Compounds used as CDK kinase inhibitors and their applications

Abstract

The present invention relates to compounds used as CDK kinase inhibitors and their applications. [Solution] The compounds of the present invention specifically have the structure shown in formula (I), wherein the definitions of each group and substituent are as described in the specification, and the present invention further discloses a method for preparing said compounds and their use in modulating CDK kinase activity or treating CDK-related diseases. [Formula 1] JPEG2026042774000142.jpg3760

Description

[Technical Field]

[0001] The present invention relates to the field of medical technology, and in particular to compounds used as CDK kinase inhibitors and their application in modulating CDK kinase activity or treating CDK-related diseases. [Background technology]

[0002] The cell cycle refers to the entire process from the completion of cell division to the end of the next division, and is divided into interphase and mitotic phase. Interphase is further divided into three phases: the early stage of DNA synthesis (G1 phase), the late stage of DNA synthesis (S phase), and the late stage of DNA synthesis (G2 phase), and mitotic phase is the M phase. Cyclins and cyclin-dependent kinases (CDKs) are key molecules in the entire cell cycle control mechanism. At least 16 mammalian cyclins have been identified, including cyclin B / CDK1 (CyclinB / CDK1), cyclin A / CDK2 (CyclinA / CDK2), cyclin E / CDK2 (CyclinE / CDK2), cyclin D / CDK4 (CyclinD / CDK4), cyclin D / CDK6 (CyclinD / CDK6), and possible other heterodynes, which are key regulators of cell cycle progression. Other functions of cyclin / CDK heterodynes include transcriptional regulation, DNA repair, differentiation, and apoptosis.

[0003] Dysregulation of the cell cycle is a common feature of human cancer, and cyclin-dependent kinase (CDK) inhibitors have been identified as playing a critical role in cell cycle control. This potential for widespread application in the field of cancer therapy is expected. For example, the CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib have been targeted for the treatment of breast cancer and other cancers. However, as with other kinase inhibitors, their efficacy may be limited by the development of primary or acquired resistance over time. Therefore, PF-06873600, developed by Pfizer, is a novel multitargeted CDK kinase inhibitor that is expected to address the resistance phenomenon that arises under existing conditions. PF-06873600 is also currently in Phase I clinical trials for the treatment of metastatic breast cancer.

[0004] Cyclin-dependent kinase (CDK) inhibitors are one of the most promising areas of cancer therapy, and the development of new compounds with CDK kinase inhibitory activity and superior pharmacodynamic and pharmacokinetic performance has become an important research project in the development of novel antitumor drugs, which will ultimately be used to treat human tumors and other diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to provide a compound of formula (I), its preparation process and its use as a CDK2 / 4 / 6 kinase inhibitor drug. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: [ka] where: R1 is a C3-C10 cycloalkyl group unsubstituted or substituted with 1 to 4 R6, a 5 to 15 membered fused ring unsubstituted or substituted with 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5 to 15 membered spiro ... a 5- to 15-membered bridged ring substituted by R6, a 3- to 10-membered heterocycloalkyl group unsubstituted or substituted by 1 to 4 R6 and containing 1 to 4 heteroatoms selected from N, O, and S, a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R6, a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R6 and containing 1 to 5 heteroatoms selected from N, O, and S, a C1-C6 alkyl group unsubstituted or substituted by 1 to 4 R6; R2 is selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group, and R2 can be linked to atoms on the ring to form a spirocyclic, bridged, or fused ring structure; R 3a and R 3b are independently selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; Here, R2, R 3a and R 3b wherein each C1-C4 alkyl group and halogenated C1-C4 alkyl group is optionally substituted with halogen, OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; R4 is selected from the group consisting of Br, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, -OR4', -SR4', and -NR4'R4", where R4' and R4" are each independently selected from the group consisting of H, COR7, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, and the substitution refers to substitution by 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R5 is selected from the group consisting of H, halogen, C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; Each R6 is H, deuterium, a hydroxy group, a halogen, a cyano group, ═O, COR7, CO2R7, CONR8R9, CO2NR8R9, SO2R7, SO2NR8R9, NR8SO2R7, NHSO2NR8R9, [ka] R''' is independently selected from the group consisting of NR8R9, a substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, a halogenated C3-C8 cycloalkyl group, a C4-C10 spiro ring, a C3-C10 fused ring, a C4-C10 bridged ring, a thio C1-C6 alkyl group, a C6-C10 aryl group, and a 3-10 membered heteroaryl group containing 1-5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R'', a C1-C4 alkyl group, and a halogenated C1-C4 alkyl group; Each R7 is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl the 3- to 10-membered aryl group is optionally substituted by 0-4 D, OH, halogen, CN, C1-C4 alkyl group, halogenated C1-C4 alkyl group, N(C1-C4 alkyl)2, NHCO(C1-C4 alkyl), SO2(C1-C4 alkyl), CO2(C1-C4 alkyl), 3- to 6-membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O and S, CO(C1-C4 alkyl), C1-C4 alkoxy group or halogenated C1-C4 alkoxy group; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; r is selected from the group consisting of 0, 1, 2, 3, and 4.

[0007] In another preferred example, R1 is selected from the group consisting of a C3-C10 cycloalkyl group unsubstituted or substituted by 1 to 4 R6, a 5- to 15-membered fused ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5- to 15-membered spiro ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5- to 15-membered bridged ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 3- to 10-membered heterocycloalkyl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 4 heteroatoms selected from N, O and S, a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R6, and a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 5 heteroatoms selected from N, O and S; R2 is selected from the group consisting of H and F; R 3a and R 3b are independently selected from the group consisting of H, F, OH, and C1-C4 alkyl groups; R4 is selected from the group consisting of substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups containing 1 to 4 heteroatoms selected from N, O, and S, -OR4', -NR4'R4", where R4' and R4" are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl groups, and the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, and C1-C4 alkyl groups; R5 is selected from the group consisting of H, C1-C2 alkyl groups; each R6 is independently selected from the group consisting of H, deuterium, a hydroxy group, a halogen, a cyano group, =O, COR7, CO2R7, CONR8R9, SO2R7, SO2NR8R9, NR8S02R7, NHSON2NR8R9, NR8R9, an R''' substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, a halogenated C3-C8 cycloalkyl group, a C4-C10 spiro ring, a C3-C10 fused ring, a C4-C10 bridged ring, a thio C1-C6 alkyl group, a C6-C10 aryl group, and a 3-10 membered heteroaryl group containing 1-5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R'', a C1-C4 alkyl group, and a halogenated C1-C4 alkyl group; Each R7 is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl the 3- to 10-membered aryl group is optionally substituted by 0-4 D, OH, halogen, CN, C1-C4 alkyl group, halogenated C1-C4 alkyl group, N(C1-C4 alkyl)2, NHCO(C1-C4 alkyl), SO2(C1-C4 alkyl), CO2(C1-C4 alkyl), 3- to 6-membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O and S, CO(C1-C4 alkyl), C1-C4 alkoxy group or halogenated C1-C4 alkoxy group; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; r is selected from the group consisting of 0, 1, 2, 3, and 4.

[0008] In another preferred example, R1 is selected from the group consisting of a C3-C10 cycloalkyl group unsubstituted or substituted by 1 to 4 R6, a 3- to 10-membered heterocycloalkyl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 4 heteroatoms selected from N, O and S, a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R6, and a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 5 heteroatoms selected from N, O and S; R2 is selected from the group consisting of H and F; R 3a and R 3b are independently selected from the group consisting of H, F, OH, and C1-C4 alkyl groups; R4 is selected from the group consisting of substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups containing 1-4 heteroatoms selected from N, O, and S, and -OR4', where R4' is independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl groups, and the substitution refers to substitution with 1-3 substituents selected from the group consisting of deuterium, halogen, and C1-C4 alkyl groups; R5 is selected from the group consisting of H, C1-C2 alkyl groups; each R6 is independently selected from the group consisting of H, deuterium, a hydroxy group, a halogen, a cyano group, =O, COR7, CO2R7, CONR8R9, SO2R7, SO2NR8R9, NR8S02R7, NHSON2NR8R9, NR8R9, an R''' substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, a halogenated C3-C8 cycloalkyl group, a C4-C10 spiro ring, a C3-C10 fused ring, a C4-C10 bridged ring, a thio C1-C6 alkyl group, a C6-C10 aryl group, and a 3-10 membered heteroaryl group containing 1-5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R'', a C1-C4 alkyl group, and a halogenated C1-C4 alkyl group; Each R7 is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl the 3- to 10-membered aryl group is optionally substituted by 0-4 D, OH, halogen, CN, C1-C4 alkyl group, halogenated C1-C4 alkyl group, N(C1-C4 alkyl)2, NHCO(C1-C4 alkyl), SO2(C1-C4 alkyl), CO2(C1-C4 alkyl), 3- to 6-membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O and S, CO(C1-C4 alkyl), C1-C4 alkoxy group or halogenated C1-C4 alkoxy group; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; r is selected from the group consisting of 0, 1, 2, 3, and 4.

[0009] In another preferred example, R1 is a C3-C10 cycloalkyl group unsubstituted or substituted by 1 to 4 R6, a 5 to 15-membered fused ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5 to 15-membered spiro ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5- to 15-membered bridged ring substituted by 1 to 4 R6 containing 1 to 4 heteroatoms selected from N, O, and S; a 3- to 10-membered heterocycloalkyl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 4 heteroatoms selected from N, O, and S; a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R6; a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 5 heteroatoms selected from N, O, and S; a C1-C6 alkyl group unsubstituted or substituted by 1 to 4 R6; R2 is selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group, and R2 can be linked to atoms on the ring to form a spirocyclic, bridged, or fused ring structure; R 3a and R 3b are independently selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; Here, R2, R 3a and R 3b wherein each C1-C4 alkyl group and halogenated C1-C4 alkyl group is optionally substituted with halogen, OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; R4 is selected from the group consisting of Br, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, -OR4', -SR4', and -NR4'R4", where R4' and R4" are each independently selected from the group consisting of H, COR7, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, and the substitution refers to substitution by 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R5 is selected from the group consisting of H, halogen, C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; Each R6 is H, deuterium, a hydroxy group, a halogen, a cyano group, ═O, COR7, CO2R7, CONR8R9, CO2NR8R9, SO2R7, SO2NR8R9, NR8SO2R7, NHSO2NR8R9, [ka] R''' is independently selected from the group consisting of NR8R9, a substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, a halogenated C3-C8 cycloalkyl group, a C4-C10 spiro ring, a C3-C10 fused ring, a C4-C10 bridged ring, a thio C1-C6 alkyl group, a C6-C10 aryl group, and a 3-10 membered heteroaryl group containing 1-5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R''; Each R7 is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl Heteroaryl groups, 3-10 membered aryl groups are optionally substituted by 0-4 D, OH, halogen, CN, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, N(C1-C4 alkyl)2, NHCO(C1-C4 alkyl), SO2(C1-C4 alkyl), 3-6 membered heterocycloalkyl groups containing 1-4 heteroatoms selected from N, O and S, CO(C1-C4 alkyl), C1-C4 alkoxy groups or halogenated C1-C4 alkoxy groups; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; r is selected from the group consisting of 0, 1, 2, 3, and 4.

[0010] In another preferred embodiment, the compound has a structure shown in formula (II) or formula (III): [ka] where: Ring A is selected from the group consisting of a 6- to 10-membered aryl group containing 0-4 R' substitutions, a C3-C8 cycloalkyl group containing 0-4 R' substitutions, and a 5- to 10-membered heteroaryl group containing 0-4 R' substitutions and 1-5 heteroatoms selected from N, O, and S; Each R1' is deuterium, halogen, OH, CN, SO2R 31 , C.O.R. 31 , CO2R 31 , N.R. 41 R 51 , NHCOR 41 ,CONR 41 R 51 , OCONR 41 R 51 , NHCONR 41 R 51 , NHCOOR 41 , a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R2' is selected from the group consisting of H and deuterium; R3' is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups, and the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, C1-C4 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; R4' is selected from the group consisting of H, deuterium, and OH; 31is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R 41 and R 51 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L'-(C3-C8 cycloalkyl), -L'-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L'-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and L' is a bond or a C1-C6 alkylene group; or R 41 and R 51 may form a substituted or unsubstituted 4- to 6-membered heterocyclic group together with the N to which they are attached, and the term "substituted" means being substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, ═O, and a C1-C6 alkyl group; n is selected from the group consisting of 0, 1, 2, 3, and 4.

[0011] In another preferred embodiment, the compound has the structure shown in formula (II): [ka] where: Ring A is selected from the group consisting of a 6- to 10-membered aryl group containing 0-4 R' substitutions, a C3-C8 cycloalkyl group containing 0-4 R' substitutions, and a 5- to 10-membered heteroaryl group containing 0-4 R' substitutions and 1-5 heteroatoms selected from N, O, and S; Each R1' is deuterium, halogen, OH, CN, SO2R31 , C.O.R. 31 , CO2R 31 , N.R. 41 R 51 , NHCOR 41 ,CONR 41 R 51 , OCONR 41 R 51 , NHCONR 41 R 51 , NHCOOR 41 , a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R2' is selected from the group consisting of H and deuterium; R 31 is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R 41 and R 51 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L'-(C3-C8 cycloalkyl), -L'-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L'-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and L' is a bond or a C1-C6 alkylene group; or R 41 and R 51 may form a substituted or unsubstituted 4- to 6-membered heterocyclic group together with the N to which they are attached, and the term "substituted" means being substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, ═O, and a C1-C6 alkyl group; n is selected from the group consisting of 0, 1, 2, 3, and 4.

[0012] In another preferred example, the A ring is a 6- to 10-membered aryl group containing 0-4 R1' substitutions. In another preferred example, R3' is a C1-C4 alkyl group. In another preferred example, the A ring is a phenyl group.

[0013] In another preferred embodiment, [ka] teeth, [ka] It has the following structure.

[0014] In another preferred embodiment, [ka] wherein R1' is selected from the group consisting of H, halogen, CN, and a C1-C4 alkoxy group.

[0015] In another preferred embodiment, [ka] In the formula, R1' is F, OMe.

[0016] In another preferred embodiment, [ka] wherein ring A is a phenyl group, n is 1, and R1' is selected from the group consisting of H, halogen, CN, and a C1-C4 alkoxy group. In another preferred example, R1' is F.

[0017] In another preferred embodiment, [ka] teeth, [ka] It has the following structure.

[0018] In another preferred embodiment, [ka] In the formula, R1' is F.

[0019] In another preferred example, the A ring is a C3-C8 cycloalkyl group containing 0 to 4 R1' substitutions. In another preferred embodiment, the compound has a structure shown in formula (IV) or formula (V): [ka] wherein q is selected from the group consisting of 1, 2, 3, 4, 5, and 6.

[0020] In another preferred example, the A ring is a 5-10 membered heteroaryl group containing 0-4 R1' substituents containing 1-5 heteroatoms selected from N, O and S.

[0021] In another preferred example, the A ring is selected from the group consisting of a 6- to 10-membered aryl group having 0-4 R' substitutions, a C3-C8 cycloalkyl group having 0-4 R' substitutions, and a 5- to 10-membered heteroaryl group having 0-4 R' substitutions containing 1-5 heteroatoms selected from N, O, and S; Each R1' is deuterium, halogen, OH, CN, SO2R31 , C.O.R. 31 , CO2R 31 , N.R. 41 R 51 , NHCOR 41 ,CONR 41 R 51 , a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S; R2' is selected from the group consisting of H and deuterium; R4' is selected from the group consisting of H and deuterium; R 31 is a C1-C4 alkyl group, R 41 and R 51 are independently selected from the group consisting of H, C1-C4 alkyl groups; n is selected from the group consisting of 0, 1, 2, 3, and 4.

