Aromatic ring compounds and their uses

Abstract

The present invention provides a novel compound that binds to the E3 ligase protein TRIM21 and its use in a drug for treating diseases related to abnormal cell proliferation. The present invention also provides an intermediate compound in the synthesis process of a bifunctional compound that targets protein degradation.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and more particularly to a ligand compound that binds to the tripartite motif (TRIM) E3 ubiquitin ligase TRIM21 protein, and a bifunctional proteolysis-targeting chimera (PROTAC) compound containing the same. [Background technology]

[0002] Protein degradation is a highly regulated process necessary for maintaining cellular homeostasis. The ubiquitin-proteasome pathway (UPP) selectively identifies and removes damaged, misfolded, or excess proteins. The UPP, responsible for the removal of residual proteins, is ATP-dependent and highly efficient and selective. Its catalytic component is a ubiquitination E3 ligase, but it must first recruit the protein to be degraded. PROTACs technology, designed based on the UPP principle, recognizes the target protein by linking the target protein ligand with the E3 ligase ligand via an appropriate chemical bond, enhancing the binding ability of the ligase E3 to the target protein and further targeting ubiquitination to forcibly degrade the target protein. This technology boasts high catalytic activity, high efficiency, and high selectivity.

[0003] Multiple ubiquitin molecules covalently link E3 ubiquitin ligases to terminal lysine residues to tag proteins for proteasomal degradation, digesting the proteins into oligopeptides and ultimately their constituent amino acids, which are used as building modules for new proteins. Defective proteasomal degradation is associated with a variety of clinical diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscle malnutrition, cardiovascular disease, and cancer.

[0004] TRIM21 belongs to the TRIM family of E3 ligases, a multi-member family involved in ubiquitin-dependent protein hydrolysis in the cellular NF-κB signaling pathway. Research has shown that TRIM21 is associated with autoimmune diseases and plays a role in the development and prognosis of various tumors. Based on protein expression database research, TRIM21 is more highly expressed in various tumors than in normal tissues. Therefore, the development of TRIM21-based ligand molecules and PROTACs can provide important research tools for the targeted degradation of pathogenic proteins in tumors with high TRIM21 expression.

[0005] The present invention discloses novel compounds that can be effective TRIM21 ligands and can further synthesize corresponding PROTACs (bifunctional compounds) capable of degrading proteins to targeted chimeras, and can be used to treat various medical conditions, particularly abnormal cell proliferation. Summary of the Invention

[0006] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. [ka] Formula I In the formula, the ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, a 3- to 10-membered cycloalkyl, and a 3- to 10-membered heterocycle, and the ring A further comprises one, two, three, or four independent R 1 may be substituted with R 1 are each independently hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, hydroxyl-substituted -C 1~6Alkyl, -C 0~4 Alkylene-OR 12 , -C 0~4 Alkylene-OC(O)R 12 , -C 0~4 Alkylene-SR 12 , -C 0~4 Alkylene-S(O)R 12 , -C 0~4 Alkylene-S(O)R 12 , -C 0~4 Alkylene-S(O)NR 12 R 13 , -C 0~4 Alkylene-S(O)NR 12 R 13 , -C 0~4 Alkylene-C(O)R 12 , -C 0~4 Alkylene-C(O)OR 12 , -C 0~4 Alkylene-C(O)NR 12 R 13 , -C 0~4 Alkylene-NR 12 R 13 , -C 0~4 Alkylene-NR 12 C(O)R 13 , -C 0~4 Alkylene-NR 12 S(O)2R 13 , -C 0~4 Alkylene-NR 12 S(O)R 13 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). R 12 , R 13 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 14 may be substituted with R 14 are each independently hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. R 2 are independently hydrogen, halogen, or -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 22 , -C 0~4 Alkylene-OC(O)R 22 , -C 0~4 Alkylene-SR 22 , -C 0~4 Alkylene-S(O)R 22 , -C 0~4 Alkylene-S(O)R 22 , -C 0~4 Alkylene-S(O)NR 22 R 23 , -C 0~4 Alkylene-S(O)NR 22 R 23 , -C0~4 Alkylene-C(O)R 22 , -C 0~4 Alkylene-C(O)OR 22 , -C 0~4 Alkylene-C(O)NR 22 R 23 , -C 0~4 Alkylene-NR 22 R 23 , -C 0~4 Alkylene-NR 22 C(O)R 23 , -C 0~4 Alkylene-NR 22 S(O)2R 23 , -C 0~4 Alkylene-NR 22 S(O)R 23 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). R 22 , R 23 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 24 may be substituted with R 24 are each independently hydrogen, halogen, cyano, nitro, -C1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. R 3 , R 4 are independently hydrogen, halogen, or -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 34 , -C 0~4 Alkylene-OC(O)R 34 , -C 0~4 Alkylene-SR 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-C(O)R 34 , -C 0~4 Alkylene-C(O)OR 34 , -C 0~4 Alkylene-C(O)NR 34 R 35 , -C 0~4 Alkylene-NR 34 R 35 , -C 0~4 Alkylene-NR 34 C(O)R 35 , -C 0~4 Alkylene-NR 34 S(O)2R 35 , -C 0~4 Alkylene-NR34 S(O)R 35 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 36 may be substituted with Each R 36 are each independently hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 34 , -C 0~4 Alkylene-OC(O)R 34 , -C 0~4 Alkylene-SR 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-C(O)R 34 , -C 0~4 Alkylene-C(O)OR 34 , -C 0~4 Alkylene-C(O)NR 34 R 35 , -C 0~4 Alkylene-NR 34 R 35 , -C 0~4 Alkylene-NR34 C(O)R 35 , -C 0~4 Alkylene-NR 34 S(O)2R 35 , -C 0~4 Alkylene-NR 34 S(O)R 35 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 37 may be substituted with R 34 , R 35 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. Each R 37 are each independently hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl.

[0007] Preferably, the A ring is selected from a 6-membered aromatic ring, a 6-membered cycloalkyl, a 9-membered heterocyclic alkyl, a 6-membered aromatic heterocyclic ring, and a 9-membered aromatic heterocyclic ring, and the aromatic ring, cycloalkyl, heterocycloalkyl, and aromatic heterocyclic ring further have one, two, three, or four independent R 1 may be substituted with

[0008] More preferably, the A ring is a benzene ring. The benzene ring may further include one, two, three, or four independent R 1 and more preferably, the benzene ring is further substituted with one R 1 may be substituted with

[0009] Preferably, in some embodiments of the present invention, the compound has formula IIA: [ka] Formula IIA

[0010] where R 1 , R 2 , R 3 , R 4 has the same meaning as claim 1.

[0011] R 1 is hydrogen, halogen, cyano, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, hydroxyl-substituted -C 1~6 Alkyl, -C 0~4 Alkylene-OR 12 , -C 0~4 Alkylene-OC(O)R 12 , -C 0~4 Alkylene-SR 12 , -C 0~4 Alkylene-NR 12 R 13 , -C 0~4 Alkylene-(3- to 6-membered cycloalkyl), -C 0~4 Alkylene-(3- to 6-membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). R 12 , R 13 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 alkyl.

[0012] Furthermore, the R 1 is hydrogen, methylthio, halogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, [ka] cyclopropyl, [ka] is selected from.

[0013] In some embodiments of the present invention, R 1 is hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, vinyloxy, ethynyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, monomethylamino, monoethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl or [ka] is selected from.

[0014] Preferably, the A ring is [ka] is selected from.

[0015] Preferably, the R 2 -C 1~3 alkyl, and further selected from R 2 is selected from methyl.

[0016] Preferably, the R 3 , R 4 are each independently hydrogen, -C 1~6 Alkyl, -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 36 where R 3 is preferably hydrogen or -C 1~6 It is alkyl. Each R 36 are each independently hydrogen, halogen, cyano, =O, -C 1~6 Alkyl, halogen substituted -C 1~6 Alkyl, -C 0~4 Alkylene-OR 34 , -C 0~4 Alkylene-C(O)R 34 , -C 0~4 Alkylene-C(O)OR 34 , -C 0~4 Alkylene-C(O)NR 34 R 35 , -C 0~4 Alkylene-NR 34 R 35 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). R34 , R 35 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl.

[0017] Furthermore, the R 3 , R 4 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C 0~2 Alkylene-(3-membered cycloalkyl), -C 0~2 Alkylene-(4-membered cycloalkyl), -C 0~2 Alkylene-(5-membered cycloalkyl), -C 0~2 Alkylene-(6-membered cycloalkyl), -C 0~2 Alkylene-(4-membered heterocycloalkyl), -C 0~2 Alkylene-(5-membered heterocycloalkyl), -C 0~2 Alkylene-(6-membered heterocycloalkyl), -C 0~2 Alkylene-(9-membered heterocycloalkyl), -C 0~2 Alkylene-(6-membered aromatic ring), -C 0~2 Alkylene-(5-membered heteroaromatic ring), -C 0~2 Alkylene-(6-membered heteroaromatic ring), -C 0~2 alkylene-(9-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R 36 where R 3 is preferably hydrogen, methyl, ethyl, propyl, butyl or pentyl. Each R 36 are independently hydrogen, halogen, =O, -C 1~3 Alkyl, halogen substituted -C 1~3 Alkyl, -OR 34 , -C(O)R 34 , -NR34 R 35 is selected from. R 34 , R 35 are each independently hydrogen, -C 1~3 alkyl.

[0018] More specifically, the R 3 , R 4 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, [ka] is selected from.

[0019] In some embodiments of the present invention, R 3 is selected from hydrogen, methyl, ethyl, propyl, butyl or pentyl, preferably hydrogen or methyl, more preferably methyl.

[0020] In some embodiments of the present invention, R 4 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, [ka] is selected from.

[0021] In some specific embodiments of the invention, the compound is specifically [ka] TIFF2026507461000010.tif225170TIFF2026507461000011.tif218170TIFF2026507461000012.tif70170.

[0022] The present invention further discloses a compound represented by formula V, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. [ka] Formula V wherein ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, a 3- to 10-membered cycloalkyl, and a 3- to 10-membered heterocycle, and said ring A further comprises one, two, three, or four independent R 1 may be substituted with R 1 are each independently hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 12 , -C 0~4 Alkylene-OC(O)R 12 , -C 0~4 Alkylene-SR 12 , -C 0~4 Alkylene-S(O)R 12 , -C 0~4 Alkylene-S(O)R 12 , -C 0~4 Alkylene-S(O)NR 12 R 13 , -C 0~4 Alkylene-S(O)NR 12 R 13 , -C 0~4 Alkylene-C(O)R 12 , -C 0~4 Alkylene-C(O)OR 12 , -C 0~4 Alkylene-C(O)NR 12 R 13 , -C 0~4 Alkylene-NR 12 R 13 , -C 0~4 Alkylene-NR 12 C(O)R 13 , -C 0~4 Alkylene-NR 12 S(O)2R 13 , -C 0~4 Alkylene-NR 12 S(O)R13 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). R 12 , R 13 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 14 may be substituted with R 14 are each independently hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. R 2 are independently hydrogen, halogen, or -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C2~6 Alkynyl, -C 0~4 Alkylene-OR 22 , -C 0~4 Alkylene-OC(O)R 22 , -C 0~4 Alkylene-SR 22 , -C 0~4 Alkylene-S(O)R 22 , -C 0~4 Alkylene-S(O)R 22 , -C 0~4 Alkylene-S(O)NR 22 R 23 , -C 0~4 Alkylene-S(O)NR 22 R 23 , -C 0~4 Alkylene-C(O)R 22 , -C 0~4 Alkylene-C(O)OR 22 , -C 0~4 Alkylene-C(O)NR 22 R 23 , -C 0~4 Alkylene-NR 22 R 23 , -C 0~4 Alkylene-NR 22 C(O)R 23 , -C 0~4 Alkylene-NR 22 S(O)2R 23 , -C 0~4 Alkylene-NR 22 S(O)R 23 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). R 22 , R 23 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 24 may be substituted with R 24 are each independently hydrogen, halogen, cyano, nitro, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. R 3 is hydrogen, halogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 34 , -C 0~4 Alkylene-OC(O)R 34 , -C 0~4 Alkylene-SR 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4Alkylene-C(O)R 34 , -C 0~4 Alkylene-C(O)OR 34 , -C 0~4 Alkylene-C(O)NR 34 R 35 , -C 0~4 Alkylene-NR 34 R 35 , -C 0~4 Alkylene-NR 34 C(O)R 35 , -C 0~4 Alkylene-NR 34 S(O)2R 35 , -C 0~4 Alkylene-NR 34 S(O)R 35 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 36 may be substituted with Each R 36 are each independently hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR 34 , -C 0~4 Alkylene-OC(O)R 34 , -C 0~4 Alkylene-SR 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4 Alkylene-S(O)R 34 , -C 0~4Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-S(O)NR 34 R 35 , -C 0~4 Alkylene-C(O)R 34 , -C 0~4 Alkylene-C(O)OR 34 , -C 0~4 Alkylene-C(O)NR 34 R 35 , -C 0~4 Alkylene-NR 34 R 35 , -C 0~4 Alkylene-NR 34 C(O)R 35 , -C 0~4 Alkylene-NR 34 S(O)2R 35 , -C 0~4 Alkylene-NR 34 S(O)R 35 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R 37 may be substituted with R 34 , R 35 are each independently hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. Each R 37 are each independently hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 Alkyl, -C 2~6Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl. T is -(L T ) q - is selected from. q is selected from integers of 1 to 50. Each L T are each independently CR T2 R T3 , C(O), -C(S)-, O, S, S(O), S(O)2, NR T2 , -CR T2 =CR T3 -, -C≡C-, a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclic alkyl, a 6- to 10-membered aromatic ring, a 5- to 10-membered heteroaromatic ring, a 5- to 12-membered spiro ring, a 5- to 12-membered spiroheterocyclic ring, a 5- to 12-membered bridged ring, and a 5- to 12-membered bridged heterocyclic ring, wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro ring, spiroheterocyclic ring, bridged ring, and bridged heterocyclic ring further comprise one, two, or three R T1 may be substituted with Each R T1 are each independently hydrogen, halogen, cyano, nitro, =O, =S, or =CR T2 R T3 , -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4 Alkylene-OR T2 , -C 0~4 Alkylene-OC(O)R T2 , -C 0~4 Alkylene-SR T2 , -C 0~4 Alkylene-S(O)R T2 , -C0~4 Alkylene-S(O)R T2 , -C 0~4 Alkylene-S(O)NR T2 R T3 , -C 0~4 Alkylene-S(O)NR T2 R T3 , -C 0~4 Alkylene-C(O)R T2 , -C 0~4 Alkylene-C(O)OR T2 , -C 0~4 Alkylene-C(O)NR T2 R T3 , -C 0~4 Alkylene-NR T2 R T3 , -C 0~4 Alkylene-NR T2 C(O)R T3 , -C 0~4 Alkylene-NR T2 S(O)2R T3 , -C 0~4 Alkylene-NR T2 S(O)R T3 , -C 0~4 Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring further comprise one, two, three, or four independent R T4 may be substituted with Each R T2 , R T3 , R T4 are each independently hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 Alkynyl, -C 0~4Alkylene-(3-10 membered cycloalkyl), -C 0~4 Alkylene-(3-10 membered heterocycloalkyl), -C 0~4 Alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring). X 2 -NH2, -NHR X21 , —OH, —SH, ethynyl, vinyl, —C(O)H or —C(O)OH—. R X21 is hydrogen, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted -C 1~6 Alkyl, halogen substituted -C 2~6 Alkenyl, halogen substituted -C 2~6 alkynyl.

[0023] Preferably, the compound of formula V is represented by formula Via below: [ka] ExpressionVia In the formula, R 1 , R 2 , R 3 , T, X 2 is synonymous with the above.

[0024] Preferably, T is [ka] is selected from.

[0025] The present invention further provides the use of the above compounds, their stereoisomers, their deuterated compounds, and their pharmaceutically acceptable salts in the preparation of a medicament for treating a disease associated with epithelial cell hyperproliferation.

[0026] Furthermore, the disease is cancer.

[0027] The present invention further provides use of the above-mentioned compound, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof in the preparation of a targeted protein degradation drug.

[0028] Furthermore, the present invention further provides the use of the compound, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof as an intermediate in a targeted protein degradation drug.

[0029] Furthermore, the targeted protein degradation drug is a drug that performs protein degradation dependent on the E3 ligase TRIM21.

[0030] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, OH) nomenclature system.

[0031] Regarding the definition of the terms of the present invention, unless otherwise specified, the initial definition provided for a group or term in this specification shall apply to that group or term throughout the specification, and terms not specifically defined herein shall be given the meaning that one skilled in the art can give them based on the disclosure and context.

[0032] "Substituted" means that a hydrogen atom in a molecule is replaced with another different atom or molecule. "Substituted" may also mean that a lone electron pair of an atom in a molecule is replaced with "=O", "=S", etc.

[0033] "May be further substituted" means "may be substituted", but does not necessarily occur, and the description includes the case where it occurs or does not occur.

[0034] The minimum and maximum carbon atom content in the hydrocarbon group is represented by a prefix, e.g., the prefix C a~b The alkyl group represents an alkyl group containing any of "a" to "b" carbon atoms. 1~4"Alkyl group" means an alkyl group containing 1 to 4 carbon atoms.

