Fluoroquinoxalinone derivatives that selectively inhibit PARP1

Abstract

The present invention discloses a series of fluorine-substituted heterocyclic compounds, specifically, compounds represented by formula (XII) and pharmaceutically acceptable salts thereof. 【Chemical 1】 JPEG2025516367000403.jpg44170

Description

[Technical Field]

[0001] This application claims the following priority: The patent application is CN202210495459.8, filed on May 7, 2022. The application is CN202210693545.X, filed on June 17, 2022. The patent application is CN202211204558.2, filed on September 29, 2022. The patent application is CN202211351783.9, filed on October 31, 2022. The patent application is CN202211408423.8, filed on November 10, 2022. The patent application is CN202211593592.3, filed on December 9, 2022. The application is CN202310088997X, filed on February 2, 2023. The application number is CN2023101237901, and the filing date is February 15, 2023. The patent application number is CN2023102323675, and the filing date is March 10, 2023. The application number is CN2023103034259, and the filing date is March 23, 2023. The application number is CN2023103408613, and the filing date is March 31, 2023. The patent application is CN202310388951X, filed on April 12, 2023.

[0002] The present invention relates to a series of fluorine-substituted heterocyclic compounds, and more specifically to compounds represented by formula (XII) and pharmaceutically acceptable salts thereof. [Background technology]

[0003] Poly(ADP-ribose) polymerases (PARPs) are a very large family of proteases. This family currently consists of 18 members and plays important roles in many cell cycle processes, including replication, recombination, chromatin remodeling, and DNA damage repair.

[0004] Among these, PARP1 and PARP2 have been widely studied for their roles in DNA damage repair. PARP1 is activated by DNA damage cleavage and catalyzes the addition of a poly(ADP-ribose) (PAR) chain to target proteins. This post-translational modification, called PARylation, mediates the recruitment of additional DNA repair factors to the DNA damage. Once this recruitment is complete, PARP is released via autoparylation, allowing it to access other DNA repair proteins and complete the repair.

[0005] Inhibition of PARP family enzymes has been developed as an antitumor strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have shown that tumor cells have BRCA1 or BRCA2 mutations, BRCA is a major tumor inhibitor protein involved in double-strand break (DSB) repair via homologous recombination (HR), and these tumors have defects in the homologous recombination repair (HRD) pathway and their survival depends on the function of PARP enzymes. The growth of BRCA-mutated tumors becomes more dependent on the PARP pathway and is particularly sensitive to PARP1 inhibitors. In addition to being effective against BRCA-mutated cancers, clinical trials have also demonstrated that PARP inhibitors show predetermined efficacy in non-BRCA-mutated tumors exhibiting homologous recombination defects.

[0006] Compared to other clinically available PARP1 / 2 inhibitors, highly selective PARP1 inhibitors offer improved selectivity for PARP1 compared to PARP2, reducing hematological toxicity caused by PARP2 inhibition and achieving superior clinical efficacy and lower toxicity. Therefore, there is an unmet medical need for effective and safe PARP inhibitors, particularly those selective for PARP1.

[0007] PARP1 selective inhibitors may be used alone for solid tumors such as ovarian cancer, breast cancer, triple-negative breast cancer, and prostate cancer with BRCA1 / 2 mutations (synthetic lethal mechanism), or as a combination therapy to enhance the effects of anticancer agents that enhance DNA damage mechanisms (such as DNA alkylating agents, topoisomerase inhibitors, and platinum-based chemotherapeutic agents) and radiotherapy. Furthermore, they may be used in combination with other targeted drugs such as PD-1 inhibitors, androgen receptor (AR) inhibitors, cell cycle checkpoint kinase (Chk) inhibitors, and c-Met inhibitors for the treatment of various BRCA-negative or positive solid tumors. [Overview of the project]

[0008] The present invention provides a compound represented by formula (XII) or a pharmaceutically acceptable salt thereof. [ka] however, X is selected from O and S. Structural unit [ka] teeth, [ka] Selected from, Ring A is selected from phenyl and 6-membered heteroaryl. Ring B is selected from 6-membered heteroaryls, L is selected from single bonds, and ring C is [ka] Selected from, [ka] It is selected from a single bond or a double bond. T2 is selected from C, N, and CH. T3 and T4 are independently N and CR, respectively. 10 Selected from, R1 is C 1-3 alkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl and C 3-5 cycloalkyl are each independently optionally substituted by 1, 2 or 3 halogens, R2 is H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, R3 is selected from H and halogen, R9 is absent or is selected from H and halogen, R4 is H, halogen, CN, C 1-3 alkyl and C 1-3 alkoxy, R5 is H, halogen, CN, C 1-3 alkyl and C 1-3 alkoxy, R6 and R7 are each independently H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 halogens, R8 is C 1-3 alkyl and C 3-5 cycloalkyl, and the C 1-3 alkyl and C 3-5 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Rs, R 10 is selected from H and halogen, R 13 and R 14 are each independently H, halogen, C 1-3 alkyl, C 1-3 alkoxy and C 3-5 cycloalkyl, and the C 1-3 alkyl, C 1-3 alkoxy and C 3-5Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R 15 and R 16 These are H, D, and C, respectively, independently. 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy is independently and optionally substituted with one, two, or three halogens. Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 The cycloalkyl group is optionally substituted with one, two, or three halogens. Alternatively, two R atoms on adjacent atoms a These, together with the atoms linked to them, form a double bond or a cyclopropyl bond. Each R b These are H, halogen, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 Selected from cycloalkyl, the C 1-3Alkyl, C 1-3 Alkoxy and C 3-5 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens, Each R c is independently H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 Cycloalkyl, and the C 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens, Each R is independently selected from halogen and D, n is selected from 0, 1, 2, 3 and 4, The condition is that the structural unit

Chemical formula

Chemical formula

Chemical formula

[0009] The present invention further provides a compound represented by formula (XII) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] The present invention further provides a compound represented by formula (XI) or a pharmaceutically acceptable salt thereof. [ka] however, X is O, S and N(R d ) are selected from, Structural unit [ka] teeth, [ka] Selected from, Ring A is selected from phenyl and 5-6 membered heteroaryls. Ring B is selected from 5-6 member heteroaryls. L is selected from single bonds, and ring C is [ka] Selected from, Alternatively, L is N(R 12 ) is selected, and ring C is, [ka] Selected from, [ka] It is selected from a single bond or a double bond. T2 is selected from C, N, and CH. T3 and T4 are independently N and CR, respectively. 10 Selected from, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is H and C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 is selected from H and halogen. R9 either does not exist, or is selected from H and halogen. R4 is selected from H and halogen. R5 is selected from H and halogen. R6 and R7 are independently selected from H and halogen, respectively. R8 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is independently and optionally substituted with 1, 2, or 3 R groups. R 10 It is selected from H and halogen, R 12 H, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Alternatively, two R atoms on adjacent atoms a These atoms, when linked together, form a double bond or cyclopropyl bond. Each R b These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R c These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R d C 1-3 Selected from alkoxy, the C 1-3 The alkoxy is optionally substituted with one, two, or three halogens. Each R is independently selected from halogen and D. n is selected from 0, 1, 2, 3, and 4. The conditions are, 1) Structural units [ka] but [ka] Selected from, L is selected from single bonds, and ring C is [ka] When selected from and one of T3 or T4 is selected from N, R2, R3 and R9 are not H at the same time, or 2) Structural units [ka] but [ka] Selected from, L is selected from single bonds, and ring C is [ka] When selected from and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time, or 3) Structural units [ka] but [ka] Selected from, L is selected from single bonds, and ring C is [ka] T3 is selected from N and T4 is CR 10 When selected from, R5 is selected from halogen, or, 4) Structural units [ka] but [ka] Selected from, L is selected from single bonds, and ring C is [ka] Selected from, T4 is selected from N, and T3 is CR 10 When selected from the options, R4 is selected from the halogen options.

[0011] The present invention further provides a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof. [ka] however, X is O, S and N(R d ) are selected from, Structural unit [ka] teeth, [ka] Selected from, Ring A is selected from phenyl and 5-6 membered heteroaryls. Ring B is selected from 5-6 member heteroaryls. [ka] It is selected from a single bond or a double bond. T2 is selected from C, N, and CH. T3 and T4 are independently N and CR, respectively. 10 Selected from, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is H and C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 is selected from H and halogen. R9 either does not exist, or is selected from H and halogen. R4 is selected from H and halogen. R5 is selected from H and halogen. R6 and R7 are independently selected from H and halogen, respectively. R8 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is independently and optionally substituted with 1, 2, or 3 R groups. R 10 It is selected from H and halogen, Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Alternatively, two R atoms on adjacent atoms a These atoms, together with the atoms linked to them, form a double bond or cyclopropyl bond. Each R b These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R c These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R d It is selected from OCH3, Each R is independently selected from halogen and D. n is selected from 0, 1, 2, 3, and 4. The conditions are, 1) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R2, R3 and R9 are not H at the same time, or 2) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time, or 3) This structural unit [ka] but [ka] Selected from, structural unit [ka] but [ka] T3 is selected from N and T4 is CR 10 When selected from, R5 is selected from halogen, or, 4) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] Selected from, T4 is selected from N, and T3 is CR 10 When selected from, R4 is selected from halogen, or, 5) Structural Units [ka] but [ka] Selected from, structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time.

[0012] The present invention further provides a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof. [ka] however, X is O, S and N(R d ) are selected from, Structural unit [ka] teeth, [ka] Selected from, Ring A is selected from phenyl and 5-6 membered heteroaryls. Ring B is selected from 5-6 member heteroaryls. [ka] It is selected from a single bond or a double bond. Structural unit [ka] teeth, [ka] Selected from, T3 and T4 are independently N and CR, respectively. 10 Selected from, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is H and C 1-3Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 and R9 are independently selected from H and halogen, respectively. R4 is selected from H and halogen. R5 is selected from H and halogen. R6 and R7 are independently selected from H and halogen, respectively. R8 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is independently and optionally substituted with 1, 2, or 3 R groups. R 10 It is selected from H and halogen, Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from T2 is selected from C, N, and CH. Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Alternatively, two R atoms on adjacent atoms a These atoms, together with the atoms linked to them, form a double bond or cyclopropyl bond. Each Rb These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R c These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R d It is selected from OCH3, Each R is independently selected from halogen and D. n is selected from 0, 1, 2, 3, and 4. The conditions are, 1) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R2, R3 and R9 are not H at the same time, or 2) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time, or 3) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] T3 is selected from N and T4 is CR 10 When selected from, R5 is selected from halogen, or, 4) Structural units [ka] but [ka] Selected from, structural unit [ka] but [ka] Selected from, T4 is selected from N, and T3 is CR 10 When selected from, R4 is selected from halogen, or, 5) Structural Units [ka] but [ka] Selected from, structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time.

[0013] The present invention further provides a compound represented by formula (VII-1) or a pharmaceutically acceptable salt thereof. [ka] however, [ka] When a double bond is selected, T2 is selected from C, R9 is absent, and R3 is selected from H and halogens. [ka] When a single bond is selected, T2 is selected from N and CH, and R9 and R3 are independently selected from H and halogen, respectively. X is O, S and N(R d ) are selected from, T1 is selected from N, Alternatively, T1 and R1 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from T3 and T4 are independently N and CR, respectively. 10 Selected from, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is H and C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R4 is selected from H and halogen. R5 is selected from H and halogen. R6 and R7 are independently selected from H and halogen, respectively. R8 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is independently and optionally substituted with 1, 2, or 3 R groups. R 10 It is selected from H and halogen, Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Alternatively, R on two adjacent atoms a It forms a double bond with an adjacent atom, Each R bThese are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R c These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R d It is selected from OCH3, Each R is independently selected from halogen and D. n is selected from 0, 1, 2, 3, and 4. The conditions are, 1) When T1 is selected from N, T2 is selected from N, and one of T3 or T4 is selected from N, R2, R3 and R9 are not H at the same time, or 2) When T1 is selected from N, T2 is selected from N, and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time, or 3) T1 is selected from N, T2 is selected from N, T3 is selected from N, and T4 is CR 10 When selected from, R5 is selected from halogen, or, 4) T1 is selected from N, T2 is selected from N, T4 is selected from N, and T3 is CR 10 When selected from, R4 is selected from halogen, or, 5) T1 is selected from N, and the structural unit [ka] but [ka] When selected from and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time.

[0014] The present invention further provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof. [ka] however, [ka] When a double bond is selected, T2 is selected from C, R9 is absent, and R3 is selected from H and halogens. [ka] When a single bond is selected, T2 is selected from N and CH, and R9 and R3 are independently selected from H and halogen, respectively. T1 is N and CR 11 Selected from, T3 and T4 are N and CR 10 Selected from, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is H and C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R4 is selected from H and halogen. R5 is selected from H and halogen. Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from R6 and R7 are independently selected from H and halogen, respectively. R8 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R 11 And R1 forms a benzene ring, forming a structural unit [ka] but [ka] Let it be selected from R 10 It is selected from H and halogen, Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R b These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R c These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. n is selected from 0, 1, 2, 3, and 4. The condition is that T1 is selected from N, T2 is selected from N, and T3 is selected from N. 1) R2, R3, and R9 are not H at the same time, or 2) R6 and R7 are not H at the same time, or 3) R5 is selected from halogen bulbs.

[0015] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [ka] however, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 is selected from H, R4 is selected from halogen, R5 is selected from H, Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R b These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 The alkyl group is optionally substituted with one, two, or three halogens.

[0016] The present invention further provides a compound represented by formula (VII-2) or a pharmaceutically acceptable salt thereof. [ka] however, T3 and T4 are independently N and CR, respectively. 10 Selected from, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R4 is selected from H and halogen. R5 is selected from H and halogen. R6 and R7 are independently selected from H and halogen, respectively. R8 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is independently and optionally substituted with 1, 2, or 3 R groups. R 10 It is selected from H and halogen, R 12 H and C 1-3 Selected from alkyl groups, Each R is independently selected from halogen and D.

[0017] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [ka] however, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 is selected from H, R4 is selected from halogen, R5 is selected from H, Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R b These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 The alkyl group is optionally substituted with one, two, or three halogens.

[0018] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [ka] however, R1 is C 1-3 Alkyl and C 3-5 Selected from cycloalkyl, the C 1-3 Alkyl and C 3-5 Each cycloalkyl group is optionally substituted independently with one, two, or three halogens. R2 is C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 is selected from H, R4 is selected from halogen, R5 is selected from H, Alternatively, R2 and R4 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Alternatively, R3 and R5 form a ring, forming a structural unit. [ka] but [ka] Let it be selected from Each R a These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. Each R b These are H, halogen, and C, respectively, independently. 1-3 Selected from alkyl, the C 1-3The alkyl group is optionally substituted with one, two, or three halogens.

[0019] In some embodiments of the present invention, X is selected from O, S, and N(OCH3), and the other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, X is selected from O and S, and the other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, X is selected from O, and the other variables are as defined in the present invention.

[0022] Some embodiments of the present invention, each of the above R a Each of these is independently selected from H, F, Cl, Br, I, CH3, CH2CH3, and CH2CH2CH3, wherein CH3, CH2CH3, and CH2CH2CH3 are optionally substituted with one, two, or three halogens, and the other variables are as defined in the present invention.

[0023] Some embodiments of the present invention, each of the above R a These are independently selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0024] Some embodiments of the present invention, each of the above R a These are independently selected from H and CH3, and the other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, the two R atoms on adjacent atoms a These, together with the atoms linked to them, form a double bond or cyclopropyl, forming a structural unit. [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, the two R atoms on adjacent atoms a These, together with the atoms linked to them, form a double bond or cyclopropyl, forming a structural unit. [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, the two R atoms on adjacent atoms a These, together with the atoms linked to them, form a double bond or cyclopropyl, forming a structural unit. [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, R on the two adjacent atoms a It forms a double bond with an adjacent atom, forming a structural unit. [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, R on the two adjacent atoms aIt forms a double bond with an adjacent atom, forming a structural unit. [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0030] Some embodiments of the present invention, each of the above R b Each of these is independently selected from H, F, Cl, Br, I, CH3, CH2CH3, and CH2CH2CH3, wherein CH3, CH2CH3, and CH2CH2CH3 are optionally substituted with one, two, or three halogens, and the other variables are as defined in the present invention.

[0031] Some embodiments of the present invention, each of the above R b These are independently selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0032] Some embodiments of the present invention, each of the above R b These are independently selected from H and CH3, and the other variables are as defined in the present invention.

[0033] Some embodiments of the present invention, each of the above R c Each of these is independently selected from H, F, Cl, Br, I, CH3, CH2CH3, and CH2CH2CH3, wherein CH3, CH2CH3, and CH2CH2CH3 are optionally substituted with one, two, or three halogens, and the other variables are as defined in the present invention.

[0034] Some embodiments of the present invention, each of the above R c These are independently selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0035] Some embodiments of the present invention, each of the above Rc These are independently selected from H and F, and the other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the above R d The first variable is selected from OCH3, and the other variables are as defined in this invention.

[0037] In some embodiments of the present invention, T3 is selected from N, CH, and CF, and the other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, T3 is selected from N and CF, and the other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, T3 is selected from N, and the other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, T4 is selected from N and CH, and other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, R1 is selected from CH3 and CH2CH3, and the other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, R1 is selected from CH3, and the other variables are as defined in the present invention.

[0043] In some embodiments of the present invention, R2 is selected from H and CH3, and the other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, R2 is selected from CH3, and the other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, R4, R5, R6, and R7 are each independently selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, R3 is selected from H and F, and the other variables are as defined in the present invention.

[0047] In some embodiments of the present invention, R4 is selected from H, F, Cl, CN, and CH3, and the other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, R4 is selected from H, F, Cl, and CN, and the other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, R4 is selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, R4 is selected from H and F, and the other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, R4 is selected from F, and the other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, R5 is selected from H, F, Cl, and CN, and the other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, R5 is selected from H, F, CN, and CH3, and the other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, R5 is selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, R5 is selected from H and F, and the other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, R5 is selected from H, and the other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, R6 and R7 are independently selected from H, F, and CH3, respectively, and the other variables are as defined in the present invention.

[0058] In some embodiments of the present invention, R6 is selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, R7 is selected from H, F, and CH3, and the other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, R6 is selected from H and F, and the other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, R7 is selected from H and F, and the other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, R8 is selected from CH3, CH2CH3, CH2CF3, cyclopropyl, and CD3, and other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, R8 is selected from CH3, CH2CF3, cyclopropyl, and CD3, and other variables are as defined in the present invention.

[0064] In some embodiments of the present invention, R8 is selected from CH3, cyclopropyl, and CD3, and other variables are as defined in the present invention.

[0065] In some embodiments of the present invention, R8 is selected from CH3 and cyclopropyl, and other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, R9 is selected from H and F, and the other variables are as defined in the present invention.

[0067] In some embodiments of the present invention, the above R 10 is selected from H and F, and the other variables are as defined in the present invention.

[0068] In some embodiments of the present invention, the above R 12 The is selected from H and CH3, and the other variables are as defined in the present invention.

[0069] In some embodiments of the present invention, the above R 13 The is selected from H and CH3, and the other variables are as defined in the present invention.

[0070] In some embodiments of the present invention, the above R 14 The is selected from H and CH3, and the other variables are as defined in the present invention.

[0071] In some embodiments of the present invention, the above R 15 The first variable is selected from H, D, and CH3, and the other variables are as defined in this invention.

[0072] In some embodiments of the present invention, the above R 16 The first element is selected from H, D, and CH3, and the other variables are as defined in this invention.

[0073] In some embodiments of the present invention, ring A is selected from phenyl and six-membered heteroaryl rings, and other variables are as defined in the present invention.

[0074] In some embodiments of the present invention, ring A is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl, and the other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, ring A is selected from phenyl, pyridyl, pyrazinyl, and pyrimidinyl, and other variables are as defined in the present invention.

[0076] In some embodiments of the present invention, ring B is selected from a 6-membered heteroaryl ring, and the other variables are as defined in the present invention.

[0077] In some embodiments of the present invention, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl, and the other variables are as defined in the present invention.

[0078] In some embodiments of the present invention, ring B is selected from pyridyl, pyrazinyl, and pyrimidinyl, and other variables are as defined in the present invention.

[0079] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0080] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0081] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0082] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0083] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0084] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0085] In some embodiments of the present invention, the above R11 And R1 forms a benzene ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0087] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0088] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0089] In some embodiments of the present invention, R2 and R4 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0090] In some embodiments of the present invention, R3 and R5 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0091] In some embodiments of the present invention, R3 and R5 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0092] In some embodiments of the present invention, R2 and R4 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0093] In some embodiments of the present invention, R3 and R5 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0094] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0095] In some embodiments of the present invention, R2 and R4 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0096] In some embodiments of the present invention, R3 and R5 form a ring, forming a structural unit [ka] but [ka] The variables are to be selected from the above, and the other variables are as defined in the present invention.

[0097] In some embodiments of the present invention, L is selected from single bonds and structural units [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0098] In some embodiments of the present invention, L is selected from single bonds and structural units [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0099] In some embodiments of the present invention, L is selected from single bonds and structural units [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0100] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0101] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0102] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0103] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0104] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] [ka] Selected from the above, the other variables are as defined in this invention.

[0105] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0106] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0107] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0108] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0109] In some embodiments of the present invention, the structural unit [ka] but [ka] When selected from, R6 and R7 are not H at the same time, and the other variables are as defined in the present invention.

[0110] In some embodiments of the present invention, the structural unit [ka] but [ka] When selected from, R6 and R7 are not H at the same time, and the other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0112] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] Selected from the above, the other variables are as defined in this invention.

[0113] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas: [ka] However, ring A is selected from pyridyl, R2, R3, R4, R5, R8, R9, R 13 , R 14 , R 15 , R 16 , R c , T2, n and [ka] This is as defined in the present invention.

[0114] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas: [ka] however, [ka] It is selected from a single bond or a double bond. T2 is selected from C and N. R2 is H and C 1-3 Selected from alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, or 3 halogens. R3 is selected from H and halogen. R4 stands for H, Halogen, CN, C 1-3 Alkyl and C 1-3 Selected from alkoxy, R5 stands for H, Halogen, CN, C 1-3 Alkyl and C 1-3 Selected from alkoxy, R9 either does not exist, or is selected from H and halogen. R7, R8, R 13 , R 14 , R 15 , R 16 , R c And n are as defined in the present invention.

[0115] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas: [ka] however, Ring A is selected from phenyl and 6-membered heteroaryl. Ring B is selected from 6-membered heteroaryls, R2, R3, R4, R5, R6, R7, R8, R9, R 13 , R 14 , R 15 , R 16 , R c , X, T2, T3, T4, n and [ka] This is as defined in the present invention.

[0116] In some embodiments of the present invention, ring A is selected from pyridine rings, and other variables are as defined in the present invention.

[0117] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas: [ka] However, ring A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, X, T3, T4 and structural units [ka] This is as defined in the present invention.

[0118] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas: [ka] However, R1, R2, R3, R4, R5, R6, R7, R8, R9, R a , R b X, T3, and T4 are as defined in the present invention.

[0119] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas: [ka] However, R1, R2, R3, R4, R5, R6, R7, R8, R9, R a , R b X, T3 and T4 are as defined in the present invention, The conditions are, 1) When a compound is selected from formula (VIII-6a) and one of T3 or T4 is selected from N, R2, R3 and R9 are not H at the same time, or 2) When a compound is selected from formula (VIII-6a) and one of T3 or T4 is selected from N, R6 and R7 are not H at the same time, or 3) The compound is selected from (VIII-6a), T3 is selected from N, and T4 is CR 10 When selected from, R5 is selected from halogen, or, 4) The compound is selected from formula (VIII-6a), T4 is selected from N, and T3 is CR. 10 When selected from, R4 is selected from halogen, or, 5) When a compound is selected from formula (VIII-7a) and T3 is selected from N, then R6 and R7 are not H at the same time.

[0120] Some embodiments of the present invention also consist of any combination of the above variables.

[0121] The present invention further provides compounds of the following formula or pharmaceutically acceptable salts thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0122] In some embodiments of the present invention, the compound of the compound or a pharmaceutically acceptable salt thereof is selected from the following formulas. [ka] [ka] [ka] [ka] [ka]

[0123] The present invention further provides a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound defined in the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0124] The present invention further provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, in the preparation of a pharmaceutical for the treatment of solid tumors.

[0125] In some embodiments of the present invention, the solid tumor refers to solid tumors such as ovarian cancer, breast cancer, prostate cancer, and glioma.

[0126] The present invention further provides the following synthesis method.

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] The present invention further provides the following biological detection methods.

[0138] Test Method 1: PARP1 Enzyme Activity Test Experiment

[0139] 1. Experimental materials: PARP1 chemiluminescence detection kit, purchased from BPS Bioscience; EnVision multi-label analyzer (PerkinElmer).

[0140] 2. Experimental steps: Reagent preparation: Preparation of PBST buffer: 1×PBS contains 0.05% Tween-20; that is, add 5 μL of 100% Tween-20 to 10 mL of PBS. Preparation of 1× test buffer: Dilute 10× PARP test buffer 10-fold with redistilled water.

[0141] Preparation of compounds: Preparation of compound solutions: Dilute the test compound five-fold with 100% DMSO to eight different concentrations, i.e., from 1000 μM to 12.8 nM. Dilute the internal control compound five-fold with 100% DMSO to eighty different concentrations, i.e., from 200 μM to 2.56 nM. Further dilute each gradient of the test compound with 1× test buffer in a 10% DMSO working solution.

[0142] Experimental method: a) Dilute the histidine solution in the kit five-fold with 1×PBS, add 25 μL / well of the diluted solution to a microplate, and incubate overnight at 4°C. b) After culturing is complete, discard the liquid in the wells, wash the plate three times with 100 μL / well PBST, and discard any remaining liquid in the wells. c) Place 100 μL / well of blocking solution into a microplate and incubate at 25°C for 90 minutes. After incubation is complete, discard the liquid in the wells, take 100 μL / well of PBST, wash the plate three times, and discard any remaining liquid in the wells. d) Place 12.5 μL / well of the substrate mixture (1.25 μL of 10×PARP test buffer, 1.25 μL of 10×PARP test mixture, 2.5 μL of activated DNA, and 7.5 μL of redistilled water) into a microplate. e) Place 2.5 μL / well of the compound working solution into a microwell plate and set up a double replication well experiment. f) Dilute the PARP1 enzyme to 2 ng / μL, take 10 μL / well and add it to a microplate. At this time, the final concentration gradient of the test compound is 10 μM to 0.128 nM, the final concentration gradient of the internal control compound is 2 μM to 0.0256 nM, and PARP1 (20 ng / well). Incubate the reaction system at 25°C for 60 minutes. g) After the culture is complete, discard the liquid in the wells, wash the plate three times with 100 μL / well PBST, and discard any remaining liquid in the wells. h) Dilute Streptavidin-HRP 50-fold with blocking solution, add 25 μL / well to a microplate, and incubate at 25°C for 30 minutes. i) After culturing is complete, discard the liquid in the wells, wash the plate three times with 100 μL / well PBST, and discard any remaining liquid in the wells. j) Mix ELISA ECL substrate A and ELISA ECL substrate B uniformly in a 1:1 (v / v) ratio, add 50 μL / well to a microplate, and read the chemiluminescence value.

[0143] 3. Method for processing experimental data Using the equation (Sample-Min) / (Max-Min) × 100%, raw data is converted to enzyme activity, and IC is calculated using curve fitting with four parameters. 50Obtain the value (using GraphPad Prism's log(inhibitor) vs. response -- obtained in Variable slope mode). Contains a maximum of 1% DMSO, PARP1, and a substrate mixture. Min: Does not contain the PARP1 enzyme.

[0144] Test Method 2: Study on the binding ability of the compound of the present invention to PARP1 and PARP2.