[0022] In another preferred example, the A ring is selected from the group consisting of a 6- to 10-membered aryl group having 0-4 R' substitutions, a C3-C8 cycloalkyl group having 0-4 R' substitutions, and a 5- to 10-membered heteroaryl group having 0-4 R' substitutions containing 1-5 heteroatoms selected from N, O, and S; Each R1' is deuterium, halogen, OH, CN, SO2R 31 , C.O.R. 31 , CO2R 31 , N.R. 41 R 51 , NHCOR 41 ,CONR 41 R 51 , a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S; R2' is selected from the group consisting of H and deuterium; R 31 is a C1-C4 alkyl group, R 41 and R 51 are independently selected from the group consisting of H, C1-C4 alkyl groups; n is selected from the group consisting of 0, 1, 2, 3, and 4.

[0023] In another preferred example, the A ring is selected from the group consisting of a 6- to 10-membered aryl group containing 0-4 R1' substitutions, a C3-C8 cycloalkyl group containing 0-4 R1' substitutions, R1' is selected from the group consisting of halogen, OH, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; R2' is selected from the group consisting of H and deuterium; n is selected from the group consisting of 0, 1, 2, 3, and 4.

[0024] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka]

[0025] In another preferred embodiment, the compound has the structure shown in formula (III): [ka] where: R2' is selected from the group consisting of H and deuterium; R3' is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups, and the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, C1-C4 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; R4' is selected from the group consisting of H, deuterium, and OH; In another preferred embodiment, R2' is H, R3' is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups, and the "substituted" refers to being substituted with 1 to 3 substituents selected from the group consisting of halogen, CN, and C1-C4 alkoxy groups;

[0026] In another preferred embodiment, the compound is selected from the group consisting of: [ka]

[0027] In another preferred embodiment, R1 is a C3-C10 cycloalkyl group unsubstituted or substituted with 1 to 4 R6, a 5 to 15 membered fused ring unsubstituted or substituted with 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5 to 15 membered spiro ... a 5- to 15-membered bridged ring substituted by R6, a 3- to 10-membered heterocycloalkyl group unsubstituted or substituted by 1 to 4 R6 and containing 1 to 4 heteroatoms selected from N, O, and S, a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R6, a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R6 and containing 1 to 5 heteroatoms selected from N, O, and S, a C1-C6 alkyl group unsubstituted or substituted by 1 to 4 R6; R2 is selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group, and R2 can be linked to atoms on the ring to form a spirocyclic, bridged, or fused ring structure; R 3a and R 3b are independently selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; Here, R2, R 3a and R 3b wherein each C1-C4 alkyl group and halogenated C1-C4 alkyl group is optionally substituted with halogen, OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; R4 is selected from the group consisting of Br, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, -OR4', -SR4', and -NR4'R4", where R4' and R4" are each independently selected from the group consisting of H, COR7, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, and the substitution refers to substitution by 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R5 is selected from the group consisting of H, halogen, C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; Each R6 is H, deuterium, a hydroxy group, a halogen, a cyano group, ═O, COR7, CO2R7, CONR8R9, CO2NR8R9, SO2R7, SO2NR8R9, NR8SO2R7, NHSO2NR8R9, [ka] R''' is independently selected from the group consisting of NR8R9, a substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, a halogenated C3-C8 cycloalkyl group, a C4-C10 spiro ring, a C3-C10 fused ring, a C4-C10 bridged ring, a thio C1-C6 alkyl group, a C6-C10 aryl group, and a 3-10 membered heteroaryl group containing 1-5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R''; each R7 is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl group, and 3- to 10-membered aryl group are optionally substituted with 0-4 OH, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, or halogenated C1-C4 alkoxy group; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; r is selected from the group consisting of 0, 1, 2, 3, and 4.

[0028] In another preferred example, R1 is selected from the group consisting of a C3-C10 cycloalkyl group unsubstituted or substituted by 1 to 4 R6, a 5- to 15-membered fused ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5- to 15-membered spiro ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a 5- to 15-membered bridged ring unsubstituted or substituted by 1 to 4 R6, which does not contain or contains 1 to 3 heteroatoms selected from N, O and S, a C6-C10 aryl group unsubstituted or substituted by 1 to 4 R6, and a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R6 containing 1 to 5 heteroatoms selected from N, O and S; R2 is selected from the group consisting of H and F; R 3a and R 3b are independently selected from the group consisting of H, F, OH, and C1-C4 alkyl groups; Here, R2, R 3a and R 3b wherein each C1-C4 alkyl group and halogenated C1-C4 alkyl group is optionally substituted with halogen, OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; R4 is selected from the group consisting of substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups containing 1 to 4 heteroatoms selected from N, O, and S, and -NR4'R4", where R4' and R4" are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl groups, and the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, and C1-C4 alkyl groups; R5 is selected from the group consisting of H, C1-C2 alkyl groups; each R6 is independently selected from the group consisting of H, deuterium, a hydroxy group, a halogen, a cyano group, =O, COR7, CO2R7, CONR8R9, SO2R7, SO2NR8R9, NR8S02R7, NHSON2NR8R9, NR8R9, an R''' substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, a halogenated C3-C8 cycloalkyl group, a C4-C10 spiro ring, a C3-C10 fused ring, a C4-C10 bridged ring, a thio C1-C6 alkyl group, a C6-C10 aryl group, and a 3-10 membered heteroaryl group containing 1-5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R''; each R7 is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl group, and 3- to 10-membered aryl group are optionally substituted with 0-4 OH, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, or halogenated C1-C4 alkoxy group; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; r is selected from the group consisting of 0, 1, 2, 3, and 4.

[0029] In another preferred embodiment, R1 is [ka] is selected from the group consisting of R4 is selected from the group consisting of a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from Br, N, O, and S, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkylthio group, and a substituted or unsubstituted C1-C4 alkylamine group; R6 is as defined in claim 1.

[0030] In another preferred embodiment, R1 is [ka] is selected from the group consisting of R4 is selected from the group consisting of a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, a substituted or unsubstituted C1-C4 alkoxy group, and a substituted or unsubstituted C1-C4 alkylamine group; R6 is as defined in claim 1.

[0031] In another preferred embodiment, each R6 is independently selected from the group consisting of H, deuterium, a hydroxy group, a halogen, a cyano group, =O, COR7, CO2R7, CONR8R9, CO2NR8R9, SO2R7, SO2NR8R9, NR8SO2R7, NHSON2NR8R9, NR8R9, an R''' substituted or unsubstituted 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O and S, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a C3-C8 cycloalkyl group, and a halogenated C3-C8 cycloalkyl group; R''' is selected from the group consisting of ═O, NR'R'', a C1-C4 alkyl group, and a halogenated C1-C4 alkyl group; R7 is selected from the group consisting of C1-C4 alkyl groups and halogenated C1-C4 alkyl groups; R8 and R9 are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, or R8 and R9 may together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic group, the substitution meaning being substituted with 1 to 3 substituents selected from the group consisting of =O, NR'R'', and a C1-C6 alkyl group; R' and R'' are independently selected from the group consisting of H, C1-C4 alkyl groups.

[0032] In another preferred example, p is 0 and r is 2. In another preferred embodiment, R4 is Br, [ka] is selected from the group consisting of:

[0033] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka]

[0034] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, the inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; The organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate, and camphorsulfonate.

[0035] A second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0036] A third aspect of the present invention provides the use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use in the preparation of a CDK2 / 4 / 6 kinase inhibitor drug.

[0037] A fourth aspect of the present invention provides the use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use in the preparation of a medicament for modulating CDK kinase activity or for treating a CDK-related disease. In another preferred embodiment, the CDK-related disease is cancer or tumor.

[0038] In another preferred example, the cancer or tumor is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, thyroid cancer, esophageal cancer, kidney cancer, liver cancer, head and neck cancer, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). In another preferred embodiment, the lung cancer is non-small cell lung cancer. [Effects of the Invention]

[0039] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief explanation of the drawings]

[0040] [Figure 1] 1 shows experimental results of the xMCF-7_Palbo-R xenograft tumor model. [Figure 2] These are experimental results of the OVCAR-3 xenograft tumor model. [Figure 3] These are experimental results of the MV4-11 xenograft tumor model. DETAILED DESCRIPTION OF THE INVENTION

[0041] As a result of extensive and thorough research, the present inventors have unexpectedly prepared a compound having excellent CDK kinase inhibitory activity and a method for preparing the same, and have completed the present invention based on this.

[0042] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0043] In the present invention, the term "C1-C6 alkyl group" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like. The terms "C1-C4 alkyl group" and "C1-C2 alkyl group" have similar meanings.

[0044] In the present invention, the term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group containing one double bond and having 2 to 6 carbon atoms, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0045] In the present invention, the term "C2-C6 alkynyl group" refers to a straight or branched alkynyl group containing one triple bond and having 2 to 6 carbon atoms, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0046] In the present invention, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms on the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The terms "C3-C10 cycloalkyl group" and "C3-C6 cycloalkyl group" have similar meanings.

[0047] In the present invention, the term "C1-C6 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. A C1-C4 alkoxy group is preferred.

[0048] In the present invention, the term "heterocycloalkyl group" refers to a 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S; [ka] This includes, but is not limited to, groups such as The term "3- to 10-membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O and S" has an analogous meaning.

[0049] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and are preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and containing no heteroatoms on the ring, such as a phenyl group or a naphthyl group. Similarly, the term "3- to 10-membered aryl group" refers to an aromatic ring group having 3 to 10 carbon atoms and containing no heteroatoms on the ring, such as a phenyl group or a naphthyl group. The term "6- to 10-membered aryl group" has a similar meaning.

[0050] In the present invention, the terms "aromatic heterocycle" and "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "3- to 10-membered heteroaryl group" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl group, heterocyclic group, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0051] In the present invention, the term "halogenated" refers to substitution with halogen.

[0052] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described as appropriate in the above description or in each example. Unless otherwise specified, a substituent may have one substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Examples of the substituent include, but are not limited to, halogen, hydroxy, carboxy (—COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, and C1-C10 sulfonyl.

[0053] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0054] compound The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: [ka] Here, the definitions of each group are as described above. In another preferred embodiment, in the compound, R1, R2, R 3a , R 3b , R4, R5, R6, R7, R8, R9, L, R', R'', R''', p and r are each independently a group corresponding to a specific compound described in the present invention.

[0055] More specifically, the present invention provides compounds of formula (II) or (III): [ka] Here, the definitions of each group are as described above.

[0056] In another preferred embodiment, in the compound, R1', R2', cyclo A, R 31 , R 41 , R 51 , L', and n are each independently a group corresponding to a specific compound described in the present invention. In another preferred embodiment, the compound is preferably a compound prepared in the examples of the present invention.

[0057] As used herein, the term "pharmaceutically acceptable salt" refers to a medicament-compatible salt formed between the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed between the compound of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0058] Other preferred salts are salts formed between the compounds of the present invention and bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0059] The term "solvate" refers to a complex in which a compound of the present invention is coordinated with solvent molecules in a specific ratio. The term "prodrug" includes compounds that may be biologically active or inactive themselves, and that, after administration in an appropriate manner, are converted into the compound of formula (I) or a salt or solution of the compound of formula (I) through metabolism or chemical reaction in the human body. The prodrug includes, but is not limited to, carboxylate esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of the compound.

[0060] Preparation method The preparation method of the compound of formula (I) of the present invention will be described in more detail below, but these specific methods do not limit the present invention in any way. The compound of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combination can be easily performed by a person skilled in the art to which the present invention belongs.

[0061] Typically, the process flow for preparing the compounds of the present invention is as shown in the examples of the present invention, where the raw materials and reagents used are commercially available unless otherwise specified.

[0062] Pharmaceutical Compositions and Methods of Administration Because the compound of the present invention has excellent antitumor activity, the compound of the present invention and its various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as a main ingredient can be used for the treatment, prevention, and alleviation of tumor-related diseases.

[0063] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0064] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly reducing the efficacy of the compounds of the present invention and with each other. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., carboxymethylcellulose sodium, ethyl cellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0065] The pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder or granule. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0066] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as, for example, sodium citrate or dicalcium phosphate, or with other suitable carriers, such as: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarders, such as paraffin; (f) absorption enhancers, such as quaternary amine compounds; (g) glyceryl monostearate and cetyl alcohol. monostearate), (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage forms can also include buffering agents.

[0067] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0068] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form can contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0069] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0070] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0071] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (eg, anti-tumor agents). The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0072] When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0073] Compared with the prior art, the present invention has the following main advantages: (1) The compound has excellent CDK kinase inhibitory activity. (2) The compound has excellent cell inhibitory activity. (3) The compound has excellent in vivo efficacy.

[0074] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are generally in accordance with conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the methods of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0076] Example. Synthetic Route: [ka] The starting material S1 is reduced with lithium aluminum hydride to give intermediate S1-1, followed by nucleophilic substitution with various substituted primary amines to give product S1-2, which is then oxidized with manganese dioxide to give aldehyde pyrimidine compound S1-3, which undergoes cyclization with acetate esters containing different substituents and then oxidized to give sulfone pyrimidinone intermediate S1-5, which is then reacted with substituted primary amines to give the final product. [ka] Substituted sulfonyl chloride S2 is reacted with 4-Boc-aminopiperidine to give the sulfonamide intermediate S2-1, which is deprotected to give intermediate S2-3.

[0077] Preparation of intermediates: Synthesis of intermediate int1: [ka] 1. Combining int1-2 Add 1-methylcyclopentene (57.0 g, 0.695 mol) and dichloromethane (1200 mL) to a 2000 mL single-neck bottle. Add m-chloroperoxybenzoic acid (211.0 g, 1.043 mol) at 0 °C. Warm the mixture to room temperature and react for 16 hours. After the reaction is complete, filter the mixture and wash the filter cake twice with dichloromethane (100 mL x 2). Wash the filtrate three times with saturated aqueous sodium carbonate (300 mL x 3), two to three times with saturated aqueous sodium bicarbonate (300 mL), and two to three times with saturated aqueous sodium chloride (300 mL x 2). Dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure while controlling the temperature below 5 °C to obtain 79 g of crude product, which was used directly in the next reaction step.

[0078] 2. Combining int1-3 In a 350 mL sealed tube, int1-2 (40.0 g, 0.347 mol), benzylamine (74.0 g, 0.694 mol), and ethanol (170 mL) were added and reacted at 90 °C for 40 hours. The mixture was then cooled to room temperature, concentrated, and water (100 mL) was added. The mixture was extracted twice with ethyl acetate (150 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 35 g of product. 1 H NMR(400MHz,CDCl3)δ=7.36-7.31(m,4H),7.28-7.23(m,1H),3.91-3.85(m,1H),3.79-3.74(m,1H), 2.86(dd,J=7.8,8.5Hz,1H),2.12-2.03(m,1H),1.75-1.53(m,5H),1.37-1.27(m,1H),1.22(s,3H).

