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 priorities. CN202210495459.8, filing date: May 7, 2022, CN202210693545.X, filing date: June 17, 2022, CN202211204558.2, filing date: September 29, 2022, CN202211351783.9, filing date: October 31, 2022, CN202211408423.8, filing date: November 10, 2022, CN202211593592.3, filing date: December 9, 2022, CN202310088997X, filing date: February 2, 2023, CN2023101237901, filing date: February 15, 2023, CN2023102323675, filing date: March 10, 2023, CN2023103034259, filing date: March 23, 2023, CN2023103408613, filing date: March 31, 2023, CN202310388951X, filing date: April 12, 2023.

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

Background Art

[0003] Poly(ADP-ribose) polymerase (PARP) is a very large protease family. This family currently consists of 18 members and plays an important role in many cell cycle processes such as replication, recombination, chromatin remodeling and DNA damage repair.

[0004] Among them, PARP1 and PARP2 have been widely studied for their roles in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyze the addition of poly(ADP-ribose) (PAR) chains to target proteins. Such post-translational modification, called PARylation, mediates the recruitment of additional DNA repair factors in response to DNA damage. When this recruitment is complete, PARP bound to DNA is released by auto-PARylation of PARP, allowing access to other DNA repair proteins to complete the repair.

[0005] Inhibition of PARP family enzymes has been developed as an anti-tumor strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have shown that tumor cells with BRCA1 or BRCA2 mutations, where BRCA is a major tumor suppressor protein involved in double-strand DNA break (DSB) repair via homologous recombination (HR), these tumors are defective in the homologous recombination repair (HRD) pathway and rely on the function of PARP enzymes for survival. The growth of tumors with mutated BRCA becomes highly dependent on the PARP pathway and is particularly sensitive to PARP1 inhibitors. In addition to being effective against BRCA-mutated cancers, PARP inhibitors have also been demonstrated in clinical trials to have a defined efficacy in non-BRCA-mutated tumors showing homologous recombination deficiency.

[0006] Compared with other clinically used PARP1 / 2 inhibitors, a highly selective PARP1 inhibitor improves the selectivity for PARP1 over PARP2, reduces the hematotoxicity caused by PARP2 inhibition, and can achieve better clinical efficacy and lower toxicity. Therefore, the medical needs for effective and safe PARP inhibitors, especially PARP inhibitors selective for PARP1, are not met.

[0007] PARP1 selective inhibitors may be used alone in solid tumors such as ovarian cancer, breast cancer, triple-negative breast cancer, and prostate cancer with BRCA1 / 2 mutations (synthetic lethality mechanism), and may also be used as a combination therapy to enhance the effects of anti-cancer agents that enhance the DNA damage mechanism (DNA alkylating agents, topoisomerase inhibitors, platinum-based chemotherapeutic agents, etc.) and radiotherapy. Furthermore, 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, it may be used for the treatment of various solid tumors, whether BRCA-negative or positive.

Summary of the Invention

[0008] The present invention provides a compound represented by formula (XII) or a pharmaceutically acceptable salt thereof.

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

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[0010] The present invention further provides a compound represented by formula (XI) or a pharmaceutically acceptable salt thereof.

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[0011] The present invention further provides a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof.

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[0012] The present invention further provides a compound represented by formula (VIII) or a pharmaceutically acceptable salt thereof. [Chem.] However, X is selected from O, S and N(R d ), and structural unit [Chem.] is [Chem.] selected from, and ring A is selected from phenyl and 5- to 6-membered heteroaryl, Ring B is selected from 5- to 6-membered heteroaryl,

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[0013] The present invention further provides a compound represented by formula (VII-1) or a pharmaceutically acceptable salt thereof.

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[0014] The present invention further provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof.

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[0015] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

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[0016] The present invention further provides a compound represented by formula (VII-2) or a pharmaceutically acceptable salt thereof.

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[0017] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

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[0018] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

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[0019] In some embodiments of the present invention, the above X is selected from O, S and N(OCH 3 ), and the other variables are as defined in the present invention.

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

[0022] In some embodiments of the present invention, each of the above R a is independently selected from H, F, Cl, Br, I, CH 3 , CH 2 CH 3 and CH 2 CH 2 CH 3 CH 3 CH 2 CH 3 and CH 2 CH 2 CH 3 is optionally substituted by 1, 2 or 3 halogens, and the other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, each of the above Rs a is independently selected from H, F, and CH 3 , and the other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, each of the above Rs a is independently selected from H and CH 3 , and the other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, two Rs on the above adjacent atoms a form a double bond or a cyclopropyl together with the atoms to which they are attached, so that the structural unit

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[0026] In some embodiments of the present invention, two Rs on the above adjacent atoms a form a double bond or a cyclopropyl together with the atoms to which they are attached, so that the structural unit

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[0027] In some embodiments of the present invention, two Rs on the above adjacent atoms a form a double bond or a cyclopropyl together with the atoms to which they are attached, so that the structural unit

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[0028] In some embodiments of the present invention, R on the above two adjacent atoms a forms a double bond together with the adjacent atom to form a structural unit [Chem.] is [Chem.] selected as being from, with other variables as defined in the present invention.

[0029] In some embodiments of the present invention, R on the above two adjacent atoms a forms a double bond together with the adjacent atom to form a structural unit [Chem.] is [Chem.] selected as being from, with other variables as defined in the present invention.

[0030] In some embodiments of the present invention, each of the above Rs b is independently H, F, Cl, Br, I, CH 3 , CH 2 CH 3 and CH 2 CH 2 CH 3 selected from, and the CH 3 , CH 2 CH 3 and CH 2 CH 2 CH 3is optionally substituted by one, two or three halogens, and the other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, each of the above R b is independently selected from H, F and CH 3 and the other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, each of the above R b is independently selected from H and CH 3 and the other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, each of the above R c is independently selected from H, F, Cl, Br, I, CH 3 CH 2 CH 3 and CH 2 CH 2 CH 3 and the CH 3 CH 2 CH 3 and CH 2 CH 2 CH 3 is optionally substituted by one, two or three halogens, and the other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, each of the above R c is independently selected from H, F and CH 3 and the other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, each of the above R c is 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 is OCH 3is selected from, and the other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the above T 3 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, the above T 3 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, the above T 3 is selected from N, and the other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above T 4 is selected from N and CH, and the other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above R 1 is CH 3 and CH 2 CH 3 is selected from, and the other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above R 1 is CH 3 is selected from, and the other variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above R 2 is H and CH 3 is selected from, and the other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above R 2 is CH 3 is selected from, and the other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, and CH 3 , and the other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the above R 3 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, the above R 4 is selected from H, F, Cl, CN, and CH 3 , and the other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, the above R 4 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, the above R 4 is selected from H, F, and CH 3 , and the other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the above R 4 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, the above R 4 is selected from F, and the other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above R 5 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, the above R 5is selected from H, F, CN, and CH 3 and the other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above R 5 is selected from H, F, and CH 3 and the other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above R 5 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, the above R 5 is selected from H, and the other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, the above R 6 and R 7 are each independently selected from H, F, and CH 3 and the other variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the above R 6 is selected from H, F, and CH 3 and the other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the above R 7 is selected from H, F, and CH 3 and the other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the above R 6 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, the above R 7 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, the above R 8 is CH 3 CH 2 CH 3 CH 2 CF 3 , cyclopropyl and CD 3 and is selected from the group consisting of, and the other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the above R 8 is CH 3 CH 2 CF 3 , cyclopropyl and CD 3 and is selected from the group consisting of, and the other variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the above R 8 is CH 3 , cyclopropyl and CD 3 and is selected from the group consisting of, and the other variables are as defined in the present invention.

[0065] In some embodiments of the present invention, the above R 8 is CH 3 and cyclopropyl and is selected from the group consisting of, and the other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, the above R 9 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 is selected from H and CH 3 and is selected from the group consisting of, and the other variables are as defined in the present invention.

[0069] In some embodiments of the present invention, the above R 13 is selected from H and CH 3 and the other variables are as defined in the present invention.

[0070] In some embodiments of the present invention, the above R 14 is selected from H and CH 3 and the other variables are as defined in the present invention.

[0071] In some embodiments of the present invention, the above R 15 is selected from H, D and CH 3 and the other variables are as defined in the present invention.

[0072] In some embodiments of the present invention, the above R 16 is selected from H, D and CH 3 and the other variables are as defined in the present invention.

[0073] In some embodiments of the present invention, ring A is selected from phenyl and a 6-membered heteroaryl ring, and the 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 the 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 the other variables are as defined in the present invention.

[0079] In some embodiments of the present invention, the above structural unit

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[0080] In some embodiments of the present invention, the above structural unit

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[0081] In some embodiments of the present invention, the above structural unit

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[0082] In some embodiments of the present invention, the above structural unit

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[0083] In some embodiments of the present invention, the above structural unit [Chemical formula] is selected from [Chemical formula] and the other variables are as defined in the present invention.

[0084] In some embodiments of the present invention, the above structural unit [Chemical formula] is selected from [Chemical formula] and the other variables are as defined in the present invention.

[0085] In some embodiments of the present invention, the above R 11 and R 1 form a benzene ring such that the structural unit [Chemical formula] is selected from [Chemical formula] and the other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, the above structural unit [Chemical formula] is selected from [Chemical formula] selected from, and other variables are as defined in the present invention.

[0087] In some embodiments of the present invention, the above structural unit [Chemical formula] is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0088] In some embodiments of the present invention, the above structural unit [Chemical formula] is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0089] In some embodiments of the present invention, the above R 2 and R 4 form a ring such that the structural unit [Chemical formula] is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0090] In some embodiments of the present invention, the above R 3 and R 5 form a ring such that the structural unit [Chemical formula] is [Chemical] is selected as such, and other variables are as defined in the present invention.

[0091] In some embodiments of the present invention, the above R 3 and R 5 form a ring, and the structural unit [Chemical] is [Chemical] is selected as such, and other variables are as defined in the present invention.

[0092] In some embodiments of the present invention, the above R 2 and R 4 form a ring, and the structural unit [Chemical] is [Chemical] is selected as such, and other variables are as defined in the present invention.

[0093] In some embodiments of the present invention, the above R 3 and R 5 form a ring, and the structural unit [Chemical] is [Chemical] is selected as such, and other variables are as defined in the present invention.

[0094] In some embodiments of the present invention, the above structural unit [Chemical] is selected from

Chem.

[0095] In some embodiments of the present invention, the above R 2 and R 4 form a ring such that the structural unit

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[0096] In some embodiments of the present invention, the above R 3 and R 5 form a ring such that the structural unit

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[0097] In some embodiments of the present invention, the above L is selected from a single bond, and the structural unit

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[0098] In some embodiments of the present invention, the above L is selected from a single bond, and the structural unit

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[0099] In some embodiments of the present invention, the above L is selected from a single bond, and the structural unit

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[0100] In some embodiments of the present invention, the above structural unit

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[0101] In some embodiments of the present invention, the above structural unit

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[0102] In some embodiments of the present invention, the above structural unit

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[0103] In some embodiments of the present invention, the above structural unit

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[0104] In some embodiments of the present invention, the above structural unit

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[0105] In some embodiments of the present invention, the above structural unit

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[0106] In some embodiments of the present invention, the above structural unit

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[0107] In some embodiments of the present invention, the above structural unit

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[0108] In some embodiments of the present invention, the above structural unit

Chemical formula

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[0109] In some embodiments of the present invention, the above structural unit

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[0110] In some embodiments of the present invention, the above structural unit [Chemical formula] is [Chemical formula] When selected from, R 6 and R 7 are not H at the same time, and other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, the above structural unit [Chemical formula] is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0112] In some embodiments of the present invention, the said structural unit [Chemical formula] is [Chemical formula] selected from, and other variables are as defined in the present invention.

[0113] In some embodiments of the present invention, the above compound or its pharmaceutically acceptable salt is selected from the following formulas, [Chemical formula] However, ring A is selected from pyridyl, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 、R 13 、R 14 、R 15 、R 16 、R c 、T 2 、n and

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[0114] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas,

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[0115] In some embodiments of the present invention, the above compound or its pharmaceutically acceptable salt is selected from the following formulae:

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

[0117] In some embodiments of the present invention, the above compound or its pharmaceutically acceptable salt is selected from the following formulae:

Chemical formula

[0118] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from the following formulas, [Chemical formula] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b , X, T 3 and T 4 is 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, [Chemical formula] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b , X, T 3 and T 4 is as defined in the present invention, The condition is, 1) When the compound is selected from formula (VIII-6a), and one of T 3 or T 4 is selected from N, R 2 , R 3 and R 9 are not simultaneously H, or 2) When the compound is selected from formula (VIII-6a), and one of T 3 or T 4 is selected from N, R 6 and R 7 are not simultaneously H, or 3) When the compound is selected from (VIII-6a), T 3 is selected from N, and T 4 is selected from CR 10 , R 5 is selected from halogen, or 4) When the compound is selected from formula (VIII-6a), T 4 is selected from N, and T 3 is selected from CR 10 , R 4 is selected from halogen, or 5) When the compound is selected from formula (VIII-7a), and T 3 is selected from N, R 6 and R 7 are not simultaneously H.

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

[0121] The present invention further provides a compound of the following formula or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

[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 double-distilled water.

[0141] Compound Preparation: Preparation of compound solution: Dilute the test compound 5-fold to 8 concentrations with 100% DMSO, that is, dilute from 1000 μM to 12.8 nM. Dilute the internal control compound 5-fold to 88 concentrations with 100% DMSO, that is, dilute from 200 μM to 2.56 nM. Further, dilute each gradient of the test compound with 1× test buffer to a working solution of 10% DMSO.

[0142] Experimental Method: a) Dilute the histidine solution in the kit 5-fold with 1×PBS, add 25 μL / well of the diluted solution to the microplate, and culture overnight at 4°C. b) After the culture is completed, discard the liquid in the well, wash the plate 3 times with 100 μL / well of PBST, and discard the remaining liquid in the well. c) Take 100 μL / well of blocking solution into the microplate, place it at 25°C and culture for 90 minutes. After the culture is completed, discard the liquid in the well, take 100 μL / well of PBST and wash the plate 3 times, and discard the remaining liquid in the well. d) Take 12.5 μL / well of substrate mixed solution (1.25 μL of 10×PARP test buffer, 1.25 μL of 10×PARP test mixture, 2.5 μL of activated DNA, 7.5 μL of double-distilled water) into the microplate. e) Pipette 2.5 μL / well of the compound working solution into a microplate and set up a duplicate well experiment. f) Dilute the PARP1 enzyme to 2 ng / μL, pipette 10 μL / well and add it to the microplate. At this time, the final concentration gradient of the test compound is 10 μM - 0.128 nM, the final concentration gradient of the internal control compound is 2 μM - 0.0256 nM, and PARP1 is 20 ng / well. Incubate the reaction system at 25 °C for 60 minutes. g) After incubation, discard the liquid in the wells, wash the plate three times with 100 μL / well of PBST, and discard the remaining liquid in the wells. h) Dilute Streptavidin-HRP 50-fold with the blocking solution, add 25 μL / well to the microplate, and incubate at 25 °C for 30 minutes. i) After incubation, discard the liquid in the wells, wash the plate three times with 100 μL / well of PBST, and discard the remaining liquid in the wells. j) Mix ELISA ECL Substrate A and ELISA ECL Substrate B uniformly at 1:1 (v / v), add 50 μL / well to the microplate, and read the chemiluminescence value.

