Protein arginase methyltransferase-5 inhibitor and medical application thereof

Abstract

The invention relates to a protein arginase methyltransferase-5 inhibitor and a medical application thereof. Specifically, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound serving as a PRMT5 (protein arginase methyltransferase-5) inhibitor to treatment of diseases related to PRMT5 activity. Wherein the definition of each group in the general formula (I) is the same as that in the specification.

Description

Protein arginase methyltransferase-5 inhibitor and its medical use Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a new class of protein arginase methyltransferase-5 (PRMT5) inhibitors, a pharmaceutical composition containing the same, a preparation method thereof, and use of the same as a PRMT5 inhibitor for treating diseases associated with PRMT5 activity. Background Art

[0002] Cancer treatment can be broadly divided into two categories: cytotoxic therapy and targeted therapy. Cytotoxic therapy may produce a wide range of toxicities, while targeted therapy has the advantage of selectively targeting tumor cells.

[0003] PRMT5 (protein arginase methyltransferase-5) is a type II arginine methyltransferase that catalyzes the symmetrical dimethylation of proteins involved in transcription and signaling by transferring the methyl group S-adenosylmethionine (SAM). This methylation enables a variety of essential cellular functions, including regulation of cell cycle progression, apoptosis, and the response to DMA damage. PRMT5 is overexpressed in various cancers, including glioblastoma, leukemia / lymphoma, prostate cancer, and colorectal cancer, and is associated with poor prognosis. Data from genome-wide genetic perturbation screens using shRNAs revealed the importance of PRMT5 activity in cancer cell lines deficient in MTAP (methylthioadenosine phosphorylase) (Kruykov et al, 2016; Marjon et al, 2016 and Markarov et al, 2016).

[0004] First-generation PRMT5 inhibitors were primarily SAM-competitive or non-competitive inhibitors that lacked selectivity for MTAP-deficient cells. Inhibition of PRMT5 in normal cells resulted in dose-limiting toxicities such as thrombocytopenia, anemia, and neutropenia.

[0005] MTAP deficiency leads to the accumulation of the cellular metabolite methylthioadenosine (MTA) in cancer cells. MTA, an intermediate in the methionine compensation pathway, has a weak inhibitory effect on PRMT5, competing with SAM to form a PRMT5 / MTA complex. The development of novel inhibitors that bind to and stabilize the PRMT5 / MTA complex enhances the inhibitory effect of MTA on PRMT5, potentially inhibiting PRMT5 activity in MTAP-deficient cancer cells while preserving PRMT5 activity in wild-type cells, thereby effectively improving the therapeutic index.

[0006] Currently, the published patent applications for the second-generation PRMT5 inhibitors are: WO2021163344A1, WO2022115377 A1, WO2022132914 A1, and WO2022169948 A1.

[0007] Summary of the Invention

[0008] After intensive research, the present inventors designed and synthesized a series of compounds that exhibited PRMT5 (protein arginase methyltransferase-5) inhibitory activity and could be developed as drugs for preventing or treating diseases associated with PRMT5 activity.

[0009] Therefore, the object of the present invention is to provide a compound of general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0010] in:

[0011] Z is selected from C(=O), S(=O), S(=O)2,

[0012] A 1 Select N or CR 7 ;

[0013] A 2 Select N or CR 8 ;

[0014] X is selected from N or CR 9 ;

[0015] R 1 Selected from: Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R aR b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0016] in,

[0017] E is selected from N or CR 16 ;

[0018] Y is selected from O or S;

[0019] Each R 10 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0020] R 11a and R 11b are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0021] R 12 Selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0022] or,

[0023] R 11a or R 11b With R 10 , or R 12 With R 10 , and the atoms to which they are attached together form a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NRa C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0024] R 13 and R 14 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or

[0025] R 13 With R 14 and the nitrogen atom to which they are attached together form a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0026] R 16 Selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)Ra 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0027] R 2 、R 3 、R 7 、R 8 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0028] R 5 、R 6 、R 9 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-B(OR a )2, alkyl, -ORa , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0029] R 4 Selected from hydrogen, -(CH2) p -R 15 、-NR a R b 、-C(=O)R a 、-S(=O)2R a , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0030] or

