirred at -65 °C under a nitrogen atmosphere for 1 h. The reaction was quenched with 20 mL of saturated ammonium chloride aqueous solution and extracted twice with 20 mL of ethyl acetate. The combined organic layers were washed with 20 mL of saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography to give a yellow oily compound 79-6 (0.65 g, yield 63.77%). MS(ESI)m / z=459.2[M+H)] +

[1025] Step 5: Synthesis of compound 79-7

[1026] Compound 79-6 (0.65 g, 959.89 μmol, 2.5 eq), potassium carbonate (159.20 mg, 1.15 mmol, 3 eq), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (56.19 mg, 76.79 μmol, 0.2 eq) were added to a mixed solution of 10 mL of dioxane and 2 mL of water. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was poured into 20 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily compound 79-7 (195 mg, yield 38.83%). MS (ESI) m / z = 948.7 [M+H] +

[1027] Step 6: Synthesis of compounds 79-8

[1028] Trifluoroacetic acid (6.14 g, 53.85 mmol, 4 mL, 704.34 eq) was added to a 2 mL solution of compound 79-7 (100 mg, 76.45 μmol, 1 eq) in dichloromethane. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated at 25 °C to obtain a residue. The residue was dissolved in 3 mL of methanol, and N,N-diisopropylethylamine was added to adjust the pH to 9. The residue was then purified by preparative liquid chromatography to obtain a crude product (~30 mg). The crude product was slurried at 25 °C with 3 mL of methanol and 0.5 mL of dimethyl sulfoxide for 20 minutes, filtered, and the filtrate was lyophilized to obtain a yellow solid compound 79-8 (10.10 mg, yield 16.83%). MS (ESI) m / z = 762.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.84 (br d, J=4.9Hz, 1H), 12.31 (...

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