[0145] PARP1 experimental procedure: Surface plasmon resonance (SPR) experiments are performed using the Biacore 8K (GE Healthcare) instrument. First, biotinylated PARP1 protein (sequence: 655-end) is coupled via a streptavidin-coated SA chip (Cytiva, 29699622) under 25°C conditions. Specific steps: Activate the chip surface with 1 mM NaCl / 50 mM NaOH. Dilute the PARP1 protein in coupling buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 10 mM MgCl2, 0.05% P20) to prepare a 10 μg / mL ligand solution and flow it over the chip surface (injection time: 50 seconds, injection flow rate: 5 μL / min) to couple the PARP1 protein to the chip surface. Block excess active sites on the chip with a 50% isopropyl / 1 M NaCl / 50 mM NaOH solution. The final coupling level in the experiment is 2000-3000 RU (Response Units). Small molecule compounds are gradient-diluted with buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10 mM MgCl2, 0.05% Tween 20) to obtain compound solutions of various concentrations. These solutions are then flowed over the surface of a protein-coupled chip at an injection flow rate of 50 μL / min, an injection time of 60 seconds, and a dissociation time of 20 minutes. The instrument detects the binding and dissociation curves of the protein-small molecule compound. The sample channel and control channel data are analyzed using Biacore 8K evaluation software to generate sensorgrams, and data fitting is performed based on the 1:1 coupling mode.

[0146] PARP2 experimental procedure: Surface plasmon resonance (SPR) experiments will be performed using the Biacore 8K (GE Healthcare) instrument. First, biotinylated PARP2 protein (sequence: 223-end) is coupled via a streptavidin-coated SA chip (Cytiva, 29699622) under 25°C conditions. Specific steps: Activate the chip surface with 1 mM NaCl / 50 mM NaOH. Dilute the PARP2 protein in coupling buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 10 mM MgCl2, 0.05% P20) to prepare a 10 μg / mL ligand solution. Flow this solution over the chip surface (injection time: 60 seconds, injection flow rate: 10 μL / min) to couple the PARP2 protein to the chip surface. Block excess active sites on the chip with a 50% isopropyl / 1 M NaCl / 50 mM NaOH solution. The final coupling level in the experiment is 3000-4000 RU (Response Units). Small molecule compounds are gradient-diluted with buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10 mM MgCl2, 0.05% Tween 20) to obtain compound solutions of various concentrations. These solutions are then flowed over the surface of a protein-coupled chip at an injection flow rate of 30 μL / min, an injection time of 60 seconds, and a dissociation time of 400 seconds. The instrument detects the binding and dissociation curves of the protein-small molecule compound. The sample channel and control channel data are analyzed using Biacore 8K evaluation software to generate sensorgrams, and data fitting is performed based on the 1:1 coupling mode.

[0147] Technical effects: The compounds of the present invention exhibit excellent binding activity to PARP1, selectively inhibiting the PARP1 protein, weak binding activity to PARP2, excellent inhibitory activity against BRCA1 mutant MDA-MB-436 cells and DLD1 (BRCA2 knockout) cells, and excellent membrane permeability. The compounds of the present invention show excellent stability in human liver microsomes and mouse liver microsomes in vitro. The compounds of the present invention exhibit excellent in vivo metabolic stability, excellent oral absorption drug exposure, and, when administered orally, excellent brain tissue drug concentration and a high cerebral blood ratio, demonstrating more significant antitumor activity.

[0148] [Related definitions] Unless otherwise specified, the following terms and phrases used herein have the following meanings. Unless otherwise specifically defined, any particular term or phrase should be understood as having its ordinary definition, not as uncertain or ambiguous. When a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0149] As used herein, “pharmaceutically acceptable” means that the compounds, materials, compositions and / or dosage forms are within the bounds of reliable medical judgment, suitable for contact with human and animal tissues, with little toxicity, irritation, allergic reaction or other problem or complication, and in a reasonable benefit / risk ratio.

[0150] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared with a relatively non-toxic acid or base of a compound having a specific substituent discovered in the present invention. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting these compounds with a sufficient amount of base in a single solution or a suitable inert solvent. pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting these compounds with a sufficient amount of acid in a single solution or a suitable inert solvent. Some specific compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any base addition salt or acid addition salt.

[0151] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional methods from a parent compound containing an acidic or basic group. Typically, such salts are produced by reacting these compounds, in the form of a free acid or base, with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0152] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention envisions all such compounds and includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures containing a large amount of enantiomers or non-enantiomers, all of which are within the scope of the present invention. Other chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present invention.

[0153] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0154] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" refer to a compound where the double bond or the single bond of the ring-forming carbon atom cannot rotate freely.

[0155] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are non-mirror images of each other.

[0156] Unless otherwise specified, "(+)" indicates dextrorotatory properties, "(-)" indicates levorotatory properties, and "(±)" indicates a racemic mixture.

[0157] Unless otherwise explained, [ka] The absolute arrangement of the center of one solid, [ka] Then, the relative arrangement of the center of the solid, [ka] in [ka] or [ka] in [ka] It represents.

[0158] Unless otherwise explained, if a compound contains double bond structures such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond has two different substituents attached to it (in the case of a double bond containing a nitrogen atom, the pair of lone electrons on the nitrogen atom are considered to be the substituents attached to it), then the atoms on the double bond of the compound and their substituents are [ka] When linked by , it means the (Z) isomer, (E) isomer, or mixture of two isomers of the compound. For example, formula (A) below means that the compound exists as a single isomer of formula (A-1) or formula (A-2), or as two isomers of formula (A-1) and formula (A-2); formula (B) below means that the compound exists as a single isomer of formula (B-1) or formula (B-2), or as two isomers of formula (B-1) and formula (B-2); formula (C) below means that the compound exists as a single isomer of formula (C-1) or formula (C-2), or as two isomers of formula (C-1) and formula (C-2). [ka]

[0159] Unless otherwise specified, the term "tautomer" or "tautomer form" refers to the dynamic equilibrium of isomers of different functional groups that exist at room temperature and can rapidly convert to one another. If tautomerism is possible (for example, in solution), then chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons. Among these, a specific example of keto-enol tautomerization is the interconversion between the two tautomers pentan-2,4-dione and 4-hydroxypento-3-en-2-one.

[0160] Unless otherwise specified, the terms “rich in one isomer,” “rich in isomers,” “rich in one enantiomer,” or “rich in enantiomers” mean that the content of one isomer or enantiomer is less than 100%, and that the content of this isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0161] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the isomer or enantiomer excess (ee value) is 80%.

[0162] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I), C-14( 14 The compounds can be labeled with radioactive isotopes such as C). Alternatively, for example, deuterium can be substituted with hydrogen to form deuterated drugs. The bond formed between deuterium and carbon is stronger than the bond formed between ordinary hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and extended biological half-life. The conversion of the isotopic composition of the compounds of the present invention is included within the scope of the present invention, whether or not it is radioactive.

[0163] The terms "optional" and "at will" mean that while possible under the circumstances described below, they do not necessarily occur, and the description includes cases where the circumstances described therein occur, as well as cases where they do not.

[0164] The term "substituted" means that one or more hydrogen atoms in a particular atom are replaced by a substituent, and the substituent may include deuterium and hydrogen variants, provided that the specific valence state is normal and the substituted compound is stable. If the substituent is a keto group (i.e., =O), it means that two hydrogen atoms have been substituted. The term "optionally substituted" means that substitution may or may not occur, and unless otherwise defined, the type and number of substituents are arbitrary as long as they can be realized in a chemically stable manner.

[0165] If any of the variables (e.g., R) appear once or more in the composition or structure of a compound, their definitions are independent in each case. Therefore, for example, if a group is substituted with 0 to 2 R atoms, that group can be substituted with any number of R atoms (2 or fewer), and in each case, R atoms are independently chosen. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0166] When the number of linking groups is 0, for example, -(CRR)0-, it means that the linking group is a single bond. If one of the variables is a single bond, the two groups connected by it are directly linked. For example, if L in ALZ represents a single bond, this structure is actually AZ.

[0167] Unless otherwise specified, if a group has one or more bondable sites, any one or more sites of that group can be bonded to other groups by chemical bonds. If the bonding mode of such chemical bonds is delocalized and hydrogen atoms are present at the bondable sites, when a chemical bond is formed, the number of hydrogen atoms at those sites decreases to a group with a corresponding valency in proportion to the number of chemical bonds formed. The chemical bonds formed when such sites bond to other groups are: [ka] This can be represented as follows. For example, a linear solid bond in -OCH3 means that the group is bonded to another group via the oxygen atom of that group. [ka] The dashed lines within the diagram indicate that both ends of the nitrogen atom within that group are bonded to other groups. [ka] The wavy lines inside indicate that the phenyl group is bonded to another group via the carbon atoms at positions 1 and 2. [ka] This means that any bondable site of the piperidinyl can be bonded to another group by one chemical bond, at least [ka] It includes these four bonding forms, and even if the H atom is depicted as -N-, [ka] for [ka] It contains a group with the following bonding configuration, but when one chemical bond is connected, one H is lost at that site, resulting in the corresponding monovalent piperidinyl. [ka] This indicates that R is connected to both sides of the double bond via any bond, i.e., [ka] It represents.

[0168] Unless otherwise defined, the "two R on adjacent atoms" in the general formula a "These atoms form a double bond together with the atoms linked to them." This is because two R atoms on adjacent carbon atoms a This shows that the single bond between two carbon atoms forms a double bond together. For example, structural units [ka] Two R's in a It forms a double bond along with the single bond between the two carbon atoms, that is, a structural unit. [ka] It forms.

[0169] Unless otherwise defined, the term "halogen" or "halo" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0170] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl contains C 1-2 and C 2-3 Alkyl compounds may be monovalent (e.g., methyl), divalent (e.g., methylene), and polyvalent (e.g., methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl).

[0171] Unless otherwise defined, the term "C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 This includes C3 and C2 alkoxys. 1-3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy or isopropoxy).

[0172] Unless otherwise defined, "C 3-5 A "cycloalkyl" is a cyclic saturated hydrocarbon group composed of 3 to 5 carbon atoms, and it represents a monocyclic ring system. 3-5 Cycloalkyls include C 3-4 or C4-5 This includes cycloalkyls, which may be monovalent, divalent, or polyvalent. 3-5 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0173] Unless otherwise stated, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" in this invention can be used interchangeably. The term "5-6 membered heteroaryl" is a monocyclic group having a conjugated π-electron system composed of 5-6 ring atoms, where the 1st, 2nd, 3rd, and 4th ring atoms are independently selected from heteroatoms of O, S, and N, and the remainder are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p (where p is 1 or 2). 5- to 6-membered heteroaryls are linked to the rest of the molecule via heteroatoms or carbon atoms. The 5- to 6-membered heteroaryls include 5-membered and 6-membered heteroaryls. Examples of the 5- to 6-membered heteroaryls include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl) This includes, but is not limited to, lyazolyl (such as riazolyl), tetrazolyl, isoxazolyl (such as 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), furanyl (including 2-furanyl and 3-furanyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, or pyrimidinyl (including 2-pyridinyl and 4-pyridinyl).

[0174] Unless otherwise defined, the terms "six-membered heteroaryl ring" and "six-membered heteroaryl" in this invention can be used interchangeably. The term "six-membered heteroaryl" is a monocyclic group having a conjugated π-electron system composed of six ring atoms, where the 1st, 2nd, 3rd, and 4th ring atoms are independently selected from heteroatoms of O, S, and N, and the remaining atom is a carbon atom. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p (where p is 1 or 2). 5-6 member heteroaryls are linked to the rest of the molecule via heteroatoms or carbon atoms.

[0175] Unless otherwise defined, C n-n+m or C n -C n+m This includes any one specific mode of n ~ n + m carbon atoms. For example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 It includes n and any one range from n to n+m. For example, C 1-12 C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 This includes, for example. Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m. For example, 3- to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings, and also any one range from n to n+m. For example, 3- to 12-membered rings include 3- to 6-membered rings, 3- to 9-membered rings, 5- to 6-membered rings, 5- to 7-membered rings, 6- to 7-membered rings, 6- to 8-membered rings, and 6- to 10-membered rings, etc.

[0176] The compounds of the present invention can be produced by various synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0177] The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single-crystal X-ray diffraction (SXRD), where cultured single crystals are collected by a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting the relevant data, the absolute configuration can be confirmed by direct methods, such as crystal structure analysis (Shelxs97).

[0178] All solvents used in this invention can be obtained from commercially available products. This invention uses the following abbreviations: hr represents hours, min represents minutes, DIEA represents N,N-diisopropylethylamine, DDQ represents 2,3-dichloro-5,6-dicyanobenzoquinone, XPHOS-PD-G2 represents chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), and TBSCl represents tert-butyldimethylsilyl chloride represents, DMAP represents 4-dimethylaminopyridine, Cs2CO3 represents cesium carbonate, RuPhos represents 2-dicyclohexylphosphino-2,6-diisopropoxybiphenyl, Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0), TBAF represents tetra-n-butylammonium fluoride, and Et3N represents tri Na2CO3 represents ethylamine, NaHCO3 represents sodium carbonate, H2O represents water, PE represents petroleum ether, EA represents ethyl acetate, DMF represents N,N-dimethylformamide, MeOH represents methanol, EtOH represents ethanol, THF represents tetrahydrofuran, DCM represents dichloromethane, and NBS represents N-bromo Succinimide is represented, Dess-Martin is represented as Dess-Martin oxidizing agent, CAS is 87413-09-0, KHMDS is represented as potassium bis(trimethylsilyl)amide, Pd(OAc)2 is represented as palladium acetate, PPh3 is represented as triphenylphosphine, Pd / C is represented as palladium carbon, HATU is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate is represented, (Boc)2O represents di-tert-butyl dicarbonate, LiAlH4 represents lithium aluminum hydride, N-Boc-piperazine represents 1-(tert-butoxycarbonyl)piperazine, Lawson's reagent represents the compound with CAS 19172-47-5, DMSO represents dimethyl sulfoxide, NaBH(OAc)3 represents sodium triacetoxyborohydride, KI represents potassium iodide, NH4Cl represents ammonium chloride, HCl represents hydrochloric acid, dioxane represents 1,4-dioxane, and Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium. [Brief explanation of the drawing]

[0179] [Figure 1] This is a graph of tumor growth volume. [Figure 2] This graph shows the change in body weight of mice during the administration period. [Modes for carrying out the invention]

[0180] The present invention will be described in detail below with reference to examples, but this does not mean that there are any unfavorable limitations to the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0181] Example 1 [ka] [ka]

[0182] Step 1: Synthesis of intermediate 1c Compound 1a (9.5 g, 39.92 mmol), DIEA (15.48 g, 119.75 mmol, 20.86 mL), and compound 1b (6.13 g, 43.91 mmol, HCl) were added to DMF (100 mL) and reacted with stirring at 25°C for 18 hours. 1000 mL of water was added to the reaction mixture, extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, dried, and concentrated to obtain the crude product. This was subjected to column chromatography (eluent:PE:EA = 4:1, V / V) to obtain intermediate 1c. MS m / z: 320.8, 322.8 [M+H] + .

[0183] Step 2: Synthesis of intermediate 1d At 0°C, intermediate 1c (7.4g, 23.05 mmol), NH4Cl (9.86g, 184.37 mmol), and zinc powder (7.7g, 117.76 mmol) were added to a mixed solution of MeOH (100 mL) and H2O (2 mL) and stirred for 2 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure to remove methanol. 100 mL of water was added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1d, which was used directly in the next step. MS m / z: 290.7, 292.7 [M+H] + .

[0184] Step 3: Synthesis of intermediate 1e At 0°C, intermediate 1d (6.7 g, 23.01 mmol) was added to a mixed solvent of hydrogen chloride-dioxane (4 M, 1.81 mL), ethyl acetate (70 mL), and methanol (70 mL), and the mixture was stirred and reacted for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1e (5.5 g, 21.23 mmol). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H) 7.42~7.57 (m, 1 H) 7.00 (dd, J=8.53, 7.28 Hz, 1 H) 6.49 (d, J=8.03 Hz, 1 H) 3.82~3.86 (m, 1 H) 1.25 (d, J=6.53 Hz, 3H).

[0185] Step 4: Synthesis of intermediate 1f At 0°C, DDQ (5.26 g, 23.16 mmol) was added in batch to intermediate 1e (5.0 g, 19.30 mmol) in DCM (250 mL). The temperature was raised to 25°C and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, and 200 mL of saturated NaHCO3 aqueous solution was added dropwise to quench the reaction system. The mixture was stirred overnight, extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, and the mixture was concentrated to obtain the target product. The product was then subjected to column chromatography (eluent: DCM:MeOH = 100:1, V / V) to obtain intermediate 1f. MS m / z: 256.7, 258.7 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (br s, 1 H) 7.45~7.55 (m, 2 H) 2.40 (s, 3 H).

[0186] Step 5: Synthesis of 1g of intermediate Intermediate 1f (1.0 g, 3.89 mmol), 1-(tributylstannyl)methanol (1.50 g, 4.67 mmol), and XPHOS-PD-G2 (153.04 mg, 194.51 μmol) were added to 1,4-dioxane (20 mL), and the reaction system was stirred at 80°C under N2 protection for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (eluent: DCM / MeOH = 20 / 1, V / V) to obtain 1 g of intermediate. MS m / z: 209.0 [M+1] + .

[0187] Step 6: Synthesis of intermediate 1h Under the protection of nitrogen gas at 0°C, tributylphosphine (388.72 mg, 1.92 mmol, 474.05 μL) was slowly added dropwise to a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (688.23 mg, 2.11 mmol, 253.96 μL) and 1 g of intermediate (200 mg, 960.67 μmol) in DCM (5 mL), and the reaction system was stirred at 20°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, to which a mixed solvent (DCM / MeOH = 20 / 1, 5 mL) was added and stirred for 30 minutes. The mixture was filtered, and the cake was concentrated under reduced pressure to obtain intermediate 1h. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.55 (s, 1 H) 7.47~7.58 (m, 1 H) 7.31~7.43 (m, 1 H) 4.80~4.90 (m, 2 H) 2.42 (s, 3 H).

[0188] Step 7: Synthesis of intermediate 1j Triethylamine (1.87 g, 18.49 mmol) was added to a 40 mL solution of intermediate 1i (2 g, 9.25 mmol), TBSCl (2.09 g, 13.87 mmol), and DMAP (112.97 mg, 924.74 μmol) in DCM, and the mixture was stirred at 20°C for 16 hours to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: DCM / MeOH = 20 / 1 to 10 / 1, V / V) to obtain intermediate 1j. 1 H NMR (400 MHz, CD3OD) δ ppm 3.88~4.12 (m, 2 H) 3.63 (d, J=5.52 Hz, 2 H) 3.01 (d, J=12.30 Hz, 1 H) 2.54~2.94 (m, 4 H) 1.48 (s, 9 H) 0.95 (s, 9 H) 0.12 (s, 6 H).

[0189] Step 8: Synthesis of intermediate 1k Cs2CO3 (197.15 mg, 605.08 μmol), RuPhos (14.12 mg, 30.25 μmol), intermediate 1j (0.1 g, 302.54 μmol), methyl 5-bromo-6-fluoropyridine-2-carboxylate (70.80 mg, 302.54 μmol), and Pd2(dba)3 (55.41 mg, 60.51 μmol) were added to a toluene (4 mL) solution and stirred at 100°C for 24 hours. The reaction mixture was filtered by suction under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent:PE:EA = 1:1, V / V) to obtain intermediate 1k. MS m / z: 484.3 [M+H] + .

[0190] Step 9: Synthesis of Intermediate 11 TBAF (1M THF solution, 258.45 μL, 2.5 eq) and intermediate 1k (50 mg, 103.38 μmol) were added to THF (4 mL) solution. The reaction system was stirred at 25°C for 16 hours, and the reaction mixture was concentrated under reduced pressure to obtain intermediate 11. MS m / z: 350.2 [M+H] + .

[0191] Step 10: Synthesis of the hydrochloride salt of intermediate 1m Intermediate 11 (30 mg, 85.87 μmol) was added to EA (2 mL) solution, and HCl / EA (4 M, 85.87 μL) was added dropwise to the reaction mixture. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 1 m. MS m / z: 250.2 [M+H] + .

[0192] Step 11: Synthesis of intermediate 1n Under a nitrogen atmosphere, 1 m (20 mg) of the hydrochloride salt of intermediate was added to EtOH (2 mL) solution, followed by methylamine (2.26 mg, 72.84 μmol). The reaction was carried out at 20°C with stirring for 1 hour. The mixture was concentrated under reduced pressure to obtain intermediate 1n. MS m / z: 249.1 [M+H] + .

[0193] Step 12: Synthesis of trifluoroacetate of compound 1 Intermediate 1n (10.50 mg, 36.89 μmol) was added to DMF (2 mL), then Et3N (7.47 mg, 73.78 μmol, 10.27 μL) was added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. Further, KI (2.70 mg, 16.24 μmol, 5.68 μL) and intermediate 1h (10 mg, 36.89 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure at 60°C using an oil pump to obtain the crude product. The crude product was separated and purified by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%~23%, 8 min) to obtain the trifluoroacetate of compound 1. MS m / z: 439.2 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 7.63~7.73 (m, 2 H) 7.36~7.50 (m, 2 H) 4.44~4.54 (m, 3 H) 4.22 (dd, J=11.26, 7.63 Hz, 1 H) 4.13 (d, J=11.01 Hz, 1 H) 3.51~3.64 (m, 3 H) 3.11~3.22 (m, 2 H) 2.92 (s, 3 H) 2.85~2.91 (m, 1 H) 2.56 (s, 3 H).

[0194] Example 2 [ka]

[0195] Step 1: Synthesis of intermediate 2c Compound 2a (0.5 g, 2.14 mmol) and compound 2b (642.89 mg, 3.21 mmol) were added to toluene (10 mL). Cs2CO3 (2.09 g, 6.42 mmol), RuPhos (199.72 mg, 428.00 μmol), and Pd2(dba)3 (195.96 mg, 214.00 μmol) were added to the reaction mixture, and after substituting three times with nitrogen gas, the reaction system was stirred at 100°C for 16 hours. The reaction mixture was filtered by suction under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 4 / 1 to 2 / 1, V / V) to obtain intermediate 2c. MS m / z: 354.2 [M+1] + , 1 H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=8.03 Hz, 1 H) 7.22~7.29 (m, 1 H) 4.01 (d, J=6.53 Hz, 1 H) 4.00~4.24 (m, 1 H) 3.98 (s, 3 H) 3.81 (d, J=13.30 Hz, 1 H) 3.29~3.44 (m, 2 H) 3.07~3.25 (m, 2 H) 1.50 (s, 9 H) 1.08 (d, J=6.53 Hz, 3 H).

[0196] Step 2: Synthesis of intermediate 2d Intermediate 2c (0.4 g, 1.13 mmol) and methylamine-tetrahydrofuran (2 M, 7.27 mL) were added to EtOH (10 mL), and the reaction system was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, intermediate 2d, which was used directly in the next step. MS m / z: 353.0 [M+H] + .

[0197] Step 3: Synthesis of the hydrochloride salt of intermediate 2e Intermediate 2d (0.4 g, 1.14 mmol) was added to EA (5 mL), and hydrogen chloride-ethyl acetate (4 M, 1.42 mL) was added to the reaction mixture. The reaction system was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, the hydrochloride salt of intermediate 2e, which was used directly in the next step. MS m / z: 253.0 [M+H] + .

[0198] Step 4: Synthesis of trifluoroacetate of compound 2 Intermediate 2e (21.30 mg) was added to DMF (2 mL), then Et3N (14.93 mg, 147.56 μmol, 20.54 μL) was added to the reaction mixture, and the reaction system was stirred at 25°C for 30 minutes. KI (5.39 mg, 32.49 μmol) and intermediate 1h (20 mg, 73.78 μmol) were then added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%~26%, 8 min) to obtain the trifluoroacetate of compound 2. MS m / z: 443.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.19 (d, J=7.28 Hz, 1 H) 6.99 (s, 1 H) 6.90 (d, J=8.78 Hz, 1 H) 6.67 (d, J=6.78 Hz, 1 H) 3.80 (s, 2 H) 2.78 (s, 1 H) 2.70 (s, 3 H) 2.39~2.48 (m, 3 H) 2.14 (s, 3 H) 1.76 (s, 3 H) 0.32 (s, 3 H).

[0199] Example 3 [ka]

[0200] Step 1: Synthesis of intermediate 3b Compound 3a (1 g, 4.62 mmol) was added to DCM (20 mL), and the reaction system was cooled to 0°C. Et3N (935.74 mg, 9.25 mmol, 1.29 mL), TBSCl (1.05 g, 6.94 mmol, 849.87 μL), and DMAP (56.49 mg, 462.37 μmol) were added to the reaction mixture, and the reaction system was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was purified by column chromatography (eluent: DCM / MeOH = 20 / 1 to 10 / 1, V / V) to obtain intermediate 3b. 1 H NMR (400 MHz, CDCl3) δ ppm 3.86 ( s, 1 H) 3.52 ( s, 1 H) 3.41 (dd, J=9.79, 7.28 Hz, 1 H) 2.92 ( d, J=11.29 Hz, 1 H) 2.63~2.84 (m, 3 H) 2.48 (s, 1 H) 1.90 (s, 1 H) 1.28~1.48 (m, 9 H) 0.72~0.97 (m, 9 H) -0.08~0.08 (m, 6 H).

[0201] Step 2: Synthesis of intermediate 3c Methyl 5-bromo-6-fluoropyridine-2-carboxylate (1 g, 4.27 mmol) and intermediate 3b (987.97 mg, 2.99 mmol) were added to toluene (20 mL). RuPhos (398.80 mg, 854.00 μmol), Pd2(dba)3 (391.30 mg, 427.00 μmol), and Cs2CO3 (4.17 g, 12.81 mmol) were added to the reaction mixture, and the system was purged three times with nitrogen gas and stirred at 100 °C for 2 hours. The mixture was filtered by suction under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 4 / 1 to 2 / 1, V / V) to obtain intermediate 3c. MS m / z: 484.3 [M+H] + .

[0202] Step 3: Synthesis of intermediate 3d Compound 3c (300 mg, 620.29 μmol) was added to THF (2 mL), and TBAF (1 M THF solution, 1.86 mL) was added to the reaction mixture. The reaction system was stirred at 20°C for 2 hours. The reaction mixture was filtered by vacuum suction, and the filtrate was concentrated under reduced pressure to obtain crude product 3d, which was used directly in the next step. MS m / z: 350.1 [M+H] + .

[0203] Step 4: Synthesis of intermediate 3e Compound 3d (200.00 mg) was added to EtOH (5 mL), and a methylamine ethanol solution (1 mL, 40%) was added to the reaction mixture. The reaction system was stirred at 20°C for 32 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step to obtain intermediate 3e. MS m / z: 349.1 [M+H] + .

[0204] Step 5: Synthesis of the hydrochloride salt of intermediate 3f Compound 3e (0.1 g) was added to EA (5 mL), and hydrogen chloride / ethyl acetate (4 M, 358.79 μL) was added to the reaction mixture. The reaction system was stirred at 20°C for 8 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, the hydrochloride salt of compound 3f, which was used directly in the next step. MS m / z: 249.1 [M+H] + .

[0205] Step 6: Synthesis of trifluoroacetate of compound 3 Compound 3f (10.50 mg, HCl) was added to DMF (2 mL), then Et3N (7.47 mg, 73.78 μmol, 10.27 μL) was added to the reaction mixture, and the reaction system was stirred at 25°C for 30 minutes. KI (2.70 mg, 16.24 μmol, 5.68 μL) and compound 1h (10 mg, 36.89 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated using an oil pump at 60°C to obtain the crude product. The crude product was purified by preparative HPLC (column chromatography: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 1%~30%, 10 min) to obtain the trifluoroacetate of compound 3. MS m / z: 439.0 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ ppm 7.66~7.71 (m, 2 H) 7.42~7.48 (m, 1 H) 7.36~7.42 (m, 1 H) 4.50 (dd, J=11.19, 2.56 Hz, 1 H) 4.43 (s, 2 H) 4.22 (dd, J=11.13, 7.75 Hz, 1 H) 4.12 (d, J=10.01 Hz, 1 H) 3.56 (br s, 1 H) 3.51 (d, J=9.38 Hz, 2 H) 3.14 (s, 2 H) 2.92 (s, 3 H) 2.85 (s, 1 H) 2.56 (s, 3H).