[0079] 3. Combining int1-4 In a 2000 mL single-neck bottle, add int1-3 (35.0 g, 0.17 mol) and ethyl acetate (350 mL). Heat to a slight reflux and add dropwise a solution of L-mandelic acid (13.0 g, 0.085 mol) in ethyl acetate (200 mL). Allow to cool to room temperature and stir for 16 hours. Filter, wash the filter cake with cold ethyl acetate, add water (150 mL) and ethyl acetate (200 mL). Adjust the pH to 1 with 4 N aqueous hydrochloric acid, separate the layers, adjust the pH of the aqueous phase to 11 with 6 N aqueous sodium hydroxide, extract with ethyl acetate (200 mL x 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and repeat the above steps until the ee value exceeds 99% to obtain 8 g of product with 99.3% ee. 1H NMR(400MHz,CDCl3)δ=7.38-7.30(m,4H),7.27-7.23(m,1H),3.94-3.75(m,2H),2.88(dd,J=7.8,8. 4Hz, 1H), 2.16-2.03 (m, 1H), 1.79-1.57 (m, 4H), 1.53-1.39 (m, 2H), 1.38-1.28 (m, 1H), 1.25 (s, 3H). The chiral HPLC analysis was performed on an Agilent LC1260 using a LuxR 5μmI-Amylose-1, 4.6*250mm, S / N: H19-351585 column. The column was heated to 30°C and eluted with a mobile phase of A (0.1% diethylamine / n-hexane): B (0.1% diethylamine / isopropanol) = 95%:5% (flow rate 1ml / min, detection wavelength 254nm) for 20 minutes. The retention time of the product was 7.659 minutes.

[0080] 4. Combining int1-5 Add int1-4 (18.7 g, 0.091 mol), Pd / C (2.0 g, 10%), and methanol (350 mL) to a 1000 mL single-neck bottle and purge with nitrogen gas three times, then with hydrogen gas three times. Allow the mixture to react at room temperature for 16 h. Filter, wash the filter cake with methanol (30 mL x 3), and concentrate to give 10 g of product, which was used directly in the next step of the reaction. 1 H NMR (400MHz, CDCl3) δ=3.03(t,J=7.4Hz,1H),2.19-2.01(m,1H),1.83-1.58(m,4H),1.42(s,3H),1.35-1.25(m,1H),1.22(s,3H).

[0081] 5. Combining int1-6 In a 250 mL single-neck bottle, add [4-chloro-2-(methylthio)pyrimidin-5-yl]methanol (8.33 g, 43.83 mmol), int1-5 (4.8 g, 41.74 mmol), ethanol (100 mL), and N,N-diisopropylethylamine (16.15 g, 125.22 mmol). Heat the mixture to 80 °C and react for 16 h. Cool to room temperature, concentrate, and purify by column chromatography using petroleum ether:ethyl acetate (5:1 to 1:1) to obtain 10.5 g of product.

[0082] 6. Int1 composition Add int1-6 (10.5 g, 39.03 mmol), dichloromethane (300 mL), and manganese dioxide (39.95 g, 390.3 mmol) to a 500 mL single-neck bottle. Stir at room temperature for 16 h. Filter, wash the filter cake with dichloromethane (30 mL x 2), and concentrate the organic phase to give 9.3 g of product. 1 H NMR(400MHz,CDCl3)δ=9.73(s,1H),8.66(brs,1H),8.35(s,1H),4.39(ddd,J=6.5,8.2,9.6Hz,1H),4.16(s, 1H),2.57(s,3H),2.33-2.22(m,1H),2.03-1.92(m,1H),1.89-1.68(m,3H),1.68-1.56(m,1H),1.17(s,3H). MS:268[M+H]+.

[0083] Synthesis of intermediate int2: [ka] In a 100 mL three-necked bottle, add int2-1 (63 g, 0.379 mol), dichloromethane / water (1:1) (38 mL), and potassium bifluoride (29.6 g, 0.379 mol). Add bromodifluoro(trimethylsilyl)methane (154 g, 0.758 mmol) dropwise with stirring at room temperature for 3 hours. Add water (50 mL) in an ice bath, extract with ethyl acetate (30 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and purify by column chromatography to obtain 31.5 g of product.

[0084] Synthesis of intermediate int3: [ka] 1. Synthesis of int3-1 Compound int2 (290 mg, 2.6 eq) was dissolved in dry THF (5 ml) and purged with nitrogen gas. The temperature was then cooled to -70 ° C., and lithium dimethylsilylamide (1.0 M, 2.06 ml, 4.0 eq) was added dropwise. After the addition was complete, the temperature was maintained at -70 ° C. for 1 hour. Then, a solution of compound 1 (137.8 mg, 1.0 eq) in tetrahydrofuran (3 ml) was added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at 40 ° C. The reaction was monitored for completion by TLC, cooled, and quenched by adding saturated aqueous ammonium chloride solution dropwise. Then, ethyl acetate (30 ml x 3) was added for extraction, separation was performed, and the ethyl acetate phase was collected, dried over anhydrous sodium sulfate, filtered, spin-dried, and passed through a column to obtain the product (90 mg).

[0085] 2.int3 composition: Compound int3-1 (90 mg, 1.0 eq) was dissolved in a mixture of tetrahydrofuran and water, cooled to 0°C, and then Oxone (310 mg, 2.0 eq) was added. The mixture was allowed to warm to room temperature overnight and react. After monitoring for completion of the reaction, the mixture was filtered, water was added to the filtrate, and ethyl acetate was added for extraction. The mixture was dried and then spin-dried to obtain compound 3 (80 mg).

[0086] Synthesis of intermediate int4: [ka] 1. Synthesis of int4-2 In a 100 mL single-neck bottle, add int3-1 (3.0 g, 13.33 mmol), 4 M HCl / dioxane (30 mL), and dichloromethane (30 mL). The reaction mixture is allowed to react at room temperature for 2 hours. The reaction mixture is concentrated to give 1.60 g of product.

[0087] 2. Synthesis of int4-3 In a 100 mL single-neck bottle, add int3-2 (1.25 g, 10.0 mmol), 15% aqueous NaOH (10 mL), and tetrahydrofuran (20 mL). Add methylsulfonyl chloride (1.72 g, 15.0 mmol) dropwise at 0 °C. After the addition is complete, the mixture is allowed to react at room temperature for 2 hours. Add water (30 mL) and extract three times with ethyl acetate (20 mL). Combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 800 mg of product.

[0088] 3. int4-4 synthesis In a 50 mL single-neck bottle, add int3-3 (800 mg, 3.94 mmol), sodium cyanoborohydride (347 mg, 5.52 mmol), glacial acetic acid (236 mg, 3.94 mmol), p-methoxybenzylamine (540 mg, 3.94 mmol), and 1,2-dichloroethane (10 mL). The mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate (5:1 to 0:1) to obtain 790 mg of the product.

[0089] 4. int4 composition In a 50 mL single-neck bottle, add int3-4 (790 mg, 2.44 mmol), Pd(OH)2 / C (80 mg, 10%), glacial acetic acid (146 mg, 2.44 mmol), and methanol (20 mL). Purge with nitrogen gas three times, then with hydrogen gas three times. Incubate at 70 °C for 16 h. Filter, wash the filter cake with methanol (50 mL x 3), and concentrate to give 350 mg of product.

[0090] Synthesis of intermediate int5: [ka] 1. Synthesis of int5-2 A 100 mL single-neck bottle was charged with 4-Boc-aminopiperidine (1.04 g, 1.0 eq), dichloromethane (10 mL), and N,N-diisopropylethylamine (1.05 g, 2.0 eq). After cooling to 0 °C, a solution of int5-1 (1.0 g, 1.0 eq) in dichloromethane (2 mL) was added dropwise. The mixture was allowed to warm to room temperature and react for 3 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using a dichloromethane:methanol ratio of 30:1 to obtain 1.59 g of product.

[0091] 2. Synthesis of int5-3 In a 100 mL single-neck bottle, add int5-2 (800 mg, 1.0 eq), CD3I (1.95 g, 6.0 eq), K2CO3 (1.24 g, 4.0 eq), and acetone (10 mL) and stir overnight at 65 °C. After the reaction is complete, the solvent is evaporated, and the reaction mixture is added with water (15 mL) and extracted with ethyl acetate (15 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to give 792 mg of product.

[0092] 3. Int5 Composition In a 100 mL single-neck bottle, add int5-3 (720 mg, 1.0 eq) and dichloromethane (10 mL), then add hydrochloric acid / dioxane (15 mL) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 500 mg of product.

[0093] Synthesis of intermediate int6: [ka] 1. int6-2 synthesis A 500 mL three-necked bottle was charged with NaH (396.3 mg, 1.5 eq) and tetrahydrofuran (200 mL). Under N2 protection, the mixture was cooled to 0 °C, and then benzylthiol (1.36 g, 1.0 eq) was added. The mixture was stirred for 10 minutes. A solution of C2-1 (2.0 g, 1.05 eq) in tetrahydrofuran (10 mL) was then added dropwise. The mixture was allowed to warm to room temperature and react for 2 hours. After the reaction was complete, the mixture was cooled to 0 °C, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using a 2:1 petroleum ether:ethyl acetate ratio to obtain 2.4 g.

[0094] 2. int6-3 synthesis A 100 mL single-neck bottle was charged with int6-2 (1.93 g, 1.0 eq) and dichloromethane (20 mL). The mixture was cooled to 0 °C, and then water (8 mL), concentrated hydrochloric acid (2.0 mL), and aqueous sodium hypochlorite (10.4%, 9 mL) were added. The reaction was completed at room temperature for 10 minutes. The reaction mixture was then added with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was cooled to 0 °C. A solution of 4-Boc-aminopiperidine (1.78 g, 1.0 eq) and triethylamine (1.8 g, 2.0 eq) in dichloromethane was added and the mixture was allowed to react at room temperature for 2 hours. After the reaction is completed, water is added to the reaction system, the liquids are separated, the organic phase is dried with anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography using dichloromethane:methanol=100:1 to obtain 1.2 g.

[0095] 3. Int6 Composition Add C1-3 (1.2 g, 1.0 eq) and dichloromethane (10 mL) to a 100 mL single-neck bottle, then add hydrochloric acid / dioxane (15 mL) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 1.0 g.

[0096] Synthesis of intermediate int7: [ka] 1. Synthesis of Int7-2: In a 250 mL single-neck bottle, add Int7-1 (11.9 g, 1.0 eq) and ethyl acetate (12 mL), then add HCl / dioxane (15 mL) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 8.06 g.

[0097] 2. Synthesis of Int7-3: In a 250 mL single-neck bottle, Int7-2 (8.06 g, 1.0 eq), dichloromethane (80 mL), and triethylamine (12.08 g, 2.0 eq) were added, cooled to 0 °C, and then methylsulfonyl chloride (7.53 g, 1.1 eq) was added dropwise. The mixture was allowed to warm to room temperature and react for 2 hours. After the reaction was complete, aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with EA:PE in a ratio of approximately 1:5. The mixture was filtered, and the filter cake was collected to give 6.67 g.

[0098] 3. Synthesis of Int7-5: Int7-3 (6.67 g, 1.0 eq), dry tetrahydrofuran (110 mL), and tert-butylsulfinamide (5 g, 1.1 eq) were added to a 250 mL single-neck bottle. Tetraethyl titanate (14.5 g, 1.7 eq) was then added at room temperature and stirred overnight at 70 °C under N2 protection. The reaction was monitored for completion by spot plate analysis. After cooling to 0 °C, NaBD4 was added in one portion and the mixture was allowed to react at room temperature for 3 h. After completion of the reaction, water (80 mL) was added to the reaction mixture, and a large amount of solid precipitated. The mixture was filtered, and the residue was washed five times with EA. The combined filtrate was concentrated and extracted three times with ethyl acetate. The ethyl acetate phase was dried, filtered, and purified by column chromatography using dichloromethane:methanol = 80:1 to give 7.14 g.

[0099] 4. Synthesis of Int7: In a 100 mL single-neck bottle, add Int7-5 (7.14 g, 1.0 eq) and dichloromethane (10 mL), then add 15 mL of hydrochloric acid / dioxane at room temperature, and react for 4 hours at room temperature. Monitor the reaction completion by TLC, filter, and collect the filter cake to obtain 5.88 g.

[0100] Synthesis of intermediate int8: [ka] 1. int8-2 composition C3-1 (4.8 g, 1.0 eq), N,N-dimethylformamide (50 mL), and potassium thioacetate (8.2 g, 2.0 eq) were added to a 100 mL single-neck bottle and reacted overnight at 60 °C. After the reaction was complete, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 10:1 to 5:1 to obtain 4.1 g.

[0101] 2. int8-3 composition A 100 mL single-neck bottle was charged with 2 M hydrochloric acid-acetonitrile solution (25 mL). The temperature was cooled to below 10 °C, followed by the addition of NCS (8.45 g, 2.0 eq). After stirring for 10 minutes while maintaining the temperature, a solution of C3-2 (4.1 g, 1.0 eq) in acetonitrile was added and the mixture was incubated at room temperature for 2 hours. After most of the acetonitrile was removed by distillation, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The ethyl acetate phase was dried with anhydrous sodium sulfate and concentrated. After this, a solution of 4-Boc-aminopiperidine (4.5 g, 0.7 eq) and triethylamine (6.4 g, 2.0 eq) in dichloromethane (20 mL) was added and the mixture was incubated at room temperature for 2 hours with stirring. After the reaction was complete, water was added to the reaction mixture, which was extracted three times with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using a dichloromethane:methanol ratio of 30:1 to obtain 280 mg of the product.

[0102] 3.int8 Composition C3-3 (80 mg, 1.0 eq) and dichloromethane (3 mL) were added to a 100 mL single-neck bottle, followed by the addition of trifluoroacetic acid (3 mL) at room temperature. The reaction was allowed to proceed for 2 hours at room temperature. After monitoring the completion of the reaction by TLC, the mixture was concentrated, ethyl acetate was added, and the mixture was sonicated to precipitate a solid. The solid was then concentrated again to give 62 mg.

[0103] Synthesis of intermediate int9: [ka] 1. int9 composition Add C4-1 (2.0 g, 1.0 eq), ethanol (70 mL), hydrazine hydrate (8 mL, 10 eq), and Raney nickel (10 mL) to a 100 mL single-neck bottle and react overnight at room temperature. After completion of the reaction, suction filter the mixture, add anhydrous sodium sulfate to dry the filtrate, suction filter it again, and concentrate to obtain 1.8 g of crude product.

[0104] Synthesis of intermediate int10: [ka] 1. Synthesis of int10-2 In a 50 mL round-bottom flask, add int10-1 (0.5 g, 2.94 mmol), add 15 mL of dichloromethane, dissolve, and stir. Then, add potassium thioacetate (0.67 g, 5.88 mmol), and heat the reaction mixture to 60 °C for 4 hours. After the reaction is complete, add ethyl acetate and saturated brine to extract the organic phase, dry it over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 2.36 g of crude product.

[0105] 2. Synthesis of int10-3 Add 2 mL of HCl:MeCN (v, 5:1) to a 50 mL three-neck flask, cool to below 10°C, add N-bromosuccinimide (619.2 mg, 4.64 mmol), and stir for 10 to 30 minutes. Then add int10-2 (382 mg, 2.32 mmol) in acetonitrile dropwise. After the addition is complete, maintain the reaction temperature at approximately 10°C and stir for 1 to 2 hours. After the reaction is complete, add dichloromethane and saturated aqueous ammonium chloride solution to extract the organic phase, dry it over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain 400 mg of crude product by column chromatography.