[0035] "Alkyl group" means a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1~6 By alkyl group is meant an alkyl group having 1 to 6 member atoms, e.g., 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl, isopropyl), butyl (n-butyl, isobutyl, tert-butyl), pentyl (n-pentyl, isopentyl, neopentyl), hexyl, and the like. The alkyl group may be part of another group, e.g., C 1~6 It is an alkoxy.

[0036] As used herein, "alkylene" refers to a divalent saturated aliphatic hydrocarbon group having the specified number of carbon atoms. a~b The term "alkylene" refers to an alkylene group having a to b carbon atoms. The alkylene group includes branched and straight-chain hydrocarbon groups. For example, "C 1~6 "Alkylene" is meant to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" refers to the following structure: [ka] Similarly, the term "dimethylbutylene" can be exemplified by, for example, the following structure: [ka] It can be exemplified by either "(C 1~6 The term "alkylene group" is meant to include branched hydrocarbon groups such as cyclopropylmethylene groups, and includes the following structure: [ka] For example, -C 0~4 The alkylene may be a C0 alkylene, a C1 alkylene (e.g., -CH2-), a C2 alkylene (e.g., -CH2CH2-), a C3 alkylene, or a C4 alkylene. C0 alkylene means that these groups are absent and are bonded in the form of a bond, and A-C0 alkylene-B means that the A group and the B group are bonded directly by a bond, as in AB.

[0037] An "alkenyl group" refers to a linear or branched hydrocarbon group having a specified number of carbon atoms, in some embodiments 2-6 carbon atoms or 2-4 carbon atoms, and at least one site of vinyl unsaturation (>C=C<). For example, C a-b Alkenyl means an alkenyl having ab carbon atoms, and examples include vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0038] According to the present invention, "alkenylene" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valences. For example, (C3-C6)alkenylene includes >C=CH-CH2-, -CH-CH=CH-CH2-, etc.

[0039] "Alkynyl" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" also includes hydrocarbyls with one triple bond and one double bond. For example, (C2-C6)alkynyl includes ethynyl, propynyl, and the like.

[0040] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0041] "Halogen alkyl" and "halogen-substituted alkyl" refer to alkyl in which one or more hydrogen atoms have been replaced with halogen atoms. For example, C 1~4Halogenalkyl refers to an alkyl having 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms.

[0042] The terms "-OR", "-NRR", etc. used in the present invention mean that the R group is bonded to an oxygen atom or a nitrogen atom via a single bond.

[0043] In the present invention, the oxygen atom in "-C(O)R", "-S(O)R" and the like is bonded to the carbon atom or sulfur atom via a double bond, and the R group is bonded to the oxygen atom or sulfur atom via a single bond.

[0044] According to the present invention, "cycloalkyl" and "cycloalkane" refer to saturated or partially saturated cyclic groups having multiple carbon atoms and no ring heteroatoms, and having a single ring or multiple rings (including fused, bridged, spirocyclic, and adamantane systems). For polycyclic ring systems having aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalen-5-yl) applies when the connection point is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyls such as cyclohexenyl. Examples of cycloalkyls include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, cyclohexenyl, etc. Examples of cycloalkyls including polybicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. For example, [ka] Adamantyl is [ka] Including, but not limited to:

[0045] The terms "heterocycle," "heterocycloalkyl," and "heterocycloalkane" used herein refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom. Typically, a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system containing multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system containing 3 to 9 ring atoms, contains one, two, or three ring heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. A bicyclic ring is composed of two rings that share two ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, [ka] Thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl, diazetidinyl, homopiperazinyl, or oxazetidinyl. Examples of bicyclo saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidine, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl. [ka] Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazoline, tetrahydro-pyridyl or dihydropyranyl.

[0046] The terms "spiroheterocyclic group" and "spiroheterocycle" are used interchangeably and refer to a non-aromatic saturated ring or a non-aromatic unsaturated ring system in which two monocyclic rings share one carbon atom and are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, a "5- to 12-membered spiroheterocycle" refers to a spiroheterocycle having 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.

[0047] A "bridged ring or bridged ring group" refers to a saturated or unsaturated cyclic group formed by two or more ring structures which share two non-adjacent atoms. Specific examples include: [ka] Including, but not limited to:

[0048] The terms "bridged heterocyclic group" and "bridged heterocycle" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more ring structures that share two non-adjacent atoms, and are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific examples include: [ka] Including, but not limited to:

[0049] The terms "aromatic ring" and "aryl" used herein refer to aromatic hydrocarbon groups having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic, or tricyclic aryl having 5 to 20 carbon atoms. The term "aryl" as used herein also refers to an aromatic substituent having a single aromatic ring or multiple fused aromatic rings. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0050] The terms "heteroaromatic ring" and "heteroaromatic group" used herein refer to an aromatic unsaturated ring containing at least one heteroatom, such as a nitrogen atom, oxygen atom, or sulfur atom. They typically contain multiple ring atoms, one or more of which are aromatic monocyclic or bicyclic hydrocarbons selected from the group consisting of O, N, and S heteroatoms. They preferably contain 1 to 3 heteroatoms. Examples of heterocyclic aryl groups include pyridyl, indolyl, quinoxaline, quinolyl, isoquinolyl, benzothienyl, benzofuryl, benzothienyl, benzopyranyl, benzothianyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0051] "Stereoisomer" includes enantiomers and diastereomers.

[0052] The term "deuterated compound" as used herein refers to a molecule or group in which one or more hydrogen atoms have been replaced with deuterium atoms, and the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0053] The term "pharmaceutically acceptable" means that the carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form and physiologically compatible with the recipient.

[0054] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed from the above-mentioned compound or its stereoisomer with an inorganic and / or organic acid and a base, including zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They may also be obtained by mixing the above-mentioned compound or its stereoisomer with a certain number of acids or bases, appropriately (e.g., in equal amounts). These salts can be produced by forming a precipitate in a solution and collecting it by filtration, recovering it after evaporating the solvent, or reacting it in an aqueous medium and then lyophilizing it. The salt in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate of the compound.

[0055] Needless to say, in accordance with the above content of the present invention, various other modifications, substitutions or changes can be made in accordance with common technical knowledge and conventional means in the relevant technical field without departing from the above basic technical idea of ​​the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0056] The above content of the present invention will be described in more detail below through specific implementation methods in the form of embodiments. However, this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

[0057] The known starting materials of the present invention can be synthesized by methods known in the art or purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc.

[0058] Unless otherwise specified in the examples, reactions are carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, solutions refer to aqueous solutions. Unless otherwise specified in the examples, reaction temperatures are room temperature. Room temperature is the most suitable reaction temperature, and is 20°C to 30°C. Unless otherwise specified in the examples, M is the number of moles per liter.

[0059] The structures of the compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and a Bruker Avance 600 nuclear magnetic resonance spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methol-d4), and the internal standard was tetramethylsilane (TMS). LC-MS measurements were performed using a Shimadzu LC-MS 2020 (ESI) continuous liquid chromatograph. HPLC measurements were performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography usually uses 200-300 mesh Yantai Yellow Sea silica gel as the carrier.

[0060] The abbreviations for the reagents used in the examples are as follows: Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DIPEA: N,N-diisopropylethylamine HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate DCE: Dichlorethylene DMF: N,N-dimethylformamide

[0061] Example 1: Synthesis of Compound 1 [ka]

[0062] Synthesis of compound S2 Under N2 protection, a microwave tube was charged with substrate S1 (200 mg, 0.682 mmol), 2-methylthiophenylboronic acid (137.57 mg, 0.818 mmol), Pd(dppf)Cl2 (49.51 mg, 0.068 mmol), and K2CO3 (282.89 mg, 2.05 mmol). 2 mL of 1,4-dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was purified by medium-pressure liquid chromatography to give a brown solid, S2 (198 mg, 0.588 mmol, 86% yield). LCMS (ESI) + ) m / z: 337.0 [M+H] + .

[0063] Synthesis of compound S3 Substrate S2 (200 mg, 0.594 mmol) was placed in a dry one-neck flask, and MeOH (2 mL) was added and stirred to dissolve. Next, 2N NaOH (71.34 mg, 1.78 mmol) solution was added to the reaction system, and the mixture was stirred at 60 °C for 2 h. LC-MS confirmed the complete reaction. After the methanol was removed by rotary evaporation, 3N HCl solution was added until the pH reached 5-6. After lyophilization, the mixture was purified by medium-pressure liquid chromatography to obtain a pale reddish-brown oily liquid, S3 (180 mg, 0.558 mmol, 93.92% yield). LCMS (ESI) + ) m / z: 321.1 [MH] - .

[0064] Synthesis of Compound 1 Substrate S3 (30 mg, 0.093 mmol) was placed in a dry one-neck flask, and DMF (3 mL) was added. The mixture was stirred to dissolve. DIPEA (120.26 mg, 0.93 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.43 mg, 0.111 mmol) was added and stirred at 0°C for 5 minutes. Methylamine (3.47 mg, 0.111 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed the complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give compound 1 (16 mg, 0.047 mmol, 50.90% yield, 99.3% purity) as a white solid. LCMS (ESI) + ) m / z: 336.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.63(d,J=4.7Hz,1H),7.94(d,J=1.8Hz,1H),7.77(dd,J=7.7,1.8Hz,1H),7.60(d,J=7.8 Hz,1H),7.50-7.38(m,2H),7.28(d,J=2.3Hz,1H),6.04(s,1H),3.41(s,3H),2.77(d,J=4.6Hz,3H),2.42(s,3H).

[0065] Example 2: Synthesis of Compound 2 [ka]

[0066] Substrate S3 (50 mg, 0.155 mmol) was placed in a dry one-neck flask, and DMF (3 mL) was added. The mixture was stirred to dissolve. DIPEA (160.35 mg, 1.24 mmol, 216.10 μL) was then added to the reaction mixture and cooled in an ice-water bath. HATU (70.8 mg, 0.186 mmol) was added and stirred at 0°C for 5 minutes. N-methylcyclohexylmethylamine (23.7 mg, 0.186 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give 2 (28.9 mg, 0.067 mmol, 43.2% yield, 99.0% purity) as an off-white solid. LCMS (ESI) + ) m / z: 432.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=1.7Hz,1H),7.80(dt,J=7.8,1.6Hz,1H),7.58-7.38(m,3H),7.31(ddd,J=7.7,6.6,1.6Hz,2H),3.28 (d,J=14.4Hz,3H),2.89(d,J=75.7Hz,3H),2.42(s,3H),1.70(dq,J=48.1,16.7,13.4Hz,7H),1.22(q,J=9.9,8.2Hz,4H),1.00(s,2H).

[0067] Example 3: Synthesis of Compound 3 [ka]

[0068] Substrate S3 (40 mg, 0.124 μmol) was added to a dry one-neck flask, and DMF (3 mL) was added and stirred to dissolve. DIPEA (160.35 mg, 1.24 mmol, 216.10 μL) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.43 mg, 0.111 mmol) was added and stirred at 0°C for 5 minutes. 3,4-methylenedioxybenzylamine (22.51 mg, 0.149 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid, 3-1 (46 mg, 0.093 mmol, 74.88% yield, 92.0% purity). LCMS (ESI) + ) m / z: 456.0 [M+H] + .

[0069] NaH (5.27 mg, 0.132 mmol, 60% purity) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 3-1 (20 mg, 0.044 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (20 mg, 0.143 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give a white solid product 3 (13 mg, 0.026 mmol, 58.83% yield, 93.3% purity). LCMS (ESI) + ) m / z: 470.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.96(t,J=2.2Hz,1H),7.83(dd,J=7.8,1.8Hz,1H),7.59(dd,J=7.8,1.6Hz,1H),7.49-7.39(m,2H),7.35-7.25(m,2) H),6.97(dd,J=7.1,2.1Hz,1H),6.89-6.84(m,2H),6.07(s,2H),4.86(s,1H),4.50(s,1H),3.33(s,3H),3.31(s,3H),2.42(d,J=4.3Hz,3H).

[0070] Example 4: Synthesis of Compound 4 [ka]

[0071] Substrate S3 (30 mg, 0.09 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added and stirred to dissolve. DIPEA (117 mg, 0.9 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.5 mg, 0.11 mmol) was added and stirred at 0°C for 5 minutes. 3-aminomethylthiophene (12.6 mg, 0.11 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid 4-1 (15.7 mg, 0.038 mmol, 42%). LCMS (ESI) + ) m / z: 418.1 [M+H] + .

[0072] NaH (3.8 mg, 0.158 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 4-1 (8 mg, 0.019 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (8.2 mg, 0.058 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to produce product 4 (3.2 mg, 8.8 μmol, 46%). LCMS (ESI + ) m / z: 432.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.96(t,J=1.8Hz,1H),7.80(ddd,J=20.0,7.8,1.8Hz,1H),7.64(dd,J=12.7,7.8Hz,1H),7.59-7.39(m,4H),7 .36-7.25(m,2H),7.16(ddd,J=23.2,4.9,1.3Hz,1H),4.83-4.23(m,2H),2.82(d,J=69.3Hz,3H),2.42(d,J=6.8Hz,4H),1.19(d,2H).

[0073] Example 5: Synthesis of Compound 5 [ka]

[0074] Substrate S3 (16.1 mg, 0.05 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added thereto and stirred to dissolve. DIPEA (65 mg, 0.5 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (22.8 mg, 0.06 mmol) was added and stirred at 0°C for 5 minutes. 2,2-Cyclohexylmethylamine (11.1 mg, 0.06 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid 5-1 (16 mg, 0.035 mmol, 71%). LCMS (ESI) + ) m / z: 454.1 [M+H] + .

[0075] NaH (3.4 mg, 0.086 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 5-1 (13 mg, 0.029 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (20 mg, 0.143 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 5 (7.4 mg, 15.8 μmol, 55%). LCMS (ESI) + ) m / z: 468.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.95(d,J=1.8Hz,1H),7.82(dd,J=7.8,1.8Hz,1H),7.62-7.39(m,3H),7.37-7.26(m,2H),3 .90-3.67(m,1H),3.60-3.40(m,1H),3.29(s,3H),2.82(s,3H),2.42(s,3H),2.14-1.59(m,5H),1.53-0.92(m,4H).

[0076] Example 6: Synthesis of Compound 6 [ka]

[0077] Substrate S1 (100 mg, 0.34 mmol) was placed in a dry one-neck flask, and MeOH (4 mL) and HO (2 mL) were added. The mixture was stirred to dissolve the substrate. Crushed NaOH (68.5 mg, 1.71 mmol) was then added to the reaction mixture, and the mixture was refluxed at 50°C for 1 hour. LC-MS confirmed the reaction was complete. The reaction mixture was neutralized by dropwise addition of 1 M hydrochloric acid solution, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give 6-1 (46 mg, 0.20 mmol, 48%) as a colorless oil. LCMS (ESI) + ) m / z: 278.9 [M+H] + .

[0078] 1-Fluorocyclohexylmethylamine (26 mg, 0.19 mmol) was added to a dry one-neck flask, followed by DMF (1.5 mL) and DIPEA (213 mg, 1.65 mmol). The mixture was cooled in an ice-water bath, and HATU (69 mg, 0.18 mmol) was added and stirred for 5 minutes in the ice-water bath. Compound 6-1 (46 mg, 0.20 mmol) was added to the reaction flask and stirred for 1 minute while maintaining the ice-water bath. The mixture was then warmed to room temperature and stirred for 10 minutes. After confirming complete reaction by LC-MS, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 6-2 (40.6 mg, 0.10 mmol, 62%). LCMS (ESI) + ) m / z: 392.2 [M+H] + .

[0079] NaH (4.9 mg, 0.20 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 6-2 (40.6 mg, 0.10 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (29 mg, 0.20 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. After confirming the complete reaction by LC-MS, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 6-3 (31 mg, 76.5 μmol, 73%). LCMS (ESI + ) m / z: 406.3 [M+H] + .

[0080] Substrate 6-3 (15 mg, 37 μmol) was added to a dry one-neck flask, followed by the addition of 1,4-dioxane (2 mL) and HO (0.2 mL). 2-Methylthiophenylboronic acid (7.5 mg, 44 μmol), KCO (15.4 mg, 111 μmol), and Pd(dppf)Cl (3 mg, 3.7 μmol) were then added to the reaction mixture. The mixture was sealed, purged with nitrogen three times, and refluxed at 100 °C for 2 h. After confirming complete reaction by LC-MS, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give compound 6 (15.5 mg, 34.5 μmol, 93%) as a green solid. LCMS (ESI) + ) m / z: 450.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.96(d,J=1.8Hz,1H),7.82(dd,J=7.8,1.8Hz,1H),7.58(d,J=7.8Hz,1H),7.50-7 .39(m,2H),7.36-7.26(m,2H),3.29(s,3H),2.88(d,J=1.1Hz,3H),2.42(s,3H),1.86(s,2H),1.56(s,9H).

[0081] Example 7: Synthesis of Compound 7 [ka]

[0082] Substrate S3 (30 mg, 93 μmol) was added to a dry one-neck flask, and DMF (1.5 mL) was added and stirred to dissolve. DIPEA (65 mg, 0.5 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42 mg, 0.11 mmol) was added and stirred at 0°C for 5 minutes. 4-aminomethylisoxazole (15 mg, 0.11 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid, 7-1 (32 mg, 80 μmol, 86%). LCMS (ESI) + ) m / z: 403.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.36(t,J=5.9Hz,1H),8.88(d,J=1.6Hz,1H),7.97(d,J=1.8Hz,1H),7.82(dd,J=7.8,1.8Hz,1H),7.68( d,J=7.8Hz,1H),7.53-7.38(m,2H),7.36-7.24(m,2H),6.67(d,J=1.7Hz,1H),4.56(d,J=5.9Hz,2H),3.44(s,3H),2.42(s,3H).