[0206] Example 4 [ka]

[0207] Step 1: Synthesis of intermediate 4a To a reaction flask containing compound 2a (500 mg, 2.14 mmol) and N-Boc-piperazine (397.93 mg, 2.14 mmol), toluene (5 mL) was added. RuPhos (199.40 mg, 427.31 μmol), cesium carbonate (1.39 g, 4.27 mmol), and Pd2(dba)3 (195.65 mg, 213.65 μmol) were then added sequentially. The mixture was heated to 100°C under nitrogen gas protection and stirred for 16 hours. The reaction mixture was filtered directly, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was separated and purified by silica gel chromatography (gradient elution: PE:EA = 100:0~80:20) to obtain intermediate 4a. MS m / z: 340.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.98~7.98 (m, 1 H) 7.91~8.06 (m, 1 H) 3.98 (s, 3 H) 3.57~3.68 (m, 4 H) 3.16~3.31 (m, 4 H) 1.51 (s, 9 H).

[0208] Step 2: Synthesis of intermediate 4b Compound 4a (200 mg, 589.34 μmol) was dissolved in ethanol (8 mL), and methylamine-ethanol solution (1.19 g, 17.68 mmol) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain intermediate 4b, which was used in the next step without further purification. MS m / z: 339.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 1.42 (s, 9 H) 2.93 (d, J=5.13 Hz, 3 H) 3.03~3.16 (m, 4 H) 3.44~3.63 (m, 4 H) 7.24 (dd, J=10.01, 8.13 Hz, 1 H) 7.44 (br d, J=4.13 Hz, 1 H) 7.93 (dd, J=8.00, 1.00 Hz, 1 H).

[0209] Step 3: Synthesis of intermediate 4c 4b (50 mg, 147.76 μmol) was dissolved in toluene (2.5 mL), and Lawson's reagent (71.72 mg, 177.32 μmol) was added. The mixture was stirred at 120°C for 16 hours. Water (1 mL) and ethyl acetate (3 mL) were added to the reaction mixture for extraction. The organic phase was taken and dried over anhydrous sodium sulfate. The reaction mixture was filtered, concentrated under reduced pressure, and separated and purified by prep-TLC (PE:EA = 5:1) to obtain intermediate 4c. MS m / z: 355.1 [M+H] + .

[0210] Step 4: Synthesis of intermediate 4d Intermediate 4c (10 mg, 28.21 μmol) was dissolved in DMF (0.5 mL), sodium hydride (2.82 mg, 70.53 μmol, purity: 60%) was added, and the mixture was stirred at 0°C for 0.5 hours. Methyl iodide (8.01 mg, 56.43 μmol, 3.51 μL) was added, and the mixture was stirred at 25°C for 2 hours. Two drops of ammonium chloride solution were added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 4d. This intermediate was used directly in the next step without purification. MS m / z: 369.2 [M+H] + .

[0211] Step 5: Synthesis of intermediate 4e Intermediate 4d (5 mg, 13.57 μmol) was dissolved in EtOH (0.5 mL), and triethylamine (6.87 mg, 67.85 μmol, 9.44 μL) and methoxyamine hydrochloride (3.40 mg, 40.71 μmol) were added. The mixture was stirred at 60°C for 1.5 hours. The reaction mixture was extracted with ethyl acetate (5 mL), the organic phase was washed with water (2 mL), dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by prep-TLC (PE:EA = 1:1), the reaction mixture was filtered and concentrated to obtain intermediate 4e. MS m / z: 368.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ ppm 7.48~7.56 (m, 1 H) 7.15~7.18 (m, 1 H) 3.79 (s, 3 H) 3.51~3.56 (m, 4 H) 3.00~3.05 (m, 4 H) 2.92 (s, 3 H)1.42 (s, 9 H).

[0212] Step 6: Synthesis of the hydrochloride salt of intermediate 4f Intermediate 4e (10 mg, 27.22 μmol) was dissolved in MeOH (0.5 mL), hydrogen chloride / dioxane (4 M, 36.74 μL) was added, and the mixture was stirred at 25°C for 1.5 hours. Most of the raw materials were detected by LC-MS, and 0.2 mL of hydrogen chloride / dioxane (4 M, 36.74 μL) was added, followed by stirring for another 1.5 hours. The reaction mixture was concentrated to obtain the hydrochloride salt of intermediate 4f, which was used directly in the next step without purification.

[0213] Step 7: Synthesis of the trifluoroacetate of compound 4 Intermediate 4f (10 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (6.66 mg, 65.84 μmol, 9.16 μL) was added, and the mixture was stirred at 25°C for 0.5 hours. Further addition of intermediate 1h (8.92 mg, 32.92 μmol) and potassium iodide (2.73 mg, 16.46 μmol) was added, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%~30%, 8 min) to obtain the trifluoroacetate of compound 4. MS m / z: 458.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 2.56 (s, 3 H) 3.03 (s, 3 H) 3.59 (br s, 8 H) 3.83~3.94 (m, 3 H) 4.64 (s, 2 H) 7.46~7.52 (m, 1 H) 7.60~7.76 (m, 3 H).

[0214] Example 5 [ka]

[0215] Step 1: Synthesis of the hydrochloride salt of intermediate 5a Intermediate 4c (19.4 mg, 54.73 μmol) was dissolved in MeOH (1 mL), hydrogen chloride / dioxane (4 M, 73.89 μL) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain the hydrochloride salt of intermediate 5a, which was used directly in the next step without purification. MS m / z: 255.0 [M+H] + .

[0216] Step 2: Synthesis of the trifluoroacetate of compound 5 Intermediate 5a (15 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (10.44 mg, 103.17 μmol, 14.36 μL) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, methyl iodide (4.28 mg, 25.79 μmol) and intermediate 1h (13.98 mg, 51.58 μmol) were added, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered to obtain the crude product, which was then subjected to preparative HPLC chromatography (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 3%~33% acetonitrile, 8 min) to obtain the trifluoroacetate of compound 5. MS m / z: 445.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 2.56 (s, 3 H) 3.27~3.29 (m, 3 H) 3.54 (br d, J=3.76 Hz, 8 H) 4.58 (s, 2 H) 7.47 (t, J=7.91 Hz, 1 H) 7.59 (dd, J=10.16, 8.41 Hz, 1 H) 7.70 (d, J=8.28 Hz, 1 H) 8.47 (d, J=8.03 Hz, 1 H) 10.18~10.34 (m, 1 H).

[0217] Example 6 [ka]

[0218] Step 1: Synthesis of intermediate 6b Dioxane (1 mL), water (0.2 mL), intermediate 2a (30 mg, 128.19 μmol), and compound 6a (43.60 mg, 141.01 μmol) were added to a 10 mL sampling bottle. Stirring was started, and the mixture was purged with nitrogen gas. Potassium phosphate (54.42 mg, 256.39 μmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (9.38 mg, 12.82 μmol) were then added sequentially. The mixture was heated to 80°C and reacted for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure to obtain the crude product, and purified by pre-TLC (eluent:PE:EA = 3:1) to obtain intermediate 6b. MS m / z: 337.1 [M+H] + .

[0219] Step 2: Synthesis of intermediate 6c Intermediate 6b (37 mg, 110.00 μmol) was dissolved in EtOH (1.5 mL), methylamine-ethanol solution (222.81 mg, 3.30 mmol) was added, and the mixture was stirred at 25°C for 6 hours. The reaction mixture was directly concentrated to obtain intermediate 6c, which was used in the next step without purification. MS m / z: 336.0 [M+H] + .

[0220] Step 3: Synthesis of the hydrochloride salt of intermediate 6d Intermediate 6c (17 mg, 50.69 μmol) was dissolved in MeOH (0.5 mL), hydrogen chloride / dioxane (4 M, 68.43 μL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was directly concentrated to obtain the hydrochloride salt of intermediate 6d, which was used in the next step without purification. MS m / z: 236.1 [M+H] + .

[0221] Step 4: Synthesis of the trifluoroacetate of compound 6 Intermediate 6d (10 mg, 36.80 μmol, hydrochloride) was dissolved in DMF (1 mL), triethylamine (7.45 mg, 73.61 μmol, 10.24 μL) was added, and the mixture was stirred at 25°C for 0.5 hours. Further addition of intermediate 1h (9.98 mg, 36.80 μmol) and potassium iodide (3.05 mg, 18.40 μmol) was added, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the trifluoroacetate of compound 6. MS m / z: 426.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.12 (dd, J=7.78, 1.51 Hz, 1 H) 7.83~7.91 (m, 1 H) 7.70~7.79 (m, 1 H) 7.57~7.68 (m, 2 H) 6.13 (br s, 1 H) 4.53 (s, 2 H) 3.74~4.00 (m, 2 H) 3.36~3.66 (m, 2 H) 3.04~3.09 (m, 3 H) 2.91~2.99 (m, 1 H)2.65 (s, 3 H).

[0222] Example 7 [ka]

[0223] Step 1: Synthesis of intermediate 7a Intermediate 6c (10 mg, 29.82 μmol) was added to a mixture of MeOH (3 mL) and ethyl acetate (1 mL), and palladium carbon (2 mg, 29.82 μmol, 10%) was added to the reaction mixture. The mixture was purged three times with argon gas, then three times with hydrogen gas, and stirred at 30°C for 16 hours under a hydrogen gas atmosphere of 16 psi. The reaction mixture was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain intermediate 7a, which was used directly in the next step. MS m / z: 360.2 [M+23] + .

[0224] Step 2: Synthesis of the hydrochloride salt of intermediate 7b Intermediate 7a (10 mg, 29.64 μmol) was added to MeOH (0.5 mL), hydrogen chloride / dioxane (4 M, 37.05 μL) was added to the reaction mixture, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was then directly concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 7b, which was used directly in the next step. MS m / z: 238.0 [M+1] + .

[0225] Step 3: Synthesis of the trifluoroacetate of compound 7 Triethylamine (6.94 mg, 68.56 μmol) was added to a solution of intermediate 7b (9.38 mg, 34.28 μmol, crude hydrochloride product) in DMF (1 mL), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 1h (9.29 mg, 34.28 μmol) and potassium iodide (569.03 μg, 3.43 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the trifluoroacetate of compound 7. MS m / z: 428.3 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.75 (s, 1 H) 8.01 (s, 2 H) 7.71 (d, J=8.28 Hz, 1 H) 7.47 (t, J=7.65 Hz, 1 H) 4.58 (s, 2 H) 3.72 (br s, 2 H) 3.18~3.30 (m, 3 H) 2.95 (d, J=5.02 Hz, 3 H) 2.56 (s, 3 H) 2.15~2.26 (m, 2 H) 2.07 (d, J=12.80 Hz, 2 H).

[0226] Example 8 [ka]

[0227] Step 1: Synthesis of intermediate 8b Compound 8a (245.05 mg, 976.20 μmol) and N-Boc-piperazine (200 mg, 1.07 mmol) were added to toluene (5 mL). Pd2(dba)3 (8.94 mg, 9.76 μmol), RuPhos (9.11 mg, 19.52 μmol), and Cs2CO3 (636.13 mg, 1.95 mmol) were added to the reaction mixture, and the mixture was purged three times with nitrogen gas. The reaction system was stirred at 100 °C for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain the crude product. Ethyl acetate and n-heptane mixed solution (ethyl acetate / n-heptane = 5 / 1, 10 mL) was added to the crude product, and the mixture was stirred at 25 °C for 0.5 hours. The mixture was filtered by suction under reduced pressure, and the cake was concentrated to obtain intermediate 8b. MS m / z: 301.2 [M-56+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (t, J=8.19 Hz, 1 H) 6.93 (t, J=8.38 Hz, 1 H) 3.83 (s, 3 H) 3.50~3.46 (m, 4 H) 3.13~3.23 (m, 4 H) 1.43 (s, 9 H).

[0228] Step 2: Synthesis of intermediate 8c Compound 2 (100 mg, 280.61 μmol) and methylamine-ethanol solution (87.15 mg, 1.29 mmol) were added to EtOH (2 mL), stirred at 25°C for 16 hours, the reaction temperature was raised to 50°C, and stirred at 50°C for 16 hours. The reaction system was directly concentrated under reduced pressure to obtain the crude product, which was purified by preparative chromatography (PE / EA = 2 / 1, shift ratio 10.1) to obtain intermediate 8c. MS m / z: 378.2 [M+23] + .

[0229] Step 3: Synthesis of the hydrochloride salt of intermediate 8d Intermediate 8c (50 mg, 140.69 μmol) was added to MeOH (0.5 mL), hydrogen chloride / dioxane (4 M, 37.05 μL) was added to the reaction mixture, and the reaction system was stirred at 25°C for 2 hours. The reaction mixture was then directly concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 8d, which was used directly in the next step. MS m / z: 256.0 [M+1] + .

[0230] Step 4: Synthesis of the trifluoroacetate of compound 8 Triethylamine (10.41 mg, 102.84 μmol) was added to DMF (1 mL) of intermediate 8d (15 mg, 51.42 μmol, crude hydrochloride product), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 1h (13.94 mg, 51.42 μmol) and potassium iodide (853.55 μg, 5.14 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure using an oil pump to obtain the crude product, which was purified by pre-HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the trifluoroacetate of compound 8. MS m / z: 468.1 [M+23] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.15 (s, 1 H) 7.70 (d, J=8.28 Hz, 1 H) 7.39~7.57 (m, 2 H) 6.89~7.03 (m, 1 H) 4.55 (s, 2 H) 3.50 (s, 8 H) 2.89~2.98 (m, 3H) 2.56 (s, 3H).

[0231] Example 9 [ka]

[0232] Step 1: Synthesis of 9g of intermediate hydrochloride Intermediate 4b (50 mg, 147.76 μmol) was dissolved in methanol (0.2 mL), and HCl / dioxane (4 M, 199.48 μL) was added. The reaction was carried out at 25°C for 2 hours. After concentrating the reaction mixture under reduced pressure, 9 g of the hydrochloride salt of the intermediate was obtained without further purification. MS m / z: 238.9 [M+1] + .

[0233] Step 2: Synthesis of intermediate 9b At 0°C, compound 9a (1 g, 4.81 mmol) was added to trifluoroacetic acid (10 mL), and potassium nitrate (760 mg, 7.52 mmol) was slowly added in batches. The mixture was then stirred at 20°C for 16 hours. The reaction mixture was poured into 90 mL of saturated sodium bicarbonate solution, then extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated sodium chloride (100 mL x 2), filtered, and concentrated. The mixture was purified by silica gel column (EA:PE = 0%~10%) to obtain intermediate 9b. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.68~7.92 (m, 1 H), 7.08 (br s, 2 H).

[0234] Step 3: Synthesis of intermediate 9c Intermediate 9b (100 mg, 395.26 μmol) was dissolved in EtOH (1 mL), cooled to 0°C, and acetic acid (237.36 mg, 3.95 mmol, 226.27 μL) was added. Then, zinc (240 mg, 3.67 mmol) was added in batches, and the mixture was reacted for 6 hours. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (PE:EA = 3:1) to obtain intermediate 9c. MS m / z: 224.9, 226.9 [M+1] + [M+3] + . 1 H NMR (400 MHz, CDCl3) δ ppm 6.69~6.80 (m, 1 H),3.52 (s, 4 H).

[0235] Step 4: Synthesis of a mixture of intermediates 9d1 and 9d2 Intermediate 9c (25 mg, 112.10 μmol) was added to EtOH (0.32 mL), then pyruvate (11.85 mg, 134.52 μmol) was added, and the mixture was reacted at 100°C for 2 hours. The mixture was then slowly cooled to 25°C and allowed to crystallize for 14 hours. The mixture was filtered, and the solid was washed once with 0.5 ml of ethanol. No further purification was performed, and a mixture of intermediates 9d1 and 9d2 was obtained. MS m / z: 274.9 [M+1] + .

[0236] Step 5: Synthesis of a mixture of intermediates 9e1 and 9e2 A mixture of intermediates 9d1 and 9d2 (95 mg) and XPHOS-PD-G2 (13.59 mg, 17.27 μmol) were dissolved in dioxane (2 mL). 1-(tributylstannyl)methanol (133.08 mg, 414.47 μmol) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at 80°C for 16 hours. Purification by preparative plate (PE:EA = 1:1) yielded a mixture of intermediates 9e1 and 9e2. MS m / z: 227.0 [M+1] + .

[0237] Step 6: Synthesis of a mixture of intermediates 9f1 and 9f2 Under the protection of nitrogen gas, tributylphosphine (80.50 mg, 397.91 μmol, 98.18 μL) was slowly added dropwise to intermediates 9f1 and 9f2 (45 mg) at 0°C, and then added dropwise to a solution of 1,2-dibromotetrachloroethane (142.54 mg, 437.71 μmol) in dichloromethane (1.2 mL), and the mixture was reacted at 25°C for 2 hours. The mixture of intermediates 9f1 and 9f2 was purified by preparative chromatography (dichloromethane:methanol = 15:1).

[0238] Step 7: Synthesis of a mixture of trifluoroacetates of compounds 9-1 and 9-2. Intermediates 9f1 and 9f2 (43 mg, mixture) were added to DMF (2 mL), triethylamine (29.92 mg, 295.65 μmol) was added, and the mixture was stirred at 25°C for 15 minutes. Potassium iodide (11.04 mg, 66.52 μmol) and 9 g of intermediate (46 mg, 147.82 μmol) were added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%~30%, 8 min). A mixture of trifluoroacetates of compounds 9-1 and 9-2 was obtained. MS m / z: 447.1 [M+1] + .

[0239] Example 10 [ka]

[0240] Step 1: Synthesis of intermediate 10c Under the protection of nitrogen gas, compound 10a (50 mg, 231.45 μmol), compound 10b (51.73 mg, 277.74 μmol), Cs2CO3 (150.82 mg, 462.89 μmol), RuPhos (21.60 mg, 46.29 μmol), and Pd2(dba)3 (21.19 mg, 23.14 μmol) were added to toluene (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was filtered through diatomaceous earth, washed with DCM (5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative chromatography (PE:EA = 0:1) to obtain intermediate 10c. MS m / z: 322.1 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, J=2.76 Hz, 1H), 7.82 (d, J=8.53 Hz, 1H), 6.93~7.02 (m, 2H), 4.04~4.13 (m, 1H), 3.74~3.80 (m, 3 H), 3.53~3.61 (m, 1H), 3.42~3.47 (m, 1H), 3.32~3.35 (m, 1H), 3.04~3.21 (m, 1H), 2.09~2.20 (m, 1H), 1.74~1.86 (m, 1H), 1.40 (br d, J=6.53 Hz, 9H).

[0241] Step 2: Synthesis of intermediate 10d Intermediate 10c (60 mg, 186.70 μmol) was added to EtOH (1 mL), then methylamine-ethanol solution (1.23 g, 11.88 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 10d, which was used directly in the next step. MS m / z: 321.2 [M+1] + .

[0242] Step 3: Synthesis of the hydrochloride salt of intermediate 10e Intermediate 10d (25 mg, 78.03 μmol) was added to MeOH (0.5 mL), then hydrogen chloride / dioxane (4 M, 105.34 μL) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 10e, which was used directly in the next step. MS m / z: 221.1 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ 9.35 (br s, 3H), 8.01 (d, J=2.51 Hz, 1H), 7.92 (dd, J=8.66, 4.39 Hz, 1H), 7.21 (dd, J=8.41, 2.38 Hz, 1H), 4.20~4.30 (m, 1H), 3.42~3.51 (m, 1H), 3.24~3.37 (m, 2H), 3.04~3.13 (m, 1H), 2.79 (d, J=4.52 Hz, 3H), 2.19~2.31 (m, 1H), 1.86~1.98 (m, 1H).

[0243] Step 4: Synthesis of Compound 10 Triethylamine (15.77 mg, 155.80 μmol, 21.69 μL) was added to DMF (1 mL) of intermediate 10e (20 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Compound 1h (21.12 mg, 77.90 μmol) and potassium iodide (1.29 mg, 7.79 μmol) were added to the reaction mixture, and the reaction system was heated to 50°C and stirred for 2 hours. The reaction mixture was washed with water (2 mL), extracted three times with a mixed solution of DCM and MeOH (DCM:MeOH = 10:1, 3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative chromatography (DCM:MeOH = 10:1) to obtain compound 10. MS m / z: 411.1 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (s, 1H), 8.27 (br d, J=4.77 Hz, 1H), 7.91 (d, J=2.51 Hz, 1H), 7.72 (d, J=8.53 Hz, 1H), 7.50 (d, J=7.78 Hz, 1H), 7.24~7.32 (m, 1H), 6.94 (dd, J=8.16, 2.64 Hz, 1H), 6.65 (d, J=6.53 Hz, 1H), 3.94~4.02 (m, 1H), 3.75 (br s, 2H), 3.37~3.42 (m, 1H), 2.86 (br t, J=8.66 Hz, 1H), 2.75 (d, J=4.77 Hz, 3H), 2.65~2.71 (m, 1H), 2.43~2.47 (m, 1H), 2.41 (s, 3H), 2.20~2.28 (m, 1H), 1.54~1.65 (m, 1H).

[0244] Example 11 [ka]

[0245] Step 1: Synthesis of intermediate 11c Under the protection of nitrogen gas, 2a (50 mg, 231.45 μmol), compound 10b (51.73 mg, 277.74 μmol), Cs2CO3 (150.82 mg, 462.89 μmol), RuPhos (21.60 mg, 46.29 μmol), and Pd2(dba)3 (21.19 mg, 23.14 μmol) were added to toluene (1 mL), and the mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was filtered through diatomaceous earth, washed with DCM (5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Pre-TLC (PE:EA=0:1) to obtain intermediate 11c. MS m / z: 340.1 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (d, J=8.00 Hz, 1H), 7.24 (br t, J=9.26 Hz, 1H), 6.88 (br d, J=6.38 Hz, 1H), 4.07~4.18 (m, 1H), 3.79 (s, 3H), 3.56~3.64 (m, 1H), 3.38~3.49 (m, 2H), 3.20 (br dd, J=11.01, 4.75 Hz, 1H), 2.11~2.22 (m, 1H), 1.86~1.96 (m, 1H), 1.40 (br d, J=5.38 Hz, 9H).

[0246] Step 2: Synthesis of intermediate 11d Intermediate 11c (60 mg, 186.70 μmol) was added to EtOH (1 mL), then methylamine-ethanol solution (1.23 g, 11.88 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 11d, which was used directly in the next step. MS m / z: 339.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (br d, J=4.63 Hz, 1H), 7.75 (d, J=8.25 Hz, 1H), 7.24~7.31 (m, 1H), 6.56 (br d, J=6.50 Hz, 1H), 4.04~4.18 (m, 1H), 3.56~3.66 (m, 1H), 3.38~3.47 (m, 2H), 3.16~3.24 (m, 1H), 2.75 (d, J=4.75 Hz, 3H), 2.08~2.24 (m, 1H), 1.84~1.97 (m, 1H) 1.40 (br d, J=6.13 Hz, 9H).

[0247] Step 3: Synthesis of the hydrochloride salt of intermediate 11e Intermediate 11d (25 mg, 78.03 μmol) was added to MeOH (0.5 mL), then hydrogen chloride / dioxane (4 M, 105.34 μL) was added, and the mixture was stirred at 25°C for 4 hours. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 11e, which was used directly in the next step. MS m / z: 239.1 [M+1] + .

[0248] Step 4: Synthesis of Compound 11 Triethylamine (11.05 mg, 109.20 μmol, 15.20 μL) was added to DMF (1 mL) of the hydrochloride salt of 11e obtained in step 3 (15 mg), and the mixture was reacted at 20°C for 0.5 hours. Compound 1h (14.80 mg, 54.60 μmol) and potassium iodide (906.37 μg, 5.46 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was washed with water (2 mL), extracted three times with a mixed solution of DCM and MeOH (DCM:MeOH = 10:1, 3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified using a preparative plate (DCM:MeOH = 10:1) to obtain compound 11. MS m / z: 429.2 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (s, 1H), 8.15 (br d, J=4.63 Hz, 1H), 7.72 (d, J=8.00 Hz, 1H), 7.50 (d, J=8.25 Hz, 1H), 7.28 (t, J=7.63 Hz, 1H), 7.16 (dd, J=10.44, 8.32 Hz, 1H), 6.41 (br d, J=5.88 Hz, 1H), 3.96~4.04 (m, 1H), 3.76 (br s, 2H), 3.29 (br s, 1H), 2.92 (br t, J=8.00 Hz, 1H), 2.74 (d, J=4.75 Hz, 3H), 2.64~2.70 (m, 1H), 2.53~2.58 (m, 1H), 2.41 (s, 3H), 2.18~2.27 (m, 1H), 1.73~1.81 (m, 1H).

[0249] Example 12 [ka]

[0250] Step 1: Synthesis of intermediate 12b Under the protection of nitrogen gas, compound 10a (50 mg, 231.45 μmol), compound 12a (51.73 mg, 277.74 μmol), Cs2CO3 (150.82 mg, 462.89 μmol), RuPhos (21.60 mg, 46.29 μmol), and Pd2(dba)3 (21.19 mg, 23.14 μmol) were added to toluene (1 mL), and the mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was filtered through diatomaceous earth, washed with DCM (5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Pre-TLC (PE:EA=0:1) to obtain intermediate 12b. MS m / z:336.2 [M+1] + .

[0251] Step 2: Synthesis of intermediate 12c Intermediate 12b (45 mg, 134.17 μmol) was added to EtOH (1 mL), then methylamine-ethanol solution (694.48 mg, 6.71 mmol) was added, and the mixture was stirred at 25°C for 16 hours. Compound 12c was obtained by concentrating under reduced pressure. MS m / z: 335.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (br d, J=4.75 Hz, 1H), 8.18 (d, J=2.88 Hz, 1H), 7.81 (d, J=8.88 Hz, 1H), 7.31 (dd, J=8.88, 3.00 Hz, 1H), 4.61~4.70 (m, 1H), 3.53 (br t, J=8.88 Hz, 1H), 3.41~3.46 (m, 1H), 3.30~3.33 (m, 3H), 3.21~3.25 (m, 1H), 2.78 (d, J=4.88 Hz, 3H), 1.95~2.11 (m, 3H), 1.41 (s, 9H).

[0252] Step 3: Synthesis of the hydrochloride salt of intermediate 12d Intermediate 12c (44 mg, 131.57 μmol) was added to MeOH (0.5 mL), followed by hydrogen chloride / dioxane (4 M, 105.34 μL), and the mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 12d, which was used directly in the next step. MS m / z: 235.1 [M+1] + .

[0253] Step 4: Synthesis of Compound 12 Triethylamine (14.95 mg, 147.73 μmol, 20.56 μL) was added to DMF (1 mL) containing 12d hydrochloride (20 mg), and the reaction system was stirred at 20°C for 0.5 hours. Compound 1h (20.02 mg, 73.87 μmol) and potassium iodide (1.23 mg, 7.39 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was washed with water (2 mL), extracted three times with a mixed solution of DCM and MeOH (DCM:MeOH = 10:1, 3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified using a preparative plate (DCM:MeOH = 10:1) to obtain compound 12. MS m / z: 425.2 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br s, 1H), 8.31 (br d, J=5.02 Hz, 1H), 8.11 (d, J=3.01 Hz, 1H), 7.77 (d, J=8.78 Hz, 1H), 7.52 (d, J=8.28 Hz, 1H), 7.30 (t, J=7.65 Hz, 1H), 7.22 (dd, J=8.78, 3.01 Hz, 1H), 4.56~4.67 (m, 1H), 3.75 (s, 2H), 3.32 (s, 3H), 2.87 (td, J=8.34, 2.89 Hz, 1H), 2.77 (d, J=5.02 Hz, 3H), 2.73 (dd, J=10.04, 3.26 Hz, 1H), 2.62 (t, J=8.78 Hz, 1H), 2.41 (s, 3H), 2.31~2.37 (m, 1H), 2.17~2.28 (m, 1H), 1.66~1.76 (m, 1H).

[0254] Example 14 [ka]

[0255] Step 1: Synthesis of intermediate 14b Compound 3a (8 g, 36.99 mmol) was added to DCM (80 mL) and H2O (80 mL), and NaHCO3 (9.32 g, 110.97 mmol) was added to the reaction mixture. The reaction system was cooled to 0°C, and benzyl chloroformate (9.47 g, 55.48 mmol) was added to the reaction mixture. The reaction system was stirred at 20°C for 16 hours. 80 mL of dichloromethane was added to the reaction mixture, extracted, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C to obtain the crude product. The crude product was separated and purified by column chromatography (eluent: PE / EA = 5 / 1 to 2 / 1, V / V) to obtain intermediate 14b.