[0106] 3. Synthesis of int10-4 In a 50 mL single-neck bottle, add int10-3 (210 mg, 1.1 mmol), add 6 mL of dichloromethane, and stir to dissolve. Then, add 4-Boc-aminopiperidine (109.6 mg, 0.55 mmol). After stirring evenly, add triethylamine (221 mg, 2.2 mmol) and react at room temperature. Stir overnight. After sufficient reaction, concentrate the reaction mixture under reduced pressure and add appropriate amounts of petroleum ether and ethyl acetate to form a slurry, yielding 319 mg of crude product as a white solid. 4. int10 composition In a 50 mL round-bottom flask, add int10 (319 mg, 0.9 mmol), add dichloromethane (5 mL) and stir to dissolve, cool the reaction system to 0 ° C, then add trifluoroacetic acid (1 mL) dropwise, and after the dropwise addition is completed, react for 2 hours. After the reaction is complete, concentrate under reduced pressure, add an appropriate amount of petroleum ether and ethyl acetate to form a slurry, and obtain 160 mg of a crude product as a white solid.

[0107] Synthesis of intermediate int11: [ka] 1. Synthesis of int11-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 mL), and triethylamine (1.01 g, 2.0 eq) to a 100 mL single-neck bottle, cool to 0 °C, add a solution of int11-1 (1.01 g, 1.0 eq) in dichloromethane (2 mL) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction solution, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 1.73 g.

[0108] 2. Synthesis of int11-3 In a 100 mL single-neck bottle, add int11-2 (600 mg, 1.0 eq) and dichloromethane (30 mL). Under nitrogen gas protection, add DAST (1.34 g, 5.0 eq) dropwise at 0 °C. After the dropwise addition, let the mixture react at room temperature overnight. After the reaction is complete, add ice water to the reaction mixture, extract twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography using petroleum ether:ethyl acetate = 8:1 to 6:1 to obtain 360 mg of the product.

[0109] 3. int11 synthesis In a 100 mL single-neck bottle, add int11-3 (480 mg, 1.0 eq) and dichloromethane (17 mL), then add hydrochloric acid / 1,4-dioxane (10 mL) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 370 mg.

[0110] Synthesis of intermediate int12: [ka] 1. Synthesis of int12-2 Add int11-2 to a 100 mL single-neck bottle, then add dichloromethane / methanol (50 mL / 5 mL), add sodium borohydride (115 mg, 1.1 eq) at 0 °C, and react overnight at room temperature. After the reaction is complete, add water to quench the reaction mixture, extract twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain 980 mg.

[0111] 2. Synthesis of int12-3 Add C3-2 (780 mg, 1.0 eq) and dichloromethane (30 mL) to a 100 mL single-neck bottle, and add DAST (381 mg, 1.1 eq) dropwise at 0 °C under nitrogen gas protection. After the addition is complete, let the mixture react at room temperature for 3 hours. After the reaction is complete, add ice water to the reaction mixture, extract twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and then purify by column chromatography using petroleum ether:ethyl acetate = 8:1 to 6:1 to obtain 120 mg of the product.

[0112] 3. int12 composition Add C3-3 (160 mg, 1.0 eq) and dichloromethane (5 mL) to a 100 mL single-neck bottle, then add hydrochloric acid / 1,4-dioxane (5 mL) at room temperature. The reaction is allowed to proceed for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 103 mg.

[0113] Synthesis of intermediate int13: [ka] 1. Synthesis of int13-2 In a 250 mL three-necked bottle under nitrogen gas protection, add int13-1 (6.8 g, 1.0 eq), DPPA (25.0 g, 1.5 eq), triethylamine (30.6 g, 5.0 eq), and 1,4-dioxane (68 mL). Incubate at 100 °C for 2 hours, then cool to 40-50 °C, add benzyl alcohol (13.1 g, 2.0 eq) dropwise, and then heat to 100 °C and incubate for 16 hours. After monitoring for reaction completion and cooling to room temperature, add saturated brine to the reaction mixture, extract three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain 9.8 g.

[0114] 2. Synthesis of int13-3 In a three-necked bottle under nitrogen gas protection, int13-2 (9.8 g, 1.0 eq) and ultra-dry tetrahydrofuran (98 mL) were added. 1.0 M borane tetrahydrofuran (88.2 mL) was added dropwise at 0 °C. After the addition was complete, the temperature was maintained for 1 hour, and then the mixture was allowed to react at room temperature overnight. After monitoring for reaction completion, the mixture was cooled to 0 °C and water (19.6 mL) and 10% aqueous sodium hydroxide (68.7 mL) were added to the reaction mixture. Then, 30% aqueous hydrogen peroxide (49 mL) was added dropwise and the mixture was allowed to react at room temperature for 5 hours. After monitoring for reaction completion, the mixture was extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain 4.8 g.

[0115] 3. Synthesis of int13-4 C5-3 (3 g, 1.0 eq) and dichloromethane (92 mL) were added to a 100 mL single-neck bottle, and under nitrogen gas protection, DAST (4.1 g, 2.0 eq) was added dropwise at -20°C. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, ice water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain 580 mg of the product.

[0116] 4. int13 synthesis C5-4 (660 mg, 1.0 eq) was dissolved in methanol (5 mL), Pd / C (13.6 mg, 10%) was added, and the mixture was reacted overnight at room temperature under nitrogen gas protection and purged with hydrogen gas three times. After monitoring the reaction completion, the mixture was filtered, hydrochloric acid / 1,4-dioxane (2 mL) was added, and the mixture was concentrated to give 360 ​​mg.

[0117] Synthesis of intermediate int14: [ka] 1. Synthesis of int14-2 In a three-necked bottle, add int14-1 (1.86 g, 1.0 eq) and dichloromethane (74 mL). After cooling to 0°C, add PCC (3.4 g, 2.0 eq) in three portions and react under nitrogen gas protection at room temperature for 48 hours. After monitoring the reaction completion, add saturated brine to the reaction mixture, filter, extract the filtrate twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject the mixture to column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain 1.62 g.

[0118] 2. Synthesis of int14-3 C6-2 (1.62 g, 1.0 eq) and dichloromethane (83 mL) were added to a 100 mL single-neck bottle, and DAST (5.5 g, 5.0 eq) was added dropwise at 0°C under nitrogen gas protection. After the addition was complete, the mixture was allowed to react at room temperature overnight. After the reaction was complete, ice water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain 910 mg of the product.

[0119] 3. int14 synthesis C6-3 (910 mg, 1.0 eq) was dissolved in methanol (5 mL), Pd / C (91 mg, 10%) was added, and the mixture was reacted overnight at room temperature under nitrogen gas protection and purged with hydrogen gas three times. After monitoring the reaction completion, the mixture was filtered, hydrochloric acid / 1,4-dioxane (5 mL) was added, and the mixture was concentrated to give 650 mg.

[0120] Synthesis of intermediate int15 : [ka] 1. Synthesis of int15-2 Glyoxal-1,1-dimethylacetal (500 mg, 1.0 eq), int15-1 (1.48 g, 1.0 eq), and methanol (10 mL) were placed in a single-neck bottle and reacted at room temperature for 2 hours. After monitoring for reaction completion, N-Boc-trans-1,4-cyclohexanediamine (1.11 g, 1.1 eq) and acetic acid (288 mg, 1.0 eq) were added to the reaction mixture, which was then heated to 75 °C and reacted overnight. After monitoring for reaction completion, the reaction mixture was adjusted to pH > 7 with aqueous sodium bicarbonate, followed by addition of water and three extractions with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 2:1 to obtain 320 mg of the product.

[0121] 2. int15 composition Add C7-2 (320 mg, 1.0 eq) and dichloromethane (3 mL) to a 100 mL single-neck bottle, then add hydrochloric acid / 1,4-dioxane (5 mL) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 240 mg.

[0122] Synthesis of intermediate int16 : [ka] 1. int16-2 composition: In a 250 mL single-neck bottle, add int16-1 (2 g, 1.0 eq) and BH3 / THF (3 eq, 1M 34 mL). Then, add tetrahydrofuran (80 mL) at room temperature and react overnight under reflux. After monitoring the completion of the reaction by TLC, cool to room temperature, add 100 mL of 1 M HCl dropwise, extract five times with ethyl acetate, cool the aqueous phase to 0 °C, adjust to neutral with saturated sodium bicarbonate solution, and extract again with ethyl acetate. Dry and concentrate the organic phase to obtain 690 mg of product.

[0123] 2. int16-3 composition: In a 100 mL single-neck bottle, add int16-2 (690 mg, 1.0 eq), dichloromethane (30 mL), and triethylamine (1.27 g, 3 eq). Cool to 0°C, then add methylsulfonyl chloride (723 mg, 1.5 eq) dropwise. Allow to warm to room temperature and react for 2 hours. After completion of the reaction, add aqueous ammonium chloride to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using dichloromethane:methanol = 200:1 - 100:1 to obtain 640 mg of the product.

[0124] 3. int16 composition: In a 100 mL three-necked bottle, int16-3 (640 mg, 1.0 eq), ethanol (64 mL), and Pd / C (64 mg) were added and reacted at 50°C for 2 hours under a hydrogen gas atmosphere. After the reaction was completed, the mixture was filtered and concentrated to obtain 165 mg.

[0125] Synthesis of intermediate int17 : [ka] 1. Synthesis of int17-2 3-{[(tert-butoxy)carbonyl]amino}bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester) (560 mg, 2.32 mmol) and methanol (5 mL) were added to a 50 mL single-neck bottle. Hydrazine hydrate was added dropwise to the reaction mixture at room temperature. After the addition was complete, the mixture was stirred at room temperature for 30 minutes, then heated to 80 °C and reacted for 2–3 hours. After confirming completion of the reaction by LC-MS, the crude product was concentrated under reduced pressure and washed twice with toluene to give a white solid (562 mg). This was used in the next step without further purification.

[0126] 2. Synthesis of int17-3 C8-1 (562 mg, 2.32 mmol) and TsOH (40 mg, 0.232 mmol) were added to triethyl orthoformate (8 mL) in a 50 mL single-neck bottle, and the mixture was heated to 80 °C and reacted for 4 h. After confirming the completion of the reaction by LC-MS, the mixture was cooled to 50 °C and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE-PE:EA = 2:1) to give 465 mg of a white solid.

[0127] 3. int17 synthesis C8-2 (465 mg, 1.852 mmol) and dichloromethane (5 mL) were added to a 50 mL single-neck bottle, cooled to 0 °C in an ice bath, and trifluoroacetic acid (1 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to warm to room temperature and react for 4 hours. After TLC showed the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product. The crude product was slurried with ethyl acetate (20 mL) and filtered to give 347 mg of a white solid.

[0128] Example 1 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0129] 1. Synthesis of C1-1 Add 2-(oxetan-3-yl)ethyl acetate (200 mg, 1.54 mmol) and dry tetrahydrofuran to a 50 mL single-neck bottle, add LiHMDS (2.15 mmol) dropwise at -78 °C, and react at -78 °C for 30 minutes. Then add int1 (165 mg, 1.54 mmol) in tetrahydrofuran and slowly warm to room temperature for 16 hours. After the reaction is complete, add saturated ammonium chloride, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and pass through a petroleum ether:ethyl acetate = 10:1 to 5:1 column to obtain 60 mg.

[0130] 2. Synthesis of C1-2 C2-1 (55 mg, 0.16 mol), tetrahydrofuran (5 mL), and water (1 mL) were added to a 50 mL single-neck bottle, cooled to 0 °C, and OXONE (240 mg, 0.40 mol) was added in batches. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, the filter cake was washed twice with EA, and the mother liquor was collected and concentrated to give 50 mg.

[0131] 3. Synthesis of C1 C2-2 (50 mg, 0.12 mmol), 1-methylsulfonyl-4-aminopiperidine (32 mg, 0.15 mmol), N,N-diisopropylethylamine (81 mg, 0.3 mmol), and dimethyl sulfoxide (5 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60 °C and reacted for 16 hours. After the reaction was complete, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated using a preparative plate with petroleum ether:ethyl acetate = 1:5 to obtain 15 mg of the product. 1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.46(d,J=1.4Hz,1H),5.74(t,J=8.5Hz,1H),5.3 5(s,2H),5.06(ddd,J=8.5,6.0,2.6Hz,2H),4.70(ddd,J=11.1,7.0,6.0Hz,2H),4.43 -4.28(m,1H),3.98(s,1H),3.90-3.73(m,2H),3.00-2.86(m,2H),2.82(s,3H),2.30 -2.13(m,3H),2.07-1.95(m,2H),1.95-1.76(m,2H),1.76-1.58(m,2H),1.13(s,3H).

[0132] Example 2 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0133] 1. Synthesis of C2 In a 50 mL single-neck bottle, add int3 (396 mg, 1.23 mmol), int4 (300 mg, 1.47 mmol), N,N-diisopropylethylamine (475 mg, 3.68 mmol), and dimethyl sulfoxide (5 mL). Heat the mixture to 60 °C and allow it to react for 16 hours. After the reaction is complete, add water to the reaction mixture, extract three times with EA, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography using petroleum ether:ethyl acetate = 5:1 to 0:1 to obtain 370 mg of product.

[0134] Example 3 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0135] Synthesis of C3 Compound int3 (80 mg) is dissolved in DMSO, and 1-methylsulfonyl-4-aminopiperidine (88.4 mg, 2.0 eq) and triethylamine (0.11 ml, 3.0 eq) are added, followed by reaction overnight at 60° C. After monitoring the completion of the reaction, water is added to the system, followed by extraction with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated using a preparative plate to obtain the product (50 mg). 1 H NMR(400MHz,CDCl3)δ8.45(s,1H),7.37(s,1H),6.77(t,J=75.0Hz,1H),5.81(s,1 H),5.44(m,1H),3.98(br,1H),3.82(t,J=12.1Hz,2H),2.99-2.87(m,2H),2.83(s ,3H),2.74(br,1H),2.35-2.16(m,3H),2.04(d,J=7.1Hz,3H),1.93(t,J=9.5Hz,1 H),1.82(dd,J=12.0,6.4Hz,1H),1.67(td,J=12.9,12.0,4.0Hz,2H),1.17(s,3H).

[0136] Example 4 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0137] Synthesis of C4-1 Add tetrahydrofuran (10 mL) to a 100 mL three-neck bottle, cool to -5 °C, and add a solution of titanium tetrachloride (3.04 g, 16 mmol) in dichloromethane (5 mL) dropwise. Stir for 10 minutes after the addition, then add a solution of int1 (1.07 g, 4 mmol) and diethyl malonate (1.28 g, 8 mmol) in tetrahydrofuran (10 mL) dropwise. Stir for 30 minutes after the addition, then add pyridine (1.58 g, 20 mmol). Allow the mixture to warm to room temperature and stir overnight. Monitor the reaction completion by TLC. Dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography using petroleum ether:ethyl acetate = 5:1 to 3:1 to obtain 1.31 g of product.

[0138] Synthesis of C4-2 Add C4-1 (1.31 g, 3.20 mmol) and tetrahydrofuran (15 mL) to a 50 mL single-neck bottle, add potassium t-butoxide (36 mg, 0.32 mmol) in tetrahydrofuran (1 mL) dropwise at room temperature, and stir at room temperature for 15 min. After monitoring the completion of the reaction by TLC, eluate 1.02 g by column chromatography using petroleum ether:ethyl acetate = 3:1 to 1:1.