[0143] 3. Method for processing experimental data Use the equation (Sample - Min) / (Max - Min)×100% to convert the raw data to enzyme activity, and obtain the IC 50 value by curve fitting using four parameters (obtained in the log(inhibitor) vs. response -- Variable slope mode of GraphPad Prism). Max: Contains 1% DMSO, PARP1 and substrate mixed solution. Min: Does not contain PARP1 enzyme.

[0144] Test method 2: Study on the binding ability of the compounds of the present invention to PARP1 and PARP2

[0145] PARP1 experimental operation: Surface plasmon resonance (SPR) experiments are performed on a Biacore 8K (GE Healthcare) instrument. First, the biotinylated PARP1 protein (sequence: 655 - end) is coupled at 25 °C via an SA chip (Cytiva, 29699622) coated with streptavidin. Specific steps: Activate the surface of the chip 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 MgCl 2 , 0.05% P20) to prepare a ligand solution of 10 μg / mL, 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 the excess active sites on the chip with a 50% isopropyl / 1 M NaCl / 50 mM NaOH solution. The final coupling level of the experiment is 2000 - 3000 RU (Response Units). Dilute the small molecule compound in buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10 mM MgCl 2 , 0.05% Tween 20) in a gradient to obtain compound solutions of various concentrations, flow the solution over the surface of the chip coupled with the protein, the injection flow rate is 50 μL / min, the injection time is 60 seconds, and the dissociation time is 20 minutes. The instrument detects the binding and dissociation curves of the protein - small molecule compound. Analyze the data of the sample channel and the control channel with Biacore 8K evaluation software to generate a sensorgram and perform data fitting based on a 1:1 binding mode.

[0146] PARP2 experimental operation: Surface plasmon resonance (SPR) experiments are performed on a Biacore 8K (GE Healthcare) instrument. First, couple the biotinylated PARP2 protein (sequence: 223-end) under the condition of 25 °C via an SA chip (Cytiva, 29699622) coated with streptavidin. Specific steps: Activate the surface of the chip with 1 mM NaCl / 50 mM NaOH. Dilute the PARP2 protein with a coupling buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 10 mM MgCl 2 2 , 0.05% P20) to prepare a ligand solution of 10 μg / mL, flow the 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 the excess active sites on the chip with a 50% isopropyl / 1 M NaCl / 50 mM NaOH solution. The final coupling level of the experiment is 3000 - 4000 RU (Response Units). Dilute the small molecule compound in a gradient with a buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10 mM MgCl 2 2 , 0.05% Tween 20) to obtain compound solutions of various concentrations, flow the solution over the surface of the chip coupled with the protein, with 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. Analyze the data of the sample channel and the control channel with Biacore 8K evaluation software to generate a sensorgram, and perform data fitting based on the 1:1 binding mode.

[0147] Technical effects: The compounds of the present invention have excellent binding activity against PARP1, can selectively inhibit PARP1 protein, have weak binding activity against PARP2, and have excellent growth inhibitory activity against BRCA1 mutant MDA-MB-436 cells and DLD1 (BRCA2 knockout) cells, and exhibit 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 have excellent in vivo metabolic stability, show excellent oral absorption drug exposure, have excellent brain tissue drug concentration and high brain-blood ratio when administered orally, and exhibit more significant antitumor activity.

[0148] [Related Definitions] Unless otherwise specified, the following terms and phrases used in this specification include the following meanings. If a particular term or phrase is not specifically defined, it should be understood as having its ordinary definition without being uncertain or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0149] As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of reliable medical judgment, suitable for contact with human and animal tissues, and have little toxicity, irritation, allergic reaction, or other problems or complications, and meet a reasonable benefit / risk ratio.

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

[0151] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid groups or basic groups by conventional methods. Usually, the method for producing such salts is to react these compounds in the form of free acid or base with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0152] The compounds of the present invention may exist in the form of specific geometric or stereoisomers. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as mixtures rich in enantiomers or diastereomers. All these mixtures are included within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included 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" are due to the inability of double bonds or single bonds of ring-forming carbon atoms to rotate freely.

[0155] Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.

[0156] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0157] Unless otherwise specified,

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[0158] Unless otherwise specified, when a compound has double bond structures such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and two different substituents are connected to each atom on the double bond (in the case of a double bond containing a nitrogen atom, a pair of lone electrons on the nitrogen atom is regarded as a substituent connected thereto), the atoms on the double bond of the compound and their substituents [Chemistry] When linked by, it means the (Z)-isomer, (E)-isomer, or a mixture of the two isomers of the compound. For example, the following formula (A) means that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2), or in the form of two isomers of formula (A-1) and formula (A-2), and the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2), or in the form of two isomers of formula (B-1) and formula (B-2). The following formula (C) means that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2), or in the form of two isomers of formula (C-1) and formula (C-2). [Chemistry]

[0159] Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert with each other. If tautomers are possible (e.g., in solution), the chemical equilibrium of the 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 by recombination of some bonding electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0160] Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer", or "enriched in enantiomers" mean that the content of one isomer or enantiomer is less than 100%, and 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, when the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 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 can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), C-14 ( 14 C), etc. Or for example, deuterium can be substituted for hydrogen to form a deuterated drug. The bond formed by deuterium and carbon is stronger than the bond formed by normal hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic side effects, enhancing drug stability, enhancing efficacy, and extending the biological half-life of the drug. The conversion of the isotope composition of the compounds of the present invention is included within the scope of the present invention regardless of whether it is radioactive.

[0163] The terms "optional" or "optionally" mean that the following matters or situations are possible but not necessarily occur, and the description includes the cases where the matters or situations described therein occur and the cases where they do not occur.

[0164] The term "substituted" means that any one or more hydrogen atoms at a particular atom are substituted by substituents. As long as the particular valence state is normal and the compound after substitution is stable, the substituents may include deuterium and hydrogen isotopes. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are substituted. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise defined, the type and number of substituents are arbitrary as long as they can be chemically stably realized.

[0165] If any of the variables (e.g., R) appears one or more times in the composition or structure of the compound, its definition is independent in each case. Therefore, for example, when one group is substituted with 0 to 2 Rs, the above group is optionally substituted with 2 or fewer Rs, and in each case, R has independent options. Also, combinations of substituents and / or their variants are only allowed if such combinations result in a stable compound.

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

[0167] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, when the chemical bond is formed, the number of H atoms at the site decreases to a group with the corresponding valence according to the number of the formed chemical bonds. The chemical bond by which the site is bonded to another group is

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[0168] Unless otherwise defined, the "two Rs on adjacent atoms in the general formula a that together with the atoms to which they are attached form a double bond" means that two Rs on adjacent carbon atoms a and the single bond between the two carbons together form a double bond. For example, the structural unit [Chemistry] Two Rs in a form a double bond together with a single bond between two carbons, i.e., the structural unit [Chemistry] is formed.

[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" represents a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc., which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0171] Unless otherwise defined, the term "C 1-3 alkoxy" represents an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), etc.

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

[0173] Unless otherwise stated, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl" in the present invention can be used interchangeably. The term "5- to 6-membered heteroaryl" is a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, and 1, 2, 3, and 4 of its ring atoms are independently selected from heteroatoms of O, S, and N, and the rest 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). The 5- to 6-membered heteroaryl is linked to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (such as 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0174] Unless otherwise defined, the terms "6-membered heteroaryl ring" and "6-membered heteroaryl" in the present invention can be used interchangeably. The term "6-membered heteroaryl" is a monocyclic group having a conjugated π-electron system composed of 6 ring atoms, and 1, 2, 3, and 4 of its ring atoms are independently selected from heteroatoms of O, S, and N, and the rest 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). The 5- to 6-membered heteroaryl is linked to the rest of the molecule via a heteroatom or a carbon atom.

[0175] Unless otherwise defined, C n-n+m or C n -C n+m includes any one specific embodiment of n to n + m carbons. For example, C1-12 is C 1 C 2 C 3 C 4 C 5 C 6 C 7 C 8 C 9 C 10 C 11 and C 12 including, and also including any one range among n to n + m. For example, C 1-12 is 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 etc. are included. Similarly, n-membered to (n + m)-membered represents that the number of atoms in the ring is from n to n + m. For example, a 3- to 12-membered ring includes a 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any one range among n to n + m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, 3- to 9-membered ring, 5- to 6-membered ring, 5- to 7-membered ring, 6- to 7-membered ring, 6- to 8-membered ring, and 6- to 10-membered ring, etc.

[0176] The compounds of the present invention can be produced by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the 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 compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. When the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by the conventional technical means of those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, after collecting the relevant data, the absolute configuration can be confirmed by further direct method (Shelxs97) crystal structure analysis.

[0178] All solvents used in the present invention can be obtained from commercially available products. The present 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), TBSCl represents tert-butyldimethylsilyl chloride, DMAP represents 4-dimethylaminopyridine, Cs 2 CO 3 represents cesium carbonate, RuPhos represents 2-dicyclohexylphosphino-2,6-diisopropoxybiphenyl, Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium(0), TBAF represents tetra-n-butylammonium fluoride, Et 3 N represents triethylamine, Na 2 CO 3 represents sodium carbonate, NaHCO 3 represents sodium hydrogen carbonate, H 2 O 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, NBS represents N-bromosuccinimide, Dess-Martin represents Dess-Martin periodinane, CAS is 87413-09-0, KHMDS represents potassium bis(trimethylsilyl)amide, Pd(OAc) 2 represents palladium acetate, PPh 3 represents triphenylphosphine, Pd / C represents palladium on carbon, HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, (Boc) 2O represents di-tert-butyl dicarbonate, LiAlH 4 represents lithium aluminum hydride, N-Boc-piperazine represents 1-(tert-butoxycarbonyl)piperazine, Lawesson's reagent represents the compound with CAS 19172-47-5, DMSO represents dimethyl sulfoxide, NaBH(OAc) 3 represents sodium triacetoxyborohydride, KI represents potassium iodide, NH 4 Cl represents ammonium chloride, HCl represents hydrochloric acid, dioxane represents 1,4-dioxane, Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.

Brief Description of the Drawings

[0179]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0180] Hereinafter, the present invention will be specifically described by way of examples, which does not mean any restrictive limitation of the present invention. The present invention is described in detail herein, and its specific embodiments are also disclosed. It is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0181] Example 1

Chemical Formula

Chemical Formula

[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 the mixture was stirred at 25 °C for 18 h to allow the reaction to proceed. 1000 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried and concentrated to obtain a crude product, which 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 (7.4 g, 23.05 mmol), NH 4 Cl (9.86 g, 184.37 mmol), and zinc powder (7.7 g, 117.76 mmol) were added to a mixed solution of MeOH (100 mL) and H 2 O (2 mL), and the mixture was stirred for 2 h to allow the reaction to proceed. The mixture was filtered, and the filtrate was evaporated under reduced pressure to remove methanol. 100 mL of water was further added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were 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 for 2 h to allow the reaction to proceed. 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-d 6 ) 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, 3 H).

[0185] Step 4: Synthesis of Intermediate 1f At 0 °C, DDQ (5.26 g, 23.16 mmol) was added in one portion to DCM (250 mL) of Intermediate 1e (5.0 g, 19.30 mmol), the temperature was raised to 25 °C, and the mixture was stirred for 2 hours to react. The solvent was evaporated under reduced pressure, 200 mL of saturated NaHCO 3 aqueous solution was added dropwise to quench the reaction system, stirred overnight, extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, concentrated to obtain the target product, and 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-d 6 ) 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 Intermediate 1g 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 N 2 protection for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluent: DCM / MeOH = 20 / 1, V / V) to obtain Intermediate 1g. 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 Intermediate 1g (200 mg, 960.67 μmol) in DCM (5 mL). The reaction system was stirred at 20 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. A mixed solvent (DCM / MeOH = 20 / 1, 5 mL) was added to the crude product, and it was stirred for 30 minutes, filtered, and the cake was concentrated under reduced pressure to obtain Intermediate 1h. 1 H NMR (400 MHz, DMSO-d 6 ) 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 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 (40 mL). The mixture was stirred at 20 °C for 16 hours to react. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: DCM / MeOH = 20 / 1~10 / 1, V / V) to obtain Intermediate 1j. 1 H NMR (400 MHz, CD 3 OD) 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 Cs 2 CO 3(197.15 mg, 605.08 μmol), RuPhos (14.12 mg, 30.25 μmol), Intermediate 1j (0.1 g, 302.54 μmol), and methyl 5-bromo-6-fluoro-pyridine-2-carboxylate (70.80 mg, 302.54 μmol) and Pd 2 (dba) 3 (55.41 mg, 60.51 μmol) was added to a toluene (4 mL) solution, and the mixture was stirred at 100 °C for 24 hours to effect the reaction. The reaction solution was suction filtered while reducing the pressure, and the filtrate was concentrated under reduced pressure to obtain a 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 (1 M THF solution, 258.45 μL, 2.5 eq), Intermediate 1k (50 mg, 103.38 μmol) was added to a THF (4 mL) solution, and the reaction system was stirred at 25 °C for 16 hours. The reaction solution 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 an EA (2 mL) solution, and HCl / EA (4 M, 85.87 μL) was added dropwise to the reaction solution. The mixture was stirred at 25 °C for 2 hours to effect the reaction. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of Intermediate 1m. MS m / z: 250.2 [M+H] + 。

[0192] Step 11: Synthesis of Intermediate 1n Under an atmosphere of nitrogen gas, the hydrochloride salt of Intermediate 1m (20 mg) was added to an EtOH (2 mL) solution, and further methylamine (2.26 mg, 72.84 μmol) was added to the reaction solution. The mixture was stirred at 20 °C for 1 hour to effect the reaction. The reaction 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), and then Et 3 N (7.47 mg, 73.78 μmol, 10.27 μL) was added to the reaction solution, 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 solution, and the reaction system was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure at 60 °C using an oil pump to obtain a 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 trifluoroacetate of Compound 1. MS m / z: 439.2 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[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), and Cs 2 CO 3 (2.09 g, 6.42 mmol), RuPhos (199.72 mg, 428.00 μmol) and Pd 2 (dba)3 (195.96 mg, 214.00 μmol) was added to the reaction solution, and after replacing the atmosphere with nitrogen gas three times, the reaction system was stirred at 100 °C for 16 hours. The reaction solution was suction filtered while reducing the pressure, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (eluent: PE / EA = 4 / 1 - 2 / 1, V / V) to obtain Intermediate 2c. MS m / z: 354.2 [M+1] + , 1 H NMR (400 MHz, CDCl 3 ) 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 solution was concentrated under reduced pressure to obtain Intermediate 2d as a crude product, which was directly used 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 solution. The reaction system was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of Intermediate 2e as a crude product, which was directly used in the next step. MS m / z: 253.0 [M+H] + 。

[0198] Step 4: Synthesis of the trifluoroacetate salt of Compound 2 Intermediate 2e (21.30 mg) was added to DMF (2 mL), and then Et 3 N (14.93 mg, 147.56 μmol, 20.54 μL) was added to the reaction solution, and the reaction system was stirred at 25 °C for 30 minutes. Further, KI (5.39 mg, 32.49 μmol) and Intermediate 1h (20 mg, 73.78 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a 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 salt of Compound 2. MS m / z: 443.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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, and Et 3N (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 solution, and the reaction system was stirred at 20 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (eluent: DCM / MeOH = 20 / 1 - 10 / 1, V / V) to obtain intermediate 3b. 1 H NMR (400 MHz, CDCl 3 ) 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-fluoro-pyridine-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), Pd 2 (dba) 3 (391.30 mg, 427.00 μmol), and Cs 2 CO 3 (4.17 g, 12.81 mmol) were added to the reaction solution, which was replaced with nitrogen gas three times, and the reaction system was stirred at 100 °C for 2 h. Filtration was carried out under suction while reducing the pressure, and the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (eluent: PE / EA = 4 / 1 - 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 h. The reaction mixture was suction filtered while reducing the pressure, and the filtrate was concentrated under reduced pressure to obtain crude product 3d, which was directly used 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 an ethanol solution of methylamine (1 mL, 40%) was added to the reaction mixture. The reaction system was stirred at 20 °C for 32 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was directly used in the next step to obtain Intermediate 3e. MS m / z: 349.1 [M+H] + .