[0083] NaH (7 mg, 0.186 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 7-1 (25 mg, 0.062 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (44 mg, 0.31 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 7 (20 mg, 48 μmol, 77%). LCMS (ESI) + ) m / z: 417.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.90(d,J=1.7Hz,1H),7.98(d,J=2.0Hz,1H),7.85(dd,J=7.8,1.8Hz,1H),7.63(d,J=7.8Hz,1H),7 .51-7.39(m,2H),7.36-7.28(m,2H),6.68(d,J=1.7Hz,1H),4.44(d,J=3.2Hz,2H),3.33(s,3H),2.81(s,3H),2.42(s,3H).

[0084] Example 8: Synthesis of Compound 8 [ka]

[0085] Substrate S3 (30 mg, 0.09 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added and stirred to dissolve. DIPEA (117 mg, 0.9 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.5 mg, 0.11 mmol) was added and stirred at 0°C for 5 minutes. (2-Ethylphenyl)methylamine (15.1 mg, 0.11 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid, 8-1 (15 mg, 0.034 mmol, 38%). LCMS (ESI + ) m / z: 440.6 [M+H] + .

[0086] NaH (5.46 mg, 0.136 mmol, 60% purity) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 8-1 (20 mg, 0.046 μmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (12.92 mg, 0.091 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 8 (5 mg, 0.011 mmol, 24% yield, 99.0% purity). LCMS (ESI) + ) m / z: 454.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.96(dd,J=14.4,1.8Hz,1H),7.84(dd,J=7.8,1.9Hz,1H),7.68-7.58(m,1H),7.42(ddd,J=16.1,13.6,7.3Hz,4H),7.35 -7.30(m,1H),7.29-7.23(m,3H),5.03(d,J=15.2Hz,1H),4.48(d,J=15. 3Hz,1H),3.34(s,3H),2.72(s,2H),2.42(s,3H),1.21(t,J=7.5Hz,3H).

[0087] Example 9: Synthesis of Compound 9 [ka]

[0088] Substrate S3 (10.0 mg, 0.031 mmol) was placed in a dry one-neck flask, and anhydrous DMF (3 mL) was added thereto and stirred to dissolve. DIPEA (65 mg, 0.5 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (14.2 mg, 0.037 mmol) was added and stirred at 0°C for 5 minutes. Cyclohexylamine (4.0 mg, 0.040 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid, 9-1 (11 mg, 0.027 mmol, 88%). LCMS (ESI) + ) m / z: 404.2 [M+H] + .

[0089] NaH (3.2 mg, 60% wt, 0.081 mmol) was added to a dry one-neck flask and protected with nitrogen gas. Anhydrous DMF (2 mL) was added and cooled in an ice-water bath. Substrate 9-1 (11 mg, 0.027 mmol) was dissolved in 1 mL of anhydrous DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while keeping the temperature at 0°C. CHCl (18.9 mg, 0.135 mmol) was then added and the reaction was allowed to proceed for 1 hour at 0°C. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 9 (6 mg, 14.4 μmol, 53%). LCMS (ESI) + ) m / z: 418.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.08(dd,J=15.2,1.8Hz,1H),7.66(dd,J=7.7,1.8Hz,1H),7.36-7.27(m,2H),7.27-7.22(m,1H),7.19(d,J=2.2Hz,1H) ),7.16(dd,J=6.7,1.7Hz,1H),3.22(s,3H),2.68(s,3H),2.33(s,3H),2. 03-1.87(m,1H),1.85-1.59(m,4H),1.57-1.34(m,4H),1.11-0.91(m,2H).

[0090] Example 10: Synthesis of Compound 10 [ka]

[0091] Substrate S3 (30 mg, 0.09 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added thereto and stirred to dissolve. DIPEA (117 mg, 0.9 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.5 mg, 0.11 mmol) was added and stirred at 0°C for 5 minutes. 3-aminopentane (11.4 mg, 0.11 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid 10-1 (12.5 mg, 0.031 mmol, 34%). LCMS (ESI) + ) m / z: 406.6 [M+H] + .

[0092] NaH (2.4 mg, 0.1 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 10-1 (8 mg, 0.029 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (8.4 mg, 0.059 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 10 (4.4 mg, 10.5 μmol, 36%). LCMS (ESI + ) m / z: 420.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.94(t,J=2.3Hz,1H),7.86-7.75(m,1H),7.58-7.39(m,3H),7.37-7.26(m,2H),3.13(d,J= 108.1Hz,2H),2.78(s,3H),2.41(d,J=7.7Hz,3H),1.81-1.04(m,7H),0.90(t,J=7.4Hz,5H),0.68(q,J=7.8Hz,2H).

[0093] Example 11: Synthesis of Compound 11 [ka]

[0094] Substrate S3 (15 mg, 0.047 mmol) was added to a dry one-neck flask, dissolved in DMF (1 mL), and cooled to 0 °C. DIPEA (40 µL, 0.23 mmol) was added. After 5 minutes, HATU (21.26 mg, 0.056 mmol) was added. After 10 minutes of reaction, N-methyl-1-(1H-pyrrolidin-3-yl)methylamine (10.25 mg, 0.093 mmol) was added. The reaction was allowed to proceed for 30 minutes, and the reaction mixture was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic) to obtain compound 11 (7.1 mg, 0.017 mmol). LCMS (ESI) m / z: 415.1 [M+H] + , HPLC method B:R T= 8.44min, purity>99.9%. 1 H NMR(600MHz,DMSO-d6)δ10.70(d,J=28.8Hz,1H),7.96-7.95(m,1H),7.81-7.7 9(m,1H),7.63-7.50(m,1H),7.48-7.44(m,1H),7.42-7.40(m,1H),7.34-7.27( m,2H),6.83-6.74(m,1H),6.73-6.71(m,1H),6.11-6.06(m,1H),4.67-4.40(m, 1H),4.18-3.02(m,1H),3.33(s,3H),2.88-2.68(m,3H),2.42(d,J=5.4Hz,3H).

[0095] Example 12: Synthesis of Compound 12 [ka] Substrate S3 (20 mg, 0.062 mmol) was added to a dry single-neck flask, dissolved in DMF (1 mL), and cooled to 0 °C. DIPEA (40 μL, 0.23 mmol) was added. After 5 minutes, HATU (28.3 mg, 0.074 mmol) was added and the mixture was allowed to react for 10 minutes. N-methylaniline (8 mg, 0.074 mmol) was then added and the mixture was allowed to react for 30 minutes. The reaction mixture was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic) to give compound 12 (2.0 mg, 4.9 μmol, 8%). LCMS (ESI) m / z: 412.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.02-7.79(m,2H),7.51-7.44(m,2H),7.43-7.32(m,4H),7.25( tt,J=7.1,6.0Hz,4H),7.20-7.12(m,2H),3.42(d,J=6.5Hz,5.5H),3.14(s,0.5H),2.44 - 2.31(m,3H).

[0096] Example 13: Synthesis of Compound 13 [ka]

[0097] Substrate S3 (30 mg, 0.093 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added and stirred to dissolve. DIPEA (117 mg, 0.9 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.1 mg, 0.111 mmol) was added and stirred at 0°C for 5 minutes. 1-Boc-3-aminomethylazetidine (20.7 mg, 0.111 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid 13-1 (11.0 mg, 0.023 mmol, 24%). LCMS (ESI) + ) m / z: 491.2 [M+H]+ .

[0098] NaH (2.8 mg, 0.115 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 13-1 (11 mg, 0.023 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (9.8 mg, 0.069 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 13-2 (10.45 mg, 0.002 mmol, 90%). LCMS (ESI) + ) m / z: 505.2 [M+H] + .

[0099] Substrate 13-2 was dissolved in DCM (2 mL), and TFA (1 mL) was slowly added dropwise to the reaction mixture. After the addition, the mixture was stirred for 20 minutes, and then the solvent in the reaction mixture was evaporated in a high-temperature water bath. The crude product 13-3 was used in the next reaction without further purification.

[0100] Substrate 13-3 (19 mg, 0.047 mmol) was placed in a dry one-neck flask, and DCM (2 mL) was added and stirred to dissolve. Excess acetic anhydride (7.2 mg, 0.071 mmol) and triethylamine (14.3 mg, 0.141 mmol) were added to the reaction system. The reaction was allowed to proceed overnight at room temperature, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a pale yellow solid 13 (4.15 mg, 9.3 μmol, 20%). LCMS (ESI + ) m / z: 447.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.98-7.92(m,1H),7.81(dd,J=7.8,1.8Hz,1H),7.63-7.53(m,1H),7.50-7.39(m,2H),7.31(q,J=3.4,2.9Hz,2H),4.2 3(t,J=8.5Hz,1H),3.95(d,J=11.3Hz,2H),3.64(m,1H),3.28(d,J=3.0Hz,4H),2.98(s,2H),2.79(s,3H),2.40(d,J=4.4Hz,3H),1.77(s,3H).

[0101] Example 14: Synthesis of Compound 14 [ka]

[0102] Substrate S3 (50 mg, 155 μmol), DMF (1 mL), and DIPEA (100 mg, 776 μmol) were added to a dry one-neck flask, placed in an ice-water bath, and HATU (64.9 mg, 170 μmol) was added. The mixture was stirred in the ice-water bath for 5 minutes. (R)-alpha-methyl-cyclobutanemethylamine hydrochloride (21 mg, 155 μmol) was added and the mixture was stirred in the ice-water bath for 20 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 14-1 (54 mg, 133.9 μmol, 86.7%) as a white solid. LCMS (ESI) + ) m / z: 404.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.48(d,J=8.5Hz,1H),7.94(d,J=1.8Hz,1H),7.79( dd,J=7.7,1.8Hz,1H),7.54(d,J=7.7Hz,1H),7.50-7.38(m,2H),7.35-7.23( m,2H),3.96(td,J=8.7,6.6Hz,1H),3.42(s,3H),2.43(s,3H),2.40-2.32(m ,1H),1.98(dq,J=9.9,3.5Hz,2H),1.92-1.73(m,4H),1.04(d,J=6.6Hz,3H).

[0103] The substrate NaH (2.16 mg, 90.2 μmol) was added to a dry one-neck flask, which was sealed and flushed with nitrogen three times. DMF (0.3 mL) was added and the flask was placed in an ice-water bath. 14-1 (28 mg, 69.4 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHCl (10.84 mg, 74.6 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 14 (13.16 mg, 31.5 μmol, 45.4%) as a white solid. LCMS (ESI) + ) m / z: 418.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.04-7.92(m,1H),7.89-7.77(m,1H),7.65-7.40(m,3H),7.40-7.25(m,2H),4.58(dq,J=10.4,6.7Hz,1H),3.29( d,J=12.4Hz,3H),2.82(s,0.75H),2.58(d,J=14.6Hz,3H),2.48(s,0.25H),2.43(d,J=4.1Hz,3H),2.16-1.52(m,6H),1.19-0.96(m,3H).

[0104] Example 15: Synthesis of Compound 15 [ka]

[0105] Substrate S3 (30 mg, 93.1 μmol) was added to a dry one-neck flask. The substrate was dissolved in DMF (1 mL). DIPEA (60 mg, 465 μmol) was slowly added dropwise to the reaction mixture. The mixture was then placed in an ice-water bath. HATU (38.9 mg, 102.4 μmol) was added and stirred for 5 minutes in the ice-water bath. 3-Aminomethyl-tetrahydrofuran (10.4 mg, 102.4 μmol) was added and stirred for 20 minutes in the ice-water bath. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give white solid 15-1 (35 mg, 86.4 μmol, 92.7%). LCMS (ESI) + ) m / z: 406.2 [M+H] + .

[0106] The substrate NaH (2.1 mg, 86.6 μmol) was added to a dry one-neck flask, which was sealed and flushed with nitrogen three times. DMF (0.3 mL) was added and the flask was placed in an ice-water bath. 15-1 (27 mg, 66.6 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHI (11.3 mg, 80 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 15 (7.12 mg, 16.9 μmol, 25.4%) as a white solid. LCMS (ESI) + ) m / z: 420.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.95(t,J=1.7Hz,1H),7.81(dd,J=7.8,1.8Hz,1H),7.63-7.53(m,1H),7.50-7 .40(m,2H),7.31(pd,J=7.5,6.9,2.6Hz,2H),3.88-3.76(m,1.61H),3.73-3.63(m,1H),3.61-3.42(m,3 H),3.30(d,J=7.8Hz,3H),3.10(dd,J=10.2,7.5Hz,0.52H),3.02(d,J=3.3Hz,0.75H),2.82(s,2.31H) ,2.73-2.55(m,1.27H),2.42(d,J=4.0Hz,3H),1.96(ddt,J=56.0,13.6,6.2Hz,1H),1.78-1.44(m,1H).

[0107] Example 16: Synthesis of Compound 16 [ka]

[0108] Substrate S3 (50 mg, 155 μmol) was added to a dry one-neck flask. The substrate was dissolved in DMF (1 mL). DIPEA (100 mg, 776 μmol) was slowly added dropwise to the reaction mixture. The mixture was then placed in an ice-water bath, and HATU (64.9 mg, 170 μmol) was added. The mixture was stirred in the ice-water bath for 5 minutes. (2-Methoxypyridin-4-yl)methylamine (23.6 mg, 170 μmol) was added, and the mixture was stirred in the ice-water bath for 20 minutes. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give white solid 16-1 (50 mg, 113 μmol, 72.8%). LCMS (ESI) + ) m / z: 443.1 [M+H] + .

[0109] The substrate NaH (3.5 mg, 147 μmol) was added to a dry one-neck flask, which was sealed and flushed with nitrogen three times. DMF (0.5 mL) was added and the flask was placed in an ice-water bath. 16-1 (50 mg, 113 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHI (19.3 mg, 135 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 16 (51 mg, 111 μmol, 98.9%) as a white solid. LCMS (ESI) + ) m / z: 457.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21-8.11(m,1H),7.98(dd,J=9.7,1.8Hz,1H),7.86(dd,J=7 .8,1.8Hz,1H),7.66(dd,J=30.1,7.8Hz,1H),7.51-7.38(m,2H),7.37-7.24(m,2H),7 .03(ddd,J=29.0,5.3,1.4Hz,1H),6.94-6.78(m,1H),4.34(d,J=2.5Hz,2H),3.86(d, J=9.9Hz,3H),3.35(d,J=4.0Hz,3H),2.86(d,J=59.8Hz,3H),2.42(d,J=11.6Hz,3H).

[0110] Synthesis of compound S4 [ka]

[0111] Synthesis of compound S1-1 Substrate S1 (500 mg, 1.71 mmol) was placed in a dry one-neck flask, and MeOH (5 mL) was added and stirred to dissolve. Next, 2N NaOH (2 M, 8.53 mL) solution was added to the reaction system, and the mixture was stirred at 50 °C for 1 h. LC-MS confirmed the complete reaction. The methanol was evaporated by rotary evaporation, and a 3N HCl solution was added to adjust the pH to 5-6. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography to give compound S1-1 (463 mg, 1.66 mmol, 97.25% yield). LCMS (ESI) + ) m / z: 280.9 [M+H] + .

[0112] Synthesis of compound S4 Substrate S1-1 (430 mg, 1.54 mmol) was placed in a dry one-neck flask, and DMF (8 mL) was added thereto and stirred to dissolve. DIPEA (597.33 mg, 4.62 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (702.95 mg, 1.85 mmol) was added and stirred at 0°C for 5 minutes. N-methyl-cyclohexylmethylamine (235.21 mg, 1.85 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed the complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give compound S4 (380 mg, 978.58 μmol, 63.52% yield). LCMS (ESI) + ) m / z: 389.2 [M+H] + .

[0113] Example 17: Synthesis of Compound 17 [ka]

[0114] In a dry one-neck flask, add substrate S4 (15 mg, 38.7 μmol), 4-fluoro-2-(methylthio)phenylboronic acid (8.6 mg, 46.5 μmol), Pd(dppf)Cl 2( 1.4 mg, 1.93 μmol) and KCO 3( The flask was sealed and purged with nitrogen gas three times. Dioxane (1 mL) and H2O (0.25 mL) were added to the flask, and the contents were diluted to 100 o The mixture was stirred at 37°C for 2 hours, and the reaction was confirmed to be complete by LC-MS. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 17 (12.37 mg, 27.5 μmol, 71%) as a white solid. LCMS (ESI + ) m / z: 450.5 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ7.92(d,J=1.8Hz,1H),7.79(dt,J=7.8,1.5Hz,1H),7.52(dd,J=10.5,7.8Hz, 1H),7.37(ddd,J=11.5,8.4,6.0Hz,1H),7.24(dd,J=10.2,2.6Hz,1H),7.12(td,J=8.4,2.5Hz,1H),3 .54(d,J=10.1Hz,1H),3.28(d,J=21.6Hz,3H),3.09(d,J=13.0Hz,1H),2.99(s,0.86H),2.95-2.82(m ,1H),2.79(s,2.2H),2.46(d,J=4.0Hz,3H),1.86-1.54(m,6H),1.29-1.16(m,3H),1.08-0.65(m,2H).