[0139] Synthesis of C4-3 C4-2 (1.01 g, 2.78 mmol), lithium hydroxide (200 mg, 8.35 mmol), tetrahydrofuran (10 mL), and water (10 mL) were added to a 50 mL single-neck bottle and stirred at room temperature for 4 h. After monitoring the completion of the reaction by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.98 g of crude product.

[0140] Synthesis of C4-4 C4-3 (335 mg, 1.00 mmol), diphenyl phosphate azide (330 mg, 1.20 mmol), triethylamine (122 mg, 1.20 mmol), and t-butanol (5 mL) were added to a 50 mL single-neck bottle and heated to 78 °C for 16 h. After monitoring the completion of the reaction by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 4:1 to 2:1 to obtain 83 mg of toluene.

[0141] C4-5 synthesis At 0°C, sodium hydride (5.6 mg, 0.139 mmol) was added to a solution of C4-4 (47 mg, 0.116 mmol) in N,N-dimethylformamide (3 mL). After the addition was complete, the mixture was allowed to warm to room temperature and react for 30 minutes. The mixture was then cooled to 0°C and iodomethane was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the reaction completion by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 48 mg of methyl ...

[0142] C4-6 synthesis At 0°C, OXONE (160 mg, 0.268 mmol) was added to a solution of C4-5 (45 mg, 0.107 mmol) in tetrahydrofuran and water. After the addition was complete, the mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 51 mg of crude product.

[0143] Synthesis of C4-7 C4-6 (51 mg, 0.113 mmol), 1-methylsulfonyl-4-aminopiperidine (49 mg, 0.226 mmol), diisopropylethylamine (59 mg, 0.452 mmol), and dimethyl sulfoxide (2 mL) were added to a 50 mL single-neck bottle and heated to 60 °C for 4 h. After monitoring the completion of the reaction by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 45 mg of methyl ...

[0144] C4 synthesis Methanesulfonic acid (78 mg, 0.82 mmol) was added dropwise to a solution of C4-7 (45 mg, 0.082 mmol) in dichloromethane (3 mL) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and react for 1 hour. After monitoring the reaction completion by TLC, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 25 mg of the product. 1 H NMR(400MHz,CDCl3)δ8.39(s,1H),6.26(s,1H),5.88(s,1H),5.22(s,1H),4.98(s,1H),3.95(s,1H),3.78(s,2H),2.95(s,2H), 2.89(d,J=4.3Hz,3H),2.83(s,3H),2.72(s,1H),2.26-2.13(m,3H),2.02(s,1H),1.93-1.78(m,3H),1.59(m,3H),1.34(s,3H).

[0145] Example 5 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0146] Synthesis of C5-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 ml), and triethylamine (1.01 g, 2.0 eq) to a 100 ml single-neck bottle, cool to 0°C, add a solution of C1-1 (1.28 g, 1.0 eq) in dichloromethane (2 ml), allow to warm to room temperature, and react for 2 hours. After the reaction is complete, add water to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 1.83 g.

[0147] Synthesis of C5-3 Add C5-2 (1.83 g, 1.0 eq) and dichloromethane (18 ml) to a 100 mL single-neck bottle, then add HCl / dioxane (10 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 1.7 g.

[0148] Synthesis of C5 To a 50 mL single-neck bottle, add C5-3 (74.3 mg, 1.2 eq), int3 (70 mg, 1.0 eq), diisopropylethylamine (70 mg, 3.0 eq), and dimethyl sulfoxide (3 mL). The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, water was added 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 to give 24 mg of the desired product by prep-TLC. MS [M+1]: 618.6. 1 H NMR(400MHz,CDCl3)δ8.38(d,J=14.1Hz,1H),7.92(d,J=8.2Hz,2H),7.83(d,J=8.3Hz,2H),7.33(s,1H),6.75(t,J=75.1Hz,1H),5.7 6(t,J=8.4Hz,1H),5.64-5.27(m,1H),3.77(t,J=43.4Hz,3H),3.06-2.43(m,3H),2.36-2.09(m,4H),2.07-1.66(m,6H),1.14(s,3H).

[0149] Example 6 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0150] Synthesis of C6-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 ml), and triethylamine (1.01 g, 2.0 eq) to a 100 ml single-neck bottle, cool to 0°C, add a solution of C2-1 (1.058 g, 1.0 eq) in dichloromethane (2 ml) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 1.74 g.

[0151] Synthesis of C6-3 Add C6-2 (1.74 g, 1.0 eq) and dichloromethane (17 ml) to a 100 mL single-neck bottle, then add HCl / dioxane (10 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 1.5 g.

[0152] Synthesis of C6 C6-3 (67 mg, 1.2 eq), int3 (70 mg, 1.0 eq), diisopropylethylamine (70 mg, 3.0 eq), and dimethyl sulfoxide (3 ml) were added to a 50 mL single-neck bottle. The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, water was added 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 to give 34 mg of the desired product by prep-TLC. 1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.36(s,1H),6.82(t,J=75.3Hz,1H),5.73(s,1H),5.32(m,J=62.4,53.3Hz,2H),4.37-4.12(m,1H) ),3.80(d,J=10.9Hz,3H),2.93(m,J=25.6,14.7Hz,4H),2.51-2.02(m,7H),1.98-1.65(m,4H),1.26(s,J=6.6Hz,3H).MS[M+1]:575.6

[0153] Example 7 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0154] Synthesis of C7-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 ml), and triethylamine (1.01 g, 2.0 eq) to a 100 mL single-neck bottle, cool to 0°C, add C3-1 (1.06 g, 1.0 eq) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 1.89 g.

[0155] Synthesis of C7-3 Add C7-2 (1.74 g, 1.0 eq) and dichloromethane (17 ml) to a 100 mL single-neck bottle, then add HCl / dioxane (10 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 1.51 g.

[0156] Synthesis of C7 To a 50 mL single-neck bottle, add C7-3 (128.7 mg, 2.0 eq), int3 (80 mg, 1.0 eq), diisopropylethylamine (105.7 mg, 4.0 eq), and dimethyl sulfoxide (4 mL). The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 42 mg of the desired product by prep-TLC. 1 H NMR(400MHz,CDCl3)δ8.42(s,1H),7.89(m,J=14.4,8.1Hz,1H),7.34(s,1H),7.06-6.95(m,2H),6.76(t,J=75.1Hz,1H),5.78(t,J=8.7Hz,1H),5 .48(d,J=34.3Hz,1H),4.08-3.73(m,3H),3.03-2.62(m,3H),2.24(m,J= 41.8,22.4,9.7Hz,3H),2.09-1.66(m,7H),1.14(s,3H).MS[M+1]:586.5.

[0157] Example 8 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0158] Synthesis of C8-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 ml), and triethylamine (1.01 g, 2.0 eq) to a 100 ml single-neck bottle, cool to 0°C, add a solution of C4-1 (1.0 g, 1.05 eq) in dichloromethane (2 ml) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction solution, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 1.88 g.

[0159] Synthesis of C8-3 Add C8-2 (1.88 g, 1.0 eq) and dichloromethane (19 ml) to a 100 mL single-neck bottle, then add HCl / dioxane (13 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 1.44 g.

[0160] Synthesis of C8 To a 50 mL single-neck bottle, add C8-3 (149.5 mg, 2.0 eq), int3 (100 mg, 1.0 eq), diisopropylethylamine (105.7 mg, 4.0 eq), and dimethyl sulfoxide (5 mL). The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 72 mg of the desired product by prep-TLC. 1 H NMR(400MHz,CDCl3)δ8.40(s,1H),7.66(d,J=8.2Hz,2H),7.39-7.30(m,3H),6.75(t,J=75.1Hz,1H),5.76(t,J=8.5Hz,1H),5.45(d,J =54.7Hz,1H),3.94-3.57(m,3H),2.79-2.49(m,3H),2.46(s,3H),2.31-2.07(m,3H),2.06-1.67(m,7H),1.13(s,3H).MS[M+1]:564.6.

[0161] Example 9 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0162] Synthesis of C9-2 Add 4-Boc-aminopiperidine (300 mg, 1.0 eq), dichloromethane (6 ml), and triethylamine (303 mg, 2.0 eq) to a 50 ml single-neck bottle, cool to 0°C, add a solution of C5-1 (303 mg, 1.01 eq) in dichloromethane (2 ml), allow to warm to room temperature, and react for 2 hours. After the reaction is complete, add water to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 550 mg of toluene.

[0163] Synthesis of C9-3 Add C9-2 (550 mg, 1.0 eq) and dichloromethane (8 ml) to a 50 mL single-neck bottle, then add HCl / dioxane (6 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 443 mg.

[0164] Synthesis of C9 To a 50 mL single-neck bottle, add C9-3 (93 mg, 1.5 eq), int3 (80 mg, 1.0 eq), diisopropylethylamine (79.3 mg, 3.0 eq), and dimethyl sulfoxide (5 mL). The reaction is allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, the reaction mixture is added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 39 mg of the desired product by prep-TLC. 1H NMR(400MHz,CDCl3)δ8.42(s,1H),8.08(d,J=7.8Hz,1H),7.90(d,J=7.5Hz,1H),7.75( dt,J=21.6,7.5Hz,2H),7.34(s,1H),6.76(t,J=75.1Hz,1H),5.79(t,J=8.5Hz,1H),5. 51(s,1H),3.92(d,J=13.1Hz,3H),2.90(d,J=54.2Hz,2H),2.70(dd,J=19.2,8.6Hz,1H ),2.24(m,J=36.2,20.3,9.9Hz,4H),2.07-1.68(m,6H),1.14(s,3H).MS[M+1]:575.6.

[0165] Example 10 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0166] Synthesis of C10-2 Add 4-Boc-aminopiperidine (300 mg, 1.0 eq), dichloromethane (6 ml), and triethylamine (303 mg, 2.0 eq) to a 50 mL single-neck bottle, cool to 0°C, add C6-1 (313 mg, 1.01 eq) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using a PE:EA ratio of 5:1 to 1:1 to obtain 530 mg of toluene.

[0167] Synthesis of C10-3 Add C10-2 (530 mg, 1.0 eq) and dichloromethane (8 ml) to a 50 mL single-neck bottle, then add HCl / dioxane (6 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 380 mg.

[0168] Synthesis of C10 To a 50 mL single-neck bottle, add C10-3 (94.5 mg, 1.5 eq), int3 (80 mg, 1.0 eq), diisopropylethylamine (79.3 mg, 3.0 eq), and dimethyl sulfoxide (5 mL). The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 38 mg of the desired product by prep-TLC. 1 H NMR(400MHz,CDCl3)δ8.40(s,1H),7.46(t,J=8.0Hz,1H),7.40-7.30(m,2H),7.28(s,1H),7.15(dd,J=8.2,1.9Hz,1H),6.75(t,J=75.1Hz,1H),5. 76(t,J=8.5Hz,1H),5.36(d,J=45.1Hz,1H),3.94-3.63(m,6H),2.71(s, 3H),2.33-2.08(m,3H),2.07-1.65(m,7H),1.14(s,3H).MS[M+1]:580.6.

[0169] Example 11 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0170] Synthesis of C11-2 4-Boc-aminopiperidine (300 mg, 1.0 eq), DCM (6 ml), and TEA (303 mg, 2.0 eq) were added to a 50 ml single-neck bottle. After cooling to 0 °C, a solution of C7-1 (385.8 mg, 1.01 eq) in DCM (3.0 ml) was added dropwise. The mixture was allowed to warm to room temperature and react for 2 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted three times with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using a PE:EA ratio of 5:1 to 1:1 to obtain 500 mg of the product.

[0171] Synthesis of C11-3 Add C7-2 (500 mg, 1.0 eq) and DCM (8 ml) to a 50 mL single-neck bottle, then add HCl / dioxane (6 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction is filtered and the filter cake is collected to give 383 mg.

[0172] Synthesis of C11 To a 50 mL single-neck bottle, add C11-3 (109.3 mg, 1.5 eq), INT (80 mg, 1.0 eq), DIPEA (79.3 mg, 3.0 eq), and DMSO (5 mL). The reaction is allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, water is added to the reaction mixture, which is then extracted three times with EA. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to give 29 mg of the desired product by prep-TLC. 1 H NMR(400MHz,CDCl3)δ8.40(s,1H),8.14(d,J=8.3Hz,2H),7.99(d,J=8.3Hz, 2H),7.33(s,1H),6.75(t,J=75.1Hz,1H),5.77(t,J=8.5Hz,1H),5.47(s,1H) ,3.83(d,J=38.5Hz,3H),3.14(s,3H),2.66(dt,J=41.4,21.1Hz,3H),2.24(m ,J=37.0,20.3,9.8Hz,3H),2.07-1.67(m,7H),1.13(s,3H).MS[M+1]:628.8.

[0173] Example 12 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0174] Synthesis of C12-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 ml), and triethylamine (1.01 g, 2.0 eq) to a 100 ml single-neck bottle, cool to 0°C, add C8-1 (1.18 g, 1.0 eq) in dichloromethane (2 ml) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction mixture, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 1.64 g.

[0175] Synthesis of C12-3 Add C12-2 (1.64 g, 1.0 eq) and dichloromethane (16 ml) to a 100 mL single-neck bottle, then add HCl / dioxane (10 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 1.32 g.

[0176] Synthesis of C12 To a 50 mL single-neck bottle, add C12-3 (120 mg, 2.0 eq), int3 (80 mg, 1.0 eq), diisopropylethylamine (80 mg, 3.0 eq), and dimethyl sulfoxide (3 mL). The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 42 mg of the desired product by prep-TLC. 1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.80(m,J=7.9,5.0,2.4Hz,2H),7.34(s,1H),7.26-7.20(m,2H),6.75(t,J=75.0Hz,1H),5.76(t,J=8.5Hz,1 H),5.40(s,1H),3.81(d,J=37.9Hz,3H),2.62(d,J=63.5Hz,3H),2.41-2.08(m,4H),2.08-1.64(m,6H),1.15(d,J=12.6Hz,3H).MS[M+1]:568.5.

[0177] Example 13 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0178] Synthesis of C13-2 Add 4-Boc-aminopiperidine (1.0 g, 1.0 eq), dichloromethane (10 ml), and triethylamine (1.01 g, 2.0 eq) to a 100 ml single-neck bottle, cool to 0°C, add C9-1 (1.0 g, 1.05 eq) in dichloromethane (2 ml) dropwise, allow to warm to room temperature, and react for 2 hours. After completion of the reaction, add water to the reaction solution, extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and subject to column chromatography using a PE:EA ratio of 5:1 to 1:1 to obtain 1.74 g.

[0179] Synthesis of C13-3 Add C9-2 (1.74 g, 1.0 eq) and dichloromethane (17 ml) to a 100 mL single-neck bottle, then add HCl / dioxane (10 ml) at room temperature. The reaction is allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture is filtered and the filter cake is collected to give 1.31 g.