[0204] Step 5: Synthesis of 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 h. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of Compound 3f as the crude product, which was directly used in the next step. MS m / z: 249.1 [M+H] + .

[0205] Step 6: Synthesis of Trifluoroacetate Salt of Compound 3 Compound 3f (10.50 mg, HCl) was added to DMF (2 mL), and then Et 3N (7.47 mg, 73.78 μmol, 10.27 μL) was added to the reaction solution, and the reaction system was stirred at 25 °C for 30 minutes. Then, KI (2.70 mg, 16.24 μmol, 5.68 μL) and compound 1h (10 mg, 36.89 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 hours. The reaction solution was concentrated at 60 °C with an oil pump to obtain a 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 salt of compound 3. MS m / z: 439.0 [M+H] + , 1 H NMR (400 MHz, CD 3 OD) 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, 3 H).

[0206] Example 4

Chemical Structure

[0207] Step 1: Synthesis of Intermediate 4a Toluene (5 mL) was added to a reaction flask containing compound 2a (500 mg, 2.14 mmol) and N-Boc-piperazine (397.93 mg, 2.14 mmol). Then, RuPhos (199.40 mg, 427.31 μmol), cesium carbonate (1.39 g, 4.27 mmol), and Pd 2 (dba) 3(195.65 mg, 213.65 μmol) was added, and the temperature was raised to 100 °C under the protection of nitrogen gas and stirred for 16 h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which 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, CDCl 3 ) 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), methylamine-ethanol solution (1.19 g, 17.68 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated to obtain intermediate 4b, which was used in the next step reaction without further purification. MS m / z: 339.1 [M+H] + 。 1 H NMR (400 MHz, CDCl 3 ) 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 Lawesson's reagent (71.72 mg, 177.32 μmol) was further added. The mixture was stirred at 120 °C for 16 h. Water (1 mL) and ethyl acetate (3 mL) were added to the reaction solution for extraction. The organic phase was taken, dried over anhydrous sodium sulfate, 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 h. Methyl iodide (8.01 mg, 56.43 μmol, 3.51 μL) was added, and the mixture was stirred at 25 °C for 2 h. Two drops of ammonium chloride solution were added to the reaction solution for quenching, 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, which was used directly in the next-step reaction 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), triethylamine (6.87 mg, 67.85 μmol, 9.44 μL) and methoxyamine hydrochloride (3.40 mg, 40.71 μmol) were added, and the mixture was stirred at 60 °C for 1.5 h. The reaction solution 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), filtered, and concentrated to obtain intermediate 4e. MS m / z: 368.1 [M+H] + 。 1 H NMR (400 MHz, CDCl 3) 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 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 h. Most of the raw materials were detected by LCMS, 0.2 mL of hydrogen chloride / dioxane (4 M, 36.74 μL) was added, and the mixture was stirred for an additional 1.5 h. The reaction solution 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 trifluoroacetate salt of Compound 4 Intermediate 4f (10 mg, hydrochloride salt) 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 h. Further, Intermediate 1h (8.92 mg, 32.92 μmol) and potassium iodide (2.73 mg, 16.46 μmol) were added, and the mixture was stirred at 50 °C for 2 h. The reaction solution was filtered to obtain a crude product, and 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 salt of Compound 4. MS m / z: 458.2 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) 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 [Chemistry]

[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 solution 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 salt of compound 5 Intermediate 5a (15 mg, hydrochloride salt) 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 hour. Further, 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 solution was filtered to obtain a crude product, and the crude product was subjected to preparative HPLC column (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 salt of compound 5. MS m / z: 445.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) 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 [Chemical formula]

[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 Schlenk flask. Stirring was initiated and the flask was purged with nitrogen gas. Subsequently, potassium phosphate (54.42 mg, 256.39 μmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (9.38 mg, 12.82 μmol) were added successively. The reaction mixture was heated to 80 °C and stirred for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by pre-TLC (eluent: PE:EA = 3:1) to afford 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), and methylamine-ethanol solution (222.81 mg, 3.30 mmol) was added. The mixture was stirred at 25 °C for 6 hours. The reaction solution was concentrated directly 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), and hydrogen chloride / dioxane (4 M, 68.43 μL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated directly 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 salt 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 h. Further, intermediate 1h (9.98 mg, 36.80 μmol) and potassium iodide (3.05 mg, 18.40 μmol) were added, and the mixture was stirred at 50 °C for 2 h. The reaction solution was filtered to obtain a crude product, and 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, CDCl 3 ) 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

Chemical Structure

[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), palladium-carbon (2 mg, 29.82 μmol, 10%) was added to the reaction solution, and the mixture was replaced with argon gas three times and then with hydrogen gas three times. The mixture was stirred at 30 °C for 16 h under an atmosphere of 16 psi hydrogen gas. The reaction solution was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain intermediate 7a, which was directly used in the next step. MS m / z: 360.2 [M+23] +。

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

[0225] Step 3: Synthesis of trifluoroacetate salt of Compound 7 Triethylamine (6.94 mg, 68.56 μmol) was added to a DMF (1 mL) solution of Intermediate 7b (9.38 mg, 34.28 μmol, crude hydrochloride product). The reaction system was stirred at 20 °C for 0.5 hour. Intermediate 1h (9.29 mg, 34.28 μmol) and potassium iodide (569.03 μg, 3.43 μmol) were added to the reaction solution. The reaction system was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a 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 salt of Compound 7. MS m / z: 428.3 [M+1] + 。 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[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), and Pd 2 (dba) 3 (8.94 mg, 9.76 μmol), RuPhos (9.11 mg, 19.52 μmol) and Cs 2 CO 3 (636.13 mg, 1.95 mmol) were added to the reaction solution. The reaction system was purged with nitrogen gas three times and stirred at 100 °C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain a 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 hour, and suction filtered while reducing the pressure. The cake was concentrated to obtain Intermediate 8b. MS m / z: 301.2 [M-56+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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), and the mixture was 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 a crude product, and the crude product was purified by preparative chromatography plate (PE / EA = 2 / 1, shift ratio value l0.1) 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 solution, the reaction system was stirred at 25 °C for 2 hours, and the reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride of intermediate 8d, which was directly used 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), the reaction system was stirred at 20 °C for 0.5 hour, intermediate 1h (13.94 mg, 51.42 μmol) and potassium iodide (853.55 μg, 5.14 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure with an oil pump to obtain a crude product, and 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 8. MS m / z: 468.1 [M+23] + 。 1 H NMR (400 MHz, CD 3 OD) 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, 3 H) 2.56 (s, 3 H).

[0231] Example 9

Chemical Structure

[0232] Step 1: Synthesis of the hydrochloride of intermediate 9g Intermediate 4b (50 mg, 147.76 μmol) was dissolved in methanol (0.2 mL), HCl / dioxane (4 M, 199.48 μL) was added, and the mixture was reacted at 25 °C for 2 hours. After the reaction solution was concentrated under reduced pressure, the hydrochloride salt of Intermediate 9g 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), potassium nitrate (760 mg, 7.52 mmol) was added slowly in portions, and then the mixture was stirred at 20 °C for 16 hours. The reaction solution was poured into 90 mL of saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride (100 mL × 2), filtered, and then concentrated. Purification by silica gel column (EA:PE = 0% - 10%) gave Intermediate 9b. 1 H NMR (400 MHz, DMSO-d 6 ) 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, acetic acid (237.36 mg, 3.95 mmol, 226.27 μL) was added, and then zinc (240 mg, 3.67 mmol) was added in portions, and the mixture was reacted for 6 hours. It was filtered and concentrated to obtain a crude product. The crude product was purified by preparative chromatography plate (PE:EA = 3:1) to give Intermediate 9c. MS m / z: 224.9, 226.9 [M+1] + , [M+3] + 。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.69~6.80 (m, 1 H), 3.52 (s, 4 H).

[0235] Step 4: Synthesis of a mixture of Intermediate 9d1 and 9d2 Intermediate 9c (25 mg, 112.10 μmol) was added to EtOH (0.32 mL), followed by the addition of pyruvic acid (11.85 mg, 134.52 μmol). The reaction was carried out at 100 °C for 2 hours and then slowly cooled to 25 °C for crystallization over 14 hours. Filtration was performed, and the solid was washed once with 0.5 mL of ethanol. Without further purification, 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, and after purging with nitrogen gas, the reaction was carried out at 80 °C for 16 hours. Purification by preparative plate (PE:EA = 1:1) gave 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 a mixture of intermediates 9f1 and 9f2 (45 mg) at 0 °C, and then added dropwise to a dichloromethane (1.2 mL) solution of 1,2-dibromotetrachloroethane (142.54 mg, 437.71 μmol). The reaction was carried out at 25 °C for 2 hours. Purification by preparative chromatography plate (dichloromethane:methanol = 15:1) gave a mixture of intermediates 9f1 and 9f2.

[0238] Step 7: Synthesis of a mixture of trifluoroacetates of compounds 9-1 and 9-2 Intermediate 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 intermediate 9g (46 mg, 147.82 μmol) were added to the reaction solution, and the mixture was stirred at 50 °C for 2 hours. The reaction solution 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 trifluoroacetate salts of compounds 9-1 and 9-2 was obtained. MS m / z: 447.1 [M+1] + 。

[0239] Example 10

Chemical formula

[0240] Step 1: Synthesis of intermediate 10c Under the protection of nitrogen gas, 10a (50 mg, 231.45 μmol), compound 10b (51.73 mg, 277.74 μmol), Cs 2 CO 3 (150.82 mg, 462.89 μmol), RuPhos (21.60 mg, 46.29 μmol), Pd 2 (dba) 3 (21.19 mg, 23.14 μmol) were added to toluene (1 mL), the temperature was raised to 100 °C and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth, washed with DCM (5 mL), the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by preparative chromatography plate (PE:EA = 0:1) to obtain intermediate 10c. MS m / z: 322.1 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6) 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, 3H), 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), and then methylamine - ethanol solution (1.23 g, 11.88 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain Intermediate 10d, which was directly used 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), and then hydrogen chloride / dioxane (4 M, 105.34 μL) was added. The mixture was stirred at 25 °C for 2 h. It was concentrated under reduced pressure to obtain the hydrochloride salt of Intermediate 10e, which was directly used in the next step. MS m / z: 221.1 [M + 1] + , 1 H NMR (400 MHz, DMSO - d 6 ) 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 h. Compound 1h (21.12 mg, 77.90 μmol) and potassium iodide (1.29 mg, 7.79 μmol) were added to the reaction solution. The reaction system was heated to 50 °C and stirred for 2 h. The reaction solution was washed with water (2 mL) and 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 a crude product. The crude product was separated and purified by preparative chromatography plate (DCM:MeOH = 10:1) to obtain Compound 10. MS m / z: 411.1 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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), Cs 2 CO 3 (150.82 mg, 462.89 μmol), RuPhos (21.60 mg, 46.29 μmol), Pd 2 (dba) 3 (21.19 mg, 23.14 μmol) were added to toluene (1 mL), and the temperature was raised to 100 °C and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth, washed with DCM (5 mL), and the filtrate was concentrated under reduced pressure to obtain a 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] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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), and then methylamine-ethanol solution (1.23 g, 11.88 mmol) was added, and stirred at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain Intermediate 11d, which was directly used in the next step. MS m / z: 339.1 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6) δ ppm 8.21 (broad d, J = 4.63 Hz, 1H), 7.75 (d, J = 8.25 Hz, 1H), 7.24 - 7.31 (m, 1H), 6.56 (broad 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 (broad d, J = 6.13 Hz, 9H).

[0247] Step 3: Synthesis of hydrochloride salt of Intermediate 11e Intermediate 11d (25 mg, 78.03 μmol) was added to MeOH (0.5 mL), and then hydrogen chloride / dioxane (4 M, 105.34 μL) was added. The mixture was stirred at 25 °C for 4 h. It 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 the hydrochloride salt of 11e (15 mg) obtained in Step 3 in DMF (1 mL). The reaction was carried out at 20 °C for 0.5 h. Compound 1h (14.80 mg, 54.60 μmol) and potassium iodide (906.37 μg, 5.46 μmol) were added to the reaction solution. The reaction system was stirred at 50 °C for 2 h. The reaction solution was washed with water (2 mL) and 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 a crude product. The crude product was separated and purified by preparative plate (DCM:MeOH = 10:1) to obtain Compound 11. MS m / z: 429.2 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6) 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 [Chemical formula]

[0250] Step 1: Synthesis of Intermediate 12b Under the protection of nitrogen gas, 10a (50 mg, 231.45 μmol), Compound 12a (51.73 mg, 277.74 μmol), Cs 2 CO 3 (150.82 mg, 462.89 μmol), RuPhos (21.60 mg, 46.29 μmol), Pd 2 (dba) 3 (21.19 mg, 23.14 μmol) were added to toluene (1 mL), heated to 100 °C and stirred for 16 h. The reaction solution was filtered through diatomaceous earth, washed with DCM (5 mL), and the filtrate was concentrated under reduced pressure to obtain a 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), and then methylamine-ethanol solution (694.48 mg, 6.71 mmol) was added. The mixture was stirred at 25 °C for 16 h. It was concentrated under reduced pressure to obtain Compound 12c. MS m / z: 335.2 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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 hydrochloride salt of Intermediate 12d Intermediate 12c (44 mg, 131.57 μmol) was added to MeOH (0.5 mL), and then hydrogen chloride / dioxane (4 M, 105.34 μL) was added. The mixture was stirred at 25 °C for 2 h. It 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 a DMF (1 mL) solution of 12d hydrochloride (20 mg), and the reaction system was stirred at 20 °C for 0.5 h. Compound 1h (20.02 mg, 73.87 μmol) and potassium iodide (1.23 mg, 7.39 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 h. The reaction solution 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, concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by a preparative plate (DCM:MeOH = 10:1) to obtain Compound 12. MS m / z: 425.2 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[0255] Step 1: Synthesis of Intermediate 14b Compound 3a (8 g, 36.99 mmol) was dissolved in DCM (80 mL) and H2 In addition to O(80 mL), NaHCO 3 (9.32 g, 110.97 mmol) was added to the reaction solution, the reaction system was cooled to 0 °C, benzyl chloroformate (9.47 g, 55.48 mmol) was added to the reaction solution, and the reaction system was stirred at 20 °C for 16 hours. 80 mL of dichloromethane was added to the reaction solution, extracted, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C to obtain a crude product. The crude product was separated and purified by column chromatography (eluent: PE / EA = 5 / 1 - 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 solution in one batch at 0 °C, and stirred at 0 °C for 3 hours. 6 g of calcium hydroxide was added to the reaction solution, stirred at 0 °C for 1 hour, filtered, the cake was washed with dichloromethane (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50 °C to obtain a crude product. The crude product was separated and purified by high-speed 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, at 20 °C, KHMDS (1 M, 3.44 mL) was added dropwise to a solution of methyltriphenylphosphonium bromide (1.23 g, 3.44 mmol) in THF (4 mL). The reaction system was stirred at 20 °C for 1 hour, then cooled to -78 °C. While stirring, a solution of intermediate 14c (0.4 g, 1.15 mmol) in THF (4 mL) was slowly added dropwise to the reaction solution (10 min). The reaction system was warmed to 20 °C and stirred at this temperature for 1 hour. 72 mL of methanol was added to the reaction solution, followed by 36 mL of saturated sodium potassium tartrate solution. The mixture was extracted with ethyl acetate (180 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C to obtain a 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), PPh 3 (22.42 mg, 85.46 μmol), Na 2 CO 3 (90.58 mg, 854.62 μmol) were added to DMF (5 mL). After replacing with nitrogen gas, the temperature was raised to 130 °C and stirred for 6 hours. 5 mL of water was added to the reaction solution, and it was extracted 3 times with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative thin-layer chromatography plate (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 solution. The reaction system was purged with argon gas three times and then with hydrogen gas three times. The reaction system was stirred at 30 °C under a hydrogen gas pressure of 30 psi for 16 hours. The reaction solution was cooled to 20 °C and suction filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain Intermediate 14f, which was directly used in the next step. MS m / z: 368.2 [M+1] + 。

[0260] Step 6: Synthesis of Intermediate 14g 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). The temperature was raised to 50 °C and the mixture was stirred for 6 hours. 5 mL of water was added to the reaction solution, 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 a crude product. The crude product was separated and purified by preparative thin-layer chromatography plate (PE:EA = 1:1) to obtain Intermediate 14g. MS m / z: 348.2 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) 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, 1H), 1.42 (s, 9H).