[0256] Step 2: Synthesis of intermediate 14c Intermediate 14b (5 g, 14.27 mmol) was added to DCM (100 mL), and Dess-Martin (9.08 g, 21.40 mmol, 6.63 mL) was added to the reaction mixture in batches at 0°C and stirred at 0°C for 3 hours. 6 g of calcium hydroxide was added to the reaction mixture and stirred at 0°C for 1 hour. The mixture was filtered, the cake was washed with dichloromethane (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure at 50°C. The crude product was separated and purified by high-performance silica gel column chromatography (eluent: PE:EA = 90:10~80:20, V / V) to obtain intermediate 14c.

[0257] Step 3: Synthesis of intermediate 14d Under the protection of nitrogen gas, KHMDS (1M, 3.44 mL) was added dropwise to methyltriphenylphosphonium bromide (1.23 g, 3.44 mmol) in THF (4 mL) at 20°C. The reaction system was stirred at 20°C for 1 hour, then cooled to -78°C. While stirring, the intermediate 14c (0.4 g, 1.15 mmol) in THF (4 mL) solution was slowly added dropwise to the reaction mixture (10 min). The reaction system was then heated to 20°C and stirred at that temperature for 1 hour. 72 mL of methanol was added to the reaction mixture, followed by 36 mL of saturated potassium sodium tartrate solution. The mixture was extracted with ethyl acetate (180 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: PE / EA = 90:10~80:20, V / V) to obtain intermediate 14d.

[0258] Step 4: Synthesis of intermediate 14e Methyl 6-bromo-5-fluoropicolinate (100 mg, 427.31 μmol), intermediate 14d (148.03 mg, 427.31 μmol), Pd(OAc)2 (9.59 mg, 42.73 μmol), PPh3 (22.42 mg, 85.46 μmol), and Na2CO3 (90.58 mg, 854.62 μmol) were added to DMF (5 mL), purged with nitrogen gas, heated to 130 °C, and stirred for 6 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted three times with EA (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (PE:EA = 2:1) to obtain intermediate 14e. MS m / z: 500.2 [M+1] + .

[0259] Step 5: Synthesis of intermediate 14f Intermediate 14e (20 mg, 40.04 μmol) was added to methanol (4 mL), and Pd / C (42.61 mg) was added to the reaction mixture. The reaction system was purged three times with argon gas, then three times with hydrogen gas, and the system was stirred at 30°C under a hydrogen gas pressure of 30 psi for 16 hours. The reaction mixture was cooled to 20°C, filtered by suction under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain intermediate 14f, which was used directly in the next step. MS m / z: 368.2 [M+1] + .

[0260] Step 6: Synthesis of 14g of intermediate Potassium carbonate (11.28 mg, 81.65 μmol) was added to a solution of intermediate 14f (15 mg, 40.83 μmol) in DMF (1 mL), and the mixture was heated to 50°C and stirred for 6 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted three times with EA (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (PE:EA = 1:1) to obtain 14 g of intermediate. MS m / z: 348.2 [M+1] + ; 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (d, J=8.63 Hz, 1H), 6.94 (d, J=8.76 Hz, 1H), 3.98~4.13 (m, 2H), 3.87 (s, 3H), 3.62~3.74 (m, 1H), 3.14 (tt, J=10.33, 3.42 Hz, 1H), 2.94~3.06 (m, 2H), 2.84~2.92 (m, 1H), 2.57~2.70 (m, 1H), 2.04 (dq, J=13.35, 4.39 Hz, 1H), 1.67~1.82 (m, 1H), 1.52~1.63 (m, 1st hole), 1.42 (s, 9th hole).

[0261] Step 7: Synthesis of intermediate 14h A methylamine-ethanol solution (0.41 g, 3.96 mmol) was added to 14 g (20 mg, 57.57 μmol) of intermediate in EtOH (1 mL) solution, and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure to obtain intermediate 14h. MS m / z: 347.2 [M+1] + .

[0262] Step 8: Synthesis of the hydrochloride salt of intermediate 14i Intermediate 14h (18 mg, 51.96 μmol) was dissolved in MeOH (0.5 mL), then hydrogen chloride / dioxane (4 M, 64.95 μL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 14i. MS m / z: 247.2 [M+1] + .

[0263] Step 9: Synthesis of Compound 14 Triethylamine (70.73 μmol, 9.84 μL) was added to a solution of intermediate 14i hydrochloride (10 mg) in DMF (1 mL), and the reaction system was stirred at 20°C for 0.5 hours. Then, intermediate 1h (9.59 mg, 35.36 μmol) and potassium iodide (587.06 μg, 3.54 μmol) were added, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was filtered, and the residue was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the crude product. Methylamine-ethanol solution (0.30 g) was added to this, and the mixture was stirred at 25°C for 24 hours and concentrated to obtain compound 14. MS m / z: 437.2 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 7.63 (d, J=8.53 Hz, 1H), 7.45 (d, J=8.53 Hz, 1H), 7.29 (t, J=7.65 Hz, 1H), 7.10 (d, J=8.78 Hz, 1H), 4.50 (br s, 1H), 3.75 (br d, J=11.29 Hz, 1H), 3.67 (s, 2H), 3.03~3.14 (m, 1H), 2.87~2.95 (m, 2H), 2.81 (s, 3H), 2.37~2.43 (m, 2H), 2.16~2.27 (m, 1H), 2.09 (t, J=7.53 Hz, 1H), 1.88~1.95 (m, 3H), 1.65~1.76 (m, 1H), 1.46~1.54 (m, 1H).

[0264] Example 15 [ka]

[0265] Step 1: Synthesis of intermediate 15b Compound 15a (0.8 g, 3.96 mmol) and methyl 3-amino-2-fluorobenzoate (803.87 mg, 4.75 mmol) were added to DMF (10 mL), HATU (1.81 g, 4.75 mmol) and triethylamine (1.20 g, 11.88 mmol, 1.65 mL) were added to the reaction mixture, and the reaction system was stirred at 25°C for 16 hours. The reaction mixture was added to 5 mL of water, then extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain the crude product. The crude product was then separated and chromatographed on a thin-layer chromatography plate (PE / EA = 2 / 1, R f The intermediate 15b was obtained by purification using (=0.14). MS m / z: 352.7,354.7 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ ppm 8.53~8.62 (m, 1 H) 8.43 (dd, J=4.75, 1.88 Hz, 2 H) 8.00 (dd, J=7.63, 1.88 Hz, 1 H) 7.65 (td, J=7.41, 1.69 Hz, 1 H) 7.36 (dd, J=7.63, 4.75 Hz, 1 H) 7.13~7.24 (m, 1 H) 3.84~3.91 (m, 3 H).

[0266] Step 2: Synthesis of intermediate 15c Intermediate 15b (700 mg, 1.98 mmol) was added to DCM (15 mL), Et3N (5.95 mmol, 827.70 μL), (Boc)2O (519.14 mg, 2.38 mmol), and DMAP (48.43 mg, 396.44 μmol) were added to the reaction mixture, and the reaction system was stirred at 25°C for 4 hours. The reaction mixture was added to 5 mL of water, then extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45°C to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 5 / 1~2 / 1, V / V) to obtain intermediate 15c. MS m / z: 452.9, 454.9 [M+1] + .

[0267] Step 3: Synthesis of intermediate 15d Intermediate 15c (20 mg, 44.12 μmol) was added to DMF (3 mL), and tributylphosphine (8.93 mg, 44.12 μmol), 1,3-bis(diphenylphosphin)propane (7.28 mg, 17.65 μmol), Pd(OAc)2 (3.96 mg, 17.65 μmol), and potassium carbonate (18.30 mg, 132.37 μmol) were added to the reaction mixture and the mixture was reacted at 140 °C under microwave radiation for 10 minutes. The reaction mixture was concentrated under reduced pressure at 60 °C to obtain the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to obtain intermediate 15d. MS m / z: 272.8 [M+1] + .

[0268] Step 4: Synthesis of intermediate 15e Intermediate 15d (20 mg, 73.47 μmol) was added to THF (2 mL), and LiAlH4 (2.79 mg, 73.47 μmol) was added to the reaction mixture at 0°C. The reaction was carried out at 0°C for 30 minutes. 2 mL of saturated potassium sodium tartrate solution was added to the reaction mixture, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45°C to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA = 2 / 1) to obtain intermediate 15e. MS m / z: 244.8 [M+1] + .

[0269] Step 5: Synthesis of intermediate 15f Intermediate 15e (11.5 mg, 47.09 μmol) was added to THF (4 mL), and manganese dioxide (40.94 mg, 470.89 μmol) was added to the reaction mixture at 20°C. The reaction system was allowed to react at 20°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain crude product 15f. MS m / z: 243.0 [M+1] + .

[0270] Step 6: Synthesis of the trifluoroacetate of compound 15 9 g (12.26 mg, hydrochloride) of intermediate was added to DMSO (2 mL), Et3N (9.03 mg, 89.22 μmol) was added to the reaction mixture, and the reaction system was stirred at 25°C for 30 minutes. 15f (10 mg, 41.29 μmol) of intermediate was added to the reaction mixture, the pH was adjusted to ~6 with acetic acid, and the reaction system was stirred at 25°C for 2 hours. NaBH(OAc)3 (18.91 mg, 89.22 μmol) was added to the reaction mixture, and the reaction system was stirred at 25°C for 1 hour. Water (2 mL) was added to the reaction mixture, and then it was extracted with dichloromethane (5 mL x 3). The organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure at 45°C. The crude product was separated and purified by preparative HPLC (column chromatography: Welch Xtimate C18 100×40mm×3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 2%~32% acetonitrile, 8 min) to obtain the trifluoroacetate of compound 15. MS m / z: 487.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (br s, 1H), 10.03~10.15 (m, 1H), 9.16 (d, J=2.40 Hz, 1H), 8.72 (d, J=3.20 Hz, 1H), 8.43~8.62 (m,2H), 7.92 (d, J=4.42 Hz, 1H), 7.71~7.84 (m, 2H), 7.45~7.52 (m, 1H), 4.66 (s, 2H), 3.70~3.81 (m, 4H), 3.19~3.25 (m, 4H), 2.81 (d, J=2.40 Hz, 3H).

[0271] Step 7: Synthesis of 15g of intermediate Intermediate 15e (50 mg, 204.73 μmol) was dissolved in DCM (3 mL), 1,2-dibromo-1,1,2,2-tetrachloroethane (146.67 mg, 450.41 μmol) was added, and tributylphosphine (82.84 mg, 409.47 μmol) was added at 0°C. The mixture was stirred at 25°C for 3 hours. The mixture was filtered to obtain a cake, which was 15 g of intermediate. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), 9.10 (d, J=4.52 Hz, 1H), 8.65 (d, J=8.03 Hz, 1H), 8.39~8.52 (m, 1H), 7.69~7.80 (m, 1H), 7.34~7.54 (m, 1H), 4.78~5.01 (m, 2H).

[0272] Step 8: Synthesis of Compound 15 9 g (38.02 mg, hydrochloride) of the intermediate was dissolved in 1 mL of DMF, and triethylamine (32.95 mg, 325.61 μmol) was added. The mixture was stirred at 25°C for 0.5 hours. Then, 15 g (50 mg, 162.80 μmol) of the intermediate and KI (2.70 mg, 16.28 μmol) were added, and the mixture was stirred at 50°C for 3 hours. Water (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. A solid precipitated, and the mixture was filtered to obtain a cake, which was compound 15. MS m / z: 465.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J=4.63, 1.75 Hz, 1H), 8.65 (dd, J=7.94, 1.81 Hz, 1H), 8.39~8.49 (m, 2H), 7.84 (dd, J=8.13, 1.25 Hz, 1H), 7.72 (dd, J=8.00, 4.50 Hz, 1H), 7.57 (dd, J=10.76, 8.13 Hz, 1H), 7.37 (dd, J=7.94, 6.44 Hz, 1H), 3.75 (s, 2H), 3.15~3.24 (m, 4H), 2.76 (d, J=4.75 Hz, 3H), 2.61~2.65 (m, 4H).

[0273] Example 16 [ka]

[0274] Step 1: Synthesis of intermediate 16b Compound 1i (5 g, 23.12 mmol) was added to H2O (40 mL) and DCM (40 mL), and NaHCO3 (5.83 g, 69.36 mmol) was added to the reaction mixture. The reaction system was cooled to 0°C, and benzyl chloroformate (5.92 g, 34.68 mmol, 4.95 mL) was added to the reaction mixture. The reaction system was stirred at 20°C for 16 hours. 40 mL of dichloromethane was added to the reaction mixture and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 50°C to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 5 / 1 to 2 / 1, V / V) to obtain intermediate 16b.

[0275] Step 2: Synthesis of intermediate 16c Intermediate 16b (8 g, 22.83 mmol) was added to DCM (120 mL), and Dess-Martin (14.52 g, 34.25 mmol, 10.61 mL) was added to the reaction mixture in batches at 0°C. The mixture was stirred at 0°C for 3 hours, 10 g of calcium hydroxide was added to the reaction mixture, and the mixture was stirred at 0°C for 1 hour. The mixture was filtered, the cake was washed with dichloromethane (60 mL x 3), the filtrate was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure at 50°C. The crude product was purified by column chromatography (eluent: ethyl acetate / n-heptane = 5 / 1~2 / 1, V / V) to obtain intermediate 16c.

[0276] Step 3: Synthesis of intermediate 16d Under the protection of nitrogen gas, KHMDS (1M, 51.67 mL) was added dropwise to methyltriphenylphosphonium bromide (18.46 g, 51.67 mmol) in THF (50 mL) at 20°C. The reaction system was stirred at 20°C for 1 hour, then cooled to -70°C. While stirring, the solution of intermediate 16c (6 g, 17.22 mmol) in THF (50 mL) was slowly added dropwise to the reaction mixture (10 min). The reaction system was then heated to 20°C and stirred at that temperature for 3 hours. 50 mL of methanol was added to the reaction mixture, followed by 50 mL of saturated sodium potassium tartrate solution. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 5 / 1 to 1 / 1, V / V) to obtain intermediate 16d. 1 H NMR (400 MHz, CDCl3) δ ppm 7.14~7.28 (m, 5 H) 5.61 (ddd, J=17.39, 10.76, 4.50 Hz, 1 H) 5.02~5.11 (m, 2 H) 5.00 (d, J=2.63 Hz, 2 H) 4.58 (br s, 1 H) 3.67~3.96 (m, 3 H) 2.58~3.04 (m, 3 H) 1.30 (s, 9 H).

[0277] Step 4: Synthesis of intermediate 16e Intermediate 16d (500.00 mg, 1.44 mmol), methyl 6-bromo-5-fluoropicolinate (337.77 mg, 1.44 mmol), PPh3 (75.71 mg, 288.67 μmol), Na2CO3 (458.93 mg, 4.33 mmol), and Pd(OAc)2 (32.40 mg, 144.33 μmol) were added to DMF (5 mL), purged three times with nitrogen gas, and stirred at 130 °C for 12 hours. 10 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 50 °C to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 4 / 1~2 / 1, V / V) to obtain intermediate 16e. MS m / z: 522.1 [M+23] + .

[0278] Step 5: Synthesis of intermediate 16f Intermediate 16e (0.2 g, 400.38 μmol) was added to a hydrogenation bottle containing MeOH (10 mL), and the mixture was purged once with argon gas. Pd / C (200 mg) was added to the reaction flask, and the mixture was purged three times with hydrogen gas. The reaction system was stirred at 30°C under 30 psi of hydrogen gas for 16 hours. The reaction mixture was filtered by suction filtration under reduced pressure using diatomaceous earth, and the filtrate was concentrated under reduced pressure at 40°C to obtain intermediate 16f. MS m / z: 368.1 [M+1] + .

[0279] Step 6: Synthesis of 16g ​​of intermediate Intermediate 16f (100 mg, 272.17 μmol) was added to DMF (4 mL), then potassium carbonate (75.23 mg, 544.34 μmol) was added to the reaction mixture. The reaction system was stirred at 50°C for 2 hours, and the reaction mixture was filtered by suction under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 16 g of intermediate. MS m / z: 348.2 [M+1] + .

[0280] Step 7: Synthesis of intermediate 16h 16 g (80 mg, 230.28 μmol) of the intermediate was added to ethanol (2 mL), then methylamine-ethanol solution (2.53 g, 24.44 mmol) was added to the reaction mixture, and the reaction system was stirred at 30°C for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain intermediate 16h. MS m / z: 347.1 [M+1] +

[0281] Step 8: Synthesis of the hydrochloride salt of intermediate 16i Intermediate 16h (40 mg, 115.47 μmol) was added to MeOH (2 mL), then hydrogen chloride / dioxane (4 M, 144.33 μL) was added to the reaction mixture, and the reaction system was stirred at 30°C for 4 hours. The reaction mixture was then concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 16i. MS m / z: 269.1 [M+23] + .

[0282] Step 9: Synthesis of the trifluoroacetate of compound 16 Et3N (10.74 mg, 106.09 μmol, 14.77 μL) was added to DMF (1 mL) containing hydrochloride of intermediate 16i (15 mg). The reaction system was stirred at 20°C for 30 minutes. Intermediate 1h (14.38 mg, 53.05 μmol) and potassium iodide (880.58 μg, 5.30 μmol) were added to the reaction mixture. The reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 24%~54% acetonitrile) to obtain the trifluoroacetate of compound 16. MS m / z: 437.2 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=8.53 Hz, 1 H) 7.71 (d, J=8.28 Hz, 1 H) 7.44~7.51 (m, 1 H) 7.37 (d, J=8.78 Hz, 1 H) 4.59 (s, 2 H) 4.23 (br d, J=14.56 Hz, 1 H) 3.61~3.75 (m, 2 H) 3.38~3.54 (m, 1 H) 3.08~3.23 (m, 3 H) 2.99~3.06 (m, 2 H) 2.94 (s, 3 H) 2.56 (s, 3 H) 2.14~2.24 (m, 1H) 1.85~1.98 (m, 1 H).

[0283] Example 17 [ka]

[0284] Step 1: Synthesis of intermediate 17b At 0°C, triethylamine (19.46 g, 192.30 mmol) was added dropwise to a solution of compound 17a (10 g, 48.08 mmol) in DCM (50 mL), and the mixture was stirred for 30 minutes. Then, acetyl chloride (6.04 g, 76.92 mmol, 5.47 mL) was slowly added dropwise, and the temperature was raised to 25°C and the reaction was allowed to proceed for 3 hours. The reaction mixture was added to 100 mL of water and extracted with dichloromethane (40 mL x 5). The organic phases were combined and washed with saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography (eluent: EA / PE = 0%~10%, V / V) to obtain intermediate 17b. MS m / z: 249.9, 251.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1 H) 7.43~7.45 (m, 2 H) 2.07 (s, 3 H).

[0285] Step 2: Synthesis of intermediate 17c Fuming nitric acid (71.99 mmol, 3.24 mL) was added to a three-necked flask and cooled to 0°C. Intermediate 17b was added in batches, and then sulfuric acid (334.75 mmol, 17.84 mL) was slowly added dropwise, completing the addition within 1 hour while maintaining the temperature at 0°C. The temperature was then raised to 25°C and the reaction was allowed to proceed for 1 hour. The reaction mixture was poured into 100 mL of 3 M sodium hydroxide solution at 0°C to adjust the pH to approximately 7. The mixture was extracted with ethyl acetate (30 mL x 5), the organic phase was combined, washed with saturated brine (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 17c. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (s, 1 H) 7.50~7.53 (m, 1 H) 2.08 (s, 3 H).

[0286] Step 3: Synthesis of intermediate 17d Intermediate 17c (9.50 g, 32.20 mmol) was dissolved in sulfuric acid (90 mL) and reacted at 50°C for 2 hours. The reaction solution was poured into 100 mL of ice water, the pH was adjusted to 7-8 with 3 M NaOH solution, filtered, and the resulting cake was washed with 10 mL of water and vacuum-dried to obtain intermediate 17d. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (br, s, 2 H) 6.74~6.77 (m, 1 H).

[0287] Step 4: Synthesis of intermediate 17e Intermediate 17d (6.2 g, 24.51 mmol) was dissolved in EtOH (70 mL), cooled to 0°C, acetic acid (14.72 g, 245.06 mmol, 14.03 mL) was added, and then zinc (14.88 g, 227.56 mmol) was added in batches, and the reaction was allowed to proceed for 1 hour. The reaction mixture was poured into 500 mL of water, extracted with ethyl acetate (80 mL x 5), the organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 17e. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.37~6.40 (m, 1 H) 5.21 (br, s, 2 H) 4.65 (br, s, 2 H).

[0288] Step 5: Synthesis of intermediate 17f Intermediate 17e (3.15 g, 14.12 mmol) was added to EtOH (30 mL), then pyruvate (1.49 g, 16.95 mmol, 1.19 mL) was added dropwise, and the mixture was reacted at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure, 10 mL of ethanol was added, and the mixture was stirred for 20 minutes. The mixture was filtered, and the cake was collected to obtain intermediate 17f. MS m / z: 274.9, 276.9 [M+1] + .

[0289] Step 6: Synthesis of 17g of intermediate The intermediate mixture 17f (3.05 g, 11.09 mmol) and 1-(tributylstannyl)methanol (4.27 g, 13.31 mmol) were dissolved in dioxane (30 mL). Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (436.24 mg, 554.45 μmol) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at 110 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (EA / PE = 0%~30%, MeOH / DCM = 0%~5%). Furthermore, the intermediate was purified by preparative HPLC (column chromatography: Welch Xtimate C18 100×40mm×3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~26% acetonitrile, 8 min) to obtain 17 g of the intermediate. MS m / z: 227.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.51(s, 1 H) 7.35~7.37 (m, 1 H) 5.25 (s, 1 H) 4.57 (s, 2 H) 2.41 (s, 3 H).

[0290] Step 7: Synthesis of intermediate 17h At 25°C, Dess-Martin (84.39 mg, 198.96 μmol) was added to 17 g (30 mg, 132.64 μmol) of intermediate in a 2 mL solution of DCM, and the mixture was stirred for 2 hours. 0.057 g of calcium hydroxide was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The mixture was filtered, the cake was washed with dichloromethane (10 mL x 3), and the filtrate was concentrated under reduced pressure at 50°C to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (PE:EA = 1:1) to obtain intermediate 17h. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.72 (s, 1H), 10.27 (s, 1H), 7.53~7.63 (m, 1H), 2.47 (s, 3H).

[0291] Step 8: Synthesis of Compound 17 9 g (21.86 mg, hydrochloride) of the intermediate was dissolved in DMSO (1 mL), and triethylamine (13.54 mg, 133.83 μmol) was added to the reaction mixture while stirring. The mixture was stirred at 25°C for 30 minutes, and 17 h (15 mg, 66.92 μmol) of the intermediate was added to the reaction mixture. The pH was adjusted to 6-7 with acetic acid, and the mixture was stirred at 25°C for 2 hours. NaBH(OAc)3 (28.36 mg, 133.83 μmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 16 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted three times with EA (5 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min). The resulting triethylamine product (3 μL) was based and further purified by preparative thin-layer chromatography (100% EA) to obtain compound 17. MS m / z: 447.1 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ ppm 7.88 (dd, J=8.16, 1.13 Hz, 1H), 7.49 (dd, J=10.29, 8.03 Hz, 1H), 7.37 (dd, J=9.79, 1.76 Hz, 1H), 3.87 (s, 2H), 3.22~3.25 (m, 4H), 2.91 (s, 3H), 2.71~2.77 (m, 4H), 2.53 (s, 3H).

[0292] Example 18 [ka]

[0293] Step 1: Synthesis of Compound 18 Intermediate 14i (19.87 mg, hydrochloride) was dissolved in DMSO (1 mL), and triethylamine (133.83 μmol, 18.63 μL) was added to the reaction mixture while stirring. The mixture was stirred at 25°C for 30 minutes, and intermediate 17h (15.00 mg, 66.92 μmol) was added to the reaction mixture. The pH was adjusted to 6-7 with acetic acid, and the mixture was stirred at 25°C for 2 hours. NaBH(OAc)3 (28.36 mg, 133.83 μmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 16 hours. 2 mL of water was added to the reaction mixture and extracted with EA (5 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the crude product. 3 μL of triethylamine was added to the crude product and purified by preparative thin-layer chromatography (100% EA) to obtain compound 18. MS m / z: 455.2 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 7.64 (d, J=8.53 Hz, 1H), 7.06~7.16 (m, 2H), 3.76 (br d, J=12.55 Hz, 1H), 3.64 (s, 2H), 3.06~3.15 (m, 1H), 2.83~2.95 (m, 4H), 2.81~2.83 (m, 3H), 2.43 (s, 3H), 2.23 (td, J=11.54, 3.26 Hz, 1H), 1.92~2.00 (m, 2H), 1.64~1.78 (m, 1H), 1.22~1.27 (m, 1H).

[0294] Example 19 [ka]

[0295] Step 1: Synthesis of the trifluoroacetate of compound 19 Intermediate 16i (12.5 mg, hydrochloride) was dissolved in DMSO (1 mL), triethylamine (74.58 μmol, 10.38 μL) was added, and the mixture was stirred at 20°C for 0.5 hours. Then, 17h (8.36 mg, 37.29 μmol) was added, the pH was adjusted to 6-7 with acetic acid, and the mixture was stirred at 20°C for 2 hours. Finally, NaBH(OAc)3 (15.81 mg, 74.58 μmol) was added, and the mixture was stirred for 16 hours. 3 mL of water was added to the reaction mixture, extracted with ethyl acetate (3 × 3 mL), combined the organic phases, washed with 3 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the trifluoroacetate of compound 19. MS m / z: 455.1 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 1.63~1.77 (m, 1 H) 1.93~2.05 (m, 2 H) 2.18~2.31 (m, 1 H) 2.42 (s, 3 H) 2.81 (s, 3 H) 2.82~2.86 (m, 2 H) 2.93 (br t, J=10.42 Hz, 2 H) 3.07 (s, 2 H) 3.72~3.81 (m, 3 H) 7.09 (d, J=8.78 Hz, 1 H) 7.27 (dd, J=9.54, 1.76 Hz, 1 H) 7.59~7.68 (m, 1 H).

[0296] Example 20 [ka]

[0297] Step 1: Synthesis of intermediate 20b At 0°C, triethylamine (7.78 g, 76.92 mmol, 10.71 mL) was added dropwise to a solution of compound 20a (4 g, 19.23 mmol) in DCM (20 mL), and the mixture was stirred for 0.5 hours. Then, acetyl chloride (2.42 g, 30.77 mmol, 2.19 mL) was slowly added dropwise, and the temperature was raised to 18°C ​​and the reaction was allowed to proceed for 3 hours. The reaction mixture was added dropwise to 100 mL of water and extracted with dichloromethane (20 ml x 5). The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Further purification by silica gel column chromatography (EA / PE = 0%~10%) yielded intermediate 20b. MS m / z: 250.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.03 (br s, 1 H) 8.02~8.17 (m, 1 H) 7.77 (dd, J=10.16, 6.40 Hz, 1 H) 2.12 (s, 3 H).

[0298] Step 2: Synthesis of intermediate 20c At 0°C, intermediate 20b (2.52 g, 10.08 mmol) was suspended in nitric acid (1.27 g, 20.16 mmol, 907.24 μL), and then sulfuric acid (9.19 g, 93.73 mmol, 5.00 mL) was slowly added dropwise. After the dropwise addition was complete, the mixture was stirred at 25°C for 1 hour. The reaction mixture was added dropwise to water, a solid precipitated, and the pH was adjusted to 6-7 by adding 2 M NaOH solution. The mixture was filtered, and the cake was dried to obtain intermediate 20c. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1 H) 8.21~8.38 (m, 1 H) 2.07 (s, 3 H).