[0115] Example 18: Synthesis of Compound 18 [ka]

[0116] Substrate 16 (25 mg, 54.8 μmol), MeCN (2 mL), and TMSI (43.8 mg, 219 μmol) were added to a dry one-neck flask and the resulting mixture was stirred for 50 minutes.o The mixture was stirred at reflux for 12 hours at 25°C, and the reaction was confirmed to be complete by LC-MS. The reaction was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 18 (2.66 mg, 6 μmol, 10.9%) as a yellow solid. LCMS (ESI + ) m / z: 443.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.97(dd,J=7.0,1.8Hz,1H),7.82(ddd,J=30.3,7.8,1.8Hz,1H),7.61(dd,J=31.3,7.8Hz,1H),7.51- 7.39(m,2H),7.38-7.25(m,3H),6.42-6.10(m,2H),4.59-4.12(m,2H),3.42(d,J=3.7Hz,3H),2.86(d,J=65.2Hz,3H),2.42(d,J=8.6Hz,3H).

[0117] Example 19: Synthesis of Compound 19 [ka]

[0118] Substrate S3 (20 mg, 62.03 mmol) was placed in a dry one-neck flask, and DMF (1 mL) was added and stirred to dissolve. DIPEA (24.05 mg, 186.10 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (28.31 mg, 74.44 μmol) was added and stirred at 0°C for 5 minutes. (R)-1-Cyclopropylethylamine hydrochloride (7.54 mg, 62.03 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give compound 19-1 (24 mg, 61.61 μmol, 99.32% yield). LCMS (ESI) +) m / z: 390.1 [M+H] + .

[0119] Under N2 protection, a dry one-neck flask was charged with NaH (2.96 mg, 73.94 μmol, 60% purity), dispersed in DMF (1 mL), and cooled in an ice-water bath. 19-1 (24 mg, 61.61 μmol) was slowly added dropwise and the reaction was allowed to proceed at 0 °C for 30 min. Iodomethane (10.49 mg, 73.94 μmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. LC-MS confirmed the complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 19 (14.8 mg, 36.16 μmol, 58.69% yield, 98.6% purity) as a white solid. LCMS (ESI) + ) m / z: 404.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.98-7.92(m,1H),7.85-7.76(m,1H),7.60-7.39(m,3H),7.35-7.26(m,2H),4.03-3.78(m,1H),3.32-3.26(m,3H),2. 99(d,J=9.3Hz,1H),2.76(d,J=9.0Hz,2H),2.42(s,3H),1.29-1.19(m,2H),1.13(dd,J=9.9,6.7Hz,1H),1.11-0.99(m,1H),0.64-0.16(m,4H).

[0120] Example 20: Synthesis of Compound 20 [ka]

[0121] Substrate S3 (20 mg, 62.03 mmol) was placed in a dry one-neck flask, and DMF (1 mL) was added and stirred to dissolve. DIPEA (24.05 mg, 186.10 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (28.31 mg, 74.44 μmol) was added and stirred at 0°C for 5 minutes. (R)-1-Cyclopentyl-1-amine hydrochloride (11.14 mg, 74.44 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give compound 20-1 (25.5 mg, 61.07 μmol, 98.44% yield). LCMS (ESI) + ) m / z: 418.2 [M+H] + .

[0122] Under N2 protection, a dry one-neck flask was charged with NaH (2.93 mg, 73.28 μmol, 60% purity), dispersed in DMF (1 mL), and cooled in an ice-water bath. 20-1 (25.5 mg, 61.07 μmol) was slowly added dropwise and the reaction was allowed to proceed at 0 °C for 30 min. Iodomethane (10.40 mg, 73.28 μmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. LC-MS confirmed the complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography to give compound 20 (16.7 mg, 38.69 μmol, 63.36% yield, 100% purity) as a white solid. LCMS (ESI) + ) m / z: 432.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.00-7.91(m,1H),7.81(d,J=6.9Hz,1H),7.54-7.39(m,3H),7.36-7.26(m,2H),4.47-4.26(m,1H),3.29(d,J=12.0 Hz,3H),2.94-2.61(m,3H),2.42(s,3H),2.10-1.99(m,1H),1.86-1.69(m,2H),1.68-1.47(m,4H),1.45-1.20(m,3H),1.14(d,J=6.9Hz,2H).

[0123] Example 21: Synthesis of Compound 21 [ka]

[0124] Substrate S3 (280 mg, 0.87 mmol) was placed in a dry one-neck flask, and DMF (3.0 mL) was added and stirred to dissolve. EDCI (176 mg, 1.3 mmol), HOBt (249 mg, 1.3 mmol), DIPEA (0.45 mL, 2.61 mmol), and 2-methylaminoethanol (78.3 mg, 1.04 mmol) were then added to the reaction mixture. The mixture was stirred at room temperature for 16 hours, and complete reaction was confirmed by LC-MS. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give white solid 21-1 (250 mg, 0.66 mmol, 75%).

[0125] Compound 21-1 (100 mg, 0.26 mmol) was added to a dry one-neck flask, and CHCl (2 mL) and DIPEA (0.14 mL, 0.78 mmol) were added thereto and cooled in an ice-water bath. MsCl (90 mg, 0.78 mmol) was slowly added dropwise to the reaction flask. After the addition, the mixture was warmed to room temperature and stirred for 30 minutes. TLC confirmed that the starting materials had reacted completely. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 21-2 (80 mg, 0.17 mmol, 66%).

[0126] Compound 21-2 (33 mg, 0.07 mmol) was weighed and placed in a 25 mL one-neck flask, and dissolved in acetonitrile (3 mL). KCO (30 mg, 0.21 mmol) and morpholine (7.5 mg, 0.08 mmol) were then added, heated to 60 °C, and reacted for 2 hours. LCMS confirmed the reaction was complete, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 21 (18 mg, 0.04 mmol, 55%). LCMS (ESI) + ) m / z: 449.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=1.8Hz,0.6H),7.92(d,J=1.8Hz,0.4H),7.81(ddd,J=8.6, 7.8,1.8Hz,1H),7.61(d,J=7.8Hz,0.4H),7.53(d,J=7.8Hz,0.6H),7.50-7.38(m,2H),7.35- 7.25(m,2H),3.82-3.38(m,5.2H),3.30(s,1.8H),3.28(s,1.2H),3.26-3.05(m,0.8H),3.03 (s,1.2H),2.83(s,1.8H),2.71-2.57(m,0.5H),2.50-2.30(m,7H),2.22(t,J=4.7Hz,1.5H).

[0127] Example 22: Synthesis of Compound 22 [ka]

[0128] Compound 21-2 (40 mg, 0.087 mmol) was weighed and placed in a 25 mL one-neck flask, and acetonitrile (3 mL) was added to dissolve it. K2CO3 (36 mg, 0.26 mmol) and piperidine (9 mg, 0.10 mmol) were then added, and the mixture was heated to 60 °C and reacted for 2 hours. LCMS confirmed the reaction was complete, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 22 (32.2 mg, 0.072 mmol, 82%). LCMS (ESI + ) m / z: 447.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=1.8Hz,0.6H),7.92(d,J=1.8Hz,0.4H),7.81(ddd ,J=11.3,7.7,1.8Hz,1H),7.63-7.50(m,1H),7.49-7.36(m,2H),7.36-7.25(m,2H), 3.76-3.39(m,1.2H),3.31(s,1.8H),3.28(s,1.2H),3.22-3.04(m,0.8H),3.02(s,1 .2H),2.83(s,1.8H),2.65-2.35(m,7.5H),2.26-2.09(m,1.5H),1.61-1.28(m,6H).

[0129] Example 23: Synthesis of Compound 23 [ka]

[0130] Substrate S3 (30 mg, 0.093 mmol) was placed in a dry one-neck flask, and DMF (1 mL) was added. The mixture was stirred to dissolve. DIPEA (60.13 mg, 0.465 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (42.43 mg, 0.112 mmol) was added and stirred at 0 °C for 5 min. N-methyltetrahydropyran (12.86 mg, 0.111 mmol) was then added to the reaction mixture. The mixture was allowed to react at 0 °C for 20 min, and LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give 23-1 (35 mg, 0.0083 mmol, 89.65% yield) as a white solid. LCMS (ESI+) m / z: 420.2 [M+H]+.

[0131] NaH (2.86 mg, 0.07 mmol, 60% purity) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 23-1 (15 mg, 0.036 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHI (15.22 mg, 0.107 mmol) was then added and the reaction was continued at 0°C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 23 (6 mg, 0.014 mmol, 38.51% yield, 99.5% purity) as a white solid. LCMS (ESI+) m / z: 434.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ7.94(d,J=1.7Hz,1H),7.80(ddd,J=7.8,5.0,1.8Hz,1H),7.55(dd,J=7.8, 6.7Hz,1H),7.50-7.39(m,2H),7.37-7.25(m,2H),3.88(ddd,J=11.3,4.5,2.0Hz,2H),3.78(s,1H), 3.48(d,J=9.0Hz,1H),3.32-3.30(m,1H),3.30(s,2H),3.26(s,1H),3.22(dd,J=11.4,2.3Hz,1H), 3.00(s,1H),2.81(s,2H),2.42(d,J=3.1Hz,3H),2.03(s,1H),1.69(s,2H),1.26(d,J=13.4Hz,2H). [ka]

[0132] Synthesis of compound S5 Under N2 protection, a microwave tube was charged with substrate S1 (1 g, 3.41 mmol), 2-methoxyphenylboronic acid (605.90 mg, 4.09 mmol), Pd(dppf)Cl2 (248.92 mg, 0.341 mmol), and K2CO3 (1.41 g, 10.23 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction mixture was confirmed to be complete by LC-MS. The solvent in the reaction solution was evaporated. Extraction was performed three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give brown solid S5 (1.2 g, 3.75 mmol, 109.80% yield). LCMS (ESI+) m / z: 321.1 [M+H]+.

[0133] Synthesis of compound S6 Substrate S5 (1.2 g, 3.75 mmol) was placed in a dry one-neck flask, and MeOH (5 mL) was added and stirred to dissolve. Next, 2N NaOH (449.49 mg, 11.24 mmol) solution was added to the reaction system, and the mixture was stirred at 60 °C for 2 h. LC-MS confirmed the complete reaction. The methanol was removed by rotary evaporation, and 3N HCl solution was added to adjust the pH to 5-6. After lyophilization, the mixture was purified by medium-pressure liquid chromatography to obtain a pale reddish-brown oily liquid, S6 (730 mg, 2.38 mmol, 63.62% yield). LCMS (ESI+) m / z: 305.2 [M−H]-.

[0134] Example 24: Synthesis of Compound 24 [ka]

[0135] Substrate S6 (30 mg, 98 μmol), DMF (1 mL), and DIPEA (63.2 mg, 490 μmol) were added to a dry one-neck flask. The reaction mixture was placed in an ice-water bath, HATU (40.9 mg, 107.8 μmol) was added, and the mixture was stirred in the ice-water bath for 5 minutes. (R)-alpha-methyl-cyclobutanemethylamine hydrochloride (14.6 mg, 107.8 μmol) was added, and the mixture was stirred in the ice-water bath for 20 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 24-1 (31 mg, 80 μmol, 81.6%) as a white solid. LCMS (ESI) + ) m / z: 388.3 [M+H] + .

[0136] The substrate NaH (2.5 mg, 104 μmol) was added to a dry one-neck flask, sealed, and flushed with nitrogen three times. DMF (0.3 mL) was added, and the reaction mixture was placed in an ice-water bath. 24-1 (31 mg, 80 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHCl (12.5 mg, 88 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 24 (10.18 mg, 25.3 μmol, 31.6%) as a white solid. LCMS (ESI) + ) m / z: 402.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.16-8.01(m,1H),8.00-7.85(m,1H),7.62-7.34( m,3H),7.26-7.15(m,1H),7.14-7.04(m,1H),4.58(dq,J=10.4,6.7Hz,0.73 H),3.82(d,J=6.1Hz,3H),3.51-3.39(m,0.31H),3.33-3.25(m,3H),2.82(s ,0.85H),2.58(d,J=14.7Hz,2.75H),2.15-1.49(m,6H),1.16-0.97(m,3H).

[0137] Example 25: Synthesis of Compound 25 [ka]

[0138] Substrate S6 (30 mg, 98 μmol), DMF (1 mL), and DIPEA (63.2 mg, 490 μmol) were added to a dry one-neck flask, which was then placed in an ice-water bath. HATU (40.9 mg, 107.8 μmol) was added and stirred for 5 minutes in the ice-water bath. 615-1 (10.9 mg, 107.8 μmol) was added and stirred for 20 minutes in the ice-water bath. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 25-1 (36.8 mg, 94.5 μmol, 96.4%) as a white solid. LCMS (ESI) + ) m / z: 390.2 [M+H] + .

[0139] The substrate NaH (1.9 mg, 80.1 μmol) was added to a dry one-neck flask, which was sealed and flushed with nitrogen three times. DMF (0.3 mL) was added and the flask was placed in an ice-water bath. 25-1 (24 mg, 61.6 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHCl (12.5 mg, 88 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 25 (15.9 mg, 39.4 μmol, 63.9%) as a white solid. LCMS (ESI) + ) m / z: 404.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.06(dd,J=6.7,1.7Hz,1H),7.91(dd,J=7.9,1.8Hz,1H),7.57-7.49(m ,1H),7.44(t,J=7.6Hz,2H),7.23-7.16(m,1H),7.10(td,J=7.5,1.0Hz,1H),3.87-3.76(m,4.7 5H),3.74-3.62(m,1H),3.53(dt,J=19.2,8.6Hz,3H),3.31(s,3H),3.16-3.06(m,0.52H),3.01 (d,J=3.3Hz,0.76H),2.83(s,2.4H),2.73-2.55(m,1H),2.12-1.84(m,1H),1.79-1.43(m,1H).

[0140] Example 26: Synthesis of Compound 26 [ka]

[0141] Substrate S6 (35 mg, 114 μmol), DMF (2 mL), and DIPEA (73.7 mg, 571 μmol) were added to a dry one-neck flask and placed in an ice-water bath. HATU (47.8 mg, 125 μmol) was added and stirred for 5 minutes in the ice-water bath. 1-Boc-3-aminomethylazetidine (21.2 mg, 114 μmol) was added and stirred for 20 minutes in the ice-water bath. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 26-1 (50 mg, 105 μmol, 92.2%) as a white solid. LCMS (ESI) + ) m / z: 473.2 [MH] - .

[0142] The substrate NaH (3.3 mg, 137 μmol) was added to a dry one-neck flask, which was sealed and flushed with nitrogen three times. DMF (0.5 mL) was added and the flask was placed in an ice-water bath. 26-1 (50 mg, 105 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHCl (17.9 mg, 126 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 26-2 (40 mg, 81.9 μmol, 77.7%) as a white solid. LCMS (ESI) + ) m / z: 487.2 [MH] - .

[0143] Substrate 26-2 (40 mg, 81.9 μmol), DCM (1 mL), and TFA (1 mL) were added to a dry one-neck flask and stirred at room temperature for 30 minutes. LC-MS confirmed the complete reaction. The solvent in the reaction system was evaporated by rotary evaporation, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, and concentrated to give crude product 26-3 (60 mg). The crude product was used in the next reaction without further purification. LCMS (ESI) + ) m / z: 389.2 [M+H] + .

[0144] Substrate 26-3 (60 mg), DCM (2 mL), TEA (24.8 mg, 245 μmol), and acetic anhydride (12.5 mg, 122 μmol) were added to a dry one-neck flask and stirred at room temperature for 30 min. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 26 (25.7 mg, 59.7 μmol, 72.9%) as a white solid. LCMS (ESI) + ) m / z: 431.1 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.12(dd,J=18.7,1.7Hz,1H),7.97(dd,J=7.8,1.9Hz,1H),7.64-7.54(m,1H) ,7.50(td,J=7.9,3.6Hz,2H),7.24(d,J=8.2Hz,1H),7.16(t,J=7.4Hz,1H),4.34-4.13(m,1H),4.01(d dt,J=25.5,14.3,7.0Hz,2H),3.87(s,3H),3.85-3.58(m,2H),3.53-3.45(m,0.75H),3.35(d,J=3.7H z,3H),3.09-3.04(m,0.58H),3.01-2.94(m,0.27H),2.85(s,2.48H),1.81(s,3H),1.44-0.79(m,1H).

[0145] Example 27: Synthesis of Compound 27 [ka]

[0146] Substrate S6 (30 mg, 98 μmol), DMF (1 mL), and DIPEA (63.2 mg, 490 μmol) were added to a dry one-neck flask, which was then placed in an ice-water bath. HATU (40.9 mg, 107 μmol) was added and stirred for 5 minutes in the ice-water bath. (2-Methoxypyridin-4-yl)methylamine (14.9 mg, 107 μmol) was added and stirred for 20 minutes in the ice-water bath. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 27-1 (40 mg, 93.8 μmol, 95.7%) as a white solid. LCMS (ESI) + ) m / z: 427.1 [M+H] + .

[0147] The substrate NaH (2.9 mg, 122 μmol) was added to a dry one-neck flask, which was sealed and flushed with nitrogen three times. DMF (0.5 mL) was added and the flask was placed in an ice-water bath. 27-1 (40 mg, 93.8 μmol) was dissolved in DMF (1 mL) and slowly added to the reaction mixture. The mixture was stirred in the ice-water bath for 20 minutes. CHI (15.9 mg, 112 μmol) was dissolved in DMF (0.5 mL) and slowly added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 27 (39 mg, 88.6 μmol, 94.3%) as a white solid. LCMS (ESI) + ) m / z: 441.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.19-8.06(m,2H),7.90(ddd,J=36.9,7.9,1.8Hz,1H ),7.61(dd,J=26.8,7.9Hz,1H),7.43(tdd,J=10.9,5.1,2.3Hz,2H),7.33-7. 14(m,2H),7.14-6.95(m,2H),6.86(d,J=45.6Hz,1H),4.35(d,J=7.8Hz,2H), 3.83(dd,J=20.9,12.2Hz,6H),3.35(d,J=2.9Hz,3H),2.85(d,J=54.8Hz,3H).