[0261] Step 7: Synthesis of Intermediate 14h A methylamine - ethanol solution (0.41 g, 3.96 mmol) was added to a solution of Intermediate 14 g (20 mg, 57.57 μmol) in EtOH (1 mL), and the mixture was stirred at 25 °C for 16 h. It 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 h. The reaction solution 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 the hydrochloride salt of Intermediate 14i (10 mg) in DMF (1 mL), and the reaction system was stirred at 20 °C for 0.5 h. 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 h. The reaction solution 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 a crude product. A methylamine - ethanol solution (0.30 g) was added thereto, and the mixture was stirred at 25 °C for 24 h and concentrated to obtain Compound 14. MS m / z: 437.2 [M+1] + ; 1 H NMR (400 MHz, CD 3OD) 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

Chemical formula

[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), and HATU (1.81 g, 4.75 mmol) and triethylamine (1.20 g, 11.88 mmol, 1.65 mL) were added to the reaction solution. The reaction system was stirred at 25 °C for 16 hours. The reaction solution was added to 5 mL of water, and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C to obtain a crude product. The crude product was purified by preparative thin - layer chromatography plate (PE / EA = 2 / 1, R f = 0.14) to obtain Intermediate 15b. MS m / z: 352.7, 354.7 [M + 1] + ; 1 H NMR (400 MHz, CDCl 3) 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), and Et 3 N (5.95 mmol, 827.70 μL), (Boc) 2 O (519.14 mg, 2.38 mmol) and DMAP (48.43 mg, 396.44 μmol) were added to the reaction solution, and the reaction system was stirred at 25 °C for 4 hours. The reaction solution was added to 5 mL of water, and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 45 °C to obtain a crude product, and 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(diphenylphosphino)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 solution, and the reaction was carried out at 140 °C for 10 minutes by microwave. The reaction solution was concentrated under reduced pressure at 60 °C to obtain a crude product, and the crude product was purified by preparative thin - layer chromatography plate (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 LiAlH 4 (2.79 mg, 73.47 μmol) was added to the reaction solution, and the reaction was carried out at 0 °C for 30 minutes. 2 mL of saturated sodium potassium tartrate solution was added to the reaction solution, and then the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to obtain a crude product. The crude product was purified by preparative thin-layer chromatography plate (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 solution at 20 °C. The reaction system was reacted at 20 °C for 2 hours, the reaction solution 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 Trifluoroacetate Salt of Compound 15 Intermediate 9g (12.26 mg, hydrochloride) was added to DMSO (2 mL), and Et 3 N (9.03 mg, 89.22 μmol) was added to the reaction solution, and the reaction system was stirred at 25 °C for 30 minutes. Intermediate 15f (10 mg, 41.29 μmol) was added to the reaction solution, and the pH was adjusted to ~6 with acetic acid. The reaction system was stirred at 25 °C for 2 hours, and NaBH(OAc) 3(18.91 mg, 89.22 μmol) was added to the reaction solution, and the reaction system was stirred at 25 °C for 1 hour. Water (2 mL) was added to the reaction solution, and then it was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to obtain a 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: 2% - 32% acetonitrile, 8 min) to obtain the trifluoroacetate salt of compound 15. MS m / z: 487.2 [M+Na] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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 Intermediate 15g 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. It was filtered to obtain a cake, which was Intermediate 15g. 1 H NMR (400 MHz, DMSO-d 6) 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 Intermediate 9g (38.02 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (32.95 mg, 325.61 μmol) was added, and the mixture was stirred at 25 °C for 0.5 h. Then, Intermediate 15g (50 mg, 162.80 μmol) and KI (2.70 mg, 16.28 μmol) were added, and the mixture was stirred at 50 °C for 3 h. Water (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 min. A solid precipitated, which was filtered to obtain a cake, namely Compound 15. MS m / z: 465.1 [M + 1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[0274] Step 1: Synthesis of Intermediate 16b Compound 1i (5 g, 23.12 mmol) was dissolved in H2 In addition to O (40 mL) and DCM (40 mL), NaHCO 3 (5.83 g, 69.36 mmol) was added to the reaction solution, the reaction system was cooled to 0 °C, benzyl chloroformate (5.92 g, 34.68 mmol, 4.95 mL) was added to the reaction solution, and the reaction system was stirred at 20 °C for 16 hours. 40 mL of dichloromethane was added to the reaction solution, separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50 °C to obtain a 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 solution in portions at 0 °C. The mixture was stirred at 0 °C for 3 hours, 10 g of calcium hydroxide was added to the reaction solution, stirred at 0 °C for 1 hour, filtered, the cake was washed with dichloromethane (60 mL × 3), the filtrate was dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 50 °C to obtain a crude product. The crude product was purified by column chromatography (eluent: ethyl acetate / n-heptane = 5 / 1 to 2 / 1, V / V) to obtain Intermediate 16c.

[0276] Step 3: Synthesis of Intermediate 16d Under the protection of nitrogen gas, at 20 °C, KHMDS (1 M, 51.67 mL) was added dropwise to a solution of methyltriphenylphosphonium bromide (18.46 g, 51.67 mmol) in THF (50 mL). The reaction system was stirred at 20 °C for 1 hour, then cooled to -70 °C. While stirring, a solution of intermediate 16c (6 g, 17.22 mmol) in THF (50 mL) was slowly added dropwise to the reaction solution (over 10 min). The reaction system was warmed to 20 °C and stirred at this temperature for 3 hours. 50 mL of methanol was added to the reaction solution, followed by 50 mL of saturated sodium potassium tartrate solution. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C to obtain a crude product. The crude product was purified by column chromatography (eluent: PE / EA = 5 / 1 - 1 / 1, V / V) to obtain intermediate 16d. 1 H NMR (400 MHz, CDCl 3 ) 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), Na 2 CO 3 (458.93 mg, 4.33 mmol) and Pd(OAc) 2(32.40 mg, 144.33 μmol) was added to DMF (5 mL), replaced with nitrogen gas three times, and stirred at 130 °C for 12 hours. 10 mL of water was added to the reaction solution, and then extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 50 °C to obtain a 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), replaced with argon gas once, Pd / C (200 mg) was added to the reaction flask, replaced with hydrogen gas three times, and the reaction system was stirred at 30 °C under 30 psi of hydrogen gas for 16 hours. The reaction solution was suction filtered through diatomaceous earth under reduced pressure, 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 Intermediate 16g 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 solution. The reaction system was stirred at 50 °C for 2 hours. The reaction solution was suction filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain Intermediate 16g. MS m / z: 348.2 [M+1] + 。

[0280] Step 7: Synthesis of Intermediate 16h Intermediate 16g (80 mg, 230.28 μmol) was added to ethanol (2 mL), then methylamine-ethanol solution (2.53 g, 24.44 mmol) was added to the reaction solution. The reaction system was stirred at 30 °C for 16 hours. The reaction solution was 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), and then hydrogen chloride / dioxane (4 M, 144.33 μL) was added to the reaction solution. The reaction system was stirred at 30 °C for 4 hours, and the reaction solution was 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 salt of Compound 16 Et 3 N (10.74 mg, 106.09 μmol, 14.77 μL) was added to the hydrochloride salt of intermediate 16i (15 mg) in DMF (1 mL). 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 solution. The reaction system was stirred at 50 °C for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain a 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 salt of Compound 16. MS m / z: 437.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) 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, 1 H) 1.85~1.98 (m, 1 H).

[0283] Example 17

Chemical Structure

[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). After stirring for 30 minutes, acetyl chloride (6.04 g, 76.92 mmol, 5.47 mL) was slowly added dropwise, and then the temperature was raised to 25 °C and reacted for 3 hours. The reaction solution was added to 100 mL of water and extracted with dichloromethane (40 mL × 5). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which 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-d 6 ) 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, cooled to 0 °C, and Intermediate 17b was added in portions. Then, sulfuric acid (334.75 mmol, 17.84 mL) was slowly added dropwise, and the addition was completed within 1 hour while maintaining the temperature at 0 °C. Then, the temperature was raised to 25 °C and reacted for 1 hour. The reaction solution was poured into 100 mL of 3M sodium hydroxide solution at 0 °C, and the pH was adjusted to about 7. Extracted with ethyl acetate (30 mL × 5), the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate 17c. 1 H NMR (400 MHz, DMSO-d 6 ) 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 the reaction was carried out at 50 °C for 2 hours. The reaction solution was poured into 100 mL of ice water, adjusted to pH = 7 - 8 with 3 M NaOH solution, filtered, and the obtained cake was washed with 10 mL of water and dried under vacuum 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 one batch, and the reaction was carried out for 1 hour. The reaction solution was poured into 500 mL of water, extracted with ethyl acetate (80 mL × 5), the organic phase was washed with saturated brine (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 pyruvic acid (1.49 g, 16.95 mmol, 1.19 mL) was added dropwise, and the reaction was carried out at 100 °C for 2 hours. The reaction solution was concentrated under reduced pressure, 10 mL of ethanol was added and stirred for 20 minutes, filtered, and the cake was collected to obtain Intermediate 17f as a mixture. MS m / z: 274.9, 276.9 [M+1] + .

[0289] Step 6: Synthesis of Intermediate 17g The intermediate 17f (3.05 g, 11.09 mmol), which is a mixture, and 1-(tributylstannyl)methanol (4.27 g, 13.31 mmol) were dissolved in dioxane (30 mL). Next, 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. After purging with nitrogen gas, the reaction was carried out at 110 °C for 3 hours. The reaction solution was concentrated under reduced pressure. The crude product was obtained by purification using flash silica gel column chromatography (EA / PE = 0% - 30%, MeOH / DCM = 0% - 5%). Further, preparative HPLC (column chromatography: Welch Xtimate C18 100×40 mm×3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: 0% - 26% acetonitrile, 8 min) was used for purification to obtain intermediate 17g. 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 a solution of intermediate 17g (30 mg, 132.64 μmol) in DCM (2 mL), and the mixture was stirred for 2 hours. 0.057 g of calcium hydroxide was added to the reaction solution, and the mixture was stirred at 25 °C for 1 hour, filtered, and the cake was washed with dichloromethane (10 mL×3). The filtrate was concentrated under reduced pressure at 50 °C to obtain the crude product. The crude product was separated and purified using a preparative thin layer chromatography plate (PE:EA = 1:1) to obtain intermediate 17h. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Dissolve Intermediate 9g (21.86 mg, hydrochloride) in DMSO (1 mL), add triethylamine (13.54 mg, 133.83 μmol) to the reaction solution while stirring, stir at 25 °C for 30 minutes, add Intermediate 17h (15 mg, 66.92 μmol) to the reaction solution, adjust the pH to 6 - 7 with acetic acid, stir at 25 °C for 2 hours, and add NaBH(OAc) 3 (28.36 mg, 133.83 μmol) to the reaction solution, and stir at 25 °C for 16 hours. Add 2 mL of water to the reaction solution, extract 3 times with EA (5 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain a crude product. Purify the crude product by HPLC (column chromatography: Welch Xtimate C18 100×40 mm×3 μm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: 0% - 30% acetonitrile, 8 min). After basifying the obtained product with triethylamine (3 μL), further purify it by preparative thin-layer chromatography plate (100% EA) to obtain Compound 17. MS m / z: 447.1 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) 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

Chemical Structure

[0293] Step 1: Synthesis of Compound 18 Intermediate 14i (19.87 mg, hydrochloride) was dissolved in DMSO (1 mL), and while stirring, triethylamine (133.83 μmol, 18.63 μL) was added to the reaction solution. The mixture was stirred at 25 °C for 30 minutes, then Intermediate 17h (15.00 mg, 66.92 μmol) was added to the reaction solution. 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 solution, and the mixture was stirred at 25 °C for 16 hours. 2 mL of water was added to the reaction solution, and the mixture was extracted with EA (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a 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 a crude product. 3 μL of triethylamine was further added to the crude product, and the crude product was purified by preparative thin-layer chromatography plate (100% EA) to obtain Compound 18. MS m / z: 455.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[0295] Step 1: Synthesis of 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 h. Then, 17h (8.36 mg, 37.29 μmol) was added, and the pH was adjusted to 6 - 7 with acetic acid. The mixture was stirred at 20 °C for 2 h, and then NaBH(OAc) 3 (15.81 mg, 74.58 μmol) was added, and the mixture was stirred for 16 h. 3 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 3 mL). The organic phases were combined, washed with 3 mL of saturated brine, dried over anhydrous sodium sulfate, filtered to obtain a 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 salt of Compound 19. MS m / z: 455.1 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[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). After stirring for 0.5 h, acetyl chloride (2.42 g, 30.77 mmol, 2.19 mL) was slowly added dropwise. Then, the temperature was raised to 18 °C and the reaction was carried out for 3 h. The reaction solution was added dropwise to 100 mL of water and extracted with dichloromethane (20 ml × 5). The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and further purified by silica gel column chromatography (EA / PE = 0% - 10%) to obtain intermediate 20b. MS m / z: 250.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ) 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 addition was complete, the mixture was stirred at 25 °C for 1 h. The reaction solution was added dropwise to water, and a solid precipitated. 2M NaOH solution was added to adjust the pH to 6 - 7, and then filtered. The cake was dried to obtain intermediate 20c. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm10.48 (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 h. The reaction solution was added to 400 mL of water, and 2M NaOH solution was added to adjust the pH to 6 - 7. A solid precipitated, and it was filtered to obtain a cake, which was dried under vacuum to obtain intermediate 20d.1 H NMR (400 MHz, DMSO-d 6 ) 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 portions at 0 °C, and the mixture was stirred at 40 °C for 1 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a 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-d 6 ) 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 pyruvic acid (540.17 mg, 6.13 mmol, 432.14 μL) was added, and the mixture was stirred at 100 °C for 2 h, slowly cooled to 25 °C and crystallized for 14 h. The reaction solution was filtered to obtain a cake, which was Intermediate 20f (mixture). MS m / z: 274.9 [M+1] + .