[0299] Step 3: Synthesis of intermediate 20d Intermediate 20c (2.28 g, 7.73 mmol) was dissolved in sulfuric acid (22 mL) and stirred at 50°C for 2 hours. The reaction mixture was added to 400 mL of water, and 2 M NaOH solution was added to adjust the pH to 6-7. A solid precipitated, which was filtered to obtain a cake, and then vacuum-dried to obtain intermediate 20d. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76~7.89 (m, 1 H) 7.09 (s, 2 H).

[0300] Step 4: Synthesis of intermediate 20e Intermediate 20d (1.49 g, 5.89 mmol) was dissolved in EtOH (15 mL), and zinc powder (3.66 g, 55.95 mmol) and acetic acid (3.54 g, 58.89 mmol, 3.37 mL) were added in batches at 0°C. The mixture was stirred at 40°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 100:0~90:10, V / V) to obtain intermediate 20e. MS m / z: 223.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.65 (dd, J=10.04, 6.02 Hz, 1 H) 5.06 (s, 2 H) 4.90 (s, 2 H).

[0301] Step 5: Synthesis of intermediate 20f Intermediate 20e (1.14 g, 5.11 mmol) was dissolved in EtOH (12 mL), then pyruvate (540.17 mg, 6.13 mmol, 432.14 μL) was added, the mixture was stirred at 100°C for 2 hours, slowly cooled to 25°C, and allowed to crystallize for 14 hours. The reaction mixture was filtered to obtain a cake, which was intermediate 20f (mixture). MS m / z: 274.9 [M+1] + .

[0302] Step 6: Synthesis of 20g of intermediate Under the protection of nitrogen gas, intermediate 20f (500 mg, 1.82 mmol) was dissolved in dioxane (5 mL), and 1-(tributylstannyl)methanol (700.42 mg, 2.18 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (71.51 mg, 90.89 μmol) were added, and the mixture was stirred at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure and separated and purified by column chromatography (eluent: PE:EA = 90:10~50:50, V / V) to obtain the crude product. The crude product was then separated by preparative HPLC (column chromatography: Welch Xtimate C18 100×40mm×3μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~26% acetonitrile) to obtain 20 g of the intermediate. MS m / z: 226.8 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.58 (br s, 1 H) 6.99~7.25 (m, 1 H) 4.62 (br d, J=3.51 Hz, 2 H) 2.43 (br s, 3 H).

[0303] Step 7: Synthesis of intermediate 20h 20 g (100 mg, 442.13 μmol) of the intermediate was dissolved in DCM (2 mL), Dess-Martin (281.29 mg, 663.19 μmol, 205.47 μL) was added, and the mixture was stirred at 20°C for 2 hours. 0.1899 g of calcium hydroxide was added to the reaction mixture and the mixture was stirred at 20°C for 1 hour. The mixture was filtered to obtain the crude product, which was then separated and purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to obtain intermediate 20h. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.96 (br, s, 1H), 10.26 (s, 1H), 7.40~7.44 (m, 1H), 2.49 (s, 3H).

[0304] Step 8: Synthesis of Compound 20 Intermediate 14i (13.25 mg, hydrochloride) was dissolved in DMSO (1 mL), and triethylamine (9.03 mg, 89.22 μmol, 12.42 μL) was added to the reaction mixture while stirring. The mixture was stirred at 25°C for 30 minutes, and intermediate 20h (10 mg, 44.61 μmol) was added to the reaction mixture. The pH was adjusted to 6-7 with acetic acid, and the mixture was stirred at 25°C for 2 hours. NaBH(OAc)3 (18.91 mg, 89.22 μmol) was added to the reaction mixture, and the reaction system was stirred at 25°C for 16 hours. 2 mL of water was added to the reaction mixture and extracted with EA (5 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile) to obtain the crude product. 3 μL of triethylamine was added to the crude product and purified by preparative thin-layer chromatography (100% EA) to obtain compound 20. MS m / z: 455.2 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 7.75 (d, J=8.78 Hz, 1H), 7.38 (dd, J=9.41, 1.63 Hz, 1H), 7.21 (d, J=8.78 Hz, 1H), 4.59 (s, 1H), 3.83~3.90 (m, 3H), 3.14~3.23 (m, 1H), 3.01~3.11 (m, 2H), 2.94~2.99 (m, 1H), 2.92~2.94 (m, 3H), 2.85~2.92 (m, 1H), 2.54 (s, 3H), 2.31~2.41 (m, 1H), 1.93~2.23 (m, 2H), 1.75~1.88 (m, 1H).

[0305] Example 21 [ka]

[0306] Step 1: Synthesis of Compound 21 Intermediate 16i (15 mg, hydrochloride) was dissolved in DMSO (1 mL), triethylamine (9.06 mg, 89.50 μmol, 12.46 μL) was added, and the mixture was stirred at 20°C for 0.5 hours. Then intermediate 20h (12.54 mg, 44.75 μmol) was added, the pH was adjusted to 6-7 with acetic acid, and the mixture was stirred at 20°C for 2 hours. Finally, NaBH(OAc)3 (18.97 mg, 89.50 μmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was extracted with 3 mL of water and ethyl acetate (3 × 3 mL), the organic phases were combined, and the mixture was washed with 10 mL of saturated saline solution. The mixture was dried over anhydrous sodium sulfate and filtered to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile, 8 min) to obtain the crude product. After adding 3 μL of triethylamine to the crude product, it was separated and purified by preparative thin-layer chromatography (EA=100%) to obtain compound 21. MS m / z: 455.0 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 7.58~7.69 (m, 1 H) 7.10 (d, J=8.78 Hz, 2 H) 3.76 (br d, J=11.80 Hz, 1 H) 3.64 (d, J=1.51 Hz, 2 H) 3.04~3.17 (m, 1 H) 2.82~2.96 (m, 5 H) 2.82 (s, 3 H) 2.43 (s, 3 H) 2.15~2.30 (m, 1 H) 1.88~2.01 (m, 2 H) 1.61~1.79 (m, 1 H).

[0307] Example 22 [ka]

[0308] Step 1: Synthesis of the trifluoroacetate of compound 22 9 g (7.29 mg, hydrochloride) of the intermediate was dissolved in DMSO (1 mL), triethylamine (44.61 μmol, 6.21 μL) was added, and the mixture was stirred at 20°C for 0.5 hours. Then, 20 h (5 mg, 22.31 μmol) of the intermediate was added, the pH was adjusted to 6-7 with acetic acid, and the mixture was stirred for 2 hours. NaBH(OAc)3 (9.45 mg, 44.61 μmol) was added and the mixture was stirred for 4 hours. 1 mL of water and ethyl acetate (3 × 1 mL) were added to the reaction mixture for extraction. The organic phase was washed with 10 mL of saturated saline solution, dried, and filtered to obtain the crude product. The crude product was separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 1%-31% acetonitrile, 8 min) to obtain the trifluoroacetic acid salt of compound 22. MS m / z: 447.1 [M+1] + ; 1 H NMR (400 MHz, CD3OD) δ ppm 7.92~7.99 (m, 1 H) 7.54~7.68 (m, 1 H) 7.27 (dd, J=10.16, 5.40 Hz, 1 H) 4.22~4.39 (m, 2 H) 3.42~3.51 (m, 4 H) 3.23~3.31 (m, 4 H) 2.93 (s, 3 H) 2.57 (s, 3 H).

[0309] Example 23 [ka]

[0310] Step 1: Synthesis of intermediate 23a 17 g (100.00 mg, 442.13 μmol) of the compound and 1,2-dibromo-1,1,2,2-tetrachloroethane (316.74 mg, 972.68 μmol) were dissolved in 5 mL of DCM. Tri-n-butylphosphine (178.90 mg, 884.25 μmol) was added at 0°C, and after the addition was complete, the temperature was raised to 25°C and the mixture was stirred for 12 hours. The reaction mixture was filtered to obtain a cake, which was intermediate 23a. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (br s, 1H), 7.33~7.72 (m, 1H), 4.71~4.94 (m, 2H), 2.43 (s, 3H).

[0311] Step 2: Synthesis of Compound 23 Triethylamine (21.00 mg, 207.56 μmol) was added to a solution of intermediate 6d (25.64 mg, hydrochloride) in DMF (2 mL), and the mixture was stirred at 25°C for 30 minutes. Then, intermediate 23a (30 mg, 103.78 μmol) and KI (1.72 mg, 10.38 μmol) were added, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile) to obtain the crude product. Triethylamine (20 μL) was added to the crude product, and then the mixture was separated and purified by preparative plate (elution ratio: DCM:MeOH = 10:1) to obtain compound 23. MS m / z: 444.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.54 (br s, 1H), 8.63 (br d, J=5.00 Hz, 1H), 8.05 (dd, J=9.82, 7.82 Hz, 1H), 7.91 (dd, J=7.69, 1.69 Hz, 1H), 7.46 (d, J=8.88 Hz, 1H), 6.14~6.27 (m, 1H), 3.80 (s, 2H), 3.13~3.26 (m, 3H), 2.79 (d, J=4.88 Hz, 3H), 2.60~2.76 (m, 3H), 2.44 (s, 3H).

[0312] Example 24 [ka]

[0313] Step 1: Synthesis of intermediate 24a 20 g (100.00 mg, 442.13 μmol) of the compound and 1,2-dibromo-1,1,2,2-tetrachloroethane (316.74 mg, 972.68 μmol) were dissolved in 5 mL of DCM. Tri-n-butylphosphine (178.90 mg, 884.25 μmol) was added at 0°C, and after the addition was complete, the temperature was raised to 25°C and the mixture was stirred for 8 hours. The reaction mixture was filtered to obtain a cake, which was intermediate 24a. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.72 (br s, 1H), 7.32 (dd, J=10.54, 5.77 Hz, 1H), 4.76 (s, 2H), 2.44 (s, 3H).

[0314] Step 2: Synthesis of Compound 24 Triethylamine (21.00 mg, 207.56 μmol) was added to a solution of intermediate 6d (25.64 mg, hydrochloride) in DMF (2 mL), and the mixture was stirred at 25°C for 30 minutes. Then, intermediate 24a (30 mg, 103.78 μmol) and KI (1.72 mg, 10.38 μmol) were added, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile) to obtain the crude product. Triethylamine (20 μL) was added to the crude product, and then the mixture was separated and purified by preparative plate (elution ratio: DCM:MeOH = 10:1) to obtain compound 24. MS m / z: 444.1 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (br s, 1H), 8.64 (br d, J=4.63 Hz, 1H), 8.01~8.17 (m, 1H), 7.92 (br d, J=7.38 Hz, 1H), 7.07~7.28 (m, 1H), 6.25 (br s, 1H), 3.75 (s, 2H), 3.18~3.25 (m, 3H), 2.80 (br d, J=4.63 Hz, 3H), 2.65~2.76 (m, 3H), 2.44 (s, 3H).

[0315] Example 25 [ka]

[0316] Step 1: Synthesis of intermediate 25a Compound 1a (6.1 g, 25.63 mmol), methylamine acetate (3.54 g, 28.19 mmol, HCl), and N,N-diisopropylethylamine (9.94 g, 76.90 mmol) were added to DMF (60 mL) and reacted at 25°C for 18 hours. The reaction mixture was poured into 300 mL of water, extracted with ethyl acetate (100 mL x 5), the organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (EA / PE = 0%~10%) to obtain intermediate 25a. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54~7.68 (m, 2H), 6.70 (d, J=7.8 Hz, 1H), 4.20 (d, J=4.2 Hz, 2H), 3.68 (s, 3H).

[0317] Step 2: Synthesis of intermediate 25b Intermediate 25a (1.82 g, 5.93 mmol) and NH4Cl (2.54 g, 47.42 mmol) were added to a mixed solution of MeOH (26 mL) and H2O (0.468 mL). Then, Zn (1.98 g, 30.29 mmol) was added, and the mixture was reacted at 0°C for 2 hours. After filtration, 50 mL of water was added to the filtrate, and it was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with 50 mL of saturated brine. After drying over anhydrous sodium sulfate, the filtrate was filtered, and the mixture was concentrated under reduced pressure to obtain intermediate 25b. MS m / z: 276.9, 278.9 [M+1] + .

[0318] Step 3: Synthesis of intermediate 25c At 0°C, intermediate 25b (1.35 g, 4.87 mmol) was added to a mixture of hydrogen chloride / dioxane (4 M, 15.64 mL), EA (13.5 mL), and MeOH (13.5 mL), and reacted for 2 hours. The reaction mixture was directly concentrated under reduced pressure to obtain intermediate 25c. MS m / z: 245.0, 247.0 [M+1] + .

[0319] Step 4: Synthesis of intermediate 25d At 0°C, DDQ (1.56 g, 6.86 mmol) was added to a solution of intermediate 25c (1.4 g, 5.71 mmol) in DCM (14 mL), and the mixture was heated to 25°C and reacted for 4 hours. The reaction mixture was concentrated under reduced pressure, and 70 mL of saturated sodium bicarbonate solution was slowly added. The mixture was stirred overnight. Extraction was performed with ethyl acetate (3 × 50 mL), the organic phases were combined and washed with 70 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution rate: MeOH / DCM = 0%~5%) to obtain intermediate 25d. MS m / z: 243.0, 245.0 [M+1] + . 1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (br s, 1H), 8.24 (s, 1H), 7.53~7.60 (m, 2H).

[0320] Step 5: Synthesis of intermediate 25e Intermediate 25d (660 mg, 2.72 mmol) was dissolved in DMF (1 mL), and potassium carbonate (563.00 mg, 4.07 mmol), potassium iodide (67.62 mg, 407.35 μmol), and p-methoxybenzyl chloride (510.36 mg, 3.26 mmol) were added. The mixture was stirred at 20°C for 3 hours. Water (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated by flash silica gel column chromatography (PE:EA = 3:1) to obtain intermediate 25e. MS m / z: 362.8, 364.8 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1H), 7.50~7.64 (m, 2H), 7.24 (d, J=4.2 Hz, 2H), 6.85 (d, J=4.2 Hz, 2H), 5.60 (s, 2H), 3.72 (s, 3H).

[0321] Step 6: Synthesis of intermediate 25f At 0°C, p-toluenesulfonylmethyl isocyanide (451.57 mg, 2.31 mmol) was dissolved in THF (10 mL), added to sodium hydride (154.19 mg, 3.85 mmol), and stirred for 10 minutes. Intermediate 25e (700.00 mg, 1.93 mmol) was then added, and the mixture was stirred at 25°C for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash silica gel column chromatography (first PE:EA = 3:1 to 1:1, then DCM:MeOH = 10:1) to obtain intermediate 25f. MS m / z: 402.0, 404.0 [M+1] + , 1 1H NMR (400 MHz, CDCl3) δ ppm 8.44 (s, 1H), 8.13 (s, 1H), 7.40~7.51 (m, 2H),7.22 (d, J=4.2 Hz, 2H), 6.85 (d, J=4.2 Hz, 2H), 5.61 (s, 2H), 3.79 (s, 3H).

[0322] Step 7: Synthesis of 25g of intermediate 1-(tributylstannyl)methanol (191.59 mg, 596.69 μmol) and intermediate 25f (200 mg, 497.24 μmol) were dissolved in 1,4-dioxane (5 mL), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (39.12 mg, 49.72 μmol) was added, and the mixture was stirred at 80°C for 1.5 hours. Next, 1-(tributylstannyl)methanol (31.93 mg, 99.44 μmol) was added, and the mixture was stirred at 80°C for 2 hours, then the temperature was raised to 100°C and the mixture was stirred for 2 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was then purified by flash silica gel column chromatography (elution rate: PE:EA = 1:1 -- DCM:MeOH = 10:1) to obtain 25 g of the intermediate. MS m / z: 354.1 [M+1] + .

[0323] Step 8: Synthesis of intermediate 25h At 15-25°C, 25 g (80 mg, 226.41 μmol) of the intermediate was added to a reaction flask, trifluoroacetic acid (3.07 g, 26.93 mmol, 2.00 mL) was added, and trifluoromethanesulfonic acid (4.52 mmol, 400.00 μL) was added. The mixture was stirred for 2 hours. 5 mL of water was added to the reaction mixture, 5 mL of methanol was added, and potassium carbonate solid was added to adjust the pH to 10. The mixture was then stirred for 1 hour. Dichloromethane (20 mL) was added to the reaction mixture for extraction. The organic phase was combined, washed with water (15 mL x 2), the organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 25h. MS m / z: 234.1 [M+1] + .

[0324] Step 9: Synthesis of intermediate 25i Intermediate 25h (80 mg, 343.06 μmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (245.77 mg, 754.72 μmol) were added to DCM (1.5 mL), and tri-n-butylphosphine (138.81 mg, 686.11 μmol) was added. The mixture was stirred at 20°C for 3 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product, intermediate 25i.

[0325] Step 10: Synthesis of trifluoroacetate of compound 25 Intermediate 25i (30 mg) and compound 9 g (28.97 mg, hydrochloride) were dissolved in DMF (1 mL), Et3N (10.25 mg, 101.32 μmol) and KI (16.82 mg, 101.32 μmol) were added, and the mixture was stirred at 50°C for 2 hours. 5 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative chromatography (elution ratio: DCM:MeOH = 10:1), and further separated by preparative HPLC (column chromatography: Welch Xtimate C18 100 × 40 mm × 3 μm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: 0%~30% acetonitrile) to obtain the trifluoroacetate of compound 25. MS m / z: 454.2 [M+1] + , 1 1H NMR (400 MHz, CD3OD) δ ppm 8.99 (s, 1H), 8.05 (d, J=4.4 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J=4.4 Hz, 1H), 7.58~7.63 (m, 1H), 7.46~7.49 (m, 1H), 4.46 (s, 2H), 3.71~3.75 (m, 4H), 3.40~3.51 (m, 4H), 2.92 (s, 3H).

[0326] Example 26 [ka]

[0327] Step 1: Synthesis of intermediate 26a Methyl 2-pyrrole carboxylate (262.88 mg, 2.10 mmol) and compound 1a (500 mg, 2.10 mmol) were dissolved in DMF (10 mL). Sodium hydride (126.05 mg, 3.15 mmol, purity: 60%) was added in batches, and the mixture was stirred at room temperature (20°C) for 3 hours. The reaction mixture was slowly added dropwise to 20 mL of saturated ammonium chloride solution, and ethyl acetate (2 × 30 mL) was added for extraction. The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash silica gel column chromatography (eluent: PE:EA = 90:10, V / V) to obtain intermediate 26a (ratio: approximately 2:1), a mixture. MS m / z: 342.8, 344.8 [M+1] + .

[0328] Step 2: Synthesis of intermediate 26b Intermediate compound 26a (370 mg), a mixture, was dissolved in dioxane (10 mL). 1-(tributylstannyl)methanol (415.51 mg, 1.29 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (42.42 mg, 53.92 μmol) were added, and the mixture was stirred at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash silica gel column chromatography (gradient elution: PE:EA = 100:0~60:40) to obtain intermediate compound 26b, a mixture. MS m / z: 294.9 [M+1] + .

[0329] Step 3: Synthesis of intermediate 26c Intermediate 26b (185 mg), a mixture, was dissolved in MeOH (3 mL), purged with argon gas, and palladium hydroxide (8.83 mg, 62.87 μmol) was added. The reaction flask was purged with hydrogen gas and stirred at 30°C under 50 psi for 16 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, 2 mL of DMF and 5 drops of triethylamine were added, and the mixture was stirred at 90°C for 16 hours. The DMF was removed with an oil pump to obtain the crude product. A mixed solution of DCM and MeOH (DCM:MeOH = 1:1, 3 mL) was added to the crude product, and the mixture was filtered to obtain a cake, which was intermediate 26c. MS m / z: 232.8 [M+1] + . 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (br s, 1H), 8.18~8.19 (m, 1H), 7.87 (d, J=4.40 Hz 1H), 7.26 (t, J=8.20 Hz, 1H), 7.07~7.08 (m, 1H), 6.70~6.72 (m, 1H), 5.35 (t, J=5.60 Hz, 1H), 4.60 (d, J=2.80 Hz, 2H).

[0330] Step 4: Synthesis of intermediate 26d Intermediate 26c (20 mg, 86.13 μmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (28.05 mg, 86.13 μmol) were dissolved in DCM (0.5 mL), and tri-n-butylphosphine (17.43 mg, 86.13 μmol) was added at 0°C. After the addition was complete, the mixture was stirred at room temperature (20°C) for 16 hours, and then 1,2-dibromo-1,1,2,2-tetrachloroethane (28.05 mg, 86.13 μmol) and tri-n-butylphosphine (17.43 mg, 86.13 μmol) were added, and stirring was continued for 1 hour. The reaction mixture was filtered to obtain a cake, which was intermediate 26d. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.41 (br s, 1H), 8.20~8.21 (m, 1H), 7.85 (d, J=4.40 Hz 1H), 7.36 (t, J=8.20 Hz, 1H), 7.10~7.11 (m, 1H), 6.73~6.75 (m, 1H), 4.79 (s, 2H).

[0331] Step 5: Synthesis of Compound 26 9 g (11.83 mg, hydrochloride) of intermediate was dissolved in DMF (1 mL), triethylamine (17.43 mg, 172.26 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Intermediate 26d (10 mg, 43.06 μmol) and potassium iodide (3.57 mg, 21.53 μmol) were then added, and the mixture was stirred at 50°C for 2 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (DCM:MeOH = 30:1) to obtain compound 26. MS m / z: 453.0 [M+1] + .

[0332] Example 27 [ka]

[0333] Step 1: Synthesis of intermediate 27a Intermediate 15e (61.9 mg, 253.46 μmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (82.54 mg, 253.46 μmol) were dissolved in DCM (2 mL), and tri-n-butylphosphine (51.28 mg, 253.46 μmol) was added at 0°C. After the addition was complete, the mixture was stirred at room temperature (20°C) for 19 hours. The reaction mixture was filtered to obtain a cake, which was intermediate 27a. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (s, 1 H) 9.05~9.13 (m, 1 H) 8.61~8.68 (m, 1 H) 8.41~8.49 (m, 1 H) 7.77 (br d, J=2.01 Hz, 1 H) 7.35~7.50 (m, 1 H) 4.94 (s, 2 H).

[0334] Step 2: Synthesis of Compound 27 Intermediate 6d (21.23 mg, 78.15 μmol, HCl) was dissolved in DMF (2 mL), triethylamine (19.77 mg, 195.36 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, intermediate 27a (30 mg, 97.68 μmol) and potassium iodide (1.62 mg, 9.77 μmol) were added, and the mixture was stirred at 50°C for 2 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted three times with 5 mL of mixed solution (DCM:MeOH = 10:1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was stirred with EA (0.5 mL) for 10 minutes, filtered, and a cake was obtained, which was compound 27. MS m / z: 462.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J=4.82, 1.81 Hz, 1H), 8.65 (br dd, J=8.00, 1.88 Hz, 2H), 8.43 (d, J=8.50 Hz, 1H), 8.05~8.12 (m, 1H), 7.88~7.96 (m, 1H), 7.72 (dd, J=7.88, 4.88 Hz, 1H), 7.39 (br t, J=7.44 Hz, 1H), 6.26 (br s, 1H), 3.80 (s, 2H), 3.21~3.22 (m, 2H), 2.79 (d, J=4.75 Hz, 3H), 2.72~2.76 (m, 4H).

[0335] Example 28 [ka]

[0336] Step 1: Synthesis of Compound 28 Compound 26d (25 mg, 84.72 μmol) was dissolved in DMF (1 mL), triethylamine (34.29 mg, 338.86 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Compound 6d (23 mg, hydrochloride) and potassium iodide (7.03 mg, 42.36 μmol) were then added, and the mixture was stirred at 50°C for 2 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 0.5 mL of ethyl acetate was added to the crude product and the mixture was stirred for 10 minutes. The mixture was then filtered to obtain a cake, which was compound 28. MS m / z: 450.0 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (s, 1 H), 8.64 (br d, J=4.77 Hz, 1 H), 8.20 (s, 1 H), 8.01~8.14 (m, 1 H), 7.83~7.97 (m, 2 H), 7.26 (t, J=7.78 Hz, 1 H), 7.09 (d, J=3.01 Hz, 1 H), 6.72 (t, J=3.26 Hz, 1 H), 6.25 (br s, 1 H), 3.72 (s, 2 H), 3.32 (s, 2 H), 3.13~3.22 (m, 2 H), 2.79 (d, J=4.77 Hz, 3 H), 2.66~2.75 (m, 2 H).

[0337] Example 29 [ka]

[0338] Step 1: Synthesis of intermediate 29a Deuterated methylamine hydrochloride (124.71 mg, 1.77 mmol) was added to H2O (1 mL), then sodium tert-butoxide (84.95 mg, 884.01 μmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. A solution of compound 4a (30 mg, 88.40 μmol) in MeOH (2 mL) was added to the reaction mixture, and the reaction system was heated to 60°C and reacted for 4 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product, which was intermediate 29a. MS m / z: 342.1 [M+1] + .

[0339] Step 2: Synthesis of the hydrochloride salt of intermediate 29b Intermediate 29a (20 mg) was dissolved in MeOH (0.6 mL), and HCl / dioxane (4 M, 0.2 mL) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 29b. MS m / z: 242.2 [M+1] + .

[0340] Step 3: Synthesis of Compound 29 Intermediate 29b (19.22 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (162.80 μmol, 22.66 μL) was added, and the mixture was stirred at 25°C for 30 minutes. Then compound 27a (25 mg, 81.40 μmol) and potassium iodide (1.35 mg, 8.14 μmol) were added, and the temperature was raised to 50°C and stirred for 3 hours. 2 mL of water was added to the reaction mixture, and the mixture was filtered to obtain a cake, which was compound 29. MS m / z: 468.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J=4.63, 1.75 Hz, 1H), 8.65 (dd, J=8.00, 1.75 Hz, 1H), 8.43 (d, J=8.13 Hz, 1H), 8.38 (s, 1H), 7.85 (d, J=7.88 Hz, 1H), 7.72 (dd, J=8.00, 4.50 Hz, 1H), 7.57 (dd, J=10.57, 8.19 Hz, 1H), 7.37 (t, J=7.32 Hz, 1H), 3.75 (s, 2H), 3.15~3.22 (m, 4H), 2.62~2.65 (m, 4H).

[0341] Example 30 [ka]

[0342] Step 1: Synthesis of Compound 30 Intermediate 16i (29.46 mg, hydrochloride) was dissolved in DMF (2 mL), triethylamine (52.72 mg, 520.97 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Intermediate 27a (40 mg, 130.24 μmol) and KI (21.62 mg, 130.24 μmol) were then added, and the mixture was stirred at 50°C for 2 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 3 mL). The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. 0.5 mL of ethyl acetate was added to the crude product and stirred for 10 minutes. The mixture was filtered to obtain a cake, which was then separated and purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to obtain compound 30. MS m / z: 473.0 [M+1] + . 1H NMR (400 MHz, CDCl3) δ ppm 8.95~9.02 (m, 1 H), 8.73~8.79 (m, 1 H), 8.68 (dd, J=8.16, 1.88 Hz, 1 H), 8.46 (br d, J=8.03 Hz, 1 H), 7.77~7.88 (m, 1 H), 7.65~7.75 (m, 1 H), 7.48~7.54 (m, 1 H), 7.34~7.43 (m, 1 H), 6.98 (d, J=8.53 Hz, 1 H), 3.63~3.86 (m, 3 H), 2.97~3.33 (m, 2 H), 2.92 (d, J=5.27 Hz, 3 H), 2.82~2.89 (m, 2 H), 2.03~2.43 (m, 1 H), 1.90~1.94 (m, 1 H), 1.68~1.83 (m, 1 H), 1.33~1.39 (m, 1 H), 1.23~1.31 (m, 2 H).

[0343] Example 31 [ka]

[0344] Step 1: Synthesis of intermediate 31a Deuterated methylamine hydrochloride (167.77 mg, 2.38 mmol) was added to H2O (1 mL), and potassium tert-butoxide (133.44 mg, 1.19 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 1 hour, and a solution of compound 6b (40 mg, 118.92 μmol) in MeOH (2 mL) was added to the reaction mixture. The reaction system was heated to 60°C and reacted for 16 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product, which was intermediate 31a. MS m / z: 339.1 [M+1] + .