[0148] Example 28: Synthesis of Compound 28 [ka]

[0149] Substrate 27 (25 mg, 56.8 μmol), MeCN (2 mL), and TMSI (45.4 mg, 227 μmol) were added to a dry one-neck flask and stirred for 50 minutes. oThe mixture was stirred at reflux for 12 hours at 25°C, and the reaction was confirmed to be complete by LC-MS. The reaction was quenched by adding water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 28 (18.3 mg, 42.9 μmol, 75.6%) as a yellow solid. LCMS (ESI + ) m / z: 427.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.14(dd,J=4.8,1.7Hz,1H),7.97(ddd,J=30.2,7.8,1.7Hz,1H),7.63(dd,J=35.2,7.9Hz,1H),7.55-7. 38(m,3H),7.27-7.11(m,2H),6.53-6.24(m,2H),4.68-4.18(m,2H),3.87(d,J=9.5Hz,3H),3.39(s,3H),2.92(d,J=59.0Hz,3H).

[0150] Example 29: Synthesis of Compound 29 [ka]

[0151] The substrates, pyrrole-3-carboxaldehyde (190.2 mg, 2 mmol) and methylamine hydrochloride (162 mg, 2.4 mmol), were added to a dry one-neck flask and dissolved in methanol (5 mL). DIPEA (1.25 mL, 7.2 mmol) was then added and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then cooled to 0°C, and sodium borohydride (379.5 mg, 10 mmol) was added. The mixture was allowed to react at 0°C for 1 hour. The reaction mixture was monitored by LC-MS. After completion of the reaction, water was added to the mixture, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 29-1 (150 mg, crude product). This was used directly in the next reaction. LCMS (ESI) m / z: 111.2 [M+H] + .

[0152] Substrate S6 (15 mg, 0.048 mmol) was added to a dry one-neck flask, dissolved in DMF (1 mL), and cooled to 0 °C. DIPEA (41 μL, 0.24 mmol) was added. After 5 min, HATU (21.66 mg, 0.057 mmol) was added and the mixture was allowed to react for 10 min. 29-1 (10.44 mg, 0.095 mmol) was then added and the mixture was allowed to react for 30 min. The reaction mixture was monitored by LC-MS. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic) to give 29 (10.1 mg, 0.025 mmol, 52.0%) as a white solid. LCMS (ESI) m / z: 399.2 [M+H]+, HPLC method B: RT = 7.14 min, purity >99.9%. 1 H NMR(600MHz,DMSO-d6)δ10.69(d,J=26.4Hz,1H),8.06-8.05(m,1H),7.91-7.8 8(m,1H),7.59-7.45(m,1H),7.44-7.41(m,2H),7.20-7.16(m,1H),7.11-7.07( m,1H),6.83-6.73(m,1H),6.73-6.69(m,1H),6.11-6.04(m,1H),4.66-4.38(m, 1H),4.05-3.80(m,1H),3.81(d,J=3.0Hz,3H),3.34(s,3H),2.87-2.68(m,3H).

[0153] Example 30: Synthesis of Compound 30 [ka]

[0154] Substrate S3 (20 mg, 0.065 mmol) was placed in a dry one-neck flask, and DMF (1.0 mL) was added thereto and stirred to dissolve. DIPEA (0.11 mL, 0.65 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (30 mg, 0.078 mmol) was added and stirred at 0°C for 5 minutes. 3-aminomethyloxetane (6.8 mg, 0.078 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid 30-1 (24 mg, 0.064 mmol, 99%). LCMS (ESI) + ) m / z: 376.1 [M+H] + .

[0155] NaH (8 mg, 0.2 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 30-1 (24 mg, 0.064 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (28 mg, 0.2 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 30 (14 mg, 36 μmol, 56%). LCMS (ESI) + ) m / z: 390.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.07(d,J=1.8Hz,0.24H),8.02(d,J=1.8Hz,0.71H),7.92-7.85(m,1H),7.57 -7.33(m,3H),7.21-7.12(m,1H),7.13-7.04(m,1H),4.68(dd,J=7.9,6.1Hz,1.58H),4.62-4.51(m,0 .57H),4.53-4.35(m,1.56H),4.23-4.12(m,0.64H),4.08-3.95(m,0.72H),3.78(s,0.79H),3.77(s, 2.21H),3.66-3.52(m,0.72H),3.46-3.26(m,1.64H),3.23(s,3H),2.89(s,0.76H),2.72(s,2.24H).

[0156] Example 31: Synthesis of Compound 31 [ka]

[0157] Substrate S3 (20 mg, 0.062 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added thereto and stirred to dissolve. DIPEA (117 mg, 0.9 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (28.3 mg, 0.074 mmol) was added and stirred at 0°C for 5 minutes. 1-(oxetanin-3-yl)ethan-1-amine (7.5 mg, 0.074 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid 31-1 (15.6 mg, 0.04 mmol, 65%). LCMS (ESI) + ) m / z: 390.5 [M+H] + .

[0158] NaH (1.8 mg, 0.077 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 31-1 (6 mg, 0.015 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (6.6 mg, 0.046 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 31 (2.34 mg, 5.8 μmol, 39%). LCMS (ESI) + ) m / z: 404.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.02(d,J=1.8Hz,1H),8.00-7.84(m,1H),7.62-7.35(m,3H),7.16(t,J=7.1Hz,1H),7.13-7.05(m ,1H),4.94(t,J=8.3Hz,1H),4.78-4.14(m,4H),3.78(d,J=8.9Hz,3H),3.29-3.12(m,4H),2.75(s,1H),1.23-1.01(m,4H).

[0159] Example 32: Synthesis of Compound 32 [ka]

[0160] Substrate S6 (20 mg, 65.29 mmol) was placed in a dry one-neck flask, and DMF (1 mL) was added and stirred to dissolve. DIPEA (25.31 mg, 195.87 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (29.79 mg, 78.35 μmol) was added and stirred at 0°C for 5 minutes. (R)-1-Cyclopropylethylamine hydrochloride (9.53 mg, 78.35 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 32-1 (21 mg, 56.23 μmol, 86.13% yield). LCMS (ESI) + ) m / z: 374.2 [M+H] + .

[0161] Under N2 protection, a dry one-neck flask was charged with NaH (1.93 mg, 48.20 μmol, 60% purity), dispersed in DMF (1 mL), and cooled in an ice-water bath. 32-1 (15 mg, 40.16 μmol) was slowly added dropwise and the reaction was allowed to proceed at 0 °C for 30 min. Iodomethane (6.84 mg, 48.20 μmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. LC-MS confirmed the complete reaction. Water was added to quench the reaction, followed by extraction with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 32 (5.03 mg, 12.98 μmol, 32.32% yield, 100% purity) as a white solid. LCMS (ESI) + ) m / z: 388.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.87-7.80(m,1H),7.70-7.62(m,1H),7.32-7.17(m,3H),7.01-6.93(m,1H),6.91-6.84(m,1H),3.78-3.61(m,1H) ),3.59(s,3H),3.09-3.03(m,3H),2.75(d,J=9.2Hz,1H),2.54(d,J=9.6Hz,2H),1.07-0.95(m,3H),0.93-0.86(m,1H),0.41--0.05(m,4H)

[0162] Example 33: Synthesis of Compound 33 [ka]

[0163] Substrate S6 (20 mg, 65.29 mmol) was placed in a dry one-neck flask, and DMF (1 mL) was added and stirred to dissolve. DIPEA (25.31 mg, 195.87 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (29.79 mg, 78.35 μmol) was added and stirred at 0°C for 5 minutes. (R)-1-Cyclopentyl-1-amine hydrochloride (11.73 mg, 78.35 mmol) was then added to the reaction mixture and allowed to react at 0°C for 20 minutes. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 33-1 (23 mg, 57.28 μmol, 87.74% yield). LCMS (ESI) + ) m / z: 402.2 [M+H] + .

[0164] Under N2 protection, a dry one-neck flask was charged with NaH (1.79 mg, 44.83 μmol, 60% purity), dispersed in DMF (1 mL), and cooled in an ice-water bath. 33-1 (15 mg, 37.36 μmol) was slowly added dropwise, and the reaction was allowed to proceed at 0 °C for 30 min. Iodomethane (6.36 mg, 44.83 μmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. LC-MS confirmed the complete reaction. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 33 (6.3 mg, 15.16 μmol, 40.58% yield, 100% purity) as a white solid. LCMS (ESI) + ) m / z: 416.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.18-8.08(m,1H),8.01-7.92(m,1H),7.53-7.44(m,3H),7.25(d,J=7.9Hz,1H),7.20-7.12(m,1H) ,4.50-4.33(m,1H),3.88(s,3H),3.36(s,3H),2.94-2.69(m,3H),2.23-2.02(m,1H),1.91-1.53(m,6H),1.38-1.17(m,5H).

[0165] Example 34: Synthesis of Compound 34 [ka]

[0166] Substrate S1 (50 mg, 0.179 mmol) was placed in a dry one-neck flask, and DMF (1 mL) was added. The mixture was stirred to dissolve. DIPEA (115.76 mg, 0.896 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (70.92 mg, 0.215 mmol) was added and stirred at 0 °C for 5 min. 4-aminomethyltetrahydropyran (20.63 mg, 0.179 mmol) was then added to the reaction mixture. The mixture was allowed to react at 0 °C for 20 min, and LC-MS confirmed the reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give 34-1 (50 mg, 0.134 mmol, 74.18% yield) as a white solid. LCMS (ESI+) m / z: 377.9 [M+H]+.

[0167] Under N2 protection, a microwave tube was charged with the substrate 34-1 (50 mg, 0.134 mmol), 2-methoxyphenylboronic acid (24.36 mg, 0.160 mmol), Pd(dppf)Cl2 (9.75 mg, 0.013 mmol), and K2CO3 (55.39 mg, 0.400 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting solid was purified by medium-pressure liquid chromatography to give a brown solid 34-2 (50 mg, 0.124 mmol, 92.76% yield). LCMS (ESI+) m / z: 404.1 [M+H]+

[0168] NaH (5.98 mg, 0.149 mmol, 60% purity) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 34-2 (20.10 mg, 0.050 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (14.14 mg, 0.100 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 34 (10 mg, 0.023 mmol, 46.50% yield, 96.7% purity) as a white solid. LCMS (ESI+) m / z: 418.3 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ8.05(dd,J=6.0,1.8Hz,1H),7.89(dd,J=7.9,1.8Hz,1H),7.50 (t,J=7.8Hz,1H),7.43(dd,J=9.0,7.0Hz,2H),7.18(d,J=8.2Hz,1H),7.14-7.05(m,1H) ,3.88(ddd,J=11.3,4.5,2.0Hz,2H),3.81(d,J=2.0Hz,3H),3.48(d,J=9.3Hz,1H),3.3 2-3.18(m,6H),3.00(s,1H),2.82(s,2H),2.02(s,1H),1.69(s,2H),1.39-1.16(m,2H).

[0169] Example 35: Synthesis of Compound 35 [ka]

[0170] Substrate S6 (40 mg, 0.131 mmol) was added to a dry one-neck flask, and DMF (1 mL) was added and stirred to dissolve. DIPEA (84.38 mg, 0.653 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (59.54 mg, 0.157 mmol) was added and stirred at 0 °C for 5 min. 4-Hydroxycyclohexylmethylamine (20.24 mg, 0.157 mmol) was then added to the reaction mixture and allowed to react at 0 °C for 20 min. LC-MS confirmed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give a white solid, 35-1 (40 mg, 0.096 mmol, 73.37% yield). LCMS (ESI+) m / z: 418.1 [M+H]+.

[0171] Substrate 35-1 (20 mg, 0.048 mmol) was placed in a dry one-neck flask, and DCM (3 mL) was added and stirred to dissolve. Acetic anhydride (24.45 mg, 0.240 mmol) and DMAP (5.85 mg, 0.048 mmol) were then added to the reaction mixture. The mixture was stirred at 25 °C for 0.5 h, and LC-MS confirmed the complete reaction. The solvent was evaporated to dryness, and the mixture was purified by medium-pressure liquid chromatography to give a white solid, 35-2 (22 mg, 0.048 mmol, 99.94% yield). LCMS (ESI+) m / z: 460.1 [M+H]+.

[0172] NaH (3.83 mg, 0.096 mmol, 60% purity) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 35-2 (22 mg, 0.048 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHI (20.38 mg, 0.144 mmol) was then added and the reaction was continued at 0 °C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give a white solid product 35-3 (20 mg, 0.042 mmol, 88.22% yield). LCMS (ESI+) m / z: 474.1 [M+H]+.

[0173] Substrate 35-3 (20 mg, 0.042 mmol) was placed in a dry one-neck flask, and methanol (3 mL) was added. The mixture was stirred to dissolve. Anhydrous potassium carbonate (17.51 ​​mg, 0.127 mmol) was then added to the reaction mixture. The mixture was stirred at 25 °C for 1 h, and LC-MS confirmed the complete reaction. After filtration, the solvent was removed by rotary evaporation, and the mixture was purified by medium-pressure liquid chromatography to give a white solid, 35 (10 mg, 0.023 mmol, 54.32% yield, 99.0% purity). LCMS (ESI+) m / z: 432.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=4.8Hz,1H),7.93-7.85(m,1H),7.53-7.35(m,3 H),7.17(d,J=8.3Hz,1H),7.09(t,J=7.4Hz,1H),4.52(s,1H),3.81(s,3H),3.30- 3.24(m,3H),2.97(d,J=2.4Hz,1H),2.79(d,J=2.3Hz,2H),1.91-1.74(m,3H),1.6 6(dtd,J=17.8,9.4,8.2,3.7Hz,1H),1.46(s,1H),1.22-1.06(m,2H),1.01(s,1H).

[0174] Example 36: Synthesis of Compound 36 [ka]

[0175] Compound S1 (147 mg, 0.5 mmol), cyclohexene-1-boronic acid pinacol ester (125 mg, 0.6 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), and K2CO3 (276 mg, 2 mmol) were added to a dry one-neck flask. The solvent 1,4-dioxane (4 mL) and water (1 mL) were then added. The reaction flask was sealed, purged with nitrogen gas three times, heated to 100 °C, and stirred overnight. After cooling to room temperature, EtOAc and water were added and the layers were separated. The organic phase was washed with saturated brine, dried, filtered, and concentrated. The crude product was purified by column chromatography to give the desired product 36-1 (102 mg, 0.35 mmol, 70%). LCMS (ESI) + ) m / z: 295.0 [M+H] + .

[0176] Compound 36-1 (60 mg, 0.20 mmol) was placed in a 25 mL one-neck flask and dissolved in MeOH (4 mL). Pd / C (10%, 22 mg) was added. The hydrogen was replaced three times using a hydrogen balloon, and the mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The filtrate was filtered and concentrated under reduced pressure to give the desired product 36-2 (62 mg, >99%). This was used directly in the next reaction. LCMS (ESI+) m / z: 297.0 [M+H]+.

[0177] Compound 36-2 (62 mg, 0.20 mml) was dissolved in a mixed solvent of MeOH / HO (4:1, 5 mL) and NaOH (80 mg, 2 mmol) was added. The mixture was heated at 70 °C for 2 hours, and complete reaction was confirmed by LCMS. After cooling to room temperature, 2N HCl solution was added to adjust the pH to approximately 5. The mixture was extracted with ethyl acetate, separated, and the organic phase was washed with saturated brine, dried, and concentrated to give crude product 36-3 (60 mg, crude). This was used directly in the next reaction.

[0178] Substrate 36-3 (60 mg, 0.2 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added thereto and stirred to dissolve. DIPEA (0.35 mL, 2 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (91 mg, 0.24 mmol) was added and stirred at 0°C for 5 minutes. Cyclohexylmethylamine (34 mg, 0.3 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give white solid 36-4 (58 mg, 0.15 mmol, 77%). LCMS (ESI) + ) m / z: 378.2 [M+H] + .

[0179] NaH (6 mg, 0.16 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 36-4 (20 mg, 0.053 mmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (38 mg, 0.159 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 36 (15 mg, 38 μmol, 72%). LCMS (ESI) + ) m / z: 392.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.70-7.62(m,1H),7.39-7.28(m,1H), 3.55-3.40(m,0.7H),3.23(s,2.1H),3.20(s,0.9H),3.12-3.01(m,0.7H),2. 95(s,0.9H),2.92-2.74(m,0.6H),2.72(s,2.1H),2.72-2.60(m,1H),1.89- 1.51(m,11H),1.50-1.33(m,4H),1.31-0.88(m,5.4H),0.76-0.54(m,0.6H).