[0302] Step 6: Synthesis of Intermediate 20g Under the protection of nitrogen gas, intermediate 20f (500 mg, 1.82 mmol) was dissolved in dioxane (5 mL), 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 solution was concentrated under reduced pressure, and the crude product was obtained by separation and purification by column chromatography (eluent: PE:EA = 90:10~50:50, V / V). 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%~26% acetonitrile) to obtain intermediate 20g. MS m / z: 226.8 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ) 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 Intermediate 20g (100 mg, 442.13 μmol) 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 solution and stirred at 20 °C for 1 hour. The mixture was filtered to obtain the crude product, and the crude product was separated and purified by preparative thin-layer chromatography plate (DCM:MeOH = 20:1) to obtain intermediate 20h. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Dissolve Intermediate 14i (13.25 mg, hydrochloride) in DMSO (1 mL), add triethylamine (9.03 mg, 89.22 μmol, 12.42 μL) to the reaction solution while stirring, stir at 25 °C for 30 minutes, add Intermediate 20h (10 mg, 44.61 μmol) to the reaction solution, adjust the pH to 6 - 7 with acetic acid, stir at 25 °C for 2 hours, and add NaBH(OAc) 3 (18.91 mg, 89.22 μmol) to the reaction solution, and stir the reaction system at 25 °C for 16 hours. Add 2 mL of water to the reaction solution, extract with EA (5 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain a crude product, and separate the crude product 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 a crude product. Add another 3 μL of triethylamine to the crude product, and purify by preparative thin-layer chromatography plate (100% EA) to obtain Compound 20. MS m / z: 455.2 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[0306] Step 1: Synthesis of Compound 21 Dissolve Intermediate 16i (15 mg, hydrochloride) in DMSO (1 mL), add triethylamine (9.06 mg, 89.50 μmol, 12.46 μL), stir at 20 °C for 0.5 h, then add Intermediate 20h (12.54 mg, 44.75 μmol), adjust the pH to 6 - 7 with acetic acid, stir at 20 °C for 2 h, and then add NaBH(OAc) 3 (18.97 mg, 89.50 μmol), and stir for 16 h. Add 3 mL of water and ethyl acetate (3 × 3 mL) to the reaction solution for extraction. Combine the organic phases, wash with 10 mL of saturated brine, dry over anhydrous sodium sulfate, filter to obtain the crude product. Separate the crude product 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, separate and purify it by preparative thin-layer chromatography plate (EA = 100%) to obtain Compound 21. MS m / z: 455.0 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[0308] Step 1: Synthesis of Trifluoroacetate Salt of Compound 22 Intermediate 9g (7.29 mg, hydrochloride) 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 h. Further, Intermediate 20h (5 mg, 22.31 μmol) was added, and the pH was adjusted to 6 - 7 with acetic acid, followed by stirring for 2 h. NaBH(OAc) 3 (9.45 mg, 44.61 μmol) was added and the mixture was stirred for 4 h. 1 mL of water and ethyl acetate (3 × 1 mL) were added to the reaction solution for extraction. 10 mL of saturated brine was added to the organic phase for washing, dried, filtered to obtain a 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 trifluoroacetate salt of Compound 22. MS m / z: 447.1 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[0310] Step 1: Synthesis of Intermediate 23a Compound 17g (100.00 mg, 442.13 μmol) and 1,2 - dibromo - 1,1,2,2 - tetrachloroethane (316.74 mg, 972.68 μmol) were dissolved in DCM (5 mL). Tri - n - butylphosphine (178.90 mg, 884.25 μmol) was added at 0 °C. After the addition was completed, the temperature was raised to 25 °C and the mixture was stirred for 12 h. The reaction solution was filtered to obtain a cake, which was Intermediate 23a. 11H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.63 (broad singlet, 1H), 7.33~7.72 (multiplet, 1H), 4.71~4.94 (multiplet, 2H), 2.43 (singlet, 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 solution was filtered, and the filtrate was concentrated to obtain a 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 a crude product. After adding triethylamine (20 μL) to the crude product, it was separated and purified by preparative plate (development ratio: DCM:MeOH = 10:1) to obtain Compound 23. MS m / z: 444.1 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.54 (broad singlet, 1H), 8.63 (broad doublet, J = 5.00 Hz, 1H), 8.05 (doublet of doublets, J = 9.82, 7.82 Hz, 1H), 7.91 (doublet of doublets, J = 7.69, 1.69 Hz, 1H), 7.46 (doublet, J = 8.88 Hz, 1H), 6.14~6.27 (multiplet, 1H), 3.80 (singlet, 2H), 3.13~3.26 (multiplet, 3H), 2.79 (doublet, J = 4.88 Hz, 3H), 2.60~2.76 (multiplet, 3H), 2.44 (singlet, 3H).

[0312] Example 24

Chemical Structure

[0313] Step 1: Synthesis of Intermediate 24a Compound 20g (100.00 mg, 442.13 μmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (316.74 mg, 972.68 μmol) were dissolved in DCM (5 mL), and tri-n-butylphosphine (178.90 mg, 884.25 μmol) was added at 0 °C. After the addition was completed, the temperature was raised to 25 °C and stirred for 8 hours. The reaction solution was filtered to obtain a cake, which was Intermediate 24a. 1 H NMR (400 MHz, DMSO-d 6 ) 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 DMF (2 mL) solution of Intermediate 6d (25.64 mg, hydrochloride), 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 solution was filtered, and the filtrate was concentrated to obtain a 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 a crude product. After adding triethylamine (20 μL) to the crude product, it was separated and purified by preparative plate (development ratio: DCM:MeOH = 10:1) to obtain Compound 24. MS m / z: 444.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.63 (broad singlet, 1H), 8.64 (broad doublet, J = 4.63 Hz, 1H), 8.01 - 8.17 (multiplet, 1H), 7.92 (broad doublet, J = 7.38 Hz, 1H), 7.07 - 7.28 (multiplet, 1H), 6.25 (broad singlet, 1H), 3.75 (singlet, 2H), 3.18 - 3.25 (multiplet, 3H), 2.80 (broad doublet, J = 4.63 Hz, 3H), 2.65 - 2.76 (multiplet, 3H), 2.44 (singlet, 3H).

[0315] Example 25 [Chemical Structure]

[0316] Step 1: Synthesis of Intermediate 25a Compound 1a (6.1 g, 25.63 mmol), methylamine acetate (3.54 g, 28.19 mmol, HCl), N,N - diisopropylethylamine (9.94 g, 76.90 mmol) were added to DMF (60 mL), and the reaction was carried out at 25 °C for 18 hours. The reaction solution was poured into 300 mL of water and extracted with ethyl acetate (100 mL × 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 a crude product. The crude product was purified by flash silica gel column chromatography (EA / PE = 0% - 10%) to obtain Intermediate 25a. 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 7.54 - 7.68 (multiplet, 2H), 6.70 (doublet, J = 7.8 Hz, 1H), 4.20 (doublet, J = 4.2 Hz, 2H), 3.68 (singlet, 3H).

[0317] Step 2: Synthesis of Intermediate 25b Intermediate 25a (1.82 g, 5.93 mmol), NH 4 Cl (2.54 g, 47.42 mmol) were added to MeOH (26 mL) and H 2Added to the mixed solution of O(0.468 mL), and then Zn(1.98 g, 30.29 mmol) was added, and the reaction was carried out at 0 °C for 2 hours. Filtered, 50 mL of water was added to the filtrate, extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, the filtrate was filtered, and 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 mixed system of hydrogen chloride / dioxane (4 M, 15.64 mL), EA (13.5 mL), and MeOH (13.5 mL), and the reaction was carried out for 2 hours. The reaction solution 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), the temperature was raised to 25 °C and the reaction was carried out for 4 hours. The reaction solution was concentrated under reduced pressure, slowly 70 ml of saturated sodium bicarbonate solution was added, and stirred overnight. Extracted with ethyl acetate (3 × 50 mL), the combined organic phases were washed with 70 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a 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 H NMR (400 MHz, DMSO-d 6 ) 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), 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, and 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), separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a 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 H NMR (400 MHz, DMSO-d 6 ) 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), stirred for 10 minutes, and further Intermediate 25e (700.00 mg, 1.93 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. Water (5 mL) was added to the reaction solution, 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 a crude product. The crude product was purified by flash silica gel column chromatography (first, PE:EA = 3:1~1:1, then, DCM:MeOH = 10:1) to obtain Intermediate 25f. MS m / z: 402.0, 404.0 [M+1] + , 1 H NMR (400 MHz, CDCl 3 ) 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 Intermediate 25g 1-(Tributylstannyl)methanol (191.59 mg, 596.69 μmol), Intermediate 25f (200 mg, 497.24 μmol) were dissolved in 1,4-dioxane (5 mL), 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 h. Next, 1-(tributylstannyl)methanol (31.93 mg, 99.44 μmol) was added, and the mixture was continuously stirred at 80 °C for 2 h, then heated to 100 °C and continuously stirred for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, and the crude product was purified by flash silica gel column chromatography (elution rate: PE:EA = 1:1 - DCM:MeOH = 10:1) to obtain Intermediate 25g. MS m / z: 354.1 [M+1] + .

[0323] Step 8: Synthesis of Intermediate 25h At 15 - 25 °C, Intermediate 25g (80 mg, 226.41 μmol) was added to a reaction flask, trifluoroacetic acid (3.07 g, 26.93 mmol, 2.00 mL) was added, trifluoromethanesulfonic acid (4.52 mmol, 400.00 μL) was added, and the mixture was stirred for 2 h. 5 mL of water was added to the reaction solution, 5 mL of methanol was added, solid potassium carbonate was added to adjust the pH to 10, and the mixture was continuously stirred for 1 h. Dichloromethane (20 mL) was added to the reaction solution for extraction, the organic phases were combined, washed with water (15 mL × 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), 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 solution was directly concentrated under reduced pressure to obtain Intermediate 25i as a crude product.

[0325] Step 10: Synthesis of the trifluoroacetate salt of Compound 25 Intermediate 25i (30 mg) and Compound 9g (28.97 mg, hydrochloride) were dissolved in DMF (1 mL), and Et 3 N (10.25 mg, 101.32 μmol) and KI (16.82 mg, 101.32 μmol) were added. 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 × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative chromatography plate (development 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 salt of Compound 25. MS m / z: 454.2 [M+1] + , 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[0327] Step 1: Synthesis of Intermediate 26a Methyl 2-pyrrolecarboxylate (262.88 mg, 2.10 mmol) and Compound 1a (500 mg, 2.10 mmol) were dissolved in DMF (10 mL), and sodium hydride (126.05 mg, 3.15 mmol, purity: 60%) was added in one portion. The mixture was stirred at room temperature (20 °C) for 3 hours. The reaction solution was slowly added dropwise to 20 mL of saturated ammonium chloride solution, and ethyl acetate (2 × 30 mL) was added for extraction. The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a 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 as a mixture (ratio: about 2:1). MS m / z: 342.8, 344.8 [M+1] + 。

[0328] Step 2: Synthesis of Intermediate 26b The intermediate compound 26a (370 mg) as a mixture was dissolved in dioxane (10 mL), and 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. The mixture was stirred at 110 °C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by flash silica gel column chromatography (gradient elution: PE:EA = 100:0~60:40) to obtain Intermediate 26b as a mixture. MS m / z: 294.9 [M+1] + 。

[0329] Step 3: Synthesis of Intermediate 26c The intermediate 26b (185 mg), which is a mixture, was dissolved in MeOH (3 mL), replaced with argon gas, and palladium hydroxide (8.83 mg, 62.87 μmol) was added. The reaction flask was replaced with hydrogen gas and stirred at 30 °C under 50 psi for 16 hours. It was filtered, the filtrate was concentrated under reduced pressure, 2 mL of DMF and 5 drops of triethylamine were added, and it was stirred at 90 °C for 16 hours. DMF was removed with an oil pump to obtain a crude product. A mixed solution of DCM and MeOH (DCM:MeOH = 1:1, 3 mL) was added to the crude product, and it was filtered to obtain a cake, which was intermediate 26c. MS m / z: 232.8 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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 The 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 completed, it was stirred at room temperature of 20 °C for 16 hours. 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 solution was filtered to obtain a cake, which was intermediate 26d. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.41 (broad singlet, 1H), 8.20 - 8.21 (multiplet, 1H), 7.85 (doublet, J = 4.40 Hz, 1H), 7.36 (triplet, J = 8.20 Hz, 1H), 7.10 - 7.11 (multiplet, 1H), 6.73 - 6.75 (multiplet, 1H), 4.79 (singlet, 2H).

[0331] Step 5: Synthesis of Compound 26 Intermediate 9g (11.83 mg, hydrochloride) was dissolved in DMF (1 mL), and triethylamine (17.43 mg, 172.26 μmol) was added. After stirring at 25 °C for 0.5 h, Intermediate 26d (10 mg, 43.06 μmol) and potassium iodide (3.57 mg, 21.53 μmol) were further added, and the mixture was stirred at 50 °C for 2 h. 2 mL of water was added to the reaction solution, 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 a crude product. The crude product was separated and purified by a thin-layer chromatography plate (DCM:MeOH = 30:1) to obtain Compound 26. MS m / z: 453.0 [M + 1] + .