[0031] R 4 、R 5 、R 6 、R 9 Any two of them together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, one or more groups substituted, the cycloalkyl, heterocyclic, aryl, heteroaryl optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、 -NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0032] R 15 Selected from heteroaryl, aryl, heterocyclic group, cycloalkyl, wherein the heteroaryl, aryl, heterocyclic group, cycloalkyl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, one or more groups substituted, the cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , one or more groups of haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0033] R a and R b are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, -C(=O)OR c 、-C(=O)R c 、-C(=O)NR c R d 、-OC(=O)R c 、-NR c C(=O)R d 、-S(=O)2R c 、-NR c S(=O)2R d 、-S(=O)2NR c R d 、-S(=O)R c、-P(=O)R c R d 、-NR c S(=O)2R d 、alkyl、-OR c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0034] or R a and R b Together with the atoms to which they are attached, they form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0035] R c and R d each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0036] or R c and R d Together with the atoms to which they are attached, they form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0037] p is an integer from 1 to 6.

[0038] In a specific embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0039] Among them, A 1 、A 2 , X, R 1 ~R 6 As defined in general formula (I).

[0040] In another specific embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0041] Among them, A 1 、A 2 , X, Y, Z, R 2 ~R 6 、R 10 As defined in general formula (I).

[0042] In another specific embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (I-2) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0043] Among them, A 1 、A 2 , X, Z, R 2 ~R 6 、R 10 、R 11a 、R 11b As defined in general formula (I).

[0044] In another specific embodiment, the compound of formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of formula (IV) or formula (V) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0045] in,

[0046] A 1 、A 2 , X, R 2 ~R 6 、R 10 、R 11a 、R 11b As defined in general formula (I).

[0047] In another specific embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIA) or general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0048] in:

[0049] G is selected from N or CH;

[0050] R 17 Selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably halogen, alkyl, cycloalkyl or haloalkyl; the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NRa R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , one or more groups of haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0051] m is an integer from 0 to 4, preferably 1 or 2;

[0052] A 1 、A 2 , X, R 1 ~R 3 、R 5 、R 6 、R a 、R b As defined in general formula (I).

[0053] In another specific embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IVA) or general formula (VA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0054] in,

[0055] G is selected from N or CH;

[0056] R 17 Selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a Rb 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably halogen, alkyl, cycloalkyl, or haloalkyl;

[0057] m is an integer from 0 to 4, preferably 1 or 2;

[0058] A 1 、A 2 , X, R 2 ~R 3 、R 5 、R 6 、R 10 、R 11a 、R 11b 、R a 、R b As defined in general formula (I).

[0059] In a preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein A 1 CR 7 And A 2 N; or A 1 CR7 And A 2 CR 8 , or A 1 N and A 2 N; R 7 and R 8 As defined in claim 1, preferably, R 7 and R 8 are each independently selected from hydrogen, halogen or C 1-6 alkyl.

[0060] In another preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0061] X is selected from N or CR 9 ;

[0062] R 5 and R 6 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 substituted with one or more haloalkyl groups;

[0063] R 9 Selected from hydrogen or C 1-6 alkyl.

[0064] In another preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0065] X is selected from N or CR 9 ;

[0066] R 4 、R 5 、R 6 、R 9 Any two of them together with the atoms they are connected to form C 3-10 Cycloalkyl, 5- to 10-membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl, the C 3-10 Cycloalkyl, 5- to 10-membered heterocyclic group, C 6-10Aryl or 5 to 10 membered heteroaryl is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-NR a C(=O)R b 、-OR a , haloalkoxy, C 3-6 Cycloalkyl, 5- to 10-membered heterocyclic group, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or one or more groups; 6-10 Aryl, 5 to 10 membered heteroaryl optionally further substituted with C 1-6 Alkyl substitution;

[0067] where R a 、R b As defined in general formula (I).

[0068] In another preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0069] X is selected from N or CR 9 ;

[0070] R 4 With R 5 、R 6 、R 9 One of them and the atoms to which it is attached together form a 5- to 10-membered heterocyclic group, a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-NR a C(=O)R b 、-OR a , haloalkoxy, C 3-6 Cycloalkyl, 5- to 10-membered heterocyclic group, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or one or more groups; 6-10 Aryl, 5 to 10 membered heteroaryl optionally further substituted with C 1-6 Alkyl substitution;

[0071] where R a 、Rb As defined in claim 1.