[0180] Example 37: Synthesis of Compound 37 [ka]

[0181] In a dry one-neck flask, place substrate S4 (30 mg, 77.5 μmol), 2-methoxyphenylboronic acid (14.14 mg, 93 μmol), and Pd(dppf)Cl. 2( The mixture was sealed and flushed with nitrogen three times. Dioxane (1 mL) and H2O (0.25 mL) were added and the mixture was stirred at 100 °C for 2 hours. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 37 (10.96 mg, 26.3 μmol, 30%) as a white solid. LCMS (ESI) + ) m / z: 416.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.06(dd,J=5.1,1.8Hz,1H),7.90(ddd,J=7.9,4.2,1.8 Hz,1H),7.53-7.39(m,3H),7.18(d,J=8.3Hz,1H),7.10(t,J=7.3Hz,1H),3.81(s ,3H),3.54(s,0.75H),3.28(d,J=14.1Hz,3H),3.09(s,0.79H),2.98(s,0.82H), 2.90(t,J=7.2Hz,0.53H),2.80(s,2.2H),1.84-1.54(m,6H),1.32-0.64(m,5H).

[0182] Example 38: Synthesis of Compound 38 [ka]

[0183] In a dry one-neck flask, place substrate S4 (30 mg, 77.5 μmol), 2-methylphenylboronic acid (12.65 mg, 93 μmol), and Pd(dppf)Cl. 2( 2.81 mg, 3.87 μmol) and KCO 3( The flask was sealed and purged with nitrogen gas three times. Dioxane (1 mL) and H2O (0.25 mL) were added to the flask, and the contents were diluted to 100 o The mixture was stirred at 37°C for 2 hours, and the reaction was confirmed to be complete by LC-MS. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 38 (8.12 mg, 23.9 μmol, 26.2%) as a white solid. LCMS (ESI + ) m / z: 400.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.86(t,J=1.8Hz,1H),7.79(ddd,J=7.7,4.0,1.8Hz,1H),7 .50(dd,J=7.8,5.7Hz,1H),7.34(ddt,J=15.7,4.7,2.5Hz,4H),3.55(s,0.75H),3. 30(d,J=13.5Hz,3H),3.11(s,0.75H),2.98(s,0.87H),2.89(dd,J=11.4,7.1Hz,0. 52H),2.80(s,2.22H),2.27(d,J=2.7Hz,3H),1.81-1.53(m,6H),1.30-0.65(m,5H).

[0184] Example 39: Synthesis of Compound 39 [ka]

[0185] In a dry one-neck flask, place substrate S4 (15 mg, 38.7 μmol), 2-trifluoromethylphenylboronic acid (8.1 mg, 42.6 μmol), and Pd(dppf)Cl. 2( The mixture was sealed and flushed with nitrogen three times. Dioxane (1 mL) and HO (0.25 mL) were added and stirred at 100 °C for 2 hours. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 39 (13.35 mg, 29.4 μmol, 76%) as a white solid. LCMS (ESI) + ) m / z: 454.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.94-7.85(m,2H),7.84-7.74(m,2H),7.71(t,J=7.7Hz,1H),7.61-7.51(m,2H),3.55(s,0.64H),3.28(d ,J=13.6Hz,3H),3.16-3.04(m,0.67H),2.99(s,1H),2.95-2.82(m,0.5H),2.78(s,2.19H),1.87-1.53(m,6H),1.33-0.61(m,5H).

[0186] Example 40: Synthesis of Compound 40 [ka]

[0187] In a dry one-neck flask, substrate S4 (15 mg, 38.7 μmol), 2-(dimethylamino)phenylboronic acid (6.39 mg, 42.6 μmol), and Pd(dppf)Cl were added. 2( The mixture was sealed and flushed with nitrogen three times. Dioxane (1 mL) and H2O (0.25 mL) were added and the mixture was stirred at 100 °C for 2 hours. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, filtered, concentrated, and purified by medium-pressure liquid chromatography to give 40 (11.83 mg, 27.6 μmol, 71.2%) as a white solid. LCMS (ESI) + ) m / z: 429.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.12(dd,J=10.3,1.7Hz,1H),7.96(ddd,J=7.6,5.4,1.7Hz,1H),7.4 8(d,J=7.8Hz,1H),7.38-7.26(m,2H),7.13(d,J=8.1Hz,1H),7.08(t,J=7.4Hz,1H),3.54(d,J =11.0Hz,0.69H),3.27(d,J=13.8Hz,3H),3.07(d,J=13.2Hz,0.68H),2.98(s,0.94H),2.95-2 .83(m,0.65H),2.79(s,2.10H),2.50(d,J=3.7Hz,3H),1.85-1.52(m,6H),1.31-0.62(m,5H).

[0188] Example 41: Synthesis of Compound 41 [ka]

[0189] Compound S4 (20 mg, 0.051 mmol), 2-(2-cyclopropyl-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16 mg, 0.06 mmol), Pd(dppf)Cl (7.3 mg, 0.01 mmol), and KCO (14 mg, 0.1 mmol) were added to a dry one-neck flask. Then, 1,4-dioxane (1.6 mL) and water (0.4 mL) were added. The reaction flask was sealed, purged with nitrogen gas three times, heated to 100 °C, and stirred overnight. After cooling to room temperature, EtOAc and water were added and the layers were separated. The organic phase was washed with saturated brine, dried, filtered, and concentrated. The crude product was purified by medium-pressure liquid chromatography to give product 41 (7.6 mg, 17.07 μmol, 33%). LCMS (ESI) + ) m / z: 444.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.98(d,J=1.9Hz,2H),7.91(d,J=49.0Hz,0H),7.86-7.83(m,0H),7.83(dd, J=7.8,1.8Hz,1H),7.53(d,J=7.8Hz,1H),7.51(d,J=7.8Hz,1H),7.42-7.31(m,1H),7.18-7.06(m,1H) ),6.96-6.82(m,1H),3.54(d,J=10.1Hz,1H),3.31(s,4H),3.27(s,1H),3.11(d,J=17.1Hz,2H),2.98 (s,2H),2.95-2.83(m,1H),2.80(s,4H),1.87-1.48(m,13H),1.33-1.10(m,4H),1.07-0.60(m,13H).

[0190] Example 42: Synthesis of Compound 42 [ka]

[0191] The substrate, methyl o-bromobenzoate (500 mg, 2.32 mmol), was added to a dry three-neck flask, dissolved in tetrahydrofuran (10 mL), and cooled to 0 °C under nitrogen gas protection. Methylmagnesium bromide (11.6 mL, 11.6 mmol, 1 M in THF) was then added and the reaction was allowed to proceed at room temperature for 16 h. The reaction mixture was monitored by TLC. Saturated ammonium chloride solution was added dropwise to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 42-1 (200 mg, 0.93 mmol). LCMS (ESI) m / z: 215.1 [M+H] +

[0192] Substrate 42-1 (50 mg, 0.23 mmol), bis-pinacolatodiboron (118 mg, 0.46 mmol), Pd(dppf)Cl2 (17 mg, 0.023 mmol), and potassium acetate (68 mg, 0.69 mmol) were added to a dry one-neck flask, dissolved in 1,4-dioxane (2 mL), and reacted at 100 °C under nitrogen gas protection for 2 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain crude product 42-2 (80 mg, crude product). This was used directly in the next reaction. LCMS (ESI) m / z: 263.2 [M+H] +

[0193] Substrate 42-2 (80 mg, 0.23 mmol), S4 (50 mg, 0.13 mmol), Pd(dppf)Cl2 (9.4 mg, 0.013 mmol), and potassium carbonate (53.3 mg, 0.39 mmol) were added to a dry one-neck flask, dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL), and reacted at 100 °C under nitrogen gas protection for 2 h. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (basic) to give 42 (12.9 mg, 0.029 mmol, 22.3%) as a white solid. LCMS (ESI) m / z: 444.1 [M+H] + , HPLC method B:R T= 8.37 min, purity>99.1%. 1 H NMR(400MHz,DMSO-d6)δ7.84-7.76(m,1H),7.75-7.62(m,2H),7.62-7.44(m,1. 2H),7.44-7.36(m,1.5H),7.34-7.24(m,0.8H),7.11-7.01(m,0.7H),4.91-4.86 (m,1H),3.56(s,0.7H),3.30-3.20(m,3.2H),3.09(s,0.7H),3.01-2.72(m,3.7 H),2.48-2.22(m,1H),1.87-1.51(m,6H),1.40-1.15(m,7H),1.15-0.53(m,3H).

[0194] Example 43: Synthesis of Compound 43 [ka]

[0195] Compound S4 (31 mg, 0.08 mmol), 3-methoxy-4-pyridineboronic acid (24.4 mg, 0.16 mmol), Pd(dppf)Cl2 (5.8 mg, 8 μmol), Cs2CO3 (52 mg, 0.16 mmol), and CuI (15.2 mg, 0.08 mmol) were added to a dry one-neck flask. Then, DMF (1.5 mL) was added. The reaction flask was sealed, purged with nitrogen gas three times, and stirred at 100 °C for 2 h. After cooling to room temperature, EtOAc and water were added and the layers were separated. The organic phase was washed with saturated brine, dried, filtered, and concentrated. The crude product was purified by medium-pressure liquid chromatography to give product 43 (9.3 mg, 22.3 μmol, 28%) as a white solid. LCMS (ESI) + ) m / z: 417.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.92-8.21(m,2H),8.14(d,J=1.7Hz,1H),8.04-7.92(m,1H),7.62-7.39(m,2H),3.95(s,3H),3.58 -3.47(m,0.7H),3.30(s,2.1H),3.27(s,0.9H)3.14-3.04(m,0.7H),2.97(s,0) .9H),2.95-2.81(m,0.6H),2.79(s,2.1H),1.91-1.48(m,6.3H),1.31-1.10(m ,2.4H),1.10-0.87(m,1.7H),0.77-0.61(m,0.6H).

[0196] Example 44: Synthesis of Compound 44 [ka]

[0197] Under N2 protection, a microwave tube was charged with substrate S4 (25 mg, 64.38 μmol), 3-methylphenylboronic acid (10.50 mg, 77.26 μmol), Pd(dppf)Cl2 (2.34 mg, 3.22 μmol), and K2CO3 (17.80 mg, 128.76 μmol). 1 mL of dioxane / HO (v:v = 4:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give 44 (13.3 mg, 33.29 μmol, 51.71% yield, 100% purity) as a white solid. LCMS (ESI) + ) m / z: 400.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.17-8.12(m,1H),8.10-8.03(m,1H),7.62-7.49( m,3H),7.45-7.40(m,1H),7.28(d,J=7.6Hz,1H),3.60-3.50(m,1H),3.30(d ,J=12.6Hz,3H),3.15-3.04(m,1H),2.97(s,1H),2.94-2.84(m,1H),2.78(s ,2H),2.41(s,3H),1.85-1.70(m,4H),1.67-1.55(m,2H),1.29-1.06(m,4H)

[0198] Example 45: Synthesis of Compound 45 [ka]

[0199] Under N2 protection, a microwave tube was charged with substrate S3 (25 mg, 64.38 μmol), 2-fluorophenylboronic acid (10.81 mg, 77.26 μmol), Pd(dppf)Cl2 (2.34 mg, 3.22 μmol), and K2CO3 (17.80 mg, 128.76 μmol). 1 mL of dioxane / HO (v:v = 4:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give 45 (17 mg, 41.58 μmol, 64.59% yield, 98.7% purity) as a white solid. LCMS (ESI) + ) m / z: 404.2 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.02-7.95(m,1H),7.74-7.64(m,1H),7.59-7.48(m,2H),7.44-7.35(m,2H),3.62-3.45(m,1H),3.30( d,J=14.0Hz,3H),3.20-3.00(m,1H),2.98(s,1H),2.96-2.82(m,1H), 2.79(s,2H),1.91-1.69(m,4H),1.67-1.50(m,2H),1.29-0.99(m,4H).

[0200] Example 46: Synthesis of Compound 46 [ka]

[0201] Under N2 protection, a microwave tube was charged with substrate S4 (25 mg, 64.38 μmol), 2-isopropylphenylboronic acid (12.67 mg, 77.26 μmol), Pd(dppf)Cl2 (2.34 mg, 3.22 μmol), and K2CO3 (17.80 mg, 128.76 μmol). 1 mL of dioxane / HO (v:v = 4:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give 46 (17.6 mg, 41.16 μmol, 63.93% yield, 100% purity) as a white solid. LCMS (ESI) + ) m / z: 428.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.89-7.78(m,1H),7.79-7.68(m,1H),7.62-7.47(m,2H),7.46-7.36(m,1H),7.36-7.17(m,2H),3.56-3.52(m,1H),3.2 9(d,J=14.1Hz,3H),3.14-3.04(m,1H),2.99(s,1H),2.96-2.84(m,2H), 2.81(s,2H),1.85-1.69(m,4H),1.68-1.57(m,2H),1.27-1.12(m,10H).

[0202] Example 47: Synthesis of Compound 47 [ka]

[0203] Under N2 protection, a microwave tube was charged with substrate S4 (15 mg, 38.63 μmol), benzofuran-4-ylboronic acid (7.51 mg, 46.35 μmol), Pd(dppf)Cl2 (1.40 mg, 1.93 μmol), and K2CO3 (10.68 mg, 77.26 μmol). 1 mL of dioxane / HO (v:v = 4:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give 47 (10.0 mg, 23.50 μmol, 60.84% ​​yield, 100% purity) as a white solid. LCMS (ESI) + ) m / z: 426.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.50-8.42(m,1H),8.34-8.24(m,1H),8.18-8.11(m,1H),7.77(d, J=7.7,1.2Hz,1H),7.71-7.64(m,1H),7.64-7.57(m,1H),7.46-7.38(m,1H),7.11(d,J=2.2 Hz,1H),3.65-3.45(m,1H),3.33(s,2H),3.30(s,1H),3.19-3.04(m,1H),2.99(s,1H),2.8 1(s,2H),1.87-1.69(m,4H),1.68-1.53(m,2H),1.31-1.11(m,3H),1.00(d,J=12.5Hz,2H).

[0204] Example 48: Synthesis of Compound 48 [ka]

[0205] Under N2 protection, a microwave tube was charged with substrate S4 (15 mg, 38.63 μmol), benzofuran-4-boronic acid pinacol ester (11.31 mg, 46.35 μmol), Pd(dppf)Cl2 (1.40 mg, 1.93 μmol), and K2CO3 (10.68 mg, 77.26 μmol). 1 mL of dioxane / HO (v:v = 4:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give 48 (9.26 mg, 21.76 μmol, 56.33% yield, 94.5% purity) as a white solid. LCMS (ESI) + ) m / z: 426.3 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ8.23-8.13(m,2H),8.10-8.04(m,1H),7.72(d,J=7 .9Hz,1H),7.63-7.56(m,1H),7.55-7.42(m,2H),7.20-7.14(m,1H),3.65- 3.48(m,1H),3.37(s,3H),3.17-3.02(m,1H),2.99(s,1H),2.82(s,2H),1. 86-1.70(m,4H),1.68-1.55(m,2H),1.30-1.13(m,3H),1.11-0.81(m,2H).

[0206] Example 49: Synthesis of Compound 49 [ka]

[0207] Under N2 protection, a microwave tube was charged with substrate S4 (15 mg, 38.63 μmol), 2-isopropylphenylboronic acid (7.51 mg, 46.35 μmol), Pd(dppf)Cl2 (1.40 mg, 1.93 μmol), and K2CO3 (10.68 mg, 77.26 μmol). 1 mL of dioxane / HO (v:v = 4:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography to give 49 (6.4 mg, 14.66 μmol, 37.96% yield, 97.5% purity) as a white solid. LCMS (ESI) + ) m / z: 426.6 [M+H] + 1 H NMR(600MHz,DMSO-d6)δ8.07(d,J=3.6Hz,1H),8.03-7.96(m,1H),7.48-7.41(m,2H),7.41- 7.36(m,1H),7.36-7.31(m,1H),7.08(d,J=7.6Hz,1H),3.46(t,J=10.2Hz,1H),3.24(d,J=19 .1Hz,3H),3.02(t,1H),2.90(s,1H),2.71(s,2H),2.01-1.94(m,1H),1.76-1.68(m,2H),1.6 7-1.61(m,2H),1.60-1.48(m,2H),1.23-1.06(m,3H),1.02-0.85(m,4H),0.74-0.68(m,2H).