[0332] Example 27

Chemical Structure

[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 completed, the mixture was stirred at room temperature of 20 °C for 19 h. The reaction solution was filtered to obtain a cake, which was Intermediate 27a. 1 H NMR (400 MHz, DMSO-d 6) 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 h. 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 h. 2 mL of water was added to the reaction solution, and the mixture was extracted three times with 5 mL of a mixed solution (DCM:MeOH = 10:1). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product. The crude product was stirred with EA (0.5 mL) for 10 min, filtered to obtain a cake, which was Compound 27. MS m / z: 462.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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 [Chemical formula]

[0336] Step 1: Synthesis of Compound 28 Compound 26d (25 mg, 84.72 μmol) was dissolved in DMF (1 mL), and after adding triethylamine (34.29 mg, 338.86 μmol), the mixture was stirred at 25 °C for 0.5 h. Then, Compound 6d (23 mg, hydrochloride) and potassium iodide (7.03 mg, 42.36 μmol) were added, and the mixture was stirred at 50 °C for 2 h. 2 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. 0.5 mL of ethyl acetate was added to the crude product, and the mixture was stirred for 10 min and then filtered to obtain a cake, which was Compound 28. MS m / z: 450.0 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[0338] Step 1: Synthesis of Intermediate 29a Deuterated methylamine hydrochloride (124.71 mg, 1.77 mmol) was added to H 2In addition to O(1 mL), sodium tert-butoxide (84.95 mg, 884.01 μmol) was then added to the above reaction solution, 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 solution, and the reaction system was heated to 60 °C and reacted for 4 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was intermediate 29a. MS m / z: 342.1 [M+1] + 。

[0339] Step 2: Synthesis of hydrochloride salt of intermediate 29b Intermediate 29a (20 mg) was dissolved in MeOH (0.6 mL), HCl / dioxane (4 M, 0.2 mL) was added, and the mixture was stirred at 20 °C for 2 hours. The reaction solution 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 salt) 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 solution, and the mixture was filtered to obtain a cake, which was compound 29. MS m / z: 468.2 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6) 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

Chemical Structure

[0342] Step 1: Synthesis of Compound 30 Dissolve Intermediate 16i (29.46 mg, hydrochloride) in DMF (2 mL), add triethylamine (52.72 mg, 520.97 μmol), stir at 25 °C for 0.5 h, then add Intermediate 27a (40 mg, 130.24 μmol) and KI (21.62 mg, 130.24 μmol), and stir at 50 °C for 2 h. Add 2 mL of water to the reaction mixture, extract with ethyl acetate (3 × 3 mL), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. Add 0.5 mL of ethyl acetate to the crude product, stir for 10 min, filter to obtain a cake, and further separate and purify by preparative thin-layer chromatography plate (DCM:MeOH = 20:1) to obtain Compound 30. MS m / z: 473.0 [M+1] + . 1 H NMR (400 MHz, CDCl 3) 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 [Chemical formula]

[0344] Step 1: Synthesis of Intermediate 31a Deuterated methylamine hydrochloride (167.77 mg, 2.38 mmol) was added to H 2 O (1 mL), potassium tert-butoxide (133.44 mg, 1.19 mmol) was added to the above reaction solution, and the mixture was stirred at 25 °C for 1 hour. A solution of compound 6b (40 mg, 118.92 μmol) in MeOH (2 mL) was added to the reaction solution, and the reaction system was heated to 60 °C and reacted for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain a 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 (4M, 99.74 μL) was added, and the mixture was stirred at room temperature (25 °C) for 2 hours. The reaction solution 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 h. 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 h. After cooling, 2 mL of water was added to the reaction solution, and a solid precipitated. The solid was filtered to obtain a cake, which was Compound 31. MS m / z: 465.1 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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 [Chemical formula]

[0348] Step 1: Synthesis of Intermediate 32a Intermediate 4a (0.2 g, 589.34 μmol) was dissolved in THF (5 mL) and H 2To the mixture of O(1 mL), while stirring, lithium hydroxide monohydrate (123.65 mg, 2.95 mmol) was added to the reaction solution, and the reaction system was stirred at 20 °C for 4 hours. The pH of the reaction solution was adjusted to 3 - 4 with dilute hydrochloric acid (1 mol / L), and it was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, the organic phase was 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 solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by preparative plate (PE / EA = 2 / 1) to obtain intermediate 32b. MS m / z: 351.1 [M-56+1] + 。

[0350] Step 3: Synthesis of hydrochloride of intermediate 32c Intermediate 32b (57.66 mg, 141.88 μmol) was added to MeOH (2 mL), while stirring, HCl / dioxane (4 M, 191.54 μL) was added to the reaction solution, and the reaction system was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure at 45 °C to obtain a crude product, which was the hydrochloride 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 h. Intermediate 27a (30 mg, 78.15 μmol) and potassium iodide (1.30 mg, 7.81 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 h, filtered, and the filtrate was concentrated under reduced pressure at 60 °C to obtain a crude product. The crude product was purified by preparative chromatography plate (EA: 100%) to obtain compound 32. MS m / z: 555.1 [M+23] + 。 1 H NMR (400 MHz, CDCl 3 ) 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

Chemical formula

[0353] Step 1: Synthesis of intermediate 33d Toluene (30 mL) was added to 10a (3 g, 13.89 mmol) and dissolved. Next, 1-(tert-butoxycarbonyl)piperazine (2.59 g, 13.89 mmol), RuPhos (648.01 mg, 1.39 mmol), Pd 2 (dba) 3 (381.49 mg, 416.61 μmol), Cs 2 CO 3(13.57 g, 41.66 mmol) was added, and the mixture was stirred at 100 °C for 16 h under a nitrogen gas atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a 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 the condition 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 mixture was stirred at 25 °C for 1 h for reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. 10 mL of dichloromethane was added to dissolve it, 10 mL of water was added for washing, extraction, and separation, 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, CDCl 3 ) 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 h. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 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] + 。1 H NMR (400 MHz, CDCl 3 ) 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 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 h. The reaction solution 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 salt), potassium iodide (5.41 mg, 32.56 μmol), and triethylamine (26.36 mg, 260.49 μmol) were sequentially added to DMF (1 mL), heated to 50 °C, and stirred for 12 h. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. 1.2 mL of methanol was added to the crude product, and the mixture was stirred for 10 min, then filtered to obtain a cake, which was Compound 33. MS m / z: 481.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.90 (broad singlet, 1 H), 9.08 - 9.09 (multiplet, 1 H), 8.65 (doublet, J = 2.40 Hz, 2 H), 8.43 (doublet, J = 4.20 Hz, 1 H), 7.93 (doublet, J = 3.92 Hz, 1 H), 7.66 - 7.74 (multiplet, 2 H), 7.33 - 7.39 (multiplet, 1 H), 3.77 (singlet, 2H), 3.05 - 3.15 (multiplet, 4 H), 2.79 (doublet, J = 2.40 Hz, 3 H), 2.65 - 2.68 (multiplet, 4 H).

[0358] Example 34

Chemical Structure

[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 successively RuPhos (79.76 mg, 170.92 μmol), Cs 2 CO 3 (556.90 mg, 1.71 mmol) and Pd 2 (dba) 3 (78.26 mg, 85.46 μmol) were added. Under the protection of nitrogen gas, the mixture was stirred at 100 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a 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] + , 1 H NMR (400 MHz, CDCl 3) 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, 3 H).

[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 h. The reaction solution was directly concentrated under reduced pressure to obtain Intermediate 34b. MS m / z: 367.0 [M+1] + , 1 H NMR (400 MHz, CDCl 3 ) 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, 3 H).

[0361] Step 3: Synthesis of hydrochloride salt of Intermediate 34c Intermediate 34b (170 mg, 463.94 μmol) was dissolved in MeOH (2 mL), and HCl / dioxane (4M, 0.62 mL) was added. The mixture was stirred at 25 °C for 3 h. The reaction solution 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 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 h. 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 h. The reaction solution 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, CD 3 OD) 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, 1 H), 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 [Chemical formula]

[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 successively Cs 2 CO 3 (821.00 mg, 2.52 mmol), RuPhos (39.19 mg, 83.99 μmol), and Pd 2 (dba) 3 (38.46 mg, 42.00 μmol) were added. Under the protection of nitrogen gas, the mixture was stirred at 100 °C for 16 h. The reaction solution was filtered while it was hot, and the filtrate was concentrated under reduced pressure to obtain a crude product. 2 mL of a mixed solution 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 h, then filtered by suction, and the cake was dried 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), methylamine-ethanol solution (1.13 g, 10.89 mmol, 30%) was added, and the mixture was stirred at room temperature of 25 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain Intermediate 35b. MS m / z: 367.1 [M+1] + 。

[0366] Step 3: Synthesis of hydrochloride salt of Intermediate 35c Intermediate 35b (100 mg, 272.90 μmol) was dissolved in MeOH (2 mL), HCl / dioxane (4 M, 0.38 mL) was added, and the mixture was stirred at 25 °C for 2 h. The reaction solution 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 trifluoroacetate salt 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 h. Intermediate 27a (30 mg, 78.15 μmol) and KI (1.30 mg, 7.815 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a 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, CD 3 OD) 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

Chemical formula

[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), and successively RuPhos (59.82 mg, 128.19 μmol), Cs 2 CO 3 (417.68 mg, 1.28 mmol), and Pd 2 (dba) 3 (58.69 mg, 64.10 μmol) were added. Under the protection of nitrogen gas, the mixture was stirred at 100 °C for 16 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a 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, CDCl 3 ) 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 h. The reaction solution was directly concentrated under reduced pressure to obtain Intermediate 36b. MS m / z: 353.1 [M+1] + 。 1 H NMR (400 MHz, CDCl 3) 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 hydrochloride salt of intermediate 36c Intermediate 36b (51 mg, 428.49 μmol) was dissolved in MeOH (2 mL), HCl / dioxane (4 M, 0.54 mL) was added, and the mixture was stirred at 25 °C for 2 h. The reaction solution 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 DMF (1 mL) of intermediate 36c (21.18 mg, hydrochloride salt), the reaction system was stirred at 20 °C for 0.5 h, intermediate 27a (25 mg, 81.40 μmol) and KI (6.76 mg, 40.70 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 h. 2 mL of water was added to the reaction solution, 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 a crude product. 1 mL of methanol was added to the crude product, and the mixture was stirred for 10 min, then filtered to obtain a cake, which was compound 36. MS m / z: 479.0 [M+1] + . 11H 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 [Chemical formula]

[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 successively Cs 2 CO 3 (634.47 mg, 1.95 mmol), RuPhos (30.29 mg, 64.91 μmol), and Pd 2 (dba) 3 (29.72 mg, 32.46 μmol) were added. Under the protection of nitrogen gas, the mixture was stirred at 100 °C for 16 hours. The reaction solution was filtered while it was hot, and the filtrate was concentrated under reduced pressure to obtain a crude product. 2 mL of a mixed solution 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 hour, filtered by suction while reducing the 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 a methylamine-ethanol solution (1.13 g, 10.89 mmol, 30%) was added. The mixture was stirred at 20 °C for 16 h. The reaction solution 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 h. The reaction solution 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 Intermediate 37c (15.04 mg, hydrochloride salt) in DMF (1 mL). The reaction system was stirred at 20 °C for 0.5 h, Intermediate 27a (20 mg, 52.10 μmol) and KI (864.82 μg, 5.21 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate (EA, 100%) to obtain Compound 37. MS m / z: 479.1 [M+1] + 。

[0378] Example 38

Chemical formula

[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 this temperature for 2 hours. At 0 - 5 °C, 10 mL of water was added to the reaction solution, and the mixture was extracted with DCM (10 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a 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, CDCl 3 ) 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 (1.3 g, 3.98 mmol) and potassium carbonate (1.65 g, 11.94 mmol) were added to DMF (15 mL). Next, p-methoxybenzyl chloride (747.85 mg, 4.78 mmol) was added, and the temperature was raised to 90 °C and stirred for 2 hours. After filtration, 15 mL of water was added to the filtrate, and the mixture was extracted with EA (30 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain a 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(diphenylphosphino)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 with microwave at 120 °C for 10 minutes. The reaction solution was filtered, the cake was washed with EA (30 mL), and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by a column chromatography plate (eluent: PE:EA = 100:0~90:10, V / V) to obtain intermediate 38d. MS m / z: 411.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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 stirred at 25 °C for 1 hour. 4 mL of water was added to the reaction solution, a solid precipitated, and the solid was filtered to obtain a cake, which was intermediate 38e. 1 H NMR (400 MHz, DMSO-d 6 ) 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, LiAlH 4 (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 sequentially and slowly added to the reaction solution, and then 72 μL of ice water was added to quench the reaction system. 2 mL of water was added to the reaction solution, and it was extracted with EA (3 mL × 2). The organic phases were combined, dried, concentrated to obtain a crude product, stirred with 3 mL of a mixed solution (PE:EA = 1:1) for 10 minutes, and filtered to obtain a cake, which was Intermediate 38f. MS m / z: 263.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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 Intermediate 38g 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 temperature was raised to 25 °C (room temperature) and stirred for 3 hours. The reaction solution was filtered to obtain a cake, which was Intermediate 38g. 1 H NMR (400 MHz, DMSO-d 6) 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 Intermediate 9g (16.90 mg, hydrochloride) in DMF (1 mL). After stirring for 30 minutes, Intermediate 38g (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. While stirring, 2 mL of water was added to the reaction solution, and the mixture was stirred for about 10 minutes and then filtered to obtain a cake, which was Compound 38. MS m / z: 483.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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), and successively RuPhos (79.76 mg, 170.92 μmol), Cs 2 CO 3(556.90 mg, 1.71 mmol) and Pd 2 (dba) 3 (78.26 mg, 85.46 μmol) were added, and the mixture was stirred at 100 °C for 16 h under the protection of nitrogen gas. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a 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), methylamine-ethanol solution (659.13 mg, 21.22 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain Intermediate 39b. MS m / z: 353.0 [M+1] + .

[0388] Step 3: Synthesis of 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 h. The reaction solution 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 trifluoroacetate salt 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 × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The trifluoroacetate of Compound 39 was obtained by preparative HPLC (column chromatography: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: 3% - 33% acetonitrile). MS m / z: 479.2 [M+1] + 。 1 H NMR (400 MHz, CD 3 OD) 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, 3 H), 1.13 (d, J=6.27 Hz, 3 H).

[0390] Example 40

Chemical Structure

[0391] Step 1: Synthesis of the trifluoroacetate of Compound 40 At 25 °C, triethylamine (15.56 mg, 153.80 μmol) was added to a DMF (1 mL) solution of intermediate 6d (16.72 mg, hydrochloride). After stirring for 30 minutes, intermediate 38g (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 solution 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] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude 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] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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 (1.8 g, 5.10 mmol) and potassium carbonate (2.11 g, 15.29 mmol) were added to DMF (20 mL), then p-methoxybenzyl chloride (957.90 mg, 6.12 mmol) was added. The temperature was raised to 90 °C and the mixture was stirred for 3 h. The mixture was filtered, 20 mL of water was added to the filtrate, and the mixture was extracted with EA (30 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain a 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(diphenylphosphino)propane (104.57 mg, 253.54 μmol), Pd(OAc) 2 (56.92 mg, 253.54 μmol), potassium carbonate (175.21 mg, 1.27 mmol) were added to DMF (10 mL), and the reaction system was reacted with microwave at 140 °C for 10 minutes. The reaction solution was filtered, 20 mL of water was added to the filtrate, and it was extracted 3 times with EA (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (eluent: PE:EA = 100:0~60:40, V / V) to obtain intermediate 41d. MS m / z: 393.1 [M+1] + , 1 H NMR (400 MHz, DMSO-d 6 ) 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 stirred at 25 °C for 1 hour. 2 mL of water was added to the reaction solution, 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-d 6) δ ppm 12.17 (broad singlet, 1H), 9.95 (singlet, 1H), 8.93 (doublet, J = 5.13 Hz, 1H), 8.52 (doublet, J = 8.50 Hz, 1H), 8.19 (doublet, J = 5.25 Hz, 1H), 7.72 (doublet of doublets, J = 8.44, 6.69 Hz, 1H), 3.93 (singlet, 3H).

[0397] Step 5: Synthesis of Intermediate 41f Under the protection of nitrogen gas and at 0 °C, LiAlH 4 (2.5 M solution in tetrahydrofuran, 205.71 μL) was added to a solution of Intermediate 41e (140 mg, 514.27 μmol) in THF (5 mL), 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 to the reaction solution in sequence, and then 90 μL of ice water was added for quenching. 10 mL of water was added to the reaction solution, and it was extracted with EA (20 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was Intermediate 41f. MS m / z: 245.1 [M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.96 (broad singlet, 1H), 9.89 (singlet, 1H), 8.85 (doublet, J = 5.02 Hz, 1H), 8.41 (doublet, J = 8.53 Hz, 1H), 8.14 (doublet, J = 5.02 Hz, 1H), 7.39 (triplet, J = 7.65 Hz, 1H), 5.46 (triplet, J = 5.77 Hz, 1H), 4.68 (doublet, J = 4.77 Hz, 2H).