[0072] In another specific embodiment, the compound of formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of formula (IVB) or formula (VB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0073] in,

[0074] X is selected from N or CR 9 ;

[0075] G is selected from N or CH;

[0076] G 1 and G 2 are each independently selected from N or CH;

[0077] R 5 Selected from hydrogen or C 1-6 alkyl;

[0078] R 9 Selected from hydrogen or C 1-6 alkyl;

[0079] R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the heterocyclic, aryl, heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、 -S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, alkyl-substituted heterocyclic, aryl, heteroaryl, or one or more groups; preferably halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkyl, 5-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl are optionally selected from -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 substituted by one or more haloalkoxy groups or 5-6-membered heterocyclic groups;

[0080] R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 alkyl halide;

[0081] Or, two adjacent R 18 The atoms to which it is attached together form a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 5-6 membered cycloalkyl, the 5-6 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-B(OR a )2, alkyl, -OR a , one or more groups of haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0082] R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or

[0083] R a and Rb Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally further substituted by C 1-6 Alkyl substitution;

[0084] m is an integer from 0 to 4, preferably 1 or 2;

[0085] n is an integer from 0 to 4, preferably 1 or 2;

[0086] A 1 、A 2 、R 2 、R 3 、R 10 、R 11a 、R 11b As defined in general formula (I).

[0087] In another specific embodiment, the compound represented by the general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IVC) or the general formula (VC) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0088] in,

[0089] Ring A is selected from 5- to 10-membered heteroaryl, C6-10 aryl, 3- to 10-membered heterocyclyl or 3- to 10-membered cycloalkyl, wherein the 5- to 10-membered heteroaryl, C6-10 aryl, 3- to 10-membered heterocyclyl or 3- to 10-membered cycloalkyl 6-10 aryl, 3 to 10-membered heterocyclic group or 3 to 10-membered cycloalkyl; preferably 9 to 10-membered heteroaryl, naphthyl, 9 to 10-membered heterocyclic group, 9 to 10-membered cycloalkyl, or C 3-6 Cycloalkyl;

[0090] Each R 19 are each independently selected from hydrogen, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NRa S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, phenyl, 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by C 1-6 Alkyl substitution;

[0091] G is selected from N or CH;

[0092] R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR aS(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, 5-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl;

[0093] m is an integer from 0 to 4, preferably 1 or 2;

[0094] s is an integer from 0 to 4, preferably 1 or 2;

[0095] A 1 、A 2 、R 2 、R 3 、R 10 、R 11a 、R 11b 、R a 、R b As defined in general formula (I).

[0096] In a preferred embodiment, the compound represented by general formula (IVC) or general formula (VC) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is Ring A 4 and A 5 Each independently selected from C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and phenyl; in particular, ring A 4 Selected from C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl, and ring A 5 is selected from 5- to 6-membered heteroaryl and phenyl;

[0097] Preferably, Ring A is selected from:

[0098] Ring A is optionally replaced by one or more R 19 Replacement, R 19 As defined in Formula (IVC) or Formula (VC).

[0099] In another preferred embodiment, the compound represented by general formula (I) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IVD) or general formula (VD), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0100] in,

[0101] X is selected from N or CR 9 ;

[0102] Ring G is selected from 5-10 membered heteroaryl, C 6-10 Aryl, 5-10 membered heterocyclic group, preferably 5-10 membered heteroaryl, phenyl or 5-6 membered heterocyclic group;

[0103] G 1 and G 2 are each independently selected from N or CH;

[0104] R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0105] R 9 Selected from hydrogen or C 1-6 alkyl;

[0106] R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the heterocyclic, aryl, heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, 5-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl are optionally selected from -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 substituted by one or more haloalkoxy groups or 5-6-membered heterocyclic groups;

[0107] R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2Rb 、C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 alkyl halide;

[0108] Or, two adjacent R 18 The atoms to which it is attached together form a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 5-6 membered cycloalkyl, the 5-6 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, -OR a , one or more groups of haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0109] R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or

[0110] R a and R b Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally further substituted by C 1-6 Alkyl substitution;

[0111] m is an integer from 0 to 4, preferably 1 or 2;

[0112] n is an integer from 0 to 4, preferably 1 or 2;

[0113] A 1 、A 2 、R 2 、R 3 、R 10 、R 11a 、R 11b As defined in general formula (I).

[0114] In another preferred embodiment, the compound represented by the general formula (IVD) or the general formula (VD) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring G is selected from

[0115] In another preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0116] R 10 Selected from hydrogen, -C(=O)R a 、C 1-6 alkyl;

[0117] R 11a Selected from hydrogen, -OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-(CH2) p -NR a R b 、-C(=O)OR a , nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl are optionally further substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0118] R 11b Selected from hydrogen and C 1-6 alkyl;

[0119] R a and R b are each independently selected from hydrogen and C 1-6 alkyl;

[0120] Or, R 11a 、R 11b One of them is R 10 and the atoms to which they are attached form a 5- to 6-membered heterocyclic group, R 11a 、R 11b wherein the other is hydrogen; the 5- to 6-membered heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0121] p is an integer of 1 to 6, preferably 1.