[0208] Example 50: Synthesis of Compound 50 [ka] Under N2 protection, a microwave tube was charged with substrate S4 (40 mg, 0.103 mmol), 1-indole-4-bromophenylboronic acid (19.90 mg, 0.124 mmol), Pd(dppf)Cl2 (7.52 mg, 0.010 mmol), and K2CO3 (42.71 mg, 0.309 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 90 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was purified by medium-pressure liquid chromatography to give a white solid 50 (16 mg, 0.036 mmol, 34.68% yield, 94.8% purity). LCMS (ESI+) m / z: 425.2 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.13(d,J=1.7Hz,1H),8.01(dt,J=7.8,2.1Hz,1H),7.64(dd,J=7.7,1. 2Hz,1H),7.56(dd,J=11.4,7.8Hz,1H),7.41(dt,J=5.6,2.7Hz,1H),7.26-7.09(m,2H),6.58(dt,J=3.2,1.7H z,1H),3.55(d,J=7.5Hz,1H),3.37(s,2H),3.34(s,1H),3.10(dd,J=12.8,6.0Hz,1H),2.99(s,1H),2.84(s,2 H),1.80(d,J=6.8Hz,2H),1.73(dd,J=13.5,3.8Hz,2H),1.68-1.52(m,2H),1.23(d,J=9.7Hz,3H),1.01(s,2H)

[0209] Example 51: Synthesis of Compound 51 [ka]

[0210] Under N2 protection, a microwave tube was charged with substrate S4 (20 mg, 0.052 mmol), 7-indoleboronic acid pinacol ester (15.03 mg, 0.062 mmol), K2CO3 (21.36 mg, 0.155 mmol), and Pd(dppf)Cl2 (3.76 mg, 0.005 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 90 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was purified by medium-pressure liquid chromatography to give 51 (16 mg, 0.038 mmol, 73.17% yield, 100% purity) as a white solid. LCMS (ESI+) m / z: 425.1 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.13(d,J=1.7Hz,1H),8.01(dt,J=7.8,2.1Hz,1H),7.64(dd,J=7.7,1 .2Hz,1H),7.56(dd,J=11.4,7.8Hz,1H),7.41(q,J=2.8,2.3Hz,1H),7.26-7.09(m,2H),6.58(dt,J=3.2,1.7H z,1H),3.55(d,J=7.5Hz,1H),3.37(s,3H),3.34(s,1H),3.10(dd,J=13.0,5.9Hz,1H),2.99(s,1H),2.84(s, 2H),1.88-1.77(m,2H),1.73(dd,J=13.5,3.8Hz,2H),1.63(d,J=22.6Hz,2H),1.33-1.12(m,3H),1.01(s,2H)

[0211] Example 52: Synthesis of Compound 52 [ka]

[0212] Under N2 protection, a microwave tube was charged with substrate S4 (50 mg, 0.13 mmol), 5-fluoro-2-methoxyphenylboronic acid (24.3 mg, 0.143 mmol), K2CO3 (53.8 mg, 0.39 mmol), and Pd(dppf)Cl2 (11.2 mg, 0.013 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 90 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was purified by medium-pressure liquid chromatography to give a white solid 52 (22.6 mg, 0.052 mmol, 40% yield, 94.9% purity). LCMS (ESI+) m / z: 434.1 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ8.00(dd,J=3.5,1.8Hz,1H),7.86(dd,J=7.9,1.8Hz,1H),7.44(dd t,J=8.3,6.8,3.7Hz,2H),7.04(dd,J=11.4,2.5Hz,1H),6.91(tdd,J=8.4,2.5,1.1Hz,1H) ,3.79(d,J=1.3Hz,3H),3.47(s,1H),3.21(s,1H),3.08(d,J=9.1Hz,1H),2.95(s,1H),2.7 6(s,2H),1.85-1.48(m,7H),1.19-1.09(m,3H),0.95(d,J=12.1Hz,2H),0.86-0.59(m,1H).

[0213] Example 53: Synthesis of Compound 53 [ka]

[0214] Under N2 protection, a microwave tube was charged with substrate S4 (10 mg, 0.026 mmol), 2-ethylphenylboronic acid (4.3 mg, 0.028 mmol), K2CO3 (10.8 mg, 0.078 mmol), and Pd(dppf)Cl2 (2.6 mg, 0.003 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. The mixture was stirred at 90 °C for 2 h. LC-MS confirmed the complete reaction. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was purified by medium-pressure liquid chromatography to give a white solid 53 (3.43 mg, 0.008 mmol, 31.8% yield, 97.5% purity). LCMS (ESI+) m / z: 414.2 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ7.84(d,J=1.8Hz,1H),7.76(ddd,J=7.6,5.5,1.9Hz,1H),7.51(dd,J=7.8,3.1Hz,1H),7.43-7.37(m,2H),7.36-7.24(m,2H) ),3.55(s,1H),3.29(d,J=8.2Hz,3H),3.10(s,1H),2.99(s,1H),2.80(s, 2H),1.86-1.53(m,7H),1.33-1.12(m,4H),1.06(dt,J=17.9,7.5Hz,5H).

[0215] Example 54: Synthesis of Compound 54 [ka]

[0216] Under N2 protection, a microwave tube was charged with substrate S4 (10 mg, 0.026 mmol), 4-fluorophenylboronic acid (3.9 mg, 0.028 mmol), K2CO3 (10.8 mg, 0.078 mmol), and Pd(dppf)Cl2 (2.6 mg, 0.003 mmol). 2 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 90 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was purified by medium-pressure liquid chromatography to give a white solid 54 (5.12 mg, 0.012 mmol, 48.8% yield, 99.3% purity). LCMS (ESI+) m / z: 404.1 [M+H]+ 1 H NMR(600MHz,DMSO-d6)δ8.14(dd,J=3.6,1.8Hz,1H),8.07(ddd,J=14.8,7.9,2.0Hz ,1H),7.84(ddd,J=16.5,8.7,5.5Hz,2H),7.52(dd,J=12.7,7.9Hz,1H),7.38(td,J= 8.8,1.9Hz,2H),3.53(d,J=10.3Hz,1H),3.32(s,2H),3.29(s,1H),3.09(s,1H),2.9 8(s,1H),2.79(s,2H),1.84-1.54(m,7H),1.21-1.12(m,2H),1.00(d,J=10.6Hz,2H) [ka]

[0217] Synthesis of compound S7 Compound S1 (150 mg, 0.51 mmol), 4-fluoro-2-methylthiophenylboronic acid (112 mg, 0.6 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), and K2CO3 (276 mg, 2 mmol) were added to a dry one-neck flask. The solvent 1,4-dioxane (4 mL) and water (1 mL) were then added. The reaction flask was sealed, purged with nitrogen gas three times, heated to 100 °C, and stirred overnight. After cooling to room temperature, EtOAc and water were added and the layers were separated. The organic phase was washed with saturated brine, dried, filtered, and concentrated. The crude product was purified by column chromatography to give the desired product S7 (175 mg, 0.49 mmol, 96%).

[0218] Synthesis of compound S8 Compound S7 (175 mg, 0.49 mmol) was dissolved in a mixed solvent of MeOH / HO (4:1, 5 mL) and NaOH (200 mg, 5 mmol) was added. The reaction was heated at 70 °C for 2 hours, and complete reaction was confirmed by LCMS. After cooling to room temperature, 2N HCl solution was added to adjust the pH to approximately 5. The mixture was extracted with ethyl acetate, separated, and the organic phase was washed with saturated brine, dried, concentrated, and purified by medium-pressure liquid chromatography to give a white solid, S8 (160 mg, 0.47 mmol, 96%).

[0219] Example 55: Synthesis of Compound 55 [ka] Substrate S8 (30.0 mg, 0.088 mmol) was added to a dry one-neck flask, dissolved in DMF (1.0 mL), and cooled to 0 °C. DIPEA (153.0 µL, 0.88 mmol) was added. After 5 minutes, HATU (40.1 mg, 0.106 mmol) was added and the reaction was allowed to proceed for 10 minutes. 4-aminomethyltetrahydropyran (12.2 mg, 0.106 mmol) was then added and the reaction was allowed to proceed for 30 minutes. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic) to obtain compound 55-1 (28.0 mg, 0.064 mmol). LCMS (ESI) m / z: 438.1 [M+H]+ .

[0220] Sodium hydride (5 mg, 0.128 mmol) was added to a dry three-neck flask and cooled to 0 °C under nitrogen protection. Anhydrous DMF (1 mL) was added. After 5 min, a solution of substrate 55-1 (28.0 mg, 0.064 mmol) in DMF (0.5 mL) was added and stirred for 30 min. Finally, iodomethane (18.2 mg, 0.128 mmol) was added and the reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic) to give compound 55 (8.4 mg, 0.019 mmol) as a white solid. LCMS (ESI) m / z: 452.2 [M+H] + , HPLC method B:R T= 7.53min, purity>98.8% 1 H NMR(600MHz,DMSO-d6)δ7.92(d,J=1.8Hz,1H),7.83-7.75(m,1H),7.57-7.53(m, 1H),7.40-7.35(m,1H),7.25-7.23(m,1H),7.13-7.10(m,1H),3.92-3.73(m,2H) ,3.55-3.44(m,0.7H),3.32-3.28(m,3.6H),3.28-3.20(m,2H),3.03-2.78(m,3. 7H),2.48-2.41(m,3H),2.08-1.85(m,1H),1.75-1.42(m,2H),1.28-0.95(m,2H).

[0221] Example 56: Synthesis of Compound 56 [ka]

[0222] Substrate S8 (23 mg, 67.6 μmol) was added to a dry one-neck flask, and DMF (1.5 mL) was added and stirred to dissolve. DIPEA (59 μL, 0.34 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (31 mg, 81 μmol) was added and stirred at 0°C for 5 minutes. 2-Methoxy-4-(aminomethyl)pyridine (11.2 mg, 81 μmol) was then added to the reaction mixture. The reaction mixture was allowed to react at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give white solid 56-1 (25 mg, 54.3 μmol, 80%).

[0223] NaH (8 mg, 0.2 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 56-1 (25 mg, 54.3 μmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (28 mg, 0.2 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 56-2 (22 mg, 46.3 μmol, 85%). LCMS (ESI) + ) m / z: 475.0 [M+H] + .

[0224] Substrate 56-2 (17 mg, 36 μmol) was weighed into a 25 mL one-neck flask, and 1,4-dioxane (2 mL) was added. The mixture was stirred to dissolve the substrate. Concentrated hydrochloric acid (1 mL) was then added and the mixture was heated to 90°C and stirred for 16 hours. After confirming the complete reaction by LCMS, saturated NaHCO3 was added to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give white solid 56 (10 mg, 21.7 μmol, 60%). LCMS (ESI) +) m / z: 461.1 [M+H] + 1 H NMR(600MHz,DMSO-d6)δ11.49(s,1H),7.96(d,J=1.8Hz,0.7H),7.94(d,J=1.8Hz,0.3H),7.83(dd,J=7.8,1.8Hz, 0.7H),7.76(dd,J=7.8,1.8Hz,0.3H),7.65(d,J=7.8Hz,0.7H),7.57(d,J=7.8Hz,0.3H),7.40-7.31(m,2H),7.27 -7.20(m,1H),7.15-7.07(m,1H),6.37(d,J=1.6Hz,0.7H),6.27-6.21(m,1H),6.15(dd,J=6.8,1.8Hz,0.3H),4.5 4(s,1.4H),4.14(d,J=5.7Hz,0.6H),3.33(s,3H),2.93(s,0.9H),2.77(s,2.1H),2.47(s,2.1H),2.45(s,0.9H). [ka]

[0225] Synthesis of compound S9 Compound S1 (200 mg, 0.68 mmol), 4-fluoro-2-methoxyphenylboronic acid (140 mg, 0.82 mmol), Pd(dppf)Cl2 (58 mg, 0.068 mmol), and K2CO3 (282 mg, 2.04 mmol) were added to a dry one-neck flask. The solvent 1,4-dioxane (4 mL) and water (1 mL) were then added. The reaction flask was sealed, purged with nitrogen gas three times, heated to 100 °C, and stirred overnight. After cooling to room temperature, EtOAc and water were added and the layers were separated. The organic phase was washed with saturated brine, dried, filtered, and concentrated. The crude product was purified by column chromatography to give the desired product S9 (153 mg, 0.45 mmol, 66%).

[0226] Synthesis of compound S10 Compound S9 (153 mg, 0.45 mmol) was dissolved in a mixed solvent of MeOH / HO (4:1, 5 mL) and NaOH (200 mg, 5 mmol) was added. The mixture was heated at 70 °C for 2 hours, and complete reaction was confirmed by LCMS. After cooling to room temperature, the pH was adjusted to approximately 5 by adding 2N HCl solution. The mixture was extracted with ethyl acetate, separated, and the organic phase was washed with saturated brine, dried, concentrated, and purified by medium-pressure liquid chromatography to obtain a white solid, S10 (142.7 mg, 0.44 mmol, 97%).

[0227] Example 57: Synthesis of Compound 57 [ka]

[0228] Substrate S10 (50 mg, 0.154 mmol) was placed in a dry one-neck flask, and DMF (1.5 mL) was added and stirred to dissolve. DIPEA (118 μL, 0.68 mmol) was then added to the reaction mixture and cooled in an ice-water bath. HATU (70.4 mg, 0.185 mmol) was added and stirred at 0°C for 5 minutes. 2-Methoxy-4-(aminomethyl)pyridine (25.5 mg, 0.185 mmol) was then added to the reaction mixture. The reaction was allowed to proceed at 0°C for 20 minutes, and complete reaction was confirmed by LC-MS. Water was added to quench the reaction, followed by extraction three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give white solid 57-1 (35 mg, 78.7 μmol, 51%). LCMS (ESI) + ) m / z: 445.5 [M+H] +

[0229] NaH (16 mg, 0.4 mmol) was added to a dry one-neck flask, which was then sealed and flushed with nitrogen gas three times. DMF (1 mL) was added and cooled in an ice-water bath. Substrate 57-1 (40 mg, 90 μmol) was dissolved in 0.5 mL of DMF and added dropwise to the reaction flask. After the dropwise addition, the mixture was stirred for 20 minutes while maintaining the temperature. CHCl (56 mg, 0.4 mmol) was then added and the reaction was allowed to proceed at 0°C for 1 hour. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure liquid chromatography to give product 57-2 (18.7 mg, 40.8 μmol, 45%). LCMS (ESI) + ) m / z: 459.4 [M+H] +

[0230] Substrate 57-2 (18.7 mg, 40.8 μmol) was weighed into a 25 mL one-neck flask, and 1,4-dioxane (2 mL) was added. The mixture was stirred to dissolve the substrate. Concentrated hydrochloric acid (1 mL) was then added and the mixture was heated to 90°C and stirred for 16 hours. LCMS confirmed the complete reaction. Saturated NaHCO3 was added to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to give white solid 57 (5.12 mg, 11.5 μmol, 28%). LCMS (ESI) + ) m / z: 445.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.04(dd,J=5.2,1.8Hz,1H),7.88(ddd,J= 28.9,7.9,1.8Hz,1H),7.64-7.43(m,2H),7.35(dd,J=14.4,6.7Hz,1H),7.10(dd d,J=10.7,8.0,2.5Hz,1H),7.03-6.87(m,1H),6.40-6.12(m,2H),4.53(s,1H),4 .24-4.12(m,1H),3.83(d,J=9.2Hz,3H),3.33(s,3H),2.93(s,1H),2.77(s,2H).

[0231] Example 58: Synthesis of Compound 58 [ka]

[0232] Under N2 protection, a microwave tube was charged with substrate S4 (20 mg, 0.052 mmol), phenylboronic acid (7.54 mg, 0.062 mmol), Pd(dppf)Cl2 (3.76 mg, 0.0052 mmol), and K2CO3 (21.36 mg, 0.155 mol). 1 mL of dioxane / HO (v:v = 3:1) was added and stirred to dissolve. After stirring at 100 °C for 2 h, the reaction was confirmed to be complete by LC-MS. The solvent was evaporated, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting solid was purified by medium-pressure liquid chromatography to give 58 (7 mg, 0.018 mmol, 35.25% yield, 100% purity). LCMS (ESI+) m / z: 386.1 [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ8.16(dd,J=2.7,1.8Hz,1H),8.08(ddd,J=9.9,7.9,1.9H z,1H),7.82-7.72(m,2H),7.54(dd,J=8.2,6.7Hz,3H),7.50-7.43(m,1H),3.52(d ,J=9.1Hz,1H),3.32(s,2H),3.29(s,1H),3.08(d,J=9.7Hz,1H),2.97(s,1H),2. 78(s,2H),1.87-1.66(m,4H),1.68-1.51(m,2H),1.31-1.11(m,3H),0.99(s,2H).

[0233] The effects of the compounds of the present invention will be explained below by way of test examples. Test Example 1: SPR binding test detection of TRIM21 compounds 1. Experimental materials and reagents [Table 1]

[0234] 2. SPR test method Preparation of running buffer: Protein immobilization buffer and running buffer A contained 7.6 mM NaH2OP4, 12.4 mM NaH2OP4, 150.0 mM NaCl, 0.1% Tween 20, and a pH of 7.0. Running buffer B contained 7.6 mM NaH2OP4, 12.4 mM NaH2OP4, 150.0 mM NaCl, 0.1% Tween 20, and a pH of 7.0. DMSO was 1.00% and a pH of 7.0. After preparation, the running buffer was filtered through a 0.22 μm membrane filter.

[0235] Strep Tactin XT immobilization: The surface of the CM5 chip was washed three times with 50 mM NaOH (flow rate 60.0 μL / min, 60 s each). An activation reagent was prepared using EDC (75.00 mg / mL) and NHS (11.50 mg / mL) in a 1:1 volume ratio, as provided by the Amino Coupling Kit, and the chip was activated for 420 s (activation flow rate 6.0 μL / min). Strep Tactin XT was prepared at 50.0 μg / mL using the Strep Tactin XT immobilization buffer provided by the Twin Strep Tag Capture Kit. The prepared Strep Tactin XT was injected at a flow rate of 5.0 μL / min for 600 s. After the His antibody injection, the chip surface was blocked with 1 M ethanolamine (provided in the Amino Coupling Kit) at a flow rate of 6.0 μL / min for 7 min. The final immobilized amount of Strep Tactin XT was approximately 12,000 RU.

[0236] Immobilization of TRIM21 protein: Running buffer A was used as the protein immobilization buffer. TRIM21 protein was prepared at 40.0 μg / mL in protein buffer and injected at 5.0 μL / min for 600 seconds. TRIM21 protein was captured on a CM5 chip using Strep tactin XT. The final immobilized amount of TRIM21 was approximately 2200.00 RU.

[0237] Compound dilution: Test compounds were diluted with 100% DMSO to 100x the required final concentration, mixed evenly, and then 4.0 μL was aspirated and added to 396 μL running buffer A. The mixture was centrifuged at 15,000 rpm for 5 minutes to obtain a 1X compound solution containing 1% DMSO for subsequent dilutions. Compounds were serially diluted from the starting concentration using running buffer B, with 2-fold dilutions across eight concentrations. The diluted compounds were transferred to a 96-well plate for sample injection.