[0398] Step 6: Synthesis of Intermediate 41g 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), and tributylphosphine (82.84 mg, 409.47 μmol) was added at 0 °C. The temperature was raised to 25 °C (room temperature) and stirred for 3 hours. The reaction solution was filtered to obtain a cake, which was Intermediate 41g.1 1H NMR (400 MHz, DMSO-d 6 ) 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 trifluoroacetate salt of Compound 41 At 25 °C, triethylamine (153.80 μmol, 21.41 μL) was added to a solution of Intermediate 9g (16.90 mg, hydrochloride) in DMF (1 mL). After stirring for 30 minutes, Intermediate 41g (25 mg, 81.40 μmol) and KI (1.35 mg, 8.14 μmol) were added, and the mixture was stirred at 50 °C for 2 hours. The reaction solution 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 salt of Compound 41. MS m / z: 465.2 [M+1] + . 1 1H NMR (400 MHz, CD 3 OD) 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 [Chemical formula]

[0401] Step 1: Synthesis of trifluoroacetate salt of Compound 42 Triethylamine (16.47 mg, 162.80 μmol) was added to a DMF (1 mL) solution of Intermediate 6d (17.69 mg, hydrochloride), and the mixture was stirred at 25 °C for 30 minutes. Then, Intermediate 41g (25 mg, 81.40 μmol) and KI (1.35 mg, 8.14 μmol) were added, and the temperature was raised to 50 °C and stirred for 2 hours. The reaction solution 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 salt of Compound 42. MS m / z: 462.1 [M+1] + 。 1 H NMR (400 MHz, CD 3 OD) 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

Chemical Structure

[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)Cl 2 (233.70 mg, 319.39 μmol), potassium acetate (626.91 mg, 6.39 mmol) were added to H 2It was added to a mixed solution of O(1.6 mL) and THF (8 mL), heated to 70 °C, and stirred for 16 hours. The reaction solution was filtered, the cake was washed with EA (15 mL), and the filtrate was concentrated under reduced pressure to obtain a 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, CDCl 3 ) 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 solution was concentrated under reduced pressure to obtain intermediate 43c. MS m / z: 352.1 [M+1] + 。 1 H NMR (400 MHz, CD 3 OD) 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 (4 M, 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 (4 M, 635.26 μL) was added, and the mixture was stirred for an additional 1 hour. The reaction solution 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 salt) in DMF (1 mL), and the mixture was 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 temperature was raised to 50 °C and the mixture was stirred for 2.5 hours. DMF (2 mL) was added to the reaction solution, followed by 1 mL of water, and a solid precipitated. The solid was filtered to obtain a cake, which was Compound 43. MS m / z: 478.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[0408] Step 1: Synthesis of Intermediate 44a Intermediate 15d (100 mg, 367.34 μmol) was dissolved in THF (1 mL), and lithium aluminum deuteride powder (20.91 mg, 551.00 μmol) was added at 0 °C, followed by stirring at 0 °C for 1 hour. The reaction mixture was added to a saturated sodium potassium tartrate solution (5 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, 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-d 6 ) 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, followed by stirring at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, methanol (2 mL) was added and stirred for 5 minutes, and then filtered to obtain a cake, which was Intermediate 44b. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Intermediate 9g (31.99 mg, hydrochloride) 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 h. 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 h. Water (1.5 mL) was added to the reaction solution, and the mixture was stirred for 10 min. A solid precipitated, which was filtered to obtain a cake, i.e., Compound 44. MS m / z: 489.0 [M+23] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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 h. 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 h. After cooling, water (1 mL) was added to the reaction solution and the mixture was stirred for 10 min. A solid precipitated, which was filtered to obtain a cake, i.e., Compound 45. MS m / z: 483.1 [M+1] + 。 11H NMR (400 MHz, DMSO-d 6 ) 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 = 4.8 Hz, 3H), 2.62~2.67 (m, 4H).

[0413] Example 46

Chemical Structure

[0414] Step 1: Synthesis of Intermediate 46b Intermediate 46a (2 g, 6.22 mmol) was dissolved in THF (20 mL) and H 2 O (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. After adjusting the pH of the reaction solution to 3 with dilute hydrochloric acid (1 mol / L), it was extracted with ethyl acetate (20 mL × 3). 20 mL of saturated brine was added to the organic phase for washing, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate 46b. MS m / z: 307.9 [M+1] + . 1 1H NMR (400 MHz, DMSO-d 6 ) 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), added to DIEA (336.41 mg, 2.60 mmol) and n-butylphosphoric anhydride (50% ethyl acetate solution) (937.74 mg, 2.60 mmol), stirred at 25 °C for 3 hours, 937.74 mg of n-butylphosphoric anhydride was added, and then stirred for 16 hours. The pH of the reaction solution was adjusted to 10, 5 mL of water was added, extracted with ethyl acetate (5 mL × 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-d 6 ) 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 stirred at 50 °C for 1 hour. 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL × 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-d 6 ) 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 solution 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 salt) 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 hour. 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 solution and stirred for 10 minutes. A solid precipitated and 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-d 6 ) 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

Chemical Structure

[0420] Step 1: Synthesis of Intermediate 47a Deuterated methylamine hydrochloride (399.85 mg, 5.67 mmol) was added to H 2 O (2 mL), and then sodium tert-butoxide (272.39 mg, 2.83 mmol) was added. 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, it was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. It was separated and purified by preparative chromatography plate (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 (4 M, 211.36 μL) was added to a solution of Intermediate 47a (60 mg, 169.09 μmol) in MeOH (0.5 mL), and the mixture was stirred for 2 hours. The reaction solution 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-d 6 ) 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 h. Next, 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 h. After cooling, 1.5 mL of water was added to the reaction solution, and a solid precipitated. The solid 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-d 6 ) 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

Chemical formula

[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), Cs 2 CO 3 (650.74 mg, 2.00 mmol), RuPhos (93.20 mg, 199.72 μmol) and Pd 2 (dba) 3(91.44 mg, 99.86 μmol) was added to toluene (4 mL), and the mixture was purged with nitrogen gas three times and stirred at 100 °C for 6 hours. The reaction solution was filtered under reduced pressure while it was hot, and the filtrate was concentrated under reduced pressure at 50 °C to obtain a 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, a methylamine-ethanol solution (2.27 g, 21.93 mmol) was added to the reaction solution. The reaction system was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure at 45 °C to obtain intermediate 48b as a crude product. 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 solution. 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 DMF (2 mL) of intermediate 48c (39.75 mg, hydrochloride salt). The reaction system was stirred at 20 °C for 0.5 hour, intermediate 27a (50 mg, 130.24 μmol) and KI (2.16 mg, 13.02 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography plate (100% EA) to obtain compound 48. MS m / z: 495.2, 497.2 [M+1] + 。 11H NMR (400 MHz, DMSO-d 6 ) 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, 1 H), 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 [Chemical formula]

[0429] Step 1: Synthesis of Intermediate 49a Deuterated methylamine hydrochloride (190.72 mg, 2.70 mmol) was added to H 2 O (1 mL), and sodium tert-butoxide (129.92 mg, 1.35 mmol) was added to the reaction solution, and the mixture was stirred at 25 °C for 1 hour. MeOH (2 mL) of Intermediate 48a (50 mg, 135.19 μmol) was added to the reaction solution, and the reaction system was heated to 60 °C and reacted for 4 hours. Extracted with ethyl acetate (5 mL × 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 solution. The reaction system was stirred at 25 °C for 1 hour. The reaction solution 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 DMF (2 mL) of Intermediate 49b (40.14 mg, hydrochloride salt), and the reaction system was stirred at 20 °C for 0.5 hour. Intermediate 27a (50 mg, 130.24 μmol) and KI (2.16 mg, 13.02 μmol) were added to the reaction solution, and the reaction system was stirred at 50 °C for 2 hours. It was concentrated under reduced pressure to obtain a crude product, which was purified by preparative chromatography plate (100% EA) to obtain Compound 49. MS m / z: 498.2, 500.2 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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, 2 H), 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

Chemical Structure

[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 the mixture was stirred at 25 °C for 0.5 h. Next, Intermediate 38g (50 mg, 153.80 μmol) and KI (2.55 mg, 15.38 μmol) were added, and the mixture was stirred at 50 °C for 2.5 h. After cooling, water (1 mL) was added to the reaction solution, and a solid precipitated. The solid was directly filtered to obtain a cake, which was Compound 50. MS m / z: 499.1, 501.1 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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 h. Next, Intermediate 38g (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 h. After cooling to room temperature, 1 mL of water was added to the reaction solution, and a solid precipitated. The solid 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

Chemical Structure

[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 h. 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 h. After cooling to room temperature, 1 mL of water was added to the reaction solution, and a solid precipitated. The solid was filtered to obtain a cake, which was Compound 52. MS m / z: 502.2 [M + 1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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 thereto at 0 °C, followed by stirring at 0 °C for 1 hour. 30 μL of water and 30 μL of 15% sodium hydroxide solution were sequentially and slowly added to the reaction solution, and the reaction system was quenched with 90 μL of ice water. Water (5 mL) was added to the reaction solution, and then the mixture was extracted 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-d 6 ) 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 thereto, and tributylphosphine (199.09 mg, 984.01 μmol) was added thereto at 0 °C, followed by stirring at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure, methanol (5 mL) was added thereto, and the mixture was stirred for 5 minutes, followed by filtration to obtain a cake, which was Intermediate 53b. 1 H NMR (400 MHz, DMSO-d 6 ) 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 Intermediate 9g (22.68 mg, hydrochloride) was dissolved in DMF (1 mL), triethylamine (18.56 mg, 183.42 μmol) was added, and the mixture was stirred at 25 °C for 0.5 h. 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 h. Water (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 min. A solid precipitated out, which was filtered to obtain a cake, i.e., Compound 53. MS m / z: 485.1 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6 ) 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

Chemical Structure

[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 h. 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 h. 1 mL of water was added to the reaction mixture, and a solid precipitated out, which was filtered to obtain a cake, i.e., Compound 54. MS m / z: 470.2 [M+1] + 。 1 H NMR (400 MHz, DMSO-d 6) 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 [Chemical Structure]

[0445] Step 1: Synthesis of Compound 55 Dissolve Intermediate 29b (25 mg, hydrochloride) in DMF (1 mL), add triethylamine (40.48 mg, 400.05 μmol), stir at 25 °C for 0.5 h, then add KI (8.30 mg, 50.01 μmol) and Intermediate 53b (32.72 mg, 100.01 μmol), and stir at 50 °C for 1 h. Cool, add 1 mL of water to the reaction solution, a solid precipitates, filter to obtain a cake, which is Compound 55. MS m / z: 488.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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 Experiment of the Binding Activity between a Compound and PARP1 by Fluorescence Polarization Method

[0447] Experimental Method: The fluorescence polarization experiment was carried out in a 96-well black wall plate (Greiner), and the reaction buffer was 50 mM Tris, pH 8, 0.001% Triton X100, 10 mM MgCl 2 2, and 150 mM NaCl. Both the fluorescent probe and the PARP1 protein with His-Avi tag were manufactured by Shanghai WuXi AppTec. In a 100 μL reaction system, 8 nM PARP1, 5 nM fluorescent probe and the compound were added respectively. The compound concentration started from the initial concentration and dilution gradient in Table 1. For example, Compound 1 started from 100 nM and was diluted 3-fold. It was cultured at room temperature in the dark for 4 hours, and the data was read by Envision. The obtained fluorescence polarization values and compound concentrations were non-linearly fitted using Graphpad 8.0 software to obtain the IC 50 value.

[0448] Experimental Results: [Table 1]

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

[0450] Experimental Example 2: Measurement Experiment of the Binding Activity between a Compound and PARP2 by Fluorescence Polarization Method

[0451] Experimental Method: The fluorescence polarization experiment was carried out in a 96-well black wall plate (Greiner), and the reaction buffer was 50 mM Tris, pH 8, 0.001% Triton X100, 10 mM MgCl 2, it was 150 mM NaCl. Both the fluorescent probe and the His-Avi-tagged PARP2 protein were manufactured by Shanghai WuXi AppTec. To a 100 μL reaction system, 3 nM of PARP2, 5 nM of the fluorescent probe, and the compound were added respectively. The compound concentration was set as the starting concentration and dilution gradient with reference to Table 2. Incubated at room temperature in the dark for 4 hours, and the data was read with Envision. The obtained fluorescence polarization values and compound concentrations were non-linearly fitted using Graphpad 8.0 software to obtain the IC 50 value.

[0452] Experimental results:

Table 2

[0453] Conclusion: The compound of the present invention had a weaker binding activity to PARP2.

[0454] Experimental Example 3: Anti-proliferation experiment of the compound against MDA-MB-436 cells (BRCA1 mutation)

[0455] Experimental method: MDA-MB-436 cells (BRCA1 mutant) were seeded in a black (transparent bottom) 96-well plate. 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 using a multi-channel pipette, the test compound was serially diluted 5-fold up to the 9th concentration, i.e., diluted from 4 mM to 104 nM, and two replicate well experiments were set up. 78 μL of medium was added to the central plate, and then 2 μL of the serially diluted compound per well was transferred to the central plate according to the corresponding positions. 2 μL of DMSO was added to the solvent control and blank control, mixed uniformly, and then 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 concentration of DMSO was 0.25%. The cell plate was placed in a carbon dioxide incubator and cultured for 7 days. The cell plate was taken out and left to stand for 30 minutes to equilibrate to room temperature. The cell viability chemiluminescence detection reagent was added at 75 μL / well, and the culture plate was shaken on an orbital shaker for 3 minutes to induce cell lysis and 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 the compound at various concentrations were calculated in Excel, and an inhibition curve was plotted using GraphPad Prism software, and the relevant parameters were calculated.

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

Table 3

[0457] Experimental results: The compound of the present invention had an excellent growth inhibitory effect on MDA-MB-436 cells (BRCA1 mutation).

[0458] Experimental Example 4: Proliferation inhibition experiment of the compound on DLD1 (BRCA2 KO) cells

[0459] Experimental method: DLD1 (BRCA2 KO) cells were seeded in a white 96-well plate. Each well contained 80 μL of cell suspension, which included 1000 DLD1 (BRCA2 KO) cells. The cell plate was placed in a carbon dioxide incubator and cultured overnight. The test compound was serially diluted 5-fold to the 8th concentration using a multi-channel pipette, i.e., diluted from 2 mM to 0.0256 μM, and two replicate well experiments were set up. 78 μL of medium was added to the central plate, and then 2 μL of the serially diluted compound per well was transferred to the central plate according to the corresponding positions, 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 placed in a carbon dioxide incubator and cultured 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 following equation) and involved in data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of this cell plate and cultured at room temperature for 10 minutes to stabilize the luminescence signal. Data was read using a multi-label analyzer. After the culture of the cell plate with the compound was completed, 25 μL / well of cell viability chemiluminescence detection reagent was added to the cell plate and cultured at room temperature for 10 minutes to stabilize the luminescence signal. Data was read using a multi-label analyzer. The raw data was converted to the inhibition rate using the equation (Sample - Min) / (Max - Min)×100%, and the IC 50 value was obtained by curve fitting with four parameters (acquired in the "log(inhibitor) vs. response--Variable slope" mode of GraphPad Prism).

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

Table 4

[0461] Experimental conclusion: The compound of the present invention had a better anti-proliferation inhibitory effect on DLD1 (BRCA2 KO) cells.