[0345] Step 2: Synthesis of the hydrochloride salt of intermediate 31b Intermediate 31a was dissolved in MeOH (1 mL), HCl / dioxane (4 M, 99.74 μL) was added, and the mixture was stirred at room temperature (25°C) for 2 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 31b. MS m / z: 238.9 [M+1] + .

[0346] Step 3: Synthesis of Compound 31 Intermediate 31b (15 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (27.62 mg, 272.99 μmol, 38.00 μL) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, intermediate 27a (20.96 mg, 68.25 μmol) and potassium iodide (5.66 mg, 34.12 μmol) were added, and the mixture was stirred at 50°C for 2 hours. After cooling, 2 mL of water was added to the reaction mixture, a solid precipitated, and the mixture was filtered to obtain a cake, which was compound 31. MS m / z: 465.1 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.89 (br d, J=1.76 Hz, 1 H), 9.02~9.14 (m, 1 H), 8.56~8.70 (m, 2 H), 8.43 (d, J=8.03 Hz, 1 H), 8.04~8.14 (m, 1 H), 7.89~7.96 (m, 1 H), 7.72 (dd, J=8.03, 4.52 Hz, 1 H), 7.39 (t, J=7.53 Hz, 1 H), 6.26 (br s, 1 H), 3.80 (s, 2 H), 3.31 (s, 2 H), 3.18~3.24 (m, 2 H), 2.74 (br t, J = 5.27 Hz, 2 H).

[0347] Example 32 [ka]

[0348] Step 1: Synthesis of intermediate 32a Intermediate 4a (0.2 g, 589.34 μmol) was added to a mixture of THF (5 mL) and H2O (1 mL). While stirring, lithium hydroxide monohydrate (123.65 mg, 2.95 mmol) was added to the reaction mixture, and the reaction system was stirred at 20°C for 4 hours. The reaction mixture was adjusted to pH 3-4 with dilute hydrochloric acid (1 mol / L), extracted with ethyl acetate (5 mL x 2), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure at 45°C to obtain intermediate 32a. MS m / z: 347.9 [M+23] + .

[0349] Step 2: Synthesis of intermediate 32b Under the protection of nitrogen gas, intermediate 32a (0.1 g, 307.38 μmol), 2,2,2-trifluoroethylamine (45.67 mg, 461.06 μmol), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (197.39 mg, 614.75 μmol), and diisopropylethylamine (119.18 mg, 922.13 μmol) were added to DMF (2 mL) and stirred at 40°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified using a preparative plate (PE / EA = 2 / 1) to obtain intermediate 32b. MS m / z: 351.1 [M-56+1] + .

[0350] Step 3: Synthesis of the hydrochloride salt of intermediate 32c Intermediate 32b (57.66 mg, 141.88 μmol) was added to MeOH (2 mL), and while stirring, HCl / dioxane (4 M, 191.54 μL) was added to the reaction mixture. The reaction system was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure at 45°C to obtain the crude product, which was the hydrochloride salt of intermediate 32c. MS m / z: 306.9 [M+1] +

[0351] Step 4: Synthesis of Compound 32 Triethylamine (156.29 μmol, 21.75 μL) was added to DMF (1 mL) of intermediate 32c (26.78 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 27a (30 mg, 78.15 μmol) and potassium iodide (1.30 mg, 7.81 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 60°C to obtain the crude product. The crude product was purified by preparative chromatography (EA: 100%) to obtain compound 32. MS m / z: 555.1 [M+23] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.92~9.04 (m, 1 H), 8.62~8.76 (m, 2 H), 8.44 (br d, J=8.25 Hz, 1 H), 7.93 (d, J=8.63 Hz, 1 H), 7.71 (s, 1 H), 7.45~7.55 (m, 1 H), 7.24~7.35 (m, 1 H), 3.92~4.07 (m, 2 H), 3.68~3.78 (m, 2 H), 3.21 (m, 4 H), 2.66 (m, 4 H).

[0352] Example 33 [ka]

[0353] Step 1: Synthesis of intermediate 33d 10a (3g, 13.89 mmol) was dissolved in toluene (30 mL), then 1-(tert-butoxycarbonyl)piperazine (2.59 g, 13.89 mmol), RuPhos (648.01 mg, 1.39 mmol), Pd2(dba)3 (381.49 mg, 416.61 μmol), and Cs2CO3 (13.57 g, 41.66 mmol) were added, and the mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent:PE:EA = 100:0~90:10~75:25, V / V) to obtain intermediate 33d. MS m / z: 321.9 [M+1]+ .

[0354] Step 2: Synthesis of intermediate 33a Under conditions of 25°C, intermediate 33d (1 g, 3.11 mmol) was taken and added to a methylamine-ethanol (322.13 mg, 3.11 mmol) solution, and the reaction was carried out with stirring at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, dissolved in 10 ml of dichloromethane, washed with 10 ml of water, extracted, separated, and the organic layer was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 33a. MS m / z: 320.9 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.16 (d, J=2.25 Hz, 1H), 8.08 (d, J=8.76 Hz, 1H), 7.85 (br s, 1H), 7.24 (dd, J=2.50, 8.75 Hz, 1H), 3.56~3.69 (m, 4H), 3.30 (br d, J=4.63 Hz, 4H), 3.01 (d, J=5.00 Hz, 3H), 1.49 (s, 9H).

[0355] Step 3: Synthesis of intermediate 33b Compound 33a (0.3 g, 936.37 μmol) was dissolved in DMF (1.5 mL), and N-chlorosuccinimide (137.54 mg, 1.03 mmol) was added at 20°C and the mixture was stirred for 14 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 33b. MS m / z: 355.1,357.1 [M+1] + . 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=4.2 Hz, 1 H), 7.69 (br, s, 1 H), 7.40 (d, J=4.2 Hz, 1 H), 3.63~3.66 (m, 4 H), 3.09~3.15 (m, 4 H), 3.03 (d, J=2.4 Hz, 3 H), 1.51 (s, 9 H).

[0356] Step 4: Synthesis of the hydrochloride salt of intermediate 33c Intermediate 33b (350 mg, 986.39 μmol) was dissolved in MeOH (6 mL), HCl / dioxane (4 M, 6 mL) was added, and the mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated under reduced pressure at 60°C to obtain the hydrochloride salt of intermediate 33c. MS m / z: 255.1,257.1 [M+1] + .

[0357] Step 5: Synthesis of Compound 33 Intermediate 27a (20 mg, 65.12 μmol), intermediate 33c (18.96 mg, hydrochloride), potassium iodide (5.41 mg, 32.56 μmol), and triethylamine (26.36 mg, 260.49 μmol) were sequentially added to DMF (1 mL), and the mixture was heated to 50°C and stirred for 12 hours. Water (3 mL) was added to the reaction mixture, extracted with ethyl acetate (10 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 1.2 mL of methanol was added to the crude product and stirred for 10 minutes, then filtered to obtain a cake, which was compound 33. MS m / z: 481.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (br s, 1 H), 9.08~9.09 (m, 1 H), 8.65 (d, J=2.40 Hz, 2 H), 8.43 (d, J=4.20 Hz, 1 H), 7.93 (d, J=3.92 Hz, 1 H), 7.66~7.74 (m, 2 H), 7.33~7.39 (m, 1 H), 3.77 (s, 2H), 3.05~3.15 (m, 4 H), 2.79 (d, J=2.40 Hz, 3 H), 2.65~2.68 (m, 4 H).

[0358] Example 34 [ka]

[0359] Step 1: Synthesis of intermediate 34a Intermediate 2a (200 mg, 854.62 μmol) and (2S,5R)-1-tert-butoxycarbonyl-2,5-dimethylpiperazine (183.15 mg, 854.62 μmol) were dissolved in toluene (5 mL), and RuPhos (79.76 mg, 170.92 μmol), Cs2CO3 (556.90 mg, 1.71 mmol), and Pd2(dba)3 (78.26 mg, 85.46 μmol) were added sequentially. The mixture was stirred at 100 °C for 16 hours under the protection of nitrogen gas. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 100:0~90:10~75:25, V / V) to obtain intermediate 34a. MS m / z: 368.0 [M+1] + , 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (dd, J=8.03, 1.25 Hz, 1 H), 7.20 (dd, J=10.04, 8.03 Hz, 1 H), 4.38~4.45 (m, 1 H), 4.05 (br d, J=2.26 Hz, 1 H), 3.97 (s, 3 H), 3.74~3.83 (m, 1 H), 3.47~3.52 (m, 2 H), 3.10 (d, J=13.05 Hz, 1 H), 1.51 (s, 9 H), 1.29~1.32 (m, 3 H), 1.12 (d, J=5.27 Hz, 3H).

[0360] Step 2: Synthesis of intermediate 34b Intermediate 34a (187.4 mg, 510.05 μmol) was added to EtOH (2 mL), and methylamine-ethanol solution (792.03 mg, 7.63 mmol, 30%) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was directly concentrated under reduced pressure to obtain intermediate 34b. MS m / z: 367.0 [M+1] + , 1 H NMR (400 MHz, CDCl3) δ ppm 7.99 (dd, J=8.03, 1.26 Hz, 1 H), 7.47~7.54 (m, 1 H), 7.24 (dd, J=10.16, 8.16 Hz, 1 H), 4.39~4.52 (m, 1 H), 3.93~4.02 (m, 1 H), 3.73~3.78 (m, 1 H), 3.50 (dd, J=12.17, 3.89 Hz, 2 H), 2.95~3.02 (m, 4H), 1.51 (s, 9 H), 1.31 (d, J=6.78 Hz, 3 H), 1.09 (d, J=6.53 Hz, 3H).

[0361] Step 3: Synthesis of the hydrochloride salt of intermediate 34c Intermediate 34b (170 mg, 463.94 μmol) was dissolved in MeOH (2 mL), and HCl / dioxane (4 M, 0.62 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 34c. MS m / z: 266.9 [M+1] + .

[0362] Step 4: Synthesis of the trifluoroacetate of compound 34 Intermediate 34c (26.51 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (39.54 mg, 390.73 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, intermediate 27a (30 mg, 97.68 μmol) and potassium iodide (8.11 mg, 48.84 μmol) were added, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered, and the filtrate was separated by preparative HPLC (column chromatography: Xtimate C18 100 × 30 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 14%~44% acetonitrile) to obtain the trifluoroacetate of compound 34. MS m / z: 493.1 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm 9.11 (dd, J=4.52, 1.76 Hz, 1 H), 8.78 (dd, J=8.03, 1.76 Hz, 1 H), 8.69 (d, J=8.53 Hz, 1 H), 8.01 (d, J=7.03 Hz, 1 H), 7.85~7.92 (m, 1 H), 7.76 (dd, J=8.03, 4.52 Hz, 1 H), 7.53~7.56 (m, 1 H), 4.98 (br d, J=16.56 Hz, 2 H), 4.47 (br d, J=14.31 Hz, 1 H), 3.74~3.90 (m, 1H), 3.49~3.57 (m, 2 H), 3.07~3.20 (m, 2 H), 2.95 (s, 3 H), 1.65 (d, J=6.27 Hz, 3 H), 1.02 (d, J=6.02 Hz, 3 H).

[0363] Example 35 [ka]

[0364] Step 1: Synthesis of intermediate 35a (2S,5R)-1-tert-butoxycarbonyl-2,5-dimethylpiperazine (180.00 mg, 839.93 μmol) and intermediate 2a (196.56 mg, 839.93 μmol) were dissolved in toluene (10 mL), and Cs2CO3 (821.00 mg, 2.52 mmol), RuPhos (39.19 mg, 83.99 μmol), and Pd2(dba)3 (38.46 mg, 42.00 μmol) were added sequentially. The mixture was stirred at 100°C for 16 hours under the protection of nitrogen gas. The reaction mixture was filtered while still hot, and the filtrate was concentrated under reduced pressure to obtain the crude product. A mixture of 2 mL of petroleum ether and ethyl acetate (PE / EA=5 / 1) was added to the crude product, and the mixture was stirred at 20°C for 0.5 hours. The mixture was then filtered by suction, and the cake was removed under reduced pressure to obtain intermediate 35a. MS m / z: 368.1 [M+1] + .

[0365] Step 2: Synthesis of intermediate 35b Intermediate 35a (100 mg, 272.17 μmol) was dissolved in EtOH (2 mL), and methylamine-ethanol solution (1.13 g, 10.89 mmol, 30%) was added. The mixture was stirred at room temperature (25°C) for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 35b. MS m / z: 367.1 [M+1] + .

[0366] Step 3: Synthesis of the hydrochloride salt of intermediate 35c Intermediate 35b (100 mg, 272.90 μmol) was dissolved in MeOH (2 mL), and HCl / dioxane (4 M, 0.38 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 35c. MS m / z: 267.0 [M+1] + .

[0367] Step 4: Synthesis of the trifluoroacetate of compound 35 Triethylamine (15.82 mg, 156.29 μmol) was added to DMF (1 mL) of intermediate 35c (23.66 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 27a (30 mg, 78.15 μmol) and KI (1.30 mg, 7.815 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column chromatography: Xtimate C18 100 × 30 mm × 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 14%~44% acetonitrile) to obtain the trifluoroacetate of compound 35. MS m / z: 493.2 [M+1] + 1 H NMR (400 MHz, CD3OD) δ ppm 9.11 (dd, J=4.52, 1.76 Hz, 1 H), 8.77 (dd, J=8.03, 1.76 Hz, 1 H), 8.69 (d, J=7.78 Hz, 1 H), 8.01 (d, J=7.78 Hz, 1 H), 7.86~7.93 (m, 1 H), 7.76 (dd, J=8.03, 4.77 Hz, 1 H), 7.55 (dd, J=8.28, 6.78 Hz, 1 H), 4.91~5.02(m, 2H), 4.50 (br d, J=13.55 Hz, 1 H), 3.75~3.83 (m, 1 H), 3.48~3.58 (m, 2 H), 3.10~3.23 (m, 2 H), 2.94 (s, 3 H), 1.66 (d, J=6.53 Hz, 3 H), 1.01 (d, J=6.02 Hz, 3 H).

[0368] Example 36 [ka]

[0369] Step 1: Synthesis of intermediate 36a (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine (128.37 mg, 640.96 μmol) and intermediate 2a (150 mg, 640.96 μmol) were dissolved in toluene (10 mL). RuPhos (59.82 mg, 128.19 μmol), Cs2CO3 (417.68 mg, 1.28 mmol), and Pd2(dba)3 (58.69 mg, 64.10 μmol) were added sequentially, and the mixture was stirred at 100 °C for 16 hours under the protection of nitrogen gas. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 90:10~75:25, V / V) to obtain intermediate 36a. MS m / z: 354.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ ppm 7.99 (dd, J=8.03, 1.00 Hz, 1 H), 7.26 (dd, J=10.04, 8.28 Hz, 1 H), 4.38 (br d, J=5.02 Hz, 1 H), 4.02 (br s, 1 H), 3.98 (s, 3 H), 3.44~3.57 (m, 2 H), 3.31 (td, J=12.80, 3.26 Hz, 1 H), 3.02 (dd, J=11.92, 3.64 Hz, 1 H), 2.84~2.94 (m, 1 H), 1.51 (s, 9 H), 1.35 (d, J=6.78 Hz, 3 H).

[0370] Step 2: Synthesis of intermediate 36b Intermediate 36a (100 mg, 272.17 μmol) was dissolved in EtOH (2 mL), and methylamine-ethanol solution (0.65 g, 6.29 mmol, 30%) was added. The mixture was stirred at room temperature (25°C) for 16 hours. The reaction mixture was directly concentrated under reduced pressure to obtain intermediate 36b. MS m / z: 353.1 [M+1] + . 1H NMR (400 MHz, CDCl3) δ ppm 7.94~8.06 (m, 1 H), 7.52 (br d, J=4.27 Hz, 1 H), 7.29~7.34 (m, 1 H), 4.39 (br s, 1 H), 4.01 (br d, J=13.80 Hz, 1 H), 3.38~3.49 (m, 2 H), 3.30 (td, J=12.74, 3.39 Hz, 1 H), 3.02 (d, J=5.02 Hz, 3 H), 2.97 (dd, J=11.80, 3.51 Hz, 1 H), 2.81~2.89 (m, 1 H), 1.51 (s, 9 H), 1.36 (d, J = 6.78 Hz, 3 H).

[0371] Step 3: Synthesis of the hydrochloride salt of intermediate 36c Intermediate 36b (51 mg, 428.49 μmol) was dissolved in MeOH (2 mL), and HCl / dioxane (4 M, 0.54 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 36c. MS m / z: 253.0 [M+1] + .

[0372] Step 4: Synthesis of Compound 36 Triethylamine (32.95 mg, 325.61 μmol) was added to 1 mL of DMF containing intermediate 36c (21.18 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 27a (25 mg, 81.40 μmol) and KI (6.76 mg, 40.70 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. 2 mL of water was added to the reaction mixture, and it was extracted with ethyl acetate (3 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 1 mL of methanol was added to the crude product and stirred for 10 minutes. The mixture was filtered to obtain a cake, which was compound 36. MS m / z: 479.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1 H), 9.08 (dd, J=4.64, 1.88 Hz, 1 H), 8.64 (dd, J=8.03, 1.76 Hz, 1 H), 8.34~8.49 (m, 2 H), 7.80~7.89 (m, 1 H), 7.71 (dd, J=8.03, 4.77 Hz, 1 H), 7.56 (dd, J=10.54, 8.28 Hz, 1 H), 7.33~7.44 (m, 1 H), 4.12 (d, J=13.55 Hz, 1 H), 3.50 (d, J=13.80 Hz, 1 H), 3.36~3.43 (m, 1 H), 2.87~2.98 (m, 1 H), 2.74~2.86 (m, 5 H), 2.65~2.73 (m, 1 H) 2.28~2.47 (m, 2 H) 1.22 (d, J=6.02 Hz, 3 H).

[0373] Example 37 [ka]

[0374] Step 1: Synthesis of intermediate 37a (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine (0.13 g, 649.10 μmol) and intermediate 2a (151.90 mg, 649.10 μmol) were dissolved in toluene (10 mL), and Cs2CO3 (634.47 mg, 1.95 mmol), RuPhos (30.29 mg, 64.91 μmol), and Pd2(dba)3 (29.72 mg, 32.46 μmol) were added sequentially. The mixture was stirred at 100°C for 16 hours under the protection of nitrogen gas. The reaction mixture was filtered while still hot, and the filtrate was concentrated under reduced pressure to obtain the crude product. 2 mL of a mixture of PE and EA (PE / EA = 5 / 1) was added to the crude product, and the mixture was stirred at 20°C for 0.5 hours. The mixture was filtered by suction under reduced pressure, and the cake was dried under reduced pressure to obtain intermediate 37a. MS m / z: 376.1 [M+23] + .

[0375] Step 2: Synthesis of intermediate 37b Intermediate 37a (96.18 mg, 272.17 μmol) was dissolved in EtOH (2 mL), and methylamine-ethanol solution (1.13 g, 10.89 mmol, 30%) was added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 37b. MS m / z: 375.1 [M+23] + .

[0376] Step 3: Synthesis of the hydrochloride salt of intermediate 37c Intermediate 37b (100 mg, 283.77 μmol) was dissolved in MeOH (2 mL), and HCl / dioxane (4 M, 0.38 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 37c. MS m / z: 253.0 [M+1] + .

[0377] Step 4: Synthesis of Compound 37 Triethylamine (10.54 mg, 104.19 μmol) was added to DMF (1 mL) of intermediate 37c (15.04 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 27a (20 mg, 52.10 μmol) and KI (864.82 μg, 5.21 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a preparative plate (EA, 100%) to obtain compound 37. MS m / z: 479.1 [M+1] + .

[0378] Example 38 [ka]

[0379] Step 1: Synthesis of intermediate 38b Compound 38a (1 g, 5.70 mmol), methyl 3-amino-2-fluorobenzoate (867.23 mg, 5.13 mmol), and pyridine (2.70 g, 34.18 mmol, 2.76 mL) were added to DCM (10 mL). At 0-5°C, phosphorus oxychloride (960.81 mg, 6.27 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. At 0-5°C, 10 mL of water was added to the reaction mixture, and the mixture was extracted using DCM (10 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 100:0-90:10, V / V) to obtain intermediate 38b. MS m / z: 327.0, 329.0 [M+1] + , 1 H NMR (400 MHz, CDCl3) δ ppm 8.91 (br s, 1H), 8.64~8.72 (m, 1H), 8.45 (d, J=3.00 Hz, 1H), 8.11 (dd, J=7.75, 3.00 Hz, 1H), 7.75~7.80 (m, 1H), 7.29~7.34 (m, 1H), 3.98 (s, 3H).

[0380] Step 2: Synthesis of intermediate 38c Intermediate 38b (1.3g, 3.98 mmol) and potassium carbonate (1.65g, 11.94 mmol) were added to DMF (15 mL), then p-methoxybenzyl chloride (747.85 mg, 4.78 mmol) was added, and the mixture was heated to 90°C and stirred for 2 hours. After filtration, 15 mL of water was added to the filtrate, and extraction was performed with EA (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 100:0~75:25, V / V) to obtain intermediate 38c. MS m / z: 447.1, 449.1 [M+1] + .

[0381] Step 3: Synthesis of intermediate 38d Under the protection of nitrogen gas, intermediate 38c (300 mg, 671.40 μmol), tributylphosphine (135.83 mg, 671.40 μmol), 1,3-bis(diphenylphosphin)propane (110.76 mg, 268.56 μmol), Pd(OAc)2 (60.29 mg, 268.56 μmol), and potassium carbonate (185.58 mg, 1.34 mmol) were added to DMF (8 mL), and the reaction system was reacted at 120 °C under microwave radiation for 10 minutes. The reaction mixture was filtered, the cake was washed with EA (30 mL), and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 100:0 to 90:10, V / V) to obtain intermediate 38d. MS m / z: 411.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (d, J=2.88 Hz, 1H), 8.69 (d, J=8.63 Hz, 1H), 8.51 (dd, J=8.38, 2.88 Hz, 1H), 7.80 (dd, J=8.38, 6.13 Hz, 1H), 7.15 (d, J=8.50 Hz, 2H), 6.87 (d, J=8.76 Hz, 2H), 5.60 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H).

[0382] Step 4: Synthesis of intermediate 38e Intermediate 38d (140 mg, 341.16 μmol) was added to a mixed solution of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL), and the mixture was stirred at 25°C for 1 hour. 4 mL of water was added to the reaction mixture, a solid precipitated, and the mixture was filtered to obtain a cake, which was intermediate 38e. 1 H NMR (400 MHz, DMSO-d6) δ ppm12.23 (br s, 1H), 9.18 (d, J=2.26 Hz, 1H), 8.44~8.46 (m, 2H), 7.70~7.84 (m, 1H), 3.93 (s, 3H).

[0383] Step 5: Synthesis of intermediate 38f Under the protection of nitrogen gas, at 0°C, LiAlH4 (23.54 mg, 620.22 μmol) was added to a solution of intermediate 38e (120 mg, 413.48 μmol) in THF (4 mL), and the mixture was stirred for 1 hour while maintaining the temperature. 24 μL of water and 24 μL of 15% sodium hydroxide solution were slowly added sequentially to the reaction mixture, followed by 72 μL of ice water to quench the reaction system. 2 mL of water was added to the reaction mixture, extracted with EA (3 mL x 2), the organic phases were combined, dried, and concentrated to obtain the crude product. The mixture was stirred with 3 mL of the mixed solution (PE:EA = 1:1) for 10 minutes, filtered, and a cake was obtained, which was intermediate 38f. MS m / z: 263.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br s, 1H), 9.12 (d, J=2.76 Hz, 1H), 8.41 (dd, J=8.66, 2.89 Hz, 1H), 8.37 (d, J=8.03 Hz, 1H), 7.37~7.46 (m, 1H), 5.46 (t, J=5.65 Hz, 1H), 4.68 (d, J=5.27 Hz, 2H).

[0384] Step 6: Synthesis of 38g of intermediate Intermediate 38f (50 mg, 190.69 μmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (136.61 mg, 419.51 μmol) were dissolved in DCM (0.5 mL), and tributylphosphine (77.16 mg, 381.37 μmol, 94.10 μL) was added at 0°C. The mixture was then heated to room temperature (25°C) and stirred for 3 hours. The reaction mixture was filtered to obtain a cake, which was 38 g of intermediate. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (s, 1H), 9.14 (d, J=3.01 Hz, 1H), 8.42 (dd, J=8.53, 3.01 Hz, 1H), 8.36 (d, J=8.28 Hz, 1H), 7.38~7.51 (m, 1H), 4.84 (s, 2H). Step 7: Synthesis of Compound 38 At 25°C, triethylamine (15.56 mg, 153.80 μmol) was added to a solution of 9 g (16.90 mg, hydrochloride) of intermediate in DMF (1 mL), and the mixture was stirred for 30 minutes. Then, 38 g (25 mg, 76.90 μmol) of intermediate and KI (1.28 mg, 7.69 μmol) were added, and the mixture was stirred at 50°C for 3 hours. While stirring, 2 mL of water was added to the reaction mixture, and the mixture was stirred for approximately 10 minutes. The mixture was then filtered to obtain a cake, which was compound 38. MS m / z: 483.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 9.14 (d, J=2.76 Hz, 1H), 8.35~8.43 (m, 3H), 7.81~7.88 (m, 1H), 7.57 (dd, J=10.54, 8.03 Hz, 1H), 7.35~7.41 (m, 1H), 3.74 (s, 2H) 3.15~3.23 (m, 4H), 2.76 (d, J=4.77 Hz, 3H), 2.60~2.65 (m, 4H).

[0385] Example 39 [ka]

[0386] Step 1: Synthesis of intermediate 39a Compound 2a (200 mg, 854.62 μmol) and (R)-4-tert-butoxycarbonyl-2-methylpiperazine (171.16 mg, 854.62 μmol) were dissolved in toluene (5 mL). RuPhos (79.76 mg, 170.92 μmol), Cs2CO3 (556.90 mg, 1.71 mmol), and Pd2(dba)3 (78.26 mg, 85.46 μmol) were added sequentially, and the mixture was stirred at 100 °C for 16 hours under the protection of nitrogen gas. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent:PE:EA = 100:0~90:10~75:25, V / V) to obtain intermediate 39a. MS m / z: 353.9 [M+1] + .

[0387] Step 2: Synthesis of intermediate 39b Intermediate 39a (150 mg, 424.46 μmol) was dissolved in EtOH (2 mL), and methylamine-ethanol solution (659.13 mg, 21.22 mmol) was added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 39b. MS m / z: 353.0 [M+1] + .

[0388] Step 3: Synthesis of the hydrochloride salt of intermediate 39c Intermediate 39b (150 mg, 425.65 μmol) was dissolved in MeOH (3 mL), hydrogen chloride / dioxane (4 M, 3 mL) was added, and the mixture was stirred at room temperature (25°C) for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 39c. MS m / z: 253.1 [M+1] +

[0389] Step 4: Synthesis of the trifluoroacetate of compound 39 Intermediate 27a (25 mg, 81.40 μmol), intermediate 39c (20.54 mg, hydrochloride), KI (6.76 mg, 40.70 μmol), and triethylamine (32.95 mg, 325.61 μmol) were dissolved in DMF (1 mL), heated to 50°C, and stirred for 2 hours. After cooling, 3 mL of water was added, and the mixture was extracted with ethyl acetate (4 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Separation by preparative HPLC (column chromatography: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 3%~33% acetonitrile) yielded the trifluoroacetate of compound 39. MS m / z: 479.2 [M+1] + . 1H NMR (400 MHz, CD3OD) δ ppm 9.08 (dd, J=1.76, 4.77 Hz, 1H), 8.74 (d, J=4.82 Hz, 1 H), 8.64 (d, J=8.53 Hz, 1 H), 7.96 (d, J=8.03 Hz, 1H), 7.73 (dd, J=4.52, 8.03 Hz, 1H), 7.52 (dd, J=6.78, 8.28 Hz, 1H), 7.35 (d, J=8.03 Hz, 1H), 4.54 (s, 2 H), 3.85~4.12 (m, 2 H), 3.32~3.51 (m, 4 H), 3.23~3.28 (m, 1 H), 2.93 (s, 3H), 1.13 (d, J=6.27Hz, 3H).