[0122] In another preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0123] R 10 Selected from hydrogen and C 1-6 alkyl;

[0124] R 11a Selected from C 1-6 Alkyl and hydroxyl groups;

[0125] R 11b Selected from hydrogen and C 1-6 alkyl;

[0126] R a and R b are each independently selected from hydrogen and C 1-6 alkyl;

[0127] Or, R 11a 、R 11b One of them is R 10 and the atoms to which they are attached form a 5- to 6-membered heterocyclic group, R 11a 、R 11b wherein the other is hydrogen; the 5- to 6-membered heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0128] p is an integer of 1 to 6, preferably 1, 2 or 3.

[0129] In another specific embodiment, the compound represented by the general formula (I) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (VIA) or the general formula (VIB), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0130] in,

[0131] Y is selected from O or S;

[0132] X is selected from N or CR 9 ;

[0133] G is selected from N or CH;

[0134] G 1 and G 2are each independently selected from N or CH;

[0135] R 5 Selected from hydrogen or C 1-6 alkyl;

[0136] R 9 Selected from hydrogen or C 1-6 alkyl;

[0137] R 10 Selected from hydrogen or C 1-6 alkyl;

[0138] R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0139] R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2Rb 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 alkyl halide;

[0140] m is an integer from 0 to 4, preferably 1 or 2;

[0141] n is an integer from 0 to 4, preferably 1 or 2;

[0142] A 1 、A 2 、R 2 、R 3 As defined in general formula (I).

[0143] In another specific embodiment, the compound of general formula (I) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound of general formula (VIIA), general formula (VIIB), general formula (VIIC) or general formula (VIID), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0144] in,

[0145] E is selected from N or CR 16 ;

[0146] X is selected from N or CR 9 ;

[0147] G is selected from N or CH;

[0148] G 1 and G 2 are each independently selected from N or CH;

[0149] R 5 Selected from hydrogen or C 1-6 alkyl;

[0150] R 9 Selected from hydrogen or C 1-6alkyl;

[0151] R 10 Selected from hydrogen or C 1-6 alkyl;

[0152] R 11a C 1-6 alkyl;

[0153] R 12 Selected from hydrogen or C 1-6 alkyl;

[0154] R 16 Selected from hydrogen, C 1-6 Alkoxy, C 1-6 alkyl;

[0155] R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the aryl, heteroaryl are optionally replaced by C 1-6 Alkyl substituted; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution;

[0156] R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NRa R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 alkyl halide;

[0157] m is an integer from 0 to 4, preferably 1 or 2;

[0158] n is an integer from 0 to 4, preferably 1 or 2;

[0159] A 1 、A 2 、R 2 、R 3 As defined in general formula (I).

[0160] In another specific embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VIIIA) or general formula (VIIIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0161] in,

[0162] X is selected from N or CR 9 ;

[0163] G is selected from N or CH;

[0164] G 1 and G 2 are each independently selected from N or CH;

[0165] R 5 Selected from hydrogen or C 1-6 alkyl;

[0166] R 9 Selected from hydrogen or C 1-6 alkyl;

[0167] R 13 Selected from hydrogen or C 1-6 alkyl;

[0168] R 14 is selected from 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0169] Or, R 13 With R 14 and the nitrogen atom to which they are attached together form a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0170] R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0171] R18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 alkyl halide;

[0172] m is an integer from 0 to 4, preferably 1 or 2;

[0173] n is an integer from 0 to 4, preferably 1 or 2;

[0174] A 1 、A 2 、R 2 、R 3 As defined in general formula (I).

[0175] In a preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 、R 3 、R 7 、R 8 are each independently selected from hydrogen, halogen, C 1-6 alkyl.

[0176] In another preferred embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are optionally further substituted by one or more groups selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0177] In one embodiment, according to the present invention, R 6 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, which is optionally further selected from halogen, C 1-6 substituted by an alkyl substituent.

[0178] In another embodiment, according to the present invention, R 6 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which is optionally further selected from halogen, C 1-6 substituted by an alkyl substituent.

[0179] In another embodiment, the ring A according to the present invention is selected from C 3-6 cycloalkyl or 4- to 6-membered heterocyclic group.