[0180] Synthesis of C13 To a 50 mL single-neck bottle, add C9-3 (149.5 mg, 2.0 eq), int3 (100 mg, 1.0 eq), diisopropylethylamine (105.7 mg, 4.0 eq), and dimethyl sulfoxide (5 mL). The reaction was allowed to proceed overnight at 60 °C. After monitoring the completion of the reaction by LC-MS, the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 63 mg of the desired product by prep-TLC. 1 H NMR(400MHz,CDCl3)δ8.43(s,1H),7.58(d,J=4.9Hz,2H),7.45(t,J=6.8Hz,2H),7.38(s,1H),6.74(t,J=75.2Hz,1H),5.87-5.40(m,2H),3.7 5(d,J=72.5Hz,3H),2.59(d,J=61.7Hz,3H),2.46(s,3H),2.21-1.94(m,4H),1.75(d,J=61.1Hz,6H),1.21(d,J=32.5Hz,3H).MS[M+1]:564.6.

[0181] Example 14 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0182] Synthesis of C14-2 C14-1 (500 mg, 2.4 mmol) was added to a 50 mL single-neck bottle, and 10 mL of dichloromethane was added with stirring to dissolve. 4-Boc-aminopiperidine (480 mg, 2.4 mmol) was then added. After uniform stirring, triethylamine (485 mg, 4.8 mmol) was added and the mixture was allowed to react at room temperature and stirred overnight. After sufficient reaction, the reaction mixture was concentrated under reduced pressure and slurried with an appropriate amount of petroleum ether / ethyl acetate to obtain 942 mg of a white solid product.

[0183] Synthesis of C14-3 Add C14-2 (942 mg, 2.54 mmol) to a 100 mL round-bottom flask, add dichloromethane (20 mL) and dissolve under stirring, then add HCl / dioxane (6 mL, 24 mmol) dropwise, react for 2 hours after the dropwise addition, and check the completion of the reaction by TLC. Concentrate under reduced pressure, add an appropriate amount of petroleum ether / ethyl acetate to make a slurry, and obtain 730 mg of product.

[0184] Synthesis of C14 In a 10 mL sealed tube, int3 (60 mg, 0.154 mmol) was added, followed by dimethyl sulfoxide (3 mL). After uniform stirring, C14-3 (94.4 mg, 0.308 mmol) was added, and the mixture was heated to 60 °C and stirred overnight. The reaction mixture was cooled to room temperature, and an appropriate amount of water and ethyl acetate were added to extract the organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 61 mg of methylcellulose, followed by slurrying and purifying to give 37 mg of methylcellulose.

[0185] Example 15 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0186] Synthesis of C15-2: C15-1 (1 g, 4.7 mmol), triethylamine (1.25 mL, 9.4 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (0.94 g, 4.7 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the reaction completion by LC-MS, water was added 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 to give 1.73 g. MS [M+1]: 377

[0187] Synthesis of C15-3: C15-2 (1.73 g, 4.6 mmol) and a dichloromethane solution (20 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (10 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated, washed, filtered, and dried to obtain 1.47 g of crude product. MS [M+1]: 277

[0188] Synthesis of C15: C15-3 (131 mg, 0.42 mmol), int3 (80 mg, 0.21 mmol), diisopropylethylamine (0.15 mL, 0.84 mmol), and dimethyl sulfoxide (3 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 69 mg of the product. MS [M+1]: 567 1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.32(d,J=7.3Hz,3H),7.08(t,J=8.6Hz,1H),6.76(s,1H),5.78(t,J=8.5Hz,1H) ,5.36(s,1H),3.76(m,3H),2.70(m,3H),2.17(d,J=11.7Hz,4H),2.01(d,J=11.5Hz,3H),1.80(m,3H),1.14(s,3H).

[0189] Example 16 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0190] Synthesis of C16-2: C16-1 (883 mg, 5 mmol), triethylamine (1.38 mL, 10 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (1 g, 5 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.64 g. MS [M+1]: 340

[0191] Synthesis of C16-3: C16-2 (1.64 g, 4.8 mmol) and a dichloromethane solution (10 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (10 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated. After washing, the mixture was filtered and dried to obtain 1.32 g of crude product. MS [M+1]: 240

[0192] Synthesis of C16: C16-3 (143.5 mg, 0.52 mmol), int3 (100 mg, 0.26 mmol), diisopropylethylamine (0.18 mL, 1.04 mmol), and dimethyl sulfoxide (3 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 67 mg of the product. MS [M+1]: 548 1 H NMR(400MHz,CDCl3)δ8.39(s,1H),7.79(d,J=8.0Hz,2H),7.64(t,J=7.4Hz,1H),7.56(t,J=7.7Hz,2H),7.33(s,1H),6.75(s ,1H),5.76(t,J=8.6Hz,1H),5.30(s,1H),3.79(d,J=34.0Hz,3H),2.70(m,3H),2.06(dd,J=62.3,10.2Hz,10H),1.13(s,3H).

[0193] Example 17 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0194] Synthesis of C17-2: C17-1 (1 g, 5 mmol), triethylamine (2 mL, 10 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (1 g, 5 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.8 g. MS [M+1]: 259

[0195] Synthesis of C17-3: C17-2 (1.8 g, 5 mmol) and a dichloromethane solution (18 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (10 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated. After washing, the mixture was filtered and dried to obtain 1.57 g of crude product. MS [M+1]: 259

[0196] Synthesis of C17: C17-3 (118 mg, 0.40 mmol), int3 (77 mg, 0.20 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol), and dimethyl sulfoxide (3 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 29 mg of the product. MS [M+1]: 604 1 H NMR(400MHz,CDCl3)δ8.40(s,1H),7.62-7.46(m,3H),7.33(s,2H),6.75(s,1H),5.77(t,J=8.5Hz,1H),5.40(s, 1H),3.82(d,J=45.3Hz,3H),2.70(s,3H),2.15(d,J=12.9Hz,3H),2.09-1.84(m,4H),1.78(s,3H),1.14(s,3H).

[0197] Example 18 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0198] Synthesis of C18-2: C18-1 (1.06 g, 5 mmol), triethylamine (1.38 mL, 10 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (1 g, 5 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by LC-MS, water was added 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 to give 1.69 g. MS [M+1]: 377

[0199] Synthesis of C18-3: C18-2 (1.69 g, 4.5 mmol) and ethyl acetate solution (20 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (10 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated, washed, filtered, and dried to obtain 1.57 g of crude product. MS [M+1]: 277

[0200] Synthesis of C18: C18-3 (162 mg, 0.52 mmol), int (100 mg, 0.26 mmol), diisopropylethylamine (0.18 mL, 1.04 mmol), and dimethyl sulfoxide (3 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 55 mg of the product. MS [M+1]: 567 1 H NMR(400MHz,CDCl3)δ8.34(s,1H),7.56(t,J=8.2Hz,1H),7.50(d,J=8.8Hz,1H),7.35-7.24(m,2H),6.75(s,1H),5.70(t,J=8.6H) z,1H),5.35(s,1H),3.74(d,J=53.6Hz,3H),2.63(s,3H),2.28-2.04(m,4H),2.03-1.89(m,3H),1.89-1.71(m,3H),1.07(s,3H).

[0201] Example 19 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0202] Synthesis of C19-2: C19-1 (1 g, 4.7 mmol), triethylamine (1.25 mL, 9.4 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (0.94 g, 4.7 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by LC-MS, water was added 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 to give 2.35 g. MS [M+1]: 377

[0203] Synthesis of C19-3: C19-2 (2.35 g, 6.2 mmol) and a dichloromethane solution (20 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (10 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated. After washing, the mixture was filtered and dried to obtain 1.47 g of crude product. MS [M+1]: 277

[0204] Synthesis of C19: C19-3 (162 mg, 0.52 mmol), int3 (100 mg, 0.26 mmol), diisopropylethylamine (0.18 mL, 1.04 mmol), and dimethyl sulfoxide (3 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 93 mg of the product. MS [M+1]: 567 1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.48(m,1H),7.27(s,1H),6.98(t,J=8.9Hz,2H),6.75(s,1H),5.71(d,J=8.7Hz,1H),5.01(s, 1H),3.88(d,J=11.9Hz,3H),2.87(s,2H),2.64(s,1H),2.11(d,J=10.3Hz,3H),1.96(d,J=14.7Hz,4H),1.72(s,3H),1.08(s,3H).

[0205] Example 20 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0206] Synthesis of C20-2: C20-1 (0.5 g, 2.04 mmol), triethylamine (0.54 mL, 4.08 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (0.4 g, 2.04 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by LC-MS, water was added 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 to give 850 mg. MS [M+1]: 409

[0207] Synthesis of C20-3: C20-2 (850 mg, 2.08 mmol) and a dichloromethane solution (10 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (3.8 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated. After washing, the mixture was filtered and dried to obtain 692 mg of crude product. MS [M+1]: 345

[0208] Synthesis of C20: C20-3 (144.5 mg, 0.42 mmol), int (80 mg, 0.21 mmol), diisopropylethylamine (0.15 mL, 0.84 mmol), and dimethyl sulfoxide (2 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 83 mg of the product. MS [M+1]: 618 1 H NMR(400MHz,CDCl3)δ8.40(s,1H),8.04(s,1H),7.98(d,J=7.7Hz,1H),7.90(d,J=7.8Hz,1H),7.72(t,J=7.9Hz,1H),7.33(s,1H),6.76(t,J=75 .1Hz,1H),5.76(t,J=8.6Hz,1H),5.30(s,1H),3.83(d,J=33.6Hz,3H), 2.70(m,3H),2.33-2.10(m,3H),1.99(m,4H),1.89(m,3H),1.13(s,3H).

[0209] Example 21 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0210] Synthesis of C21-2: C21-1 (0.5 g, 2.17 mmol), triethylamine (0.58 mL, 4.34 mmol), and dichloromethane (5 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (0.43 g, 2.17 mmol) in dichloromethane (5 mL) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the reaction completion by LC-MS, water was added 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 to give 860 mg. MS [M+1]: 395

[0211] Synthesis of C21-3: C21-2 (860 mg, 2.18 mmol) and a dichloromethane solution (10 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (4 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated, washed, filtered, and dried to obtain 692 mg of crude product. MS [M+1]: 331

[0212] Synthesis of C21: C21-3 (139 mg, 0.42 mmol), int (80 mg, 0.21 mmol), diisopropylethylamine (0.15 mL, 0.84 mmol), and dimethyl sulfoxide (2 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 46 mg of the product. MS [M+1]: 604 1H NMR(400MHz,CDCl3)δ8.42(s,1H),7.73(q,J=8.3Hz,1H),7.34(s,1H),7.12(m,J=9.3,6.0Hz,1H),6.76(s,J=75.1Hz,1H),5.79(t,J=8.4Hz,1H ),5.50(s,1H),3.97(m,1H),3.86(d,J=14.0Hz,2H),2.90(m,2H),2.71( m,1H),2.38-2.11(m,4H),2.10-1.97(m,3H),1.80(m,3H),1.15(s,3H).

[0213] Example 22 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0214] Synthesis of C22-2: C22-1 (2 g, 9 mmol), triethylamine (2.4 mL, 18 mmol), and dichloromethane (10 mL) were added to a 100 mL single-neck bottle. A solution of 4-Boc-aminopiperidine (1.81 g, 9 mmol) in dichloromethane (10 mL) was added dropwise at 0 °C. The mixture was allowed to warm to room temperature and react for 2 hours. After monitoring the completion of the reaction by LC-MS, water was added 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 to give 2.2 g. MS [M+1]: 386

[0215] Synthesis of C22-3: C22-2 (1 g, 2.6 mmol), methanol (10 mL), and Pd / C (0.14 g, 10%) were added to a 100 mL single-neck bottle and stirred at room temperature under H2 for 12 hours. After monitoring the completion of the reaction by LC-MS, the Pd / C was filtered off and the reaction mixture was concentrated to give 857 mg of product. MS [M+1]: 356

[0216] Synthesis of C22-4: C22-3 (750 mg, 2.11 mmol), N,N-dimethylformamide (20 mL), and iodomethane (2 mL) were added to a 100 mL single-neck bottle. Potassium hydroxide solution (0.3 g, 10 mL) was added dropwise at 0 °C. The mixture was then warmed to room temperature, heated to 50 °C, and stirred overnight under reflux. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, extracted three times with ethyl acetate, dried the organic phase over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate = 3:1 to obtain 80 mg of product. MS [M+1]: 384

[0217] Synthesis of C22-5: C22-4 (634 mg, 1.65 mmol) and a dichloromethane solution (10 mL) were added to a 100 mL single-neck bottle, and HCl / dioxane (3 mL) was added dropwise at room temperature under stirring. After the addition was complete, the reaction was allowed to proceed for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was concentrated, a small amount of ethyl acetate and a large amount of petroleum ether were added, and the mixture was sonicated. After washing, the mixture was filtered and dried to obtain 260 mg of crude product. MS [M+1]: 256

[0218] Synthesis of C22: C22-5 (166 mg, 0.42 mmol), int3 (100 mg, 0.26 mmol), diisopropylethylamine (0.18 mL, 1.04 mmol), and dimethyl sulfoxide (3 mL) were added to a 50 mL single-neck bottle. The mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (eluent: dichloromethane:methanol = 60:1) to give 15 mg of the product. MS [M+1]: 593 1H NMR(400MHz,CDCl3)δ8.39(s,1H),7.61(d,J=8.8Hz,2H),7.32(s,1H),7.03-6.88(m,1H),6.70(d,J=8.9Hz,2H),5.81-5.69(m,1H),5 .15(m,1H),3.86(d,J=17.0Hz,3H),3.07(s,6H),2.72(s,3H),2.40-2.17(m,2H),2.04(m,1H),2.00(m,4H),1.89(m,3H),1.13(s,3H).

[0219] Example 23 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0220] Synthesis of C23-2 Compound 4-tert-butoxycarbonylaminopiperidine (500 mg, 1.00 eq), C19-1 (516 mg, 1.00 eq), and dichloromethane (5 mL) were added to a 50 mL single-neck bottle. Triethylamine (504 mg, 1.00 eq) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 3 hours. After monitoring the reaction completion by TLC, water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration, the product was slurried in petroleum ether / ethyl acetate (10 / 1) and filtered to obtain 950 mg.

[0221] Synthesis of C23-3 C23-2 (900 mg, 1 eq) and dichloromethane (5 mL) were added to a 100 mL single-neck bottle, followed by slow addition of HCl / dioxane (5 mL, 3 eq). The reaction was allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated and the product was slurried in petroleum ether. After filtration, 700 mg of the product was obtained.

[0222] Synthesis of C23 In a 50 mL single-neck bottle, int3 (100 mg, 1 eq), C23-3 (139 mg, 2 eq), diisopropylethylamine (166 mg, 2 eq), and dimethyl sulfoxide (5 mL) were added. The reaction was allowed to proceed at 60 °C for 16 h. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC to give 21 mg of the product. 1 H NMR(400MHz,CDCl3)δ8.40(s,1H),7.70(d,J=8.5Hz,2H),7.63-7.51(m,2H),7.33 (s,1H),6.75(t,J=75.1Hz,1H),5.76(t,J=8.6Hz,1H),5.43(s,1H),3.80(d,J=38 .4Hz,3H),2.71(s,2H),2.52(s,1H),2.31-2.10(m,4H),2.00(q,J=10.1,9.4Hz,2 H),1.94-1.77(m,2H),1.73-1.66(m,2H),1.37(s,9H),1.13(s,3H).MS[M+1]:606

[0223] Example 24 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0224] Synthesis of C24-2 Compound 4-t-butoxycarbonylaminopiperidine (500 mg, 1.00 eq), C20-1 (516 mg, 1.00 eq), and dichloromethane (5 mL) were added to a 50 mL single-neck bottle. Triethylamine (504 mg, 1.00 eq) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 3 hours. After monitoring the completion of the reaction by TLC, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration, the product was slurried in petroleum ether / ethyl acetate (10 / 1) and filtered to obtain 900 mg of crude product.