[0390] Example 40 [ka]

[0391] Step 1: Synthesis of trifluoroacetate of compound 40 Under 25°C conditions, triethylamine (15.56 mg, 153.80 μmol) was added to a solution of intermediate 6d (16.72 mg, hydrochloride) in DMF (1 mL), and the mixture was stirred for 30 minutes. Then, 38 g of intermediate (25 mg, 76.90 μmol) and KI (1.28 mg, 7.69 μmol) were added, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was filtered and separated by preparative HPLC (column chromatography: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 6%~36% acetonitrile) to obtain the trifluoroacetate of compound 40. MS m / z: 480.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br s, 1H), 10.26 (s, 1H), 9.18 (d, J=2.63 Hz, 1H), 8.66 (d, J=5.13 Hz, 1H), 8.42~8.56 (m, 2H), 8.13 (t, J=8.63 Hz, 1H), 7.98 (d, J=7.63 Hz, 1H), 7.45~7.61 (m, 1H), 6.27 (s, 1H), 4.66 (s, 2H), 3.90~4.12 (m, 2H), 3.66~3.83 (m, 1H), 2.80 (d, J=4.75 Hz, 3H), 2.74~2.79 (m, 1H), 2.22~2.32 (m, 2H).

[0392] Example 41 [ka]

[0393] Step 1: Synthesis of intermediate 41b Compound 41a (2 g, 9.90 mmol) and methyl 3-amino-2-fluorobenzoate (867.23 mg, 5.13 mmol) were added to DMF (20 mL), then triethylamine (3.01 g, 29.70 mmol) and HATU (4.52 g, 11.88 mmol) were added, and the mixture was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was separated and purified by silica gel chromatography (eluent: DCM:MeOH = 100:0~99:1, V / V) to obtain intermediate 41b. MS m / z: 352.9, 354.9 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67~10.84 (m, 1H), 8.89 (s, 1H), 8.70 (d, J=5.02 Hz, 1H), 8.06~8.12 (m, 1H), 7.74~7.78 (m, 1H), 7.65 (d, J=4.77 Hz, 1H), 7.38 (t, J=7.91 Hz, 1H), 3.88 (s, 3H).

[0394] Step 2: Synthesis of intermediate 41c Intermediate 41b (1.8g, 5.10 mmol) and potassium carbonate (2.11g, 15.29 mmol) were added to DMF (20 mL), then p-methoxybenzyl chloride (957.90 mg, 6.12 mmol) was added, and the mixture was heated to 90°C and stirred for 3 hours. After filtration, 20 mL of water was added to the filtrate, and extraction was performed with EA (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography (eluent:PE:EA = 2:1, V / V) to obtain intermediate 41c. MS m / z: 473.0, 475.0 [M+1] + .

[0395] Step 3: Synthesis of intermediate 41d Under the protection of nitrogen gas, intermediate 41c (300 mg, 633.86 μmol), tributylphosphine (135.83 mg, 671.40 μmol), 1,3-bis(diphenylphosphin)propane (104.57 mg, 253.54 μmol), Pd(OAc)2 (56.92 mg, 253.54 μmol), and potassium carbonate (175.21 mg, 1.27 mmol) were added to DMF (10 mL), and the reaction system was reacted at 140 °C under microwaves for 10 minutes. The reaction mixture was filtered, 20 mL of water was added to the filtrate, and the mixture was extracted three times with EA (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (eluent:PE:EA = 100:0 to 60:40, V / V) to obtain intermediate 41d. MS m / z: 393.1 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.95 (d, J=5.13 Hz, 1H), 8.66 (d, J=8.50 Hz, 1H), 8.22 (d, J=5.13 Hz, 1H), 7.76 (dd, J=8.38, 6.25 Hz, 1H), 7.13 (d, J=8.50 Hz, 2H), 6.86 (d, J=8.63 Hz, 2H), 5.58 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H).

[0396] Step 4: Synthesis of intermediate 41e Intermediate 41d (250 mg, 637.14 μmol) was added to a mixed solution of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL), and the mixture was stirred at 25°C for 1 hour. 2 mL of water was added to the reaction mixture, extracted with ethyl acetate (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 41e. MS m / z: 273.1 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm12.17 (br s, 1H), 9.95 (s, 1H), 8.93 (d, J=5.13 Hz, 1H), 8.52 (d, J=8.50 Hz, 1H), 8.19 (d, J=5.25 Hz, 1H), 7.72 (dd, J=8.44, 6.69 Hz, 1H), 3.93 (s, 3H).

[0397] Step 5: Synthesis of intermediate 41f Under nitrogen gas protection and at 0°C, LiAlH4 (205.71 μL of 2.5 M tetrahydrofuran solution) was added to intermediate 41e (140 mg, 514.27 μmol) in THF (5 mL) solution, and the mixture was stirred for 1 hour while maintaining this temperature. 30 μL of water and 30 μL of 15% sodium hydroxide solution were slowly added sequentially to the reaction mixture, followed by 90 μL of ice water for quenching. 10 mL of water was added to the reaction mixture, extracted with EA (20 mL x 3), the organic phases were combined, dried, and concentrated to obtain the crude product, which was intermediate 41f. MS m / z: 245.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (br s, 1H), 9.89 (s, 1H), 8.85 (d, J=5.02 Hz, 1H), 8.41 (d, J=8.53 Hz, 1H), 8.14 (d, J=5.02 Hz, 1H), 7.39 (t, J=7.65 Hz, 1H), 5.46 (t, J=5.77 Hz, 1H), 4.68 (d, J=4.77 Hz, 2H).

[0398] Step 6: Synthesis of 41g of intermediate Intermediate 41f (50 mg, 204.73 μmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (146.67 mg, 450.41 μmol) were dissolved in DCM (0.5 mL), tributylphosphine (82.84 mg, 409.47 μmol) was added at 0°C, and the mixture was heated to room temperature (25°C) and stirred for 3 hours. The reaction mixture was filtered to obtain a cake, which was 41 g of intermediate. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.16 (s, 1H), 9.90~9.98 (m, 1H), 8.82~9.06 (m, 1H), 8.38~8.48 (m, 1H), 8.21 (d, J=5.02 Hz, 1H), 7.46 (t, J=7.65 Hz, 1H), 4.94 (s, 2H).

[0399] Step 7: Synthesis of the trifluoroacetate of compound 41 At 25°C, triethylamine (153.80 μmol, 21.41 μL) was added to a solution of 9 g (16.90 mg, hydrochloride) of intermediate in DMF (1 mL), and the mixture was stirred for 30 minutes. Then, 41 g (25 mg, 81.40 μmol) of intermediate and KI (1.35 mg, 8.14 μmol) were added, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered, and separated and purified by preparative liquid chromatography (column chromatography: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile) to obtain the trifluoroacetate of compound 41. MS m / z: 465.2 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm 9.86 (s, 1H), 8.91 (d, J=5.27 Hz, 1H), 8.49 (d, J=8.53 Hz, 1H), 8.33 (d, J=5.27 Hz, 1H), 7.96 (d, J=8.28 Hz, 1H), 7.64 (dd, J=10.29, 8.28 Hz, 1H), 7.56 (dd, J=8.28, 7.03 Hz, 1H), 4.66 (s, 2H), 3.47~3.72 (m, 8H), 2.93 (s, 3H).

[0400] Example 42 [ka]

[0401] Step 1: Synthesis of trifluoroacetate of compound 42 Triethylamine (16.47 mg, 162.80 μmol) was added to a solution of intermediate 6d (17.69 mg, hydrochloride) in DMF (1 mL), and the mixture was stirred at 25°C for 30 minutes. Then, intermediate 41 g (25 mg, 81.40 μmol) and KI (1.35 mg, 8.14 μmol) were added, and the mixture was heated to 50°C and stirred for 2 hours. The reaction mixture was filtered and separated and purified by preparative HPLC (column chromatography: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0%~30% acetonitrile) to obtain the trifluoroacetate of compound 42. MS m / z: 462.1 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 9.86 (s, 1H), 8.91 (d, J=5.27 Hz, 1H), 8.50 (d, J=7.78 Hz, 1H), 8.34 (d, J=5.77 Hz, 1H), 8.08~8.15 (m, 1H), 8.02~8.07 (m, 1H), 7.58 (dd, J=8.28, 7.03 Hz, 1H), 6.31 (s, 1H), 4.74 (s, 2H), 4.11 (s, 2H), 3.58~3.85 (m, 2H), 2.96~3.01 (m, 2H), 2.96 (s, 3H).

[0402] Example 43 [ka]

[0403] Step 1: Synthesis of intermediate 43b Under the protection of nitrogen gas, 43e (800 mg, 3.19 mmol), compound 43a (1.09 g, 3.51 mmol), Pd(dppf)Cl2 (233.70 mg, 319.39 μmol), and potassium acetate (626.91 mg, 6.39 mmol) were added to a mixed solution of H2O (1.6 mL) and THF (8 mL). The mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was filtered, the cake was rinsed with EA (15 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash column chromatography (eluent:PE:EA = 100:0 to 90:10, V / V) to obtain intermediate 43b. MS m / z: 353.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.07 (dd, J=7.78, 1.00 Hz, 1H), 7.64~7.76 (m, 1H), 5.83 (s, 1H), 4.11 (s, 2H), 3.67 (t, J=5.27 Hz, 2H), 2.50 (br s, 2H), 1.52 (s, 9H), 1.26 (s, 3H).

[0404] Step 2: Synthesis of intermediate 43c A methylamine-ethanol solution (9.05 g, 87.42 mmol, 30%) was added to a solution of intermediate 43b (300 mg, 850.31 μmol) in MeOH (1 mL), and the mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 43c. MS m / z: 352.1 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ ppm7.92 (d, J=7.78 Hz, 1H), 7.74 (d, J=7.53 Hz, 1H), 5.75 (s, 1H), 3.98 (s, 2H), 3.53~3.61 (m, 2H), 2.85 (s, 3H), 2.33~2.41 (m, 2H), 1.40 (s, 9H).

[0405] Step 3: Synthesis of the hydrochloride salt of intermediate 43d Hydrogen chloride / dioxane (4M, 1.06 mL) was added to a solution of intermediate 43c (298 mg, 847.01 μmol) in MeOH (0.5 mL), and the mixture was stirred at 25°C for 1 hour. Then, hydrogen chloride / dioxane (4M, 635.26 μL) was added, and the mixture was stirred for another hour. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 43d. MS m / z: 252.1 [M+1] + .

[0406] Step 4: Synthesis of Compound 43 Triethylamine (32.95 mg, 325.61 μmol) was added to a solution of intermediate 43d (37.53 mg, hydrochloride) in DMF (1 mL) and stirred at 25°C for 30 minutes. Next, intermediate 27a (50 mg, 162.80 μmol) and KI (2.70 mg, 16.28 μmol) were added, and the mixture was heated to 50°C and stirred for 2.5 hours. DMF (2 mL) was added to the reaction mixture, followed by the addition of 1 mL of water. A solid precipitated, which was filtered to obtain a cake, which was compound 43. MS m / z: 478.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J=4.57, 1.81 Hz, 1H), 8.65 (dd, J=8.07, 1.81 Hz, 1H), 8.61 (d, J=4.88 Hz, 1H), 8.43 (d, J=8.51 Hz, 1H), 7.88~7.93 (m, 2H), 7.72 (dd, J=8.07, 4.57 Hz, 1H), 7.36~7.43 (m, 1H), 5.86 (s, 1H), 3.82 (s, 2H), 3.67~3.74 (m, 2H), 3.18 (d, J=2.50 Hz, 2H), 2.81 (d, J=4.75 Hz, 3H), 2.45 (d, J=1.63 Hz, 2H).

[0407] Example 44 [ka]

[0408] Step 1: Synthesis of intermediate 44a Intermediate 15d (100 mg, 367.34 μmol) was dissolved in THF (1 mL), lithium aluminum deuteride powder (20.91 mg, 551.00 μmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was added to saturated potassium sodium tartrate solution (5 mL), then extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain intermediate 44a. MS m / z: 246.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1H), 9.08 (dd, J = 1.8, 4.5 Hz, 1H), 8.64 (dd, J = 1.9, 7.9 Hz, 1H), 8.43 (d, J = 7.5 Hz, 1H), 7.71 (dd, J = 4.8, 8.0 Hz, 1H), 7.40 (dd, J = 6.7, 8.2 Hz, 1H), 5.41 (s, 1H).

[0409] Step 2: Synthesis of intermediate 44b Intermediate 44a (56 mg, 227.43 μmol) was dissolved in DCM (1 mL), 1,2-dibromo-1,1,2,2-tetrachloroethane (162.93 mg, 500.34 μmol) was added, and triphenylphosphine (92.02 mg, 454.85 μmol) was added at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure, methanol (2 mL) was added, and the mixture was stirred for 5 minutes. The mixture was filtered to obtain a cake, which was intermediate 44b. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 9.09 (d, J = 4.5 Hz, 1H), 8.71~8.61 (m, 1H), 8.49~8.38 (m, 1H), 7.80~7.69 (m, 1H), 7.51~7.36 (m, 1H).

[0410] Step 3: Synthesis of Compound 44 9 g (31.99 mg, hydrochloride) of intermediate was dissolved in DMF (1 mL), triethylamine (58.92 mg, 582.28 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, intermediate 44b (45 mg, 145.57 μmol) and KI (12.08 mg, 72.78 μmol) were added, and the mixture was stirred at 50°C for 2 hours. Water (1.5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. A solid precipitated, and the mixture was filtered to obtain a cake, which was compound 44. MS m / z: 489.0 [M+23] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J = 1.8, 4.5 Hz, 1H), 8.64 (dd, J = 1.8, 8.0 Hz, 1H), 8.47~8.37 (m, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.72 (dd, J = 4.5, 8.0 Hz, 1H), 7.57 (dd, J = 8.3, 10.5 Hz, 1H), 7.37 (dd, J = 6.7, 8.2 Hz, 1H), 3.17~3.20 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.57~2.65 (m, 4H).

[0411] Example 45 [ka]

[0412] Step 1: Synthesis of Compound 45 Intermediate 33c (37.68 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (65.47 mg, 646.98 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, intermediate 44b (50 mg, 161.74 μmol) and KI (13.42 mg, 80.87 μmol) were added, and the mixture was stirred at 50°C for 1 hour. After cooling, water (1 mL) was added to the reaction mixture and stirred for 10 minutes. A solid precipitated, and the mixture was filtered to obtain a cake, which was compound 45. MS m / z: 483.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J = 1.8, 4.5 Hz, 1H), 8.65 (dd, J = 1.8, 8.0 Hz, 1H), 8.48~8.38 (m, 2H), 7.94 (d, J = 8.3 Hz, 1H), 7.72 (dd, J = 4.5, 8.0 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 6.7, 7.9 Hz, 1H), 3.10~3.15 (m, 4H), 2.79 (d, J = 4.8Hz, 3H), 2.62~2.67 (m, 4H).

[0413] Example 46 [ka]

[0414] Step 1: Synthesis of intermediate 46b Intermediate 46a (2 g, 6.22 mmol) was dissolved in THF (20 mL) and H2O (4 mL), lithium hydroxide monohydrate (1.31 g, 31.12 mmol) was added, and the mixture was stirred at room temperature (25°C) for 2 hours. The reaction mixture was adjusted to pH 3 with dilute hydrochloric acid (1 mol / L), extracted with ethyl acetate (20 mL x 3), washed with 20 mL of saturated saline solution in the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 46b. MS m / z: 307.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 3.0, 8.8 Hz, 1H), 3.50~3.46 (m, 4H), 3.39~3.36 (m, 4H), 1.43 (s, 9H).

[0415] Step 2: Synthesis of intermediate 46c Intermediate 46b (400 mg, 1.30 mmol) and deuterated methylamine hydrochloride (100.98 mg, 1.43 mmol) were dissolved in EA (4 mL), and added to DIEA (336.41 mg, 2.60 mmol) and n-butyl phosphate anhydride (50% ethyl acetate solution) (937.74 mg, 2.60 mmol). The mixture was stirred at 25°C for 3 hours, 937.74 mg of n-butyl phosphate anhydride was added, and the mixture was stirred for another 16 hours. The pH of the reaction mixture was adjusted to 10, 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 46c. MS m / z: 324.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.43~8.37 (m, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 2.8, 8.8 Hz, 1H), 3.52~3.45 (m, 4H), 3.32~3.30 (m, 4H), 1.43 (s, 9H).

[0416] Step 3: Synthesis of intermediate 46d Intermediate 46c (314 mg, 970.92 μmol) was dissolved in DMF (3.5 mL), N-chlorosuccinimide (142.61 mg, 1.07 mmol) was added, and the mixture was stirred at 50°C for 1 hour. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 46d. MS m / z: 358.0 [M+1] + , 380.0 [M+23] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 3.52~3.47 (m, 4H), 3.09~3.01 (m, 4H), 1.43 (s, 9H).

[0417] Step 4: Synthesis of the hydrochloride salt of intermediate 46e Intermediate 46d (355 mg, 992.04 μmol) was dissolved in MeOH (4 mL), hydrogen chloride / dioxane (4 M, 1.34 mL) was added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 46e. MS m / z: 257.9 [M+1] + .

[0418] Step 5: Synthesis of Compound 46 Intermediate 46e (38.32 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (65.90 mg, 651.22 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, KI (13.51 mg, 81.40 μmol) and intermediate 27a (50 mg, 162.80 μmol) were added, and the mixture was stirred at 50°C for 1 hour. After cooling, 2 mL of water was added to the reaction mixture and stirred for 10 minutes. A solid precipitated, and the mixture was filtered to obtain a cake, which was compound 46. MS m / z: 484.0 [M+1] + ,506.0[M+23] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J = 1.8, 4.5 Hz, 1H), 8.64 (dd, J = 1.8, 8.0 Hz, 1H), 8.47~8.38 (m, 2H), 7.94 (d, J = 8.3 Hz, 1H), 7.72 (dd, J = 4.5, 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 6.8, 8.0 Hz, 1H), 3.76 (s, 2H), 3.16~3.12 (m, 4H), 2.69~2.63 (m, 4H).

[0419] Example 47 [ka]

[0420] Step 1: Synthesis of intermediate 47a Deuterated methylamine hydrochloride (399.85 mg, 5.67 mmol) was added to H2O (2 mL), then sodium tert-butoxide (272.39 mg, 2.83 mmol) was added, and the mixture was stirred at 25°C for 1 hour. A solution of intermediate 43b (100 mg, 283.44 μmol) in MeOH (4 mL) was added, and the temperature was raised to 60°C and stirred for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was separated and purified by preparative chromatography (developing agent: PE:EA = 2:1) to obtain intermediate 47a. MS m / z: 355.1, 357.1 [M+1] + .

[0421] Step 2: Synthesis of the hydrochloride salt of intermediate 47b At 25°C, hydrogen chloride / dioxane (4M, 211.36 μL) was added to a solution of intermediate 47a (60 mg, 169.09 μmol) in MeOH (0.5 mL) and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 47b. MS m / z: 255.1, 257.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (br s, 2H), 8.63 (s, 1H), 8.03 (d, J=7.78 Hz, 1H), 7.89 (d, J=7.78 Hz, 1H), 5.93 (br s, 1H), 3.76 (br d, J=1.51 Hz, 2H), 3.30 (br d, J=4.52 Hz, 2H), 2.63 (br d, J=1.51 Hz, 2H).

[0422] Step 3: Synthesis of Compound 47 Triethylamine (32.95 mg, 325.61 μmol) was added to a solution of intermediate 47b (37.93 mg, hydrochloride) in DMF (1.5 mL), and the mixture was stirred at 25°C for 0.5 hours. Then, intermediate 27a (50 mg, 162.80 μmol) and KI (2.70 mg, 16.28 μmol) were added, and the mixture was stirred at 50°C for 2.5 hours. After cooling, 1.5 mL of water was added to the reaction mixture, and a solid precipitated. The mixture was filtered to obtain a cake, which was compound 47. MS m / z: 481.0, 483.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.89 (s, 1H), 9.09 (dd, J=4.50, 1.75 Hz, 1H), 8.65 (dd, J=8.00, 1.75 Hz, 1H), 8.57 (s, 1H), 8.44 (d, J=8.25 Hz, 1H), 7.95~7.99 (m, 1H), 7.88~7.93 (m, 1H), 7.72 (dd, J=8.00, 4.63 Hz, 1H), 7.36~7.43 (m, 1H), 5.87 (s, 1H), 3.82 (s, 2H), 3.19 (d, J=2.13 Hz, 2H), 2.72~2.78 (m, 2H), 2.44~2.47 (m, 2H).

[0423] Example 48 [ka]

[0424] Step 1: Synthesis of intermediate 48a (R)-1-tert-butoxycarbonyl-2-methylpiperazine (0.2 g, 998.62 μmol), 43e (250.13 mg, 998.62 μmol), Cs2CO3 (650.74 mg, 2.00 mmol), RuPhos (93.20 mg, 199.72 μmol), and Pd2(dba)3 (91.44 mg, 99.86 μmol) were added to toluene (4 mL), purged three times with nitrogen gas, and stirred at 100°C for 6 hours. The reaction mixture was filtered under reduced pressure while still hot, and the filtrate was concentrated under reduced pressure at 50°C to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 4 / 1, V / V) to obtain intermediate 48a. MS m / z: 370.0, 372.0 [M+1] + .

[0425] Step 2: Synthesis of intermediate 48b Intermediate 48a (183.15 mg, 495.21 μmol) was added to EtOH (2 mL), and while stirring, methylamine-ethanol solution (2.27 g, 21.93 mmol) was added to the reaction mixture. The reaction system was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure at 45°C to obtain the crude product, intermediate 48b. MS m / z: 312.9, 314.9 [M-56] + .

[0426] Step 3: Synthesis of the hydrochloride salt of intermediate 48c Intermediate 48b (100 mg, 271.11 μmol) was added to MeOH (2 mL), and while stirring, hydrogen chloride / dioxane (4 M, 383.08 μL) was added to the reaction mixture. The reaction system was stirred at 25°C for 2 hours. The reaction system was concentrated under reduced pressure at 45°C to obtain the hydrochloride salt of intermediate 48c. MS m / z: 268.9, 270.9 [M+1] + .

[0427] Step 4: Synthesis of Compound 48 Triethylamine (26.36 mg, 260.49 μmol) was added to 2 mL of DMF containing intermediate 48c (39.75 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 27a (50 mg, 130.24 μmol) and KI (2.16 mg, 13.02 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative chromatography (100% EA) to obtain compound 48. MS m / z: 495.2, 497.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (s, 1 H), 9.08 (dd, J=4.57, 1.69 Hz, 1 H), 8.64 (dd, J=8.00, 1.75 Hz, 1 H), 8.36~8.48 (m, 2 H), 7.94 (d, J=8.13 Hz, 1 H), 7.60~7.76 (m, 2 H), 7.33~7.47 (m, 1 H), 4.12 (d, J=13.38 Hz, 1 H), 3.53 (d, J=13.88 Hz, 1 H), 3.20~3.26 (m, 1 H), 2.85~2.95 (m, 1H), 2.80~2.85 (m, 1 H), 2.79 (d, J=4.75 Hz, 3 H), 2.67~2.77 (m, 2 H), 2.38~2.45 (m, 2 H), 1.24 (d, J=5.50 Hz, 3 H).

[0428] Example 49 [ka]

[0429] Step 1: Synthesis of intermediate 49a Deuterated methylamine hydrochloride (190.72 mg, 2.70 mmol) was added to H2O (1 mL), and sodium tert-butoxide (129.92 mg, 1.35 mmol) was added to the reaction mixture. The mixture was stirred at 25°C for 1 hour. Intermediate 48a (50 mg, 135.19 μmol) was added to MeOH (2 mL) and the reaction system was heated to 60°C and reacted for 4 hours. The mixture was extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 49a. MS m / z: 394.1, 396.1 [M+23] + .

[0430] Step 2: Synthesis of the hydrochloride salt of intermediate 49b Intermediate 49a (50 mg, 134.45 μmol) was added to MeOH (2 mL), and while stirring, hydrogen chloride / dioxane (4 M, 383.08 μL) was added to the reaction mixture. The reaction system was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate 49b. MS m / z: 272.0, 274.0 [M+1] + .

[0431] Step 3: Synthesis of Compound 49 Triethylamine (26.36 mg, 260.49 μmol) was added to 2 mL of DMF containing intermediate 49b (40.14 mg, hydrochloride), and the reaction system was stirred at 20°C for 0.5 hours. Intermediate 27a (50 mg, 130.24 μmol) and KI (2.16 mg, 13.02 μmol) were added to the reaction mixture, and the reaction system was stirred at 50°C for 2 hours. The crude product was concentrated under reduced pressure and purified by preparative chromatography (100% EA) to obtain compound 49. MS m / z: 498.2, 500.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (s, 1 H), 9.08 (dd, J=4.57, 1.69 Hz, 1 H), 8.64 (dd, J=7.94, 1.81 Hz, 1 H), 8.33~8.50 (m, 2 H), 7.94 (d, J=8.25 Hz, 1 H), 7.58~7.78 (m, 2 H), 7.31~7.48 (m, 1 H), 4.12 (d, J=13.38 Hz, 1 H), 3.53 (d, J=13.76 Hz, 1 H), 3.24 (s, 1 H), 2.80~2.93 (m, 2H), 2.70~2.79 (m, 2 H), 2.43 (t, J=9.01 Hz, 2 H), 1.24 (d, J=5.50 Hz, 3 H).

[0432] Example 50 [ka]

[0433] Step 1: Synthesis of Compound 50 Triethylamine (31.12 mg, 307.59 μmol) was added to a solution of intermediate 33c (35.83 mg, hydrochloride) in DMF (1 mL) and stirred at 25°C for 0.5 hours. Then, intermediate 38 g (50 mg, 153.80 μmol) and KI (2.55 mg, 15.38 μmol) were added and stirred at 50°C for 2.5 hours. After cooling, water (1 mL) was added to the reaction mixture, and a solid precipitated. The solid was then filtered directly to obtain a cake, which was compound 50. MS m / z: 499.1, 501.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (br s, 1H), 9.13 (d, J=2.88 Hz, 1H), 8.39~8.46 (m, 2H), 8.36 (d, J=8.25 Hz, 1H), 7.93 (d, J=8.25 Hz, 1H), 7.66 (d, J=8.25 Hz, 1H), 7.38 (dd, J=8.00, 6.75 Hz, 1H), 3.76 (s, 2H), 3.08~3.16 (m, 4H), 2.79 (d, J=4.88 Hz, 3H), 2.63~2.69 (m, 4H).

[0434] Example 51 [ka]

[0435] Step 1: Synthesis of Compound 51 Triethylamine (18.67 mg, 184.55 μmol) was added to a solution of intermediate 29b (23.07 mg, hydrochloride) in DMF (1 mL), and the mixture was stirred at 25°C for 0.5 hours. Then, 38 g of intermediate (30 mg, 92.28 μmol) and KI (1.53 mg, 9.23 μmol) were added, and the mixture was stirred at 50°C for 2.5 hours. After cooling to room temperature, 1 mL of water was added to the reaction mixture, and a solid precipitated. The mixture was filtered to obtain a cake, which was compound 51. MS m / z: 486.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 9.13 (d, J=3.00 Hz, 1H), 8.42 (dd, J=8.57, 2.94 Hz, 1H), 8.34~8.39 (m, 2H), 7.84 (d, J=7.50 Hz, 1H), 7.56 (dd, J=10.57, 8.19 Hz, 1H), 7.34~7.41 (m, 1H), 3.74 (s, 2H), 3.15~3.22 (m, 4H), 2.59~2.65 (m, 4H).

[0436] Example 52 [ka]

[0437] Step 1: Synthesis of Compound 52 Intermediate 46e (21.72 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (37.35 mg, 369.11 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, KI (7.66 mg, 46.14 μmol) and intermediate 38e (30 mg, 92.28 μmol) were added, and the mixture was stirred at 50°C for 2 hours. After cooling to room temperature, 1 mL of water was added to the reaction mixture, and a solid precipitated. The mixture was filtered to obtain a cake, which was compound 52. MS m / z: 502.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 9.14 (d, J = 3.0 Hz, 1H), 8.44~8.40 (m, 2H), 8.37 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 3.76 (s, 2H), 3.12 (m, 4H), 2.69~2.62 (m, 4H).