[0462] Experimental Example 5: Pharmacokinetic evaluation and brain penetration evaluation of the compound of the present invention in mice

[0463] Experimental method: The mice used for the trifluoroacetate salt of Compound 16 were female BALB / C mice, and the mice used for the trifluoroacetate salt of Compound 15 were male CD-1 mice. A clear solution prepared by dissolving the test compound at 0.4 mg / mL in 10% 2-hydroxypropyl-β-cyclodextrin and 90% water was injected into the mice (fasted overnight, 7 - 9 weeks old) via the tail vein, and the dosage was 2 mg / kg. A clear solution prepared by dissolving the test compound at 1 mg / mL in 0.5% methylcellulose and water was orally administered to the mice (fasted overnight, 7 - 9 weeks old) at a dosage of 10 mg / kg. After administering to the two groups of animals respectively, about 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, 24 hours, and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24 hours, placed in an anticoagulant tube containing EDTA-K2, and the plasma was centrifuged. Among them, the trifluoroacetate salt of Compound 15 was intravenously administered (IV, 2 mg / kg) to one group (blood collection according to the above times), orally administered (PO, 10 mg / kg) to one group (blood collection according to the above times), and furthermore, one group of oral administration (PO, 10 mg / kg) was set, and the plasma and brain tissue homogenate were collected 2 hours later. The blood drug concentration was measured by LC-MS / MS method, and WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters using the non-compartmental model linear logarithm trapezoidal method.

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

[0465] [Table 6]

[0466] Experimental conclusion: The compound of the present invention had excellent in vivo metabolic stability and excellent oral absorption drug exposure, and had excellent brain tissue drug concentration and high brain-blood ratio by oral administration.

[0467] Experimental Example 6: Permeability evaluation of the compound of the present invention

[0468] Cell line: In this experiment, the MDR1-MDCK II cell line approved by the laboratory of Piet Borst of the Netherlands Cancer Institute was used as the in vitro model for permeability evaluation experiments, and was seeded in a Transwell 96-well cell plate at a density of 2.3×10 5 cells / cm 2 and cultured in a carbon dioxide incubator for 4 to 7 days, and then used for transport experiments.

[0469] Experimental conditions: Administration concentration of the test article: 2.00 μM Test direction and number of replicate samples: Bidirectional A - B and B - A, 2 replicates Transport buffer (TB): HBSS solution containing 10 mM HEPES (pH 7.40 ± 0.05) Culture conditions: 37 ± 1 °C, 5% CO 2 , cultured for 150 minutes Control compounds: Nadolol and metoprolol were used as low - permeability and high - permeability control compounds, and digoxin was used as a substrate for P - glycoprotein. The administration concentrations of nadolol and metoprolol were 2.00 μM, and the administration concentration of digoxin was 10.0 μM.

[0470] Integrity test of the monolayer cell membrane: After the transport experiment, the Lucifer Yellow Rejection Assay was used to detect the integrity of the MDR1 - MDCK II cell layer. The solutions remaining in the upper and lower wells were removed, 75 μL of TB containing 100 μM lucifer yellow was added to the upper well, 250 μL of TB was added to the lower well, and the cell plate was cultured in a cell incubator at 37 ± 1 °C, 5% CO 2 and saturated humidity conditions for 30 minutes. Then, 20 μL of the sample was taken from the upper part and mixed with 60 μL of TB, 80 μL of the sample was taken from the lower part, and using a microplate reader, its relative fluorescence unit (RFU) at the 425 / 528 nm (excitation / emission) spectrum was detected.

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

[0472] Data analysis:

Number

[0473] The lucifer yellow permeability rate (% Lucifer Yellow) is calculated by 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 as shown in Table 7.

Table 7

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

[0476] Experimental Example 7: Pharmacokinetic evaluation and brain permeability evaluation of the compound of the present invention in rats

[0477] Experimental method: A transparent solution prepared by dissolving a test compound of 0.2 mg / mL in 10% 2-hydroxypropyl-β-cyclodextrin and 90% water was injected into male SD rats (fasted overnight, 200 - 230 g) via the tail vein, and the dosage was 1 mg / kg. A solution prepared by dissolving a test compound of 0.5 mg / mL in 10% 2-hydroxypropyl-β-cyclodextrin and 90% water was administered intragastrically to male SD rats (fasted overnight, 200 - 230 g), and the dosage was 5 mg / kg. After administering the two groups of animals respectively, about 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, 24 hours, and from the tail vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 24 hours, put into an anticoagulant tube added with EDTA-K2, and the plasma was centrifuged. The trifluoroacetate salt of Compound 15 was intravenously administered to one group (IV, 1 mg / kg) (blood sampling according to the above time), orally administered to one group (PO, 5 mg / kg) (blood sampling according to the above time), and furthermore, one group of oral administration (PO, 5 mg / kg) was set, and the plasma and brain tissue homogenate were collected 2 hours later. The blood drug concentration was measured by LC-MS / MS method, and WinNonlin TMUsing the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA), the relevant pharmacokinetic parameters were calculated using the non-compartmental model linear logarithm trapezoidal method.

[0478] Experimental results: The pharmacokinetic data of rats are as shown in Table 8. The brain penetration data of rats are as shown in Table 9.

Table 8

[0479]

Table 9

[0480] Experimental conclusion: The compound of the present invention had excellent in vivo metabolic stability and excellent oral absorption drug exposure, and had excellent brain tissue drug concentration and high brain-blood ratio by oral administration.

[0481] Experimental Example 8: In vitro hepatic microsomal stability of the compound of the present invention

[0482] Experimental purpose: 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 the condition of 37 °C, 1 μM of the compound was cultured with human liver microsomes added with the NADPH regeneration system for up to 60 minutes for a predetermined time, and the concentration of the compound in the obtained sample was measured using the LC-MS / MS method.

[0484] Experimental procedure: 96-well culture plates were named T0, T5, T15, T30, T45, T60, Blank60, and NCF60 respectively. The corresponding culture times of the culture plates were 0, 5, 15, 30, 45, and 60 minutes respectively. No test compound or control compound was added to the Blank60 plate, and the sample was collected after 60 minutes of culture. The NCF60 plate was cultured with potassium phosphate buffer for 60 minutes instead of the NADPH regeneration system solution. The samples at all time points were all in single wells. 5 μL of the test article or control article working solution and 100 μL of the microsome working solution (liver microsome protein concentration: 0.5 mg / mL) were added to each of the T0, T5, T15, T30, T45, T60, and NCF60 plates. Only the microsome working solution was added to the Blank60 plate. 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 about 10 minutes. To the sample of the T0 plate, first, 180 μL of the stop solution (the stop solution is an acetonitrile:methanol (95:5, V / V) solution containing 100 ng / mL of tolbutamide) was added, and then the working solution of the NADPH regeneration system was added. 50 μL of potassium phosphate buffer was added to each well of the NCF60 plate and cultured for 60 minutes. After the pre-culture of the Blank60, T5, T15, T30, T45, and T60 culture plates was completed, 44 μL of the NADPH regeneration system working solution was added to each sample well to initiate the reaction. Therefore, in the case of the sample well of the working solution containing the test article or control article, 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 culturing for appropriate times (5, 15, 30, 45, and 60 minutes), 180 μL of stop solution was added to each test sample well and control sample well of Blank60, T5, T15, T30, T45, T60, and NCF60 plates respectively to stop the reaction. All the sample plates were shaken and centrifuged for 10 minutes. Then, 80 μL of the test sample supernatant 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 remaining compound at each corresponding time point, the half-life T of the compound in human liver microsome metabolism 1 / 2 and clearance rate CL int(liver) were obtained.

Number

[0486] Experimental results: As shown in Table 10.

Table 10

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

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

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

[0490] Experimental method: 1) Cell culture: 5% CO2 Normal cell culture was performed in MEM medium containing 37°C and 10% fetal bovine serum, digested and passaged with 0.25% trypsin, and passaged 2 - 3 times a week at a passage ratio of 1:3 - 1:6 according to cell growth.

[0491] 2) Establishment of animal model Animal: Female Balb / c nude mice, 6 - 8 weeks old. MDA - MB - 436 cells in the logarithmic growth phase were collected. After counting the cells, they were resuspended in 50% Matrigel containing 50% serum - free MEM medium, and the cell concentration was adjusted to 5.0×10 7 cells / mL. After uniformly dispersing the cells using a pipette, they were placed in a 50 mL centrifuge tube, and the centrifuge tube was placed in an ice box. The cell suspension was aspirated with a 1 mL syringe and subcutaneously injected into the axilla of the right forelimb of nude mice, with 200 μL (1.1×10 7 cells / animal) inoculated into each animal to construct an MDA - MB - 436 nude mouse xenograft tumor model. After inoculation, the status of the animals and the growth of the tumors were observed regularly. The diameter of the tumors was measured using an electronic caliper, and the data was directly input into an Excel spreadsheet to calculate the tumor volume. When the tumor volume reached 100 - 200 mm 3 , animals with good health status and similar tumor volumes were selected, randomly divided into groups (n = 6) according to tumor volume, and at the same time, it was ensured that the average body weight of each group was as consistent as possible. The day of grouping was set as the first day of the experiment (D1). After the start of the experiment, the diameter of the tumors was measured twice a week to calculate the tumor volume, and at the same time, the body weight of the animals was measured and recorded.

[0492] The calculation formula for tumor volume (TV) is as follows. TV(mm 3 ) = a×w 2 / 2, where a represents the long diameter (mm) of the tumor and w represents the short diameter (mm) of the tumor.

[0493] 3) Dosage: 1.0 mg / kg, Administration method: intragastric administration (oral), once a day (QD).

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

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

[0496] Calculation formula for tumor growth inhibition rate (TGI): TGI = 100% × [1 - (TVt(T) - TVinitial(T)) / (TVt(C) - TVinitial(C))], where 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 grouping 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 grouping administration.

[0497] Experimental results: The tumor growth volume is as shown in Figure 1. The change in mouse body weight during the administration period is as shown in Figure 2. The tumor growth inhibition rate and relative tumor growth rate are as shown in Table 11.

Table 11

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

Claims

1. A compound represented by formula (XII) or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (However, X is selected from O and S, The structural unit [Chemical 2] is [Chemical Formula 3] selected from Ring A is selected from phenyl and 6-membered heteroaryl, Ring B is selected from 6-membered heteroaryl, L is selected from a single bond, and ring C is 【Chemical 4】 selected from 【Chemical Formula 5】 is selected from a single bond or a double bond, T ２ is selected from C, N, and CH, T ３ and T ４ are each independently selected from N and CR １０ and R １ is selected from 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 one, two or three halogens, R ２ is selected from H and C １－３ alkyl, and said C １－３ alkyl is optionally substituted by one, two or three halogens R ３ is selected from H and halogen, R ９ is absent or is selected from H and halogen, R ４ is selected from H, halogen, CN, C １－３ alkyl and C １－３ alkoxy, and R ５ is selected from H, halogen, CN, C １－３ alkyl and C １－３ alkoxy, and R ６ and R ７ are each independently selected from H, halogen, C １－３ alkyl and C １－３ alkoxy, wherein said C １－３ alkyl and C １－３ alkoxy are each independently optionally substituted by one, two or three halogens, R ８ is selected from C １－３ alkyl and C ３－５ cycloalkyl, and said C １－３ alkyl and C ３－５ cycloalkyl are each independently optionally substituted by one, two or three Rs, R １０ is selected from H and halogen, R １３ and R １４ each independently represents H, halogen, C １－３ alkyl, C １－３ alkoxy and C ３－５ cycloalkyl, wherein said C １－３ alkyl, C １－３ alkoxy and C ３－５ cycloalkyl are each independently optionally substituted by 1, 2 or 3 halogens, R １５ and R １６ are each independently H, D, C １－３ alkyl and C １－３ alkoxy selected from, said C １－３ alkyl and C １－３ alkoxy are each independently optionally substituted by 1, 2 or 3 halogens, Alternatively, R ２ and R ４ form a ring to form a structural unit ​ such that 【Chemical Formula 7】 is selected from Alternatively, R ３ and R ５ form a ring to form a structural unit 【Chemical 8】 such that 【Chemical Formula 9】 is selected from Each R ａ is independently selected from 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 are optionally substituted by one, two or three halogens, Alternatively, two Rs on adjacent atoms ａ together with the atoms to which they are attached form a double bond or cyclopropyl, Each R ｂ is independently selected from 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 are optionally substituted by one, two or three halogens, Each R ｃ is independently selected from 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 are optionally substituted by 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 condition is that the structural unit 【Chemical Formula 10】 such that 【Chemical 11】 is selected from 【Chemical 12】 When selected from, R ２ and R ４ form a ring, or R ３ and R ５ form a ring, which is The halogen represents F, Cl, Br, and I atoms, The "hetero" in the 5- to 6-membered heteroaryl represents 1, 2, 3, or 4 heteroatoms or heteroatomic groups independently selected from -O-, -S-, and -N- respectively. )

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure represented by formula (XII-1). 【Chemical 13】 (However, Ring A is selected from 6-membered heteroaryl, R ２ 、 R ３ 、 R ４ 、 R ５ 、 R ６ 、 R ７ 、 R ８ 、 R ９ 、 R １３ 、 R １４ 、 R １５ 、 R １６ 、 R ｃ 、 X, T ２ 、 T ３ 、 T ４ 、 n and 【Chemical Formula 14】 is as defined in claim 1. )

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from O.

4. Each R ａ 、each R ｂ and each R ｃ is independently selected from H, F and CH ３ and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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

6. T ４ is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from N and CH.

7. R １ is CH ３ and CH ２ CH ３ selected from, or R １ is selected from CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R ２ is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from H and CH ３ ​

9. R ６ and R ７ are each independently selected from H, F and CH ３ or, R ６ and R ７ are each independently selected from H and F, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R ４ and R ５ are each independently H, F, Cl, CN, and CH ３ selected from the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R ８ is CH ３ , CH ２ CH ３ , CH ２ CF ３ , cyclopropyl and CD ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

12. R ３ and R ９ is each independently selected from H and F, a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R １０ is a compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from H and F.

14. R １３ and R １４ each independently is selected from H and CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from

15. R １５ and R １６ are each independently selected from H, D and CH ３ and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from phenyl, pyridyl, pyrazinyl, and pyrimidinyl.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is selected from pyridyl, pyrazinyl, and pyrimidinyl.

18. The structural unit 【Chemical Formula 15】 is 【Chemical 16】 selected from

19. The structural unit 【Chemical 17】 is 【Chemical Formula 18】 selected from

20. The structural unit 【Chemical 19】 is 【Chemical 20】 selected from

21. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from a single bond, and the structural unit 【Chemical 21】 is 【Chemical 22】 【Chemical 23】 selected from

22. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure represented by formula (P-1). 【Chemical 24】 (However, ring A is selected from 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 【Chemical 25】 is as defined in claim 1.)

23. The compound is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (P-2). 【Chemical 26】 (However,[ 【Chemical 27】 is selected from a single bond or a double bond,[ T ２ is selected from C and N, R ２ is selected from H and C １－３ alkyl, and said C １－３ alkyl is optionally substituted by one, two or three halogens R ３ is selected from H and halogen, R ４ is selected from H, halogen, CN, C １－３ alkyl and C １－３ alkoxy, R ５ is selected from H, halogen, CN, C １－３ alkyl and C １－３ alkoxy, R ９ is absent or is selected from H and halogen, R ７ 、R ８ 、R １３ 、R １４ 、R １５ 、R １６ 、R ｃ and n are as defined in claim 1.)

24. A compound represented by the following formula or a pharmaceutically acceptable salt thereof.[ 【Chemical 28】 【Chemical Formula 29】 【Chemical Formula 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】

25. The compound is the compound according to claim 24 or a pharmaceutically acceptable salt thereof, selected from the following formulas.[ 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, diluent or excipient.[

27. Use of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or the composition according to claim 26, in the preparation of a medicament for treating solid tumors.[

28. The use according to claim 27, wherein the solid tumor is a solid tumor such as ovarian cancer, breast cancer, prostate cancer and glioma.[

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