[0180] In another embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein, wherein X is CR 9 ; R 6 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, which is optionally further selected from halogen, C 1-6 Alkyl is substituted by a substituent; R 5 Selected from hydrogen or C 1-6 Alkyl; R 9 Selected from hydrogen.

[0181] In another embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein, wherein, X is N; R 6 Selected from C6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, which is optionally further selected from halogen, C 1-6 Alkyl is substituted by a substituent; R 5 Selected from hydrogen or C 1-6 alkyl.

[0182] In another embodiment, according to the present invention, R 4 Selected from C 1-6 alkyl.

[0183] In another embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein, wherein,

[0184] R 10 Selected from hydrogen or C 1-6 alkyl;

[0185] R 11a Selected from hydrogen, -OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-(CH2) p -NR a R b 、-C(=O)OR a , nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0186] R 11b Selected from hydrogen and C 1-6 alkyl;

[0187] R a and R b are each independently selected from hydrogen and C 1-6 alkyl;

[0188] p is 1.

[0189] In another embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein, wherein,

[0190] R 10 Selected from -C(=O)R a ;

[0191] R 11a Selected from hydrogen or C 1-6 alkyl;

[0192] R 11b Selected from hydrogen and C 1-6 alkyl;

[0193] R a Selected from C 1-6 alkyl.

[0194] In another embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein, wherein,

[0195] R 13 selected from hydrogen;

[0196] R 14 is selected from 5- to 6-membered heteroaryl groups.

[0197] In another embodiment, the compound of the general formula according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein, wherein, R 13 With R 14 Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered heteroaryl group, which is optionally further substituted with an amino group.

[0198] Typical compounds of the present invention include, but are not limited to:

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or its pharmaceutically acceptable salt.

[0207] The present invention further provides a method for preparing the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0208] Compounds of formula (IA) and compound HR 1 Performing a substitution reaction or a coupling reaction to obtain a compound represented by the general formula (I) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0209] Wherein, L is a halogen;

[0210] A 1 、A 2 、R 1 ~R 6 , X, and Z are as defined in the general formula (I).

[0211] The present invention further provides a method for preparing the compound represented by general formula (I-1) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0212] The compound of formula (I-1a) is subjected to a condensation reaction with the compound of formula (IB) to obtain a compound represented by general formula (I-1) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0213] Among them A 1 、A 2 , X, Y, Z, R 2 ~R 6 、R 10 As defined in general formula (I-1).

[0214] The present invention further provides a method for preparing the compound represented by general formula (I-2) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0215] The compound of formula (I-2a) is subjected to a substitution reaction with the compound of formula (IC) to obtain the compound of formula (I-2b); the compound of formula (I-2b) is then reacted with the compound of formula (IB) to obtain the compound represented by general formula (I-2) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0216] Among them A 1 、A 2 , X, Z, R 2 ~R 6 、R 10 、R 11a 、R 11bAs defined in general formula (I-2).

[0217] The present invention further provides a method for preparing the compound represented by general formula (I-2) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0218] The compound of formula (I-2a) is subjected to a substitution reaction with the compound of formula (IB) to obtain a compound of formula (I-2c); the compound of formula (I-2c) is then reacted with a compound of formula (IC) to obtain a compound represented by general formula (I-2) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0219] Among them A 1 、A 2 , X, Z, R 2 ~R 6 、R 10 、R 11a 、R 11b As defined in general formula (I-2).

[0220] The present invention further provides a method for preparing the compound represented by general formula (I-2) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0221] The compound of formula (I-2d) is subjected to condensation or substitution reaction with the compound of formula (ID) to obtain the compound represented by general formula (I-2) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0222] Wherein, L is halogen; A 1 、A 2 , X, Z, R 2 ~R 6 、R 10 、R 11a 、R 11b As defined in general formula (I-2).

[0223] The present invention further provides a method for preparing the compound represented by general formula (I-2) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0224] Compound of formula (I-2e) and compound H2NR 10Carrying out a condensation or substitution reaction to obtain a compound represented by the general formula (I-2) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0225] Among them A 1 、A 2 , X, Z, R 2 ~R 6 、R 10 、R 11a 、R 11b As defined in general formula (I-2).

[0226] The present invention further provides a pharmaceutical composition comprising the compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0227] The present invention further relates to the use of the compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a PRMT5 inhibitor.

[0228] The present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a drug for preventing and / or treating diseases related to PRMT5 activity, preferably cancer and tumor-related diseases.