[0438] Example 53 [ka]

[0439] Step 1: Synthesis of intermediate 53a Intermediate 38e (150 mg, 516.85 μmol) was dissolved in THF (2 mL), and lithium aluminum deuteride powder (29.42 mg, 775.27 μmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. 30 μL of water and 30 μL of 15% sodium hydroxide solution were slowly added sequentially to the reaction mixture, and the reaction system was quenched with 90 μL of ice water. Water (5 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C to obtain intermediate 53a. MS m / z: 265.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (d, J = 2.8 Hz, 1H), 8.34~8.41 (m,2H), 7.36 (t, J =8.0 Hz, 1H), 5.38 (s, 1H).

[0440] Step 2: Synthesis of intermediate 53b Intermediate 53a (130 mg, 492.01 μmol) was dissolved in DCM (3 mL), 1,2-dibromo-1,1,2,2-tetrachloroethane (352.48 mg, 1.08 mmol) was added, and tributylphosphine (199.09 mg, 984.01 μmol) was added at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure, methanol (5 mL) was added, and the mixture was stirred for 5 minutes. The mixture was filtered to obtain a cake, which was intermediate 53b. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.16 (s, 1H), 9.13 (d, J = 2.8 Hz, 1H), 8.41~8.43 (m, 1H), 8.34~8.37 (m, 1H), 7.44 (t, J =8.0 Hz, 1H).

[0441] Step 3: Synthesis of Compound 53 9 g (22.68 mg, hydrochloride) of intermediate was dissolved in 1 mL of DMF, and triethylamine (18.56 mg, 183.42 μmol) was added. The mixture was stirred at 25°C for 0.5 hours, then intermediate 53b (30 mg, 91.71 μmol) and KI (1.52 mg, 9.17 μmol) were added, and the mixture was stirred at 50°C for 2 hours. 1 mL of water was added to the reaction mixture and stirred for 10 minutes. A solid precipitated, which was then filtered to obtain a cake, which was compound 53. MS m / z: 485.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 9.14 (d, J=3.01 Hz, 1H), 8.39~8.45 (m, 2H), 8.37 (d, J=8.03 Hz, 1H), 7.84 (d, J=7.28 Hz, 1H), 7.56 (dd, J=10.54, 8.28 Hz, 1H), 7.38 (t, J=7.15 Hz, 1H), 3.14~3.24 (m, 4H), 2.76 (d, J=4.77 Hz, 3H), 2.60~2.66 (m, 4H).

[0442] Example 54 [ka]

[0443] Step 1: Synthesis of Compound 54 Intermediate 29b (23.87 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (43.49 mg, 429.80 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, KI (8.92 mg, 53.73 μmol) and intermediate 44b (33.22 mg, 107.45 μmol) were added, and the mixture was stirred at 50°C for 1 hour. 1 mL of water was added to the reaction mixture, a solid precipitated, and the mixture was filtered to obtain a cake, which was compound 54. MS m / z: 470.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 9.09 (dd, J = 1.8, 4.5 Hz, 1H), 8.64 (dd, J = 1.6, 7.9 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 4.5, 8.0 Hz, 1H), 7.57 (dd, J = 8.2, 10.7 Hz, 1H), 7.39~7.34 (m, 1H), 3.17~3.21 (m, 4H), 2.59~2.65 (m, 4H).

[0444] Example 55 [ka]

[0445] Step 1: Synthesis of Compound 55 Intermediate 29b (25 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (40.48 mg, 400.05 μmol) was added, and the mixture was stirred at 25°C for 0.5 hours. Then, KI (8.30 mg, 50.01 μmol) and intermediate 53b (32.72 mg, 100.01 μmol) were added, and the mixture was stirred at 50°C for 1 hour. After cooling, 1 mL of water was added to the reaction mixture, a solid precipitated, and the mixture was filtered to obtain a cake, which was compound 55. MS m / z: 488.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 9.14 (d, J = 2.8 Hz, 1H), 8.42 (dd, J = 3.0, 8.5 Hz, 1H), 8.39~8.34 (m, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.0, 10.5 Hz, 1H), 7.38 (dd, J = 6.5, 8.3 Hz, 1H), 3.15~3.19 (m, 4H), 2.56~2.64 (m, 4H).

[0446] [Biological test data] Experimental Example 1: Measurement of compound-to-PARP1 binding activity using fluorescence polarization method

[0447] Experimental method: Fluorescence polarization experiments were performed in 96-well black-wall plates (Greiner), with reaction buffer consisting of 50 mM Tris, pH 8, 0.001% Triton X100, 10 mM MgCl2, and 150 mM NaCl. Both the fluorescent probe and the His-Avi-tagged PARP1 protein were prepared by Shanghai WuXi AppTec. 8 nM PARP1, 5 nM fluorescent probe, and the compound were added to 100 μL of the reaction system. Compound concentrations followed the starting concentrations and dilution gradients in Table 1; for example, compound 1 started at 100 nM and was diluted 3-fold. The cells were incubated at room temperature in the dark for 4 hours, and data were read using Envision. The obtained fluorescence polarization values ​​and compound concentrations were non-linearly fitted using Graphpad 8.0 software for IC50. 50 The value was obtained.

[0448] Experimental results: [Table 1]

[0449] Conclusion: The compounds of the present invention exhibited excellent binding activity to PARP1.

[0450] Experimental Example 2: Measurement of the binding activity of a compound to PARP2 using fluorescence polarization.

[0451] Experimental method: Fluorescence polarization experiments were performed in 96-well black-wall plates (Greiner), with reaction buffer consisting of 50 mM Tris, pH 8, 0.001% Triton X100, 10 mM MgCl2, and 150 mM NaCl. Both the fluorescent probe and the His-Avi-tagged PARP2 protein were prepared by Shanghai WuXi AppTec. 3 nM PARP2, 5 nM fluorescent probe, and the compound were added to 100 μL of the reaction system. Compound concentrations were defined as the starting concentration and dilution gradient, as shown in Table 2. The cells were incubated at room temperature in the dark for 4 hours, and data were read using Envision. The obtained fluorescence polarization values ​​and compound concentrations were non-linearly fitted using Graphpad 8.0 software to obtain IC50. 50 The value was obtained.

[0452] Experimental results: [Table 2]

[0453] Conclusion: The compounds of the present invention exhibited weaker binding activity to PARP2.

[0454] Experimental Example 3: Antiproliferative experiment of compounds against MDA-MB-436 cells (BRCA1 mutation)

[0455] Experimental method: MDA-MB-436 cells (BRCA1 mutant) were seeded in a 96-well plate with a black (clear bottom) surface. Each well contained 135 μL of cell suspension, with 3500 MDA-MB-436 (BRCA1 mutant) cells. The cell plate was placed in a carbon dioxide incubator and cultured overnight. A 400-fold stock solution of the test compound was prepared, and the test compound was diluted 5-fold to the 9th concentration using a multichannel pipette, i.e., from 4 mM to 104 nM, to set up two replication well experiments. 78 μL of medium was added to the center plate, then 2 μL of the gradient-diluted compound per well was transferred to the center plate according to the corresponding position, 2 μL of DMSO was added to the solvent control and blank control, and after homogeneous mixing, the mixture was transferred to the cell plate at 15 μL / well. The concentration range of the compound transferred to the cell plate was 10 μM to 0.26 nM, and the final DMSO concentration was 0.25%. Cell plates were cultured in a carbon dioxide incubator for 7 days. The cell plates were removed and allowed to equilibrate to room temperature for 30 minutes. 75 μL / well of cell viability chemiluminescence detection reagent was added, and the culture plates were shaken on an orbital shaker for 3 minutes to induce cell lysis. The cells were then cultured at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence signal was detected using a 2104 EnVision plate reader. The inhibition rate (IR) of the test compound was calculated using the following formula. IR(%) = (1 - (RLU compound - RLU blank control) / (RLU solvent control - RLU blank control)) × 100%. The inhibition rates of compounds at various concentrations were calculated using Excel, and inhibition curves were plotted and relevant parameters calculated using GraphPad Prism software.

[0456] Experimental results: As shown in Table 3. [Table 3]

[0457] Experimental results: The compound of the present invention exhibited excellent growth inhibitory effects against MDA-MB-436 cells (BRCA1 mutation).

[0458] Experimental Example 4: Experiment on inhibiting the proliferation of DLD1 (BRCA2 KO) cells with a compound.

[0459] Experimental method: DLD1(BRCA2 KO) cells were seeded in a white 96-well plate. Each well contained 80 μL of cell suspension, with 1000 DLD1(BRCA2 KO) cells. The cell plate was incubated overnight in a carbon dioxide incubator. The test compound was diluted 5-fold to the 8th concentration using a multichannel pipette, i.e., from 2 mM to 0.0256 μM, and two replication well experiments were set up. 78 μL of medium was added to the center plate, and then 2 μL of the gradient-diluted compound per well was transferred to the center plate according to the corresponding position, mixed uniformly, and then transferred to the cell plate at 20 μL / well. The concentration range of the compound transferred to the cell plate was 10 μM to 0.128 nM. The cell plate was incubated in a carbon dioxide incubator for 7 days. Another cell plate was prepared, and the signal value on the day of drug addition was read as the maximum value (Max value in the equation below) and used for data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of this cell plate, and the cells were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The data was read using a multi-label analyzer. After the cell plate with the compound added had finished culturing, 25 μL / well of cell viability chemiluminescence detection reagent was added to the cell plate, and the cells were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The data was read using a multi-label analyzer. The raw data was converted to inhibition rate using the equation (Sample-Min) / (Max-Min)×100%, and IC was calculated. 50 The values ​​were obtained by curve fitting using four parameters (acquired in GraphPad Prism's "log(inhibitor) vs. response--Variable slope" mode).

[0460] Experimental results: As shown in Table 4. [Table 4]

[0461] Experimental conclusion: The compounds of the present invention exhibited superior antiproliferative inhibitory effects against DLD1 (BRCA2 KO) cells.

[0462] Experimental Example 5: Evaluation of pharmacokinetics and brain penetration of the compound of the present invention in mice.

[0463] Experimental method: The mice used for compound 16 trifluoroacetate were BALB / C female mice, and the mice used for compound 15 trifluoroacetate were CD-1 male mice. A clear solution of 0.4 mg / mL of the test compound dissolved in 10% 2-hydroxypropyl-β-cyclodextrin and 90% water was injected into the bodies of mice (overnight fasted, 7-9 weeks old) via the tail vein, with a dose of 2 mg / kg. A clear solution of 1 mg / mL of the test compound dissolved in 0.5% methylcellulose and water was administered intragastricly to mice (overnight fasted, 7-9 weeks old) at a dose of 10 mg / kg. After administering the drug to two groups of animals, approximately 30 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours, and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours. The blood was placed in anticoagulant tubes containing EDTA-K2, and the plasma was centrifuged. Compound 15 trifluoroacetate was administered intravenously to one group (IV, 2 mg / kg) (blood collected according to the above times), orally to the other group (PO, 10 mg / kg) (blood collected according to the above times), and further oral administration (PO, 10 mg / kg) was set for the other group. Homogenates of plasma and brain tissue were collected 2 hours later, and blood drug concentrations were measured by LC-MS / MS. TM Relevant pharmacokinetic parameters were calculated using the non-compartmental model linear log-trapezoid method with pharmacokinetic software version 6.3 (Pharsight, Mountain View, CA).

[0464] Experimental results: The pharmacokinetic data for mice are shown in Table 5. The brain penetration data for mice are shown in Table 6. [Table 5] Note: "-" indicates that the parameter cannot be calculated. C0 represents the starting concentration. max This represents the peak concentration. max This represents the peak time. 1 / 2 Vd represents the disappearance half-life. ss represents the apparent volume distribution in the steady state. Cl represents the total clearance. T last AUC represents the time point at which the last quantifiable test drug concentration was reached. 0-last This represents the area under the plasma concentration-time curve from 0 hours to the last quantifiable time point.

[0465] [Table 6]

[0466] Experimental conclusion: The compound of the present invention exhibits excellent in vivo metabolic stability and excellent oral absorption drug exposure, resulting in excellent brain tissue drug concentration and a high cerebral blood ratio upon oral administration.

[0467] Experimental Example 6: Evaluation of the permeability of the compound of the present invention

[0468] Cell line: In this experiment, the MDR1-MDCK II cell line, approved by the Piet Borst Laboratory at the Netherlands Cancer Institute, was used as an in vitro model for permeability evaluation, with a sample size of 2.3 × 10⁶. 5 cells / cm 2 The cells were seeded at a density in Transwell 96-well cell plates, cultured in a carbon dioxide incubator for 4-7 days, and then used for transport experiments.

[0469] Experimental conditions: Test sample concentration: 2.00 μM Test direction and number of repeat samples: Bidirectional AB and BA, 2 repeats Transport buffer (TB): HBSS solution containing 10 mM HEPES (pH 7.40 ± 0.05) Culture conditions: 37±1℃, 5% CO2, culture for 150 minutes. Control compounds: Nadolol and metoprolol were used as low-permeability and high-permeability control compounds, respectively, and digoxin was used as a substrate for P-glycoprotein. The administered concentrations of nadolol and metoprolol were 2.00 μM, and the administered concentration of digoxin was 10.0 μM.

[0470] Integrity testing of monolayer cell membranes: After the transport experiment, the integrity of the MDR1-MDCK II cell layer was detected using the Lucifer Yellow Rejection Assay. The remaining solution in the upper and lower wells was removed, and 75 μL of TB containing 100 μM Lucifer Yellow was added to the upper well, and 250 μL of TB was added to the lower well. The cell plates were incubated in a cell incubator at 37 ± 1°C, 5% CO2, and saturated humidity for 30 minutes. Then, 20 μL of sample was taken from the upper well and mixed with 60 μL of TB, and 80 μL of sample was taken from the lower well. The relative fluorescence intensity (RFU) in the 425 / 528 nm (excitation / emission) spectrum was detected using a microplate reader.

[0471] Analysis of the sample: In this experiment, sample analysis of the test compound and control compounds, nadolol, metoprolol, and digoxin, was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Retention times of the analytes and internal standards, chromatogram acquisition, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, MA, USA). Sample analysis was semi-quantitatively measured by the peak area of ​​the analyte and the internal standard.

[0472] Data analysis:

number

[0473] The transmittance of Lucifer Yellow (%Lucifer Yellow) is calculated using the following formula.

number

[0474] Experimental results: The results of the permeability test of the compound of the present invention against the MDR1-MDCKII cell line are shown in Table 7. [Table 7] Note: Low permeability: P app ≤ 1.0 (×10 -6 cm / s), medium permeability: 1.0 <P app <5.5 (x10 -6 cm / s), high transparency: P app ≥ 5.5 (×10 -6 (cm / s).

[0475] Experimental conclusion: The compounds of the present invention showed excellent membrane permeability in cell membrane permeability studies.

[0476] Experimental Example 7: Evaluation of pharmacokinetics and brain permeability of the compound of the present invention in rats.

[0477] Experimental method: A clear solution of 0.2 mg / mL of the test compound dissolved in 10% 2-hydroxypropyl-β-cyclodextrin and 90% water was injected into the tail vein of male SD rats (fasted overnight, 200-230 g), with a dose of 1 mg / kg. A solution of 0.5 mg / mL of the test compound dissolved in 10% 2-hydroxypropyl-β-cyclodextrin and 90% water was administered intragastricly to male SD rats (fasted overnight, 200-230 g), with a dose of 5 mg / kg. After administration to both groups of animals, approximately 30 μL of blood was collected from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours, and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours. The blood was placed in an anticoagulant tube containing EDTA-K2, and the plasma was centrifuged. One group received intravenous administration of compound 15 trifluoroacetate (IV, 1 mg / kg) (blood samples were collected according to the above time), and the other group received oral administration (PO, 5 mg / kg) (blood samples were collected according to the above time). Furthermore, two hours after oral administration (PO, 5 mg / kg) in the first group, plasma and brain tissue homogenates were collected, and blood drug concentrations were measured by LC-MS / MS. TM Relevant pharmacokinetic parameters were calculated using the non-compartmental model linear log-trapezoid method with pharmacokinetic software version 6.3 (Pharsight, Mountain View, CA).

[0478] Experimental results: The pharmacokinetic data for rats are shown in Table 8. The brain penetration data for rats are shown in Table 9. [Table 8] Note: "-" indicates that the parameter cannot be calculated. C0 represents the starting concentration.max This represents the peak concentration. max This represents the peak time. 1 / 2 Vd represents the disappearance half-life. ss represents the apparent volume distribution in the steady state. Cl represents the total clearance. T last AUC represents the time point at which the last quantifiable test drug concentration was reached. 0-last This represents the area under the plasma concentration-time curve from 0 hours to the last quantifiable time point.

[0479] [Table 9]

[0480] Experimental conclusion: The compound of the present invention exhibits excellent in vivo metabolic stability and excellent oral absorption drug exposure, resulting in excellent brain tissue drug concentration and a high cerebral blood ratio upon oral administration.

[0481] Experimental Example 8: In vitro liver microsome stability of the compound of the present invention

[0482] Experimental Objective: To investigate the in vitro metabolic stability of the compound of the present invention in humans through the metabolic stability of human liver microsomes.

[0483] Experimental conditions: Under 37°C conditions, 1 μM of each compound was cultured in human liver microsomes with an NADPH regeneration system for a predetermined time of up to 60 minutes. The concentration of the compounds in the resulting samples was measured using LC-MS / MS.

[0484] Experimental Procedure: 96-well culture plates were named T0, T5, T15, T30, T45, T60, Blank60, and NCF60, respectively. The corresponding incubation times for the culture plates were 0, 5, 15, 30, 45, and 60 minutes, respectively. Blank60 plates contained neither the test compound nor the control compound, and samples were taken after 60 minutes of incubation. NCF60 plates were incubated for 60 minutes in potassium phosphate buffer instead of NADPH regeneration system solution. All samples at all time points were single-well samples. 5 μL of the test sample or control working solution and 100 μL of the microsomal working solution (liver microsomal protein concentration: 0.5 mg / mL) were added to T0, T5, T15, T30, T45, T60, and NCF60 plates, respectively. Only the microsomal working solution was added to the Blank60 plate, and the culture plates Blank60, T5, T15, T30, T45, and T60 (excluding T0 and NCF60) were placed in a 37°C water bath and pre-cultured for approximately 10 minutes. First, 180 μL of stop solution (an acetonitrile:methanol (95:5, V / V) solution containing 100 ng / mL of tolbutamide) was added to the sample in the T0 plate, followed by the working solution of the NADPH regeneration system. 50 μL of potassium phosphate buffer was added to each well of an NCF60 plate, and the cells were incubated for 60 minutes. After the preliminary culture of Blank60, T5, T15, T30, T45, and T60 culture plates was completed, 44 μL of NADPH regeneration system working solution was added to each sample well to initiate the reaction. Consequently, in the sample wells containing the working solution of the test or control sample, the final concentration of the reaction system was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively. After incubation for appropriate times (5, 15, 30, 45, and 60 minutes), 180 μL of stop solution was added to each of the test sample wells and countermeasure sample wells in Blank60, T5, T15, T30, T45, T60, and NCF60 plates, respectively, to stop the reaction. All sample plates were shaken and centrifuged for 10 minutes. 80 μL of the supernatant from each sample was taken and diluted in 240 μL of acetonitrile:water (1:9, V / V) solution containing 0.1% formic acid for LC-MS / MS analysis.

[0485] By calculating the percentage of the compound remaining at each corresponding time point, the half-life T of the compound in human liver microsomal metabolism can be determined. 1 / 2 and clearance ratio CL int(liver) I obtained it.

number

[0486] Experimental results: As shown in Table 10. [Table 10] NA: Not detected.

[0487] Conclusion: The compounds of the present invention showed excellent stability against human liver microsomes and mouse liver microsomes in vitro.

[0488] Experimental Example 9: In vivo pharmacodynamic studies of the compound of the present invention in a BALB / c nude mouse model of human breast cancer MDA-MB-436 cell subcutaneous xenograft tumor.

[0489] Experimental objective: The purpose is to study the in vivo tumor growth inhibitory effect of the compounds of the present invention on a human breast cancer MDA-MB-436 xenograft nude mouse model.

[0490] Experimental method: 1) Cell culture: Standard cell culture was performed in MEM medium containing 5% CO2, 37°C, and 10% fetal bovine serum. The cells were digested and subcultured with 0.25% trypsin, and subcultured 2-3 times per week at a subculture ratio of 1:3 to 1:6 depending on cell proliferation.

[0491] 2) Manufacturing of animal models Animals: Female Balb / c nude mouse, 6-8 weeks old. Logarithmic growth phase MDA-MB-436 cells were harvested, counted, and then resuspended in 50% Matrigel containing 50% serum-free MEM medium to a cell concentration of 5.0 × 10⁶. 7The concentration was adjusted to cells / mL. After uniformly dispersing the cells using a pipette, they were placed in a 50 mL centrifuge tube, which was then placed in an icebox. The cell suspension was aspirated with a 1 mL syringe and subcutaneously injected into the axilla of the right forelimb of nude mice, with each animal receiving 200 μL (1.1 × 10⁶). 7 A MDA-MB-436 nude mouse transplant tumor model was constructed by inoculating with cells (animals). After inoculation, the condition of the animals and tumor growth were observed regularly, the tumor diameter was measured using electronic calipers, and the tumor volume was calculated by directly entering the data into an Excel spreadsheet. Tumor volume was 100-200 mm². 3 When the group size was reached, animals in good health with similar tumor volumes were selected and randomly divided into groups (n=6) according to tumor volume, while simultaneously ensuring that the average body weight of each group was as similar as possible. The day of group division was designated as day 1 of the experiment (D1), and after the start of the experiment, the diameter of the tumor was measured twice a week to calculate the tumor volume, and the body weight of the animals was measured and recorded at the same time.

[0492] The formula for calculating tumor volume (TV) is as follows: TV (mm 3 ) = a × w 2 / 2, Here, 'a' represents the longest diameter (mm) of the tumor, and 'w' represents the shortest diameter (mm) of the tumor.

[0493] 3) Dosage: 1.0 mg / kg, Method of administration: Intragastric administration (oral), once daily (QD).

[0494] 4) Recording data Formula for calculating relative tumor volume (RTV): RTV = TVt / TVinitial, Here, TVinitial is the tumor volume measured at the time of group administration, and TVt is the tumor volume measured at each time point during the administration period.

[0495] Formula for calculating relative tumor growth rate (%T / C): %T / C = 100% × (RTVT / RTVC), Here, RTVT represents the RTV of the treatment group, and RTVC represents the RTV of the solvent control group.

[0496] Formula for calculating tumor growth inhibition rate (TGI): TGI=100%×[1-(TVt(T)-TVinitial(T)) / (TVt(C)-TVinitial(C))], Here, TVt(T) represents the tumor volume measured each time in the treatment group. TVinitial(T) represents the tumor volume of the treatment group at the time of group administration. TVt(C) represents the tumor volume measured each time in the solvent group. TVinitial(C) represents the tumor volume of the solvent group at the time of group administration.

[0497] Experimental results: The tumor growth volume is shown in Figure 1. The change in mouse body weight during the administration period is shown in Figure 2. The tumor growth inhibition rate and relative tumor growth rate are shown in Table 11. [Table 11] 1 The comparison between the two groups was analyzed using a t-test, where p<0.05 is considered statistically significant, and * represents p<0.05, ** represents p<0.01, *** represents p<0.001, and **** represents p<0.0001.

[0498] Experimental conclusion: The compound of the present invention showed significant antitumor activity.

Claims

1. A compound represented by formula (XII-1) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, Ring A is a six-membered heteroaryl, X is O, 【Chemistry 2】 It is selected from a single bond or a double bond. T2 is selected from C and N, T3 and T4 are independently selected from N and CR10, R2 is H, R3 is H, R 9 does not exist or is H. R4 is a halogen, R 5 is H, R6 and R7 are each independently H, R8 is a C1-3 alkyl group, and each of the C1-3 alkyl groups is independently and optionally substituted with one, two, or three R groups. R 10 is H, R13 and R14 are each independently selected from H and C1-3 alkyl groups. R15 and R16 are independently selected from H and D, respectively. Each R c is independently selected from H and halogen, Each R is independently D, n is selected from 0, 1, or 3. The aforementioned halogens represent F, Cl, Br, and I atoms. In the aforementioned six-membered heteroaryl aryl, "hetero" represents a single -N- heteroatom.

2. A compound represented by formula (XII) or a pharmaceutically acceptable salt thereof. 【Transformation 3】 (however, X is O, Structural unit 【Chemistry 4】 teeth, 【Transformation 5】 And, L is a single bond, and the ring C is 【Transformation 6】 And, 【Transformation 7】 It is a single bond, T ２ N is, T ３ and T ４ These are N and CR, respectively, independently １０ Selected from, R １ C １－３ It is alkyl, R ３ H is, R ９ H is, R ５ is H, R ６ and R ７ These are each independently selected from H and halogen, R ８ C １－３ It is alkyl, R １０ H is, R １３ and R １４ Each of these is independently H, R １５ and R １６ Each of these is independently H, R ２ and R ４ It forms a ring, a structural unit 【Transformation 8】 but 【Chemistry 9】 Let it be selected from Each R ａ Each of these is independently H, The aforementioned halogens represent F, Cl, Br, and I atoms.

3. (1) Each R ｃ The conditions under which each is independently selected from H and F, (2) Conditions under which R4 is selected from F and Cl, (3) Caution ８ ga CH ３ ,CH ２ CH3 and CD ３ Conditions selected from, (4) R ９ The conditions for H, (5) Caution １３ and R １４ H and CH are independent of each other. ３ Conditions selected from, (6) Conditions under which ring A is pyridyl, A compound according to claim 1 or a pharmaceutically acceptable salt thereof that satisfies one or more of the following conditions.

4. (1) Conditions under which R1 is selected from CH3 and CH2CH3, (2) Conditions under which R6 and R7 are independently selected from H and F, (3) Conditions under which R8 is selected from CH3 and CH2CH3, A compound according to claim 2 or a pharmaceutically acceptable salt thereof that satisfies one or more of the following conditions.

5. T ３ is a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from N.

6. R １ CH ３ A compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the above.

7. Structural unit 【Chemistry 10】 teeth, 【Chemistry 11】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

8. Structural unit 【Chemistry 12】 teeth, 【Chemistry 13】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

9. Structural unit 【Chemistry 14】 teeth, 【Chemistry 15】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

10. Structural unit 【Chemistry 16】 teeth, 【Chemistry 17】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

11. Structural unit [Chemistry 18] teeth, 【Chemistry 19】 A compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the above.

12. The compound is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (P-1). 【Chemistry 20】 (However, ring A is pyridyl, R ２ 、R ３ 、R ４ 、R ５ 、R ７ 、R ８ 、R ９ 、R １３ 、R １４ 、R １５ 、R １６ 、R ｃ 、T ２ 、n and 【Chemistry 21】 (This is as defined in claim 1.)

13. The compound is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (P-2). 【Chemistry 22】 (however, 【Chemistry 22】 , T 2 , R 2 , R 3 , R 4 , R 5 , R 9 , R ７ , R ８ , R １３ , R １４ , R １５ , R １６ , R ｃ (and n are as defined in claim 1.)

14. A compound represented by the following formula or a pharmaceutically acceptable salt thereof. 【Chemistry 23】 【Chemistry 24】

15. The compound is the compound according to claim 14 or a pharmaceutically acceptable salt thereof, selected from the following formulas. 【Chemistry 25】

16. A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1, 2, 14, and 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

17. A compound according to any one of claims 1, 2, 14, and 15, or a pharmaceutically acceptable salt thereof, used for the treatment of solid tumors.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, used for the treatment of a solid tumor, wherein the solid tumor is selected from ovarian cancer, breast cancer, prostate cancer and glioma.

19. A pharmaceutical composition according to claim 16, used for the treatment of solid tumors.

20. The pharmaceutical composition according to claim 19, used for the treatment of a solid tumor, wherein the solid tumor is selected from ovarian cancer, breast cancer, prostate cancer, and glioma.

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