[0225] Synthesis of C24-3 C24-2 (900 mg, 1 eq) and dichloromethane (5 mL) were added to a 100 mL single-neck bottle, followed by slow addition of HCl / dioxane (5 mL, 3 eq). The reaction was allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated and the product was slurried in petroleum ether. After filtration, 650 mg of the product was obtained.

[0226] Synthesis of C24 In a 50 mL single-neck bottle, int3 (100 mg, 1 eq), C24-3 (139 mg, 2 eq), diisopropylethylamine (166 mg, 2 eq), and dimethyl sulfoxide (5 mL) were added. The reaction was allowed to proceed at 60 °C for 16 h. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC to give 11 mg of the product. 1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.72(d,J=8.6Hz,2H),7.33(s,1H),7.02(d,J=8.6Hz,2H),6. 75(t,J=75.1Hz,1H),5.76(t,J=8.5Hz,1H),5.42(s,1H),3.90(s,3H),3.87-3.62(m,3H),2.62(d ,J=67.4Hz,3H),2.31-2.20(m,1H),2.13(d,J=12.8Hz,2H),2.01(dd,J=16.1,6.9Hz,3H),1.90(t ,J=9.2Hz,1H),1.79(s,1H),1.26(t,J=7.2Hz,1H),1.14(s,3H),0.92-0.82(m,2H).MS[M+1]:580

[0227] Example 25 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0228] Synthesis of C25-2 Compound 4-t-butoxycarbonylaminopiperidine (1 g, 1.00 eq), C21-1 (1.02 g, 1.00 eq), and dichloromethane (20 mL) were added to a 50 mL single-neck bottle. Triethylamine (1.04 g, 1.00 eq) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 3 hours. After monitoring the completion of the reaction by TLC, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration, the product was slurried in petroleum ether / ethyl acetate (10 / 1) and filtered to obtain 2.03 g.

[0229] Synthesis of C25-3 C25-2 (2.03 g, 1 eq) and dichloromethane (20 mL) were added to a 100 mL single-neck bottle, followed by slow addition of HCl / dioxane (15 mL, 3 eq). The reaction was allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated and the product was slurried in petroleum ether. After filtration, 1.64 g of the resulting mixture was obtained.

[0230] Synthesis of C25 In a 50 mL single-neck bottle, int3 (100 mg, 1 eq), C25-3 (80 mg, 2 eq), diisopropylethylamine (66 mg, 2 eq), and dimethyl sulfoxide (5 mL) were added. The reaction was allowed to proceed at 60 °C for 16 h. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC to give 30 mg of the product. 1 H NMR(400MHz,CDCl3)δ8.42(s,1H),7.87(td,J=7.4,1.8Hz,1H),7.66-7.56(m,1H),7.39-7.29(m,2H),7.26 -7.21(m,1H),6.76(t,J=75.1Hz,1H),5.78(t,J=8.5Hz,1H),5.43(s,1H),3.88(d,J=11.7Hz,3H),2.79(d, J=57.9Hz,3H),2.26(td,J=12.0,11.5,7.0Hz,1H),2.15(d,J=12.9Hz,2H),2.01(q,J=10.1,8.9Hz,3H),1. 89(q,J=8.3,7.6Hz,1H),1.80(d,J=11.1Hz,1H),1.26(s,1H),1.14(s,3H),0.93-0.81(m,1H).MS[M+1]:568

[0231] Example 26 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0232] Synthesis of C26-2 Compound 4-t-butoxycarbonylaminopiperidine (0.94 g, 1.00 eq), C22-1 (1 g, 1.00 eq), and dichloromethane (20 mL) were added to a 50 mL single-neck bottle. Triethylamine (0.95 g, 1.00 eq) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 3 hours. After monitoring the completion of the reaction by TLC, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration, the product was slurried in petroleum ether / ethyl acetate (10 / 1) and filtered to obtain 1.64 g.

[0233] Synthesis of C26-3 C26-2 (1.64 g, 1 eq) and dichloromethane (20 mL) were added to a 100 mL single-neck bottle, followed by slow addition of HCl / dioxane (15 mL, 3 eq). The reaction was allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated and the product was slurried in petroleum ether. After filtration, 1.4 g of the product was obtained.

[0234] Synthesis of C26 In a 50 mL single-neck bottle, int3 (100 mg, 1 eq), C26-3 (85 mg, 2 eq), diisopropylethylamine (66 mg, 2 eq), and dimethyl sulfoxide (5 mL) were added. The reaction was allowed to proceed at 60 °C for 16 h. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC to give 35 mg of the product. 1H NMR(400MHz,CDCl3)δ8.42(s,1H),7.65-7.53(m,1H),7.35(s,1H),7.32-7.28(m,1H),7.22(td,J=9.0 ,4.0Hz,1H),6.76(t,J=75.1Hz,1H),5.79(t,J=8.5Hz,1H),5.46(s,1H),4.06-3.78(m,2H),2.90(s,2H) ),2.72(s,1H),2.27(td,J=11.5,7.0Hz,1H),2.17(d,J=12.8Hz,2H),2.02(td,J=10.7,10.1,5.8Hz,3H ),1.97-1.75(m,3H),1.27(q,J=8.0,7.5Hz,1H),1.14(s,3H),0.86(q,J=7.4,5.9Hz,1H).MS[M+1]:586

[0235] Example 27 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0236] Synthesis of C27-2 Compound 4-t-butoxycarbonylaminopiperidine (0.56 g, 1.00 eq), C23-1 (0.52 g, 1.00 eq), and dichloromethane (10 mL) were added to a 50 mL single-neck bottle. Triethylamine (0.57 g, 1.00 eq) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 3 hours. After monitoring the completion of the reaction by TLC, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration, the product was slurried in petroleum ether / ethyl acetate (10 / 1) and filtered to obtain 0.86 g.

[0237] Synthesis of C27-3 C27-2 (0.86 g, 1 eq) and dichloromethane (10 mL) were added to a 100 mL single-neck bottle, followed by slow addition of HCl / dioxane (15 mL, 3 eq). The reaction was allowed to proceed at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated and the product was slurried in petroleum ether. After filtration, 0.42 g of the product was obtained.

[0238] Synthesis of C27 In a 50 mL single-neck bottle, int3 (50 mg, 1 eq), C27-3 (62 mg, 2 eq), diisopropylethylamine (33 mg, 2 eq), and dimethyl sulfoxide (5 mL) were added. The reaction was allowed to proceed at 60 °C for 16 h. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC to give 18 mg of the product. 1 H NMR(400MHz,CDCl3)δ8.74(d,J=4.8Hz,1H),8.42(s,1H),8.02-7.89(m,2H),7.57-7.49(m,1H), 7.35(d,J=10.2Hz,1H),6.76(t,J=75.1Hz,2H),5.78(t,J=8.6Hz,1H),5.44(s,1H),3.96(d,J=1 2.7Hz,3H),3.14-2.98(m,2H),2.73(s,1H),2.29-2.21(m,1H),2.14(d,J=11.6Hz,2H),2.01(p, J=8.8Hz,3H),1.95-1.87(m,1H),1.82(s,1H),1.17(d,J=2.9Hz,1H),1.14(s,3H).MS[M+1]:551

[0239] Example 28 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0240] Synthesis of C28-2 Compound 4-t-butoxycarbonylaminopiperidine (1 g, 1.00 eq), C24-1 (1.15 g, 1.05 eq), and dichloromethane (10 mL) were added to a 50 mL single-neck bottle. Triethylamine (1.01 g, 2.00 eq) was added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and react for 3 hours. After monitoring the completion of the reaction by TLC, water was added to the reaction mixture, which was then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration, the product was slurried in petroleum ether / ethyl acetate (10 / 1) and filtered to obtain 1.8 g.

[0241] Synthesis of C28-3 Add C28-2 (1.8 g, 1 eq) and dichloromethane (15 mL) to a 100 mL single-neck bottle, then slowly add HCl / dioxane (15 mL, 3 eq). React at room temperature for 2 hours. Monitor the completion of the reaction by TLC, then concentrate. After concentration, add petroleum ether to the product to make a slurry. After filtration, obtain 1.2 g.

[0242] Synthesis of C28 In a 50 mL single-neck bottle, int3 (100 mg, 1 eq), C28-3 (164 mg, 2 eq), diisopropylethylamine (132 mg, 4 eq), and dimethyl sulfoxide (3 mL) were added. The reaction was allowed to proceed at 60 °C for 16 h. After monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC to give 60 mg of the product. 1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.68(d,J=8.1Hz,2H),7.37-7.33(m,2H),6.75(s,1H),5.76(t ,J=8.6Hz,1H),5.46(s,1H),3.80(d,J=38.1Hz,3H),2.68(t,J=7.7Hz,3H),2.52(s,1H),2.29-2. 19(m,1H),2.13(d,J=12.6Hz,2H),2.08-1.94(m,3H),1.92-1.76(m,2H),1.70(dt,J=15.0,7.4Hz ,4H),1.26(q,J=5.1Hz,2H),1.13(s,3H),0.97(t,J=7.3Hz,3H),0.92-0.82(m,2H).MS[M+1]:592

[0243] Example 29 Compounds synthesized according to the present invention: [ka] The synthetic route and experimental procedures are as follows. [ka]

[0244] Compound int3 (80 mg) is dissolved in DMSO, and int7 (89 mg, 2.0 eq) and triethylamine (0.11 ml, 3.0 eq) are added, followed by overnight reaction at 60° C. After monitoring the completion of the reaction, water is added to the system, followed by extraction with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated using a preparative plate to obtain the product (50 mg). 1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.36(s,1H),6.77(t,J=75.1Hz,1H),5.82(s,1H),5.57(d,J=55.6Hz,1H),3.89-3.73(m,2H),2.91(m,J=11.8, 2.8Hz,2H),2.83(s,3H),2.74(s,1H),2.34-2.11(m,4H),2.10-1.98(m, 2H),1.99-1.78(m,2H),1.78-1.58(m,2H),1.16(s,3H).MS[M+1]:488.5.

[0245] Using synthetic methods similar to those described above, the compounds in the table below are synthesized. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0246] Cell proliferation inhibition test 1. Experimental materials [Table 2]

[0247] Reference compound WO2018033815A1:PF-06873600, palbociclib (palbociclib) [ka]

[0248] 2. Experimental plan MCF7, T47D, OVCAR3, and HCC1806 cells were seeded into a 96-well plate at 3,000, 3,000, 2,500, and 2,000 cells / well, respectively, and cultured overnight in a 37°C, 5% CO2 incubator.

[0249] 1. Compound Dilution a) Preparation of gradient dilutions of test compounds: Palbociclib (Palbociclib) and the compounds of the examples were prepared as 10 mM stock solutions. 2.5 μl of the stock solution was then dissolved in 497.5 μl of DMSO-free medium and diluted three-fold with 0.1% DMSO medium to obtain nine concentrations. The concentrations of the compounds after dilution were as follows: 10000nM, 3333.33nM, 1111.11nM, 370.34nM, 123.45nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM b) After thorough mixing, 20 μL of each incubation compound solution is added to a cell-free culture plate containing 80 μL of cells in four duplicate wells for each concentration. c) The cells are transferred to an incubator and incubated for 7 days, and on the fourth day of culture, the medium is replaced with fresh medium containing the same concentration of compound.

[0250] 2.MTT detection a) Remove the cell culture plate and add 10 μL of 5 mg / ml MTT to the hood. b) Return the cell culture plate to the incubator and continue to incubate for 3 hours. c) Remove the cell culture plate, remove the culture medium, add 100 μL of isopropanol (0.4 mM HCl, 0.4% NP40), shake at room temperature for 30 minutes, and read the plate at 570 nm.

[0251] 3. Data Analysis Calculate the %CellSurvival using the following formula: Cell survival rate (%Cell Survival)=100%×(OD_sample-OD_LCave) / (OD_HC-OD_LCave) OD_HC: 0.1‰ DMSO control cell reading OD_sample: reading of cells with compound OD_LC: Reading of blank medium Analysis with Prizm: Dose-Response-Inhibition-Log(Inhibitor) vs Response (Three parameters for best fit) IC50 (nM) values ​​are calculated by concentration-response curve fitting.

[0252] The results of the cell growth inhibition test are shown in Table 1 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0253] A represents an IC50 value ≦50 nM, B represents an IC50 value >50 nM and ≦200 nM, C represents an IC50 value >200 nM and ≦1000 nM, and D represents an IC50 value >1000 nM.

[0254] From the above table, it can be seen that the compounds of this patent have excellent inhibitory effects on both palbociclib-sensitive and drug-resistant cells, and the compounds of this patent have activity equal to or greater than that of PF-06873600, and are expected to be further developed as modulators of CDK kinase activity or therapeutic agents for CDK-related disease states.

[0255] MCF-7-Palbo-R cell proliferation inhibition experiment 1. Experimental materials MCF-7 / palbo-R EMEM medium (ATCC,30-2003), DMEM / F12 medium (Gibco-11330-032) Fetal bovine serum (cellmax-SA211.02) DMSO (SIGMA, D2650) BrdUELISA cell proliferation kit (Roche, 11647229001) Microplate reader (e.g., MD-SpectraMax ID5 or EnVision)

[0256] 2. Experimental plan 1. Cell Plating 1) Count the cells and adjust the concentration of the cell suspension. 2) Inoculate a 96-well plate with the MCF7 / Palbo-R cell suspension in a volume of 90 μl so that each well contains 4,000 to 5,000 cells. 3) Add 90 μl of medium to the blank control group.

[0257] 2. Compound Dilution a) Preparation of gradient dilutions of test compounds: Palbociclib (Palbociclib) and the compounds of the examples were used as stock solutions at 10 μM. They were serially diluted 3-fold with 0.1% DMSO medium to obtain nine concentrations. The concentrations of the compounds after dilution were as follows: 10000nM, 3333.33nM, 1111.11nM, 370.34nM, 123.45nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM

[0258] b) 72 hours after compound treatment: 1) Dilute 10 mM Brdu stock solution in RPMI medium, add 20 μL / well to a 96-well plate, and shake at 350 rpm for 10 minutes. 2) Place the 96-well plate back into the incubator for 1 or 2 hours. 3) Remove the medium from the 96-well plate and add 200 ul / well of Fixation / Denaturation solution and incubate at room temperature for 30 minutes. 4) Remove the fixative and add 100 μl of peroxidase-conjugated anti-Brdu antibody solution (antibody dilution solution prepared by diluting 1:100). Incubate at room temperature and 350 rpm for 1 hour. 6) Wash the 96-well plate three times with 300 ul / well of PBS. 8) Add 100 μl of peroxidase substrate solution and shake at 350 rpm at room temperature for approximately 10-20 minutes until the DMSO-treated cell control wells turn a medium blue color. If the color is too dark, the absorbance value may be outside the reading range. 9) Add 25 μl of 1M sulfuric acid to stop the reaction. Shake to ensure a uniform color. 10) Record the absorbance at 450 nm.

[0259] 3. Data Processing The percent inhibition is calculated using the following formula: IR(%)=(1-(RLU compound-RLU blank) / (RLU control-RLU blank))*100%.