[0238] Program running: Biacore 8K Control software was opened. The experiment was performed at 25°C. Running buffer B was used for the program, with a flow rate of 30.0 μL / min. After three injections of buffer B to complete equilibration, compounds were injected sequentially from lowest to highest concentration. The binding and dissociation times were both 60 seconds. After each injection, the injection needle was washed with 50% DMSO. The solvent difference due to DMSO was corrected with 0.50%, 0.75%, 1.00%, 1.25%, and 1.50% DMSO.

[0239] 3. Data analysis The response values ​​of compounds binding to TRIM21 were analyzed after subtracting the reference channel and zero concentration, and the affinity Kd was fitted using a steady-state affinity model (1:1 binding model) using Biacore Insight evaluation software.

[0240] The affinity of TRIM21 for the compounds of the examples was determined according to the above method. The test results are shown in Table 1. The measured Kd values ​​of each compound are classified as follows: "-" indicates a Kd value greater than 10 μM. "+" indicates a Kd value less than or equal to 10 μM and greater than 1 μM. "++" indicates a Kd value of 1 μM or less and greater than 100 nM. "+++" indicates a Kd value less than or equal to 100 nM and greater than 10 nM. "++++" indicates a Kd value of 10 nM or less and greater than 1 nM.

[0241] Table 1: Affinity of compounds of the present invention for TRIM21 protein [Table 2] TIFF2026507461000089.tif184170

[0242] Experimental data show that the compounds of the present invention have moderate to good affinity for TRIM21 protein and may be therapeutic agents for TRIM21-related diseases such as tumors and autoimmune diseases. The compounds of the present invention may also be ligands or intermediate compounds for developing proteolytic bifunctional drug molecules based on TRIM21.

Claims

1. A compound of formula I, a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 Formula I wherein ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, a 3- to 10-membered cycloalkyl, and a 3- to 10-membered heterocycle, and said ring A further comprises one, two, three, or four independent R １ may be substituted with The R １ are each independently hydrogen, halogen, cyano, nitro, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, hydroxyl substituted -C １～６ Alkyl, —C ０～４ Alkylene-OR １２ , -C ０～４ Alkylene -OC(O)R １２ , -C ０～４ Alkylene-SR １２ , -C ０～４ Alkylene-S(O) ２ R １２ , -C ０～４ Alkylene-S(O)R １２ , -C ０～４ Alkylene-S(O) ２ NR １２ R １３ , -C ０～４ Alkylene-S(O)NR １２ R １３ , -C ０～４ Alkylene -C(O)R １２ , -C ０～４ Alkylene -C(O)OR １２ , -C ０～４ Alkylene-C(O)NR １２ R １３ , -C ０～４ Alkylene -NR １２ R １３ , -C ０～４ Alkylene -NR １２ C(O)R １３ , -C ０～４ Alkylene -NR １２ S (O) ２ R １３ , -C ０～４ Alkylene -NR １２ S(O)R １３ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); R １２ , R １３ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R １４ may be substituted with The R １４ are each independently hydrogen, halogen, cyano, nitro, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, The R ２ are each independently hydrogen, halogen, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ２２ , -C ０～４ Alkylene -OC(O)R ２２ , -C ０～４ Alkylene-SR ２２ , -C ０～４ Alkylene-S(O) ２ R ２２ , -C ０～４ Alkylene-S(O)R ２２ , -C ０～４ Alkylene-S(O) ２ NR ２２ R ２３ , -C ０～４ Alkylene-S(O)NR ２２ R ２３ , -C ０～４ Alkylene -C(O)R ２２ , -C ０～４ Alkylene -C(O)OR ２２ , -C ０～４ Alkylene-C(O)NR ２２ R ２３ , -C ０～４ Alkylene -NR ２２ R ２３ , -C ０～４ Alkylene -NR ２２ C(O)R ２３ , -C ０～４ Alkylene -NR ２２ S (O) ２ R ２３ , -C ０～４ Alkylene -NR ２２ S(O)R ２３ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); R ２２ , R ２３ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R ２４ may be substituted with The R ２４ are each independently hydrogen, halogen, cyano, nitro, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, R ３ , R ４ are each independently hydrogen, halogen, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ３４ , -C ０～４ Alkylene -OC(O)R ３４ , -C ０～４ Alkylene-SR ３４ , -C ０～４ Alkylene-S(O) ２ R ３４ , -C ０～４ Alkylene-S(O)R ３４ , -C ０～４ Alkylene-S(O) ２ NR ３４ R ３５ , -C ０～４ Alkylene-S(O)NR ３４ R ３５ , -C ０～４ Alkylene -C(O)R ３４ , -C ０～４ Alkylene -C(O)OR ３４ , -C ０～４ Alkylene-C(O)NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ C(O)R ３５ , -C ０～４ Alkylene -NR ３４ S (O) ２ R ３５ , -C ０～４ Alkylene -NR ３４ S(O)R ３５ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R ３６ may be substituted with Each R ３６ are each independently hydrogen, halogen, cyano, nitro, ═O, ═S, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ３４ , -C ０～４ Alkylene -OC(O)R ３４ , -C ０～４ Alkylene-SR ３４ , -C ０～４ Alkylene-S(O) ２ R ３４ , -C ０～４ Alkylene-S(O)R ３４ , -C ０～４ Alkylene-S(O) ２ NR ３４ R ３５ , -C ０～４ Alkylene-S(O)NR ３４ R ３５ , -C ０～４ Alkylene -C(O)R ３４ , -C ０～４ Alkylene -C(O)OR ３４ , -C ０～４ Alkylene-C(O)NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ C(O)R ３５ , -C ０～４ Alkylene -NR ３４ S (O) ２ R ３５ , -C ０～４ Alkylene -NR ３４ S(O)R ３５ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R ３７ may be substituted with R ３４ , R ３５ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, Each R ３７ are each independently hydrogen, halogen, cyano, nitro, ═O, ═S, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl.)

2. The compound according to claim 1, characterized in that the compound is represented by the following formula IIA: 【Chemistry 2】 Formula IIA (In the formula, R １ , R ２ , R ３ , R ４ has the same meaning as in claim 1.)

3. The A ring is selected from a 6-membered aromatic ring, a 6-membered cycloalkyl, a 9-membered heterocyclic alkyl, a 6-membered aromatic heterocyclic ring, and a 9-membered aromatic heterocyclic ring, and the aromatic ring, cycloalkyl, heterocycloalkyl, and aromatic heterocyclic ring further have one, two, three, or four independent R １ may be substituted with The R １ is hydrogen, halogen, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, hydroxyl substituted -C １～６ Alkyl, —C ０～４ Alkylene-OR １２ , -C ０～４ Alkylene -OC(O)R １２ , -C ０～４ Alkylene-SR １２ , -C ０～４ Alkylene -NR １２ R １３ , -C ０～４ alkylene-(3- to 6-membered cycloalkyl), —C ０～４ alkylene-(3- to 6-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); R １２ , R １３ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ 2. The compound according to claim 1, characterized in that it is selected from alkyl.

4. The R １ is hydrogen, methylthio, halogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, 【Transformation 3】 cyclopropyl, 【Chemistry 4】 4. The compound according to claim 3, characterized in that it is selected from:

5. The A ring is 【Transformation 5】 4. The compound according to claim 3, characterized in that it is selected from:

6. The R ２ is -C １～３ 3. Compounds according to claim 1 or 2, characterized in that they are selected from alkyl.

7. The R ３ , R ４ are each independently hydrogen, —C １～６ Alkyl, —C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R ３６ may be substituted with Each R ３６ are each independently hydrogen, halogen, cyano, ═O, or —C １～６ Alkyl, halogen-substituted —C １～６ Alkyl, —C ０～４ Alkylene-OR ３４ , -C ０～４ Alkylene -C(O)R ３４ , -C ０～４ Alkylene -C(O)OR ３４ , -C ０～４ Alkylene-C(O)NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ R ３５ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); R ３４ , R ３５ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ 3. Compounds according to claim 1 or 2, characterized in that they are selected from alkynyl.

8. The R ３ , R ４ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C ０～２ alkylene-(3-membered cycloalkyl), -C ０～２ alkylene-(4-membered cycloalkyl), -C ０～２ alkylene-(5-membered cycloalkyl), -C ０～２ alkylene-(6-membered cycloalkyl), -C ０～２ alkylene-(4-membered heterocycloalkyl), —C ０～２ alkylene-(5-membered heterocycloalkyl), —C ０～２ alkylene-(6-membered heterocycloalkyl), —C ０～２ alkylene-(9-membered heterocycloalkyl), —C ０～２ Alkylene-(6-membered aromatic ring), -C ０～２ alkylene-(5-membered heteroaromatic ring), -C ０～２ alkylene-(6-membered heteroaromatic ring), -C ０～２ alkylene-(9-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R ３６ may be substituted with Each R ３６ are each independently hydrogen, halogen, ═O, or —C １～３ Alkyl, halogen-substituted —C １～３ Alkyl, -OR ３４ , -C(O)R ３４ , -NR ３４ R ３５ is selected from R ３４ , R ３５ are each independently hydrogen, —C １～３ 8. The compound according to claim 7, characterized in that it is selected from alkyl.

9. The R ３ , R ４ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, 【Transformation 6】 9. The compound according to claim 8, characterized in that it is selected from:

10. The compound is specifically 【Transformation 7】 【change】 【change】 【change】 10. A compound according to any one of claims 1 to 9.

11. A compound represented by formula V, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 8】 Formula V wherein ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, a 3- to 10-membered cycloalkyl, and a 3- to 10-membered heterocycle, and said ring A further comprises one, two, three, or four independent R １ may be substituted with The R １ are each independently hydrogen, halogen, cyano, nitro, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR １２ , -C ０～４ Alkylene -OC(O)R １２ , -C ０～４ Alkylene-SR １２ , -C ０～４ Alkylene-S(O) ２ R １２ , -C ０～４ Alkylene-S(O)R １２ , -C ０～４ Alkylene-S(O) ２ NR １２ R １３ , -C ０～４ Alkylene-S(O)NR １２ R １３ , -C ０～４ Alkylene -C(O)R １２ , -C ０～４ Alkylene -C(O)OR １２ , -C ０～４ Alkylene-C(O)NR １２ R １３ , -C ０～４ Alkylene -NR １２ R １３ , -C ０～４ Alkylene -NR １２ C(O)R １３ , -C ０～４ Alkylene -NR １２ S (O) ２ R １３ , -C ０～４ Alkylene -NR １２ S(O)R １３ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); R １２ , R １３ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R １４ may be substituted with The R １４ are each independently hydrogen, halogen, cyano, nitro, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, The R ２ are each independently hydrogen, halogen, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ２２ , -C ０～４ Alkylene -OC(O)R ２２ , -C ０～４ Alkylene-SR ２２ , -C ０～４ Alkylene-S(O) ２ R ２２ , -C ０～４ Alkylene-S(O)R ２２ , -C ０～４ Alkylene-S(O) ２ NR ２２ R ２３ , -C ０～４ Alkylene-S(O)NR ２２ R ２３ , -C ０～４ Alkylene -C(O)R ２２ , -C ０～４ Alkylene -C(O)OR ２２ , -C ０～４ Alkylene-C(O)NR ２２ R ２３ , -C ０～４ Alkylene -NR ２２ R ２３ , -C ０～４ Alkylene -NR ２２ C(O)R ２３ , -C ０～４ Alkylene -NR ２２ S (O) ２ R ２３ , -C ０～４ Alkylene -NR ２２ S(O)R ２３ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); R ２２ , R ２３ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may further comprise one, two, three, or four independent R ２４ may be substituted with The R ２４ are each independently hydrogen, halogen, cyano, nitro, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, R ３ is hydrogen, halogen, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ３４ , -C ０～４ Alkylene -OC(O)R ３４ , -C ０～４ Alkylene-SR ３４ , -C ０～４ Alkylene-S(O) ２ R ３４ , -C ０～４ Alkylene-S(O)R ３４ , -C ０～４ Alkylene-S(O) ２ NR ３４ R ３５ , -C ０～４ Alkylene-S(O)NR ３４ R ３５ , -C ０～４ Alkylene -C(O)R ３４ , -C ０～４ Alkylene -C(O)OR ３４ , -C ０～４ Alkylene-C(O)NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ C(O)R ３５ , -C ０～４ Alkylene -NR ３４ S (O) ２ R ３５ , -C ０～４ Alkylene -NR ３４ S(O)R ３５ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring further comprises one, two, three, or four independent R ３６ may be substituted with Each R ３６ are each independently hydrogen, halogen, cyano, nitro, ═O, ═S, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR ３４ , -C ０～４ Alkylene -OC(O)R ３４ , -C ０～４ Alkylene-SR ３４ , -C ０～４ Alkylene-S(O) ２ R ３４ , -C ０～４ Alkylene-S(O)R ３４ , -C ０～４ Alkylene-S(O) ２ NR ３４ R ３５ , -C ０～４ Alkylene-S(O)NR ３４ R ３５ , -C ０～４ Alkylene -C(O)R ３４ , -C ０～４ Alkylene -C(O)OR ３４ , -C ０～４ Alkylene-C(O)NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ R ３５ , -C ０～４ Alkylene -NR ３４ C(O)R ３５ , -C ０～４ Alkylene -NR ３４ S (O) ２ R ３５ , -C ０～４ Alkylene -NR ３４ S(O)R ３５ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, and one, two, three, or four independent R ３７ may be substituted with R ３４ , R ３５ are each independently hydrogen, —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, Each R ３７ are each independently hydrogen, halogen, cyano, nitro, ═O, ═S, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl, T is -(L Ｔ ) ｑ - is selected from, q is selected from an integer from 1 to 50; Each L Ｔ are each independently, CR Ｔ２ R Ｔ３ , C(O), -C(S)-, O, S, S(O), S(O) ２ , N.R. Ｔ２ , -CR Ｔ２ =CR Ｔ３ -, -C≡C-, a 3- to 12-membered cycloalkyl, a 3- to 12-membered heterocyclic alkyl, a 6- to 10-membered aromatic ring, a 5- to 10-membered heteroaromatic ring, a 5- to 12-membered spiro ring, a 5- to 12-membered spiroheterocyclic ring, a 5- to 12-membered bridged ring, and a 5- to 12-membered bridged heterocyclic ring, wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro ring, spiroheterocyclic ring, bridged ring, and bridged heterocyclic ring further comprise one, two, or three R Ｔ１ may be substituted with Each R Ｔ１ are each independently hydrogen, halogen, cyano, nitro, ═O, ═S, or ═CR Ｔ２ R Ｔ３ , -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ Alkylene-OR Ｔ２ , -C ０～４ Alkylene -OC(O)R Ｔ２ , -C ０～４ Alkylene-SR Ｔ２ , -C ０～４ Alkylene-S(O) ２ R Ｔ２ , -C ０～４ Alkylene-S(O)R Ｔ２ , -C ０～４ Alkylene-S(O) ２ NR Ｔ２ R Ｔ３ , -C ０～４ Alkylene-S(O)NR Ｔ２ R Ｔ３ , -C ０～４ Alkylene -C(O)R Ｔ２ , -C ０～４ Alkylene -C(O)OR Ｔ２ , -C ０～４ Alkylene-C(O)NR Ｔ２ R Ｔ３ , -C ０～４ Alkylene -NR Ｔ２ R Ｔ３ , -C ０～４ Alkylene -NR Ｔ２ C(O)R Ｔ３ , -C ０～４ Alkylene -NR Ｔ２ S (O) ２ R Ｔ３ , -C ０～４ Alkylene -NR Ｔ２ S(O)R Ｔ３ , -C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may further comprise one, two, three, or four independent R Ｔ４ may be substituted with R Ｔ２ , R Ｔ３ , R Ｔ４ are each independently hydrogen, halogen, cyano, nitro, ═O, ═S, or —C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ Alkynyl, —C ０～４ alkylene-(3- to 10-membered cycloalkyl), —C ０～４ alkylene-(3- to 10-membered heterocycloalkyl), —C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ alkylene-(5- to 10-membered heteroaromatic ring); X ２ is -NH ２ , -NHR Ｘ２１ , —OH, —SH, ethynyl, vinyl, —C(O)H or —C(O)OH—; R Ｘ２１ is hydrogen, -C １～６ Alkyl, —C ２～６ Alkenyl, -C ２～６ Alkynyl, halogen-substituted —C １～６ Alkyl, halogen-substituted —C ２～６ Alkenyl, halogen-substituted —C ２～６ alkynyl.)

12. The compound according to claim 11, wherein the compound represented by formula V is represented by the following formula Via: 【Chemistry 9】 ExpressionVia (In the formula, R １ , R ２ , R ３ , T, X ２ has the same meaning as in claim 11.)

13. The T is 【Chemistry 10】 13. The compound according to claim 12, characterized in that it is selected from:

14. 14. Use of a compound according to any one of claims 1 to 13, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with abnormal cell proliferation.

15. The use according to claim 14, characterized in that the disease is cancer.

16. Use of a compound according to any one of claims 1 to 13, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof in the preparation of a targeted protein degradation drug.

17. The use according to claim 16, wherein the compound, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof is used as an intermediate in the preparation of a targeted protein degradation drug.

18. The use according to claim 16, wherein the targeted protein degradation drug is a drug that performs protein degradation dependent on E3 ligase TRIM21.

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