[0229] The present invention further relates to a compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PRMT5 inhibitor.

[0230] The present invention further relates to a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a drug for preventing and / or treating diseases associated with PRMT5 activity, preferably cancer and tumor-related diseases.

[0231] The present invention further relates to a method for inhibiting PRMT5, which comprises administering to a patient in need thereof an effective amount of a compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0232] The present invention further relates to a method for preventing and / or treating diseases associated with PRMT5 activity, which comprises administering to a patient in need thereof a preventively or therapeutically effective amount of a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0233] In a preferred embodiment, the cancer and tumor-related disease according to the present invention is bladder cancer.

[0234] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

[0235] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0236] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; or dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose, saccharin, or aspartame.

[0237] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0238] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain demulcents, preservatives, colorants, and antioxidants.

[0239] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

[0240] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0241] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thereby dissolves and releases the drug in the rectum. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0242] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. In addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the general formula compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment protocols.

[0243] The present invention may contain a compound and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compounds of the present invention can be used as the sole active ingredient or in combination with other anticancer agents or immune checkpoint inhibitors. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

[0244] Terminology

[0245] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0246] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0247] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0248] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0249] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0250] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0251] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0252] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 6-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0253] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0254] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0255] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 6 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0256] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 8 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0257] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 8 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0258] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0259] wait.

[0260] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0261] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, i.e., a fused ring aryl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0262] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0263] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, i.e., a fused ring heteroaryl, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0264] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0265] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl and cycloalkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0266] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0267] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0268] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0269] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0270] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above.

[0271] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0272] The term "hydroxy" refers to an -OH group.

[0273] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0274] The term "amino" refers to -NH2.

[0275] The term "cyano" refers to -CN.

[0276] The term "nitro" refers to -NO2.

[0277] The term "oxo" refers to =0.

[0278] The term "thio" refers to =S.

[0279] The term "carboxy" refers to -C(O)OH.

[0280] The term "mercapto" refers to -SH.

[0281] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0282] The compounds of the present invention may be in deuterated form. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art are able to synthesize deuterated compounds with reference to the relevant literature. Commercially available deuterated starting materials may be used to prepare deuterated compounds, or they may be synthesized using conventional techniques employing deuterated reagents.

[0283] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0284] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0285] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0286] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0287] The compounds of the present invention and their preparation will be further understood by way of the examples, which illustrate some methods of preparing or using the compounds. However, it will be appreciated that these examples do not limit the scope of the present invention. Variations of the present invention as now known or further developed are considered to fall within the scope of the invention as described herein and as claimed.

[0288] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0289] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts' "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0290] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0291] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using an Oxford WNMR-I-400 MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0292] MS measurements were performed using a 1260 Infinity II 6125B single quadrupole LC / MS instrument (Agilent), using a Kinetex XB-C18 100A 1.7 μm (30 × 3 mm) column (Finomed), and using acetonitrile / water (0.1% FA) as the mobile phase. Preparative liquid chromatography was performed using a 1260 Infinity II preparative liquid chromatography system (Agilent), using an Xtimate C18 5 μm (21.2 × 250 mm) column (Yuexu Technology), and using acetonitrile / water as the mobile phase. Thin-layer chromatography (TLC) was performed using Qingdao Ocean Chemical GF254 silica gel plates. Reaction monitoring used 0.20 mm to 0.25 mm silica gel plates, while separation and purification used 0.5 mm silica gel plates.

[0293] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0294] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, exploration platforms, Booker Mall, Lanbo.com, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinoke, Anaiji Chemical, Shanghai Bid, Shanghai Leyan, Nanjing Yaoshi and other companies.

[0295] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0296] Argon atmosphere, nitrogen atmosphere or hydrogen atmosphere means that the reaction bottle is connected to an argon, nitrogen or hydrogen balloon with a volume of about 1 L.

[0297] The reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), ethanol (EtOH), dimethyl sulfoxide (DMSO), 1,4-dioxane, nitrogen-methylpyrrolidone (NMP), pyridine, water, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0298] The chemical reactions described herein are generally carried out under normal pressure. Reaction times and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0299] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0300] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0301] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0302] Example

[0303] Example 1: Synthesis of 6-((amino(methylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (1)

[0304] Step 1: Preparation of 6-(3-benzoylthioureido)nicotinate (1-2)

[0305] Methyl 6-aminonicotinate (1-1) (500 mg, 3.3 mmol) was dissolved in a single-necked flask containing THF (10 mL), and benzoyl isothiocyanate