[0260] The results of the MCF-7-Palbo-R cell growth inhibition experiments are shown in Table 2. [Table 4]

[0261] The compounds of this patent show good inhibition rates against palbociclib-resistant cell lines, and are superior to PF-06873600.

[0262] Enzyme activity test Compound preparation : 1. Prepare the test compound and palbociclib in 0.5 nM DMSO solution. 2. Using the Echo 550, transfer 20 nL of the stock solution to a 384-well plate. DMSO is used as a blank control.

[0263] Experimental Phase: 1. Prepare a 1.3X enzyme solution containing enzyme, substrate, and cofactor according to the following table: 2. Add 15uL of 1.3X enzyme solution to each well and incubate at room temperature for 30 minutes. The reaction is initiated by adding 3.5 uL of ATP solution, with the final volume in each well being 20 uL. 4. After 150 minutes of incubation at room temperature, the experiment is terminated by adding 75 uL of stop buffer. 5. Analyze the samples using the EZreader. [Table 5]

[0264] Data Analysis: Calculate the % inhibition using the following equation: DMSO treatment was the positive control (PC). No enzyme was included as a negative control (NC). % Inhibition = 100-100*((CRPC-CR sample) / (CRPC-CRNC))

[0265] The results of the enzyme inhibition experiments are shown in Table 3. [Table 6-1] [Table 6-2] [Table 6-3]

[0266] A represents an IC50 value ≦10 nM, B represents an IC50 value >10 nM and ≦100 nM, C represents an IC50 value >100 nM and ≦500 nM, and D represents an IC50 value >500 nM. The data show that the compounds of this patent have excellent kinase inhibitory activity against CDK2, CDK4, and CDK6.

[0267] Xenograft tumor experiments: xMCF-7 / Palbo-R model: To establish xenograft tumor models, 1 x 10 7 xMCF-7 / Palbo-R cells were suspended in 0.2 mL of a mixture of Matrigel and mouse (1:1) and subcutaneously injected into 6-8 week-old Balb / cnube female mice. Tumor growth was monitored periodically and measured using a vernier caliper to determine the volume (volume = 1 / 2 x (length x width)). 2 )) The volume was measured, and the tumor had an average volume of 100-150 mm 3 Once the tumors reached the target size, the mice were randomly assigned to treatment groups according to tumor size and mouse weight (12 days after inoculation). The mice were randomly assigned to five groups, each containing three animals, with the following doses: (a) vehicle, (b) 10 mg / kg PF-06873600, (c) 20 mg / kg C27, (d) 10 mg / kg C3, and (h) 20 mg / kg C3. The mice were orally administered twice daily by gavage for 20 days. Tumor volume and animal weight were measured twice weekly until the end of the study. The day of administration was defined as day 0. Measurement time points were days 0, 3, 7, 10, 14, 17, and 20. All mice were euthanized by cervical dislocation. At the end of the experiment, tumors were collected, and TGI values ​​(shown in Table 4) were calculated. The results of the experiment are shown in Figure 1. [Table 7]

[0268] OVCAR-3 model: 1.Cell culture OVCAR-3 cells were cultured in RPMI 1640 medium containing 20% ​​fetal bovine serum and 10 μg / mL of insulin. Cells in the exponential growth phase were harvested and resuspended in a 1:1 mixture of PBS and Matrigel to a concentration suitable for subcutaneous tumor inoculation in nude mice.

[0269] 2. Animal Modeling To establish xenograft tumor models, 1 x 10 7 OVCAR-3 cells were suspended in 0.2 mL of a 1:1 mixture of PBS and Matrigel and injected subcutaneously into the right back of 6-8 week-old BALB / cnube female mice. Tumor growth was monitored periodically and measured using a caliper to determine the volume (volume = 1 / 2 x (length x width)). 2The tumor volume was measured, and when the tumors grew to an average volume of 100-150 mm3, the mice were randomly divided into groups according to tumor size and mouse weight and administered the treatment (27 days after inoculation). The mice were randomly assigned to six groups, each containing five animals, and the doses used in each group were as follows: (a) vehicle, (b) 60 mg / kg palbociclib, (c) 30 mg / kg PF-06873600, (d) 30 mg / kg C3, (e) 30 mg / kg C29, and (f) 50 mg / kg C29. The vehicle was DMSO / Solutol / Saline (5% / 10% / 85%), and palbociclib, PF-06873600, C3, and C29 were dissolved in the vehicle at concentrations of 6 mg / mL, 3 mg / mL, 3 mg / mL, 3 mg / mL, and 5 mg / mL, respectively. Mice in the vehicle, 30 mg / kg PF-06873600, 30 mg / kg C3, 30 mg / kg C29, and 50 mg / kg C29 groups were administered orally by gavage twice daily for 21 days, while mice in the 60 mg / kg palbociclib group were administered orally by gavage once daily for 21 days. Tumor volume and animal weight were measured twice weekly until the study was terminated. The day of administration was defined as Day 0. Measurement time points were Days 0, 3, 7, 10, 14, 17, and 21. All mice were euthanized by cervical dislocation. At the end of the experiment, tumors were collected and weighed to calculate the TGI values ​​(shown in Table 5). The results of the experiment are shown in Figure 2. [Table 8]

[0270] MV4-11 model: 1.Cell culture MV-4-11 cells were cultured in IMEM medium containing 10% fetal bovine serum. Cells in the exponential growth phase were harvested and resuspended in PBS to a concentration suitable for subcutaneous tumor inoculation in nude mice.

[0271] 2. Animal Modeling To establish xenograft tumor models, 5 x 106 MV4-11 cells were suspended in 0.1 mL of a 1:1 mixture of PBS and Matrigel and injected subcutaneously into the right back of 6-8 week-old NOD / SCID mice. Tumor growth was monitored periodically and measured using a caliper to determine the volume (volume = 1 / 2 x (length x width)). 2 The volume of the tumor was measured, and the average volume was 100-150 mm 3 Once tumors reached a certain size, mice were randomly assigned to groups based on tumor size and mouse weight (12 days after inoculation). Mice were randomly assigned to five groups, each containing five animals, and received: (a) vehicle, (b) 20 mg / kg palbociclib, (c) 10 mg / kg PF-06873600, (d) 10 mg / kg C3, and (e) 20 mg / kg C3. The vehicle was DMSO / Solutol / Saline (5% / 10% / 85%), and palbociclib, PF-06873600, and TYK-00127 were dissolved in the vehicle at concentrations of 2 mg / mL, 1 mg / mL, 1 mg / mL, and 2 mg / mL, respectively. Here, mice in the vehicle, 10 mg / kg TY-3301, 10 mg / kg C3, and 20 mg / kg C3 groups were administered orally by gavage twice daily for 15 days, and mice in the 20 mg / kg TY-3300 group were administered orally by gavage once daily for 15 days. Tumor volume and animal weight were measured twice weekly and continued until the end of the study. The day of administration was defined as day 0. Measurement time points were days 0, 3, 7, 10, 14, and 15. All mice were euthanized by cervical dislocation. At the end of the experiment, tumors were collected and weighed to calculate the TGI value (shown in Table 6). The experimental results are shown in Figure 3. [Table 9]

[0272] In vivo efficacy experiments in animal models showed that the patented compound exhibited excellent tumor inhibitory effects, with experimental effects far superior to those of the palbociclib control group and greater advantages compared to PF-06873600.

[0273] The present invention provides compounds with excellent kinase, cellular, and in vivo efficacy, and methods for synthesizing the same. It is expected that compounds of this type will be developed to solve the existing clinical resistance problem of palbociclib and the like, and to provide new treatment options for this type of patient.

[0274] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, 【Chemistry 1】 where: R １ is unsubstituted or 1 to 4 R ６ a C3-C10 cycloalkyl group unsubstituted or containing or containing 1 to 3 heteroatoms selected from N, O and S; ６ a 5- to 15-membered fused ring substituted by 1 to 4 R, unsubstituted or containing or containing 1 to 3 heteroatoms selected from N, O and S; ６ a 5- to 15-membered spiro ring unsubstituted or substituted by 1-4 R ６ a 5-15 membered bridged ring substituted by 1-4 R ６ a 3- to 10-membered heterocycloalkyl group, unsubstituted or substituted by 1 to 4 R ６ a C6-C10 aryl group unsubstituted or containing 1-5 heteroatoms selected from N, O and S, substituted by 1-4 R ６ a 3- to 10-membered heteroaryl group unsubstituted or substituted by 1 to 4 R ６ C1-C6 alkyl groups substituted with R ２ is selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group, and R ２ can be attached to ring atoms to form spiro, bridged, or fused ring structures; R ３ａ and R ３ｂ are independently selected from the group consisting of H, F, OH, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; Here, R ２ , R ３ａ and R ３ｂ wherein each C1-C4 alkyl group and halogenated C1-C4 alkyl group is optionally substituted with halogen, OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; R ４ is a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from Br, N, O and S; —OR ４ ', -SR ４ ', -NR ４ 'R ４ ", wherein R ４ ' and R ４ " are each independently H, COR ７ , a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R ５ is selected from the group consisting of H, halogen, C1-C2 alkyl groups, halogenated C1-C2 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; Each R ６ represents H, deuterium, a hydroxy group, a halogen, a cyano group, ═O, COR ７ , CO ２ R ７ , C.O.R. ８ R ９ , CO ２ NR ８ R ９ , S.O. ２ R ７ , S.O. ２ NR ８ R ９ , N.R. ８ SO ２ R ７ , NHSO ２ NR ８ R ９ , 【Chemistry 2】 NR ８ R ９ , R''' substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, C3-C8 cycloalkyl groups, halogenated C3-C8 cycloalkyl groups, C4-C10 spiro rings, C3-C10 fused rings, C4-C10 bridged rings, thio C1-C6 alkyl groups, C6-C10 aryl groups, and 3- to 10-membered heteroaryl groups containing 1 to 5 heteroatoms selected from N, O, and S; R''' is selected from the group consisting of ═O, NR'R'', a C1-C4 alkyl group, and a halogenated C1-C4 alkyl group; Each R ７ is independently selected from the group consisting of a C1-C4 alkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1 to 5 heteroatoms selected from N, O, and S), and -L-(3- to 10-membered aryl), wherein said C1-C4 alkyl group, C3-C8 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, 3- to 10-membered heteroaryl group, and 3- to 10-membered aryl group are independently selected from the group consisting of 0-4 D, OH, halogen, CN, C1-C4 alkyl group, halogenated C1-C4 alkyl group, N(C1-C4 alkyl) ２ , NHCO(C1-C4 alkyl), SO ２ (C1-C4 alkyl), CO ２ (C1-C4 alkyl), a 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S, CO(C1-C4 alkyl), a C1-C4 alkoxy group or a halogenated C1-C4 alkoxy group; R ８ and R ９ are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L-(C3-C8 cycloalkyl), -L-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S); R ８ and R ９ may be taken together with the N to which they are attached to form a substituted or unsubstituted 4- to 6-membered heterocyclic group, where the substituted group refers to being substituted with 1 to 3 substituents selected from the group consisting of ═O, NR′R″, and a C1-C6 alkyl group; each R' and R'' is independently selected from the group consisting of H, a C1-C4 alkyl group; each L is independently a bond or a C1-C4 alkylene group, said C1-C4 alkylene group being optionally substituted with OH, a C1-C4 alkoxy group, or a halogenated C1-C4 alkoxy group; p is selected from the group consisting of 0, 1, 2, 3, and 4; The compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein r is selected from the group consisting of 0, 1, 2, 3 and 4.

2. The compound has a structure shown in formula (II) or formula (III): 【Transformation 3】 where: The A ring is a ring having 0 to 4 R １ ' a substituted or unsubstituted 6- to 10-membered aryl group, 0 to 4 R １ ' an optionally substituted C3-C8 cycloalkyl group, 0-4 R １ ' is selected from the group consisting of optionally substituted 5- to 10-membered heteroaryl groups; Each R １ ' is deuterium, halogen, OH, CN, SO ２ R ３１ , C.O.R. ３１ , CO ２ R ３１ , N.R. ４１ R ５１ , NHCOR ４１ , C.O.R. ４１ R ５１ , OCONR ４１ R ５１ , NHCONR ４１ R ５１ , NHCOOR ４１ , a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution by 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R ２ ' is selected from the group consisting of H, deuterium, R ３ ' is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups, where the substitution refers to substitution with 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, C1-C4 alkyl groups, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; R ４ is selected from the group consisting of H, deuterium, and OH; ３１ is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the substitution refers to substitution by 1 to 3 substituents selected from the group consisting of deuterium, halogen, OH, CN, ═O, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a halogenated C1-C4 alkoxy group; R ４１ and R ５１ are independently selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a C3-C8 cycloalkyl group, -L'-(C3-C8 cycloalkyl), -L'-(3- to 10-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S), -L'-(3- to 10-membered heteroaryl containing 1-5 heteroatoms selected from N, O, and S), and L' is a bond or a C1-C6 alkylene group; or R ４１ and R ５１ may be taken together with the N to which they are attached to form a substituted or unsubstituted 4- to 6-membered heterocyclic group, where the substituted group is substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, ═O, and a C1-C6 alkyl group; n is selected from the group consisting of 0, 1, 2, 3, and 4. The compound of claim 1.

3. The A ring is a ring having 0 to 4 R １ ' is a 6- to 10-membered aryl group containing a substituent; The compound of claim 2.

4. The A ring is a ring having 0 to 4 R １ ' is a C3-C8 cycloalkyl group containing a substituent; The compound of claim 2.

5. The A ring is a ring having 0 to 4 R １ ' a substituted or unsubstituted 6- to 10-membered aryl group, 0 to 4 R １ ' an optionally substituted C3-C8 cycloalkyl group, 0-4 R １ ' is selected from the group consisting of optionally substituted 5- to 10-membered heteroaryl groups; Each R １ ' is deuterium, halogen, OH, CN, SO ２ R ３１ , C.O.R. ３１ , CO ２ R ３１ , N.R. ４１ R ５１ , NHCOR ４１ , C.O.R. ４１ R ５１ , a halogenated C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from N, O and S; R ２ ' is selected from the group consisting of H, deuterium, R ４ ' is selected from the group consisting of H, deuterium, R ３１ is a C1-C4 alkyl group, R ４１ and R ５１ are independently selected from the group consisting of H, C1-C4 alkyl groups; n is selected from the group consisting of 0, 1, 2, 3, and 4. The compound of claim 2.

6. The A ring is a ring having 0 to 4 R １ ' a substituted or unsubstituted 6- to 10-membered aryl group, 0 to 4 R １ ' is selected from the group consisting of optionally substituted C3-C8 cycloalkyl groups, R １ ' is selected from the group consisting of halogen, OH, C1-C4 alkoxy groups, and halogenated C1-C4 alkoxy groups; R ２ ' is selected from the group consisting of H, deuterium, n is selected from the group consisting of 0, 1, 2, 3, and 4. The compound of claim 2.

7. A compound comprising: The compound is selected from the group consisting of: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 The compound is selected from the group consisting of:

8. 1. A pharmaceutical composition comprising:

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

9. 10. Use of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, in 10. Use of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the preparation of a CDK2 / 4 / 6 kinase inhibitor drug.

10. 10. Use of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the preparation of a drug for modulating CDK kinase activity or for treating a CDK-related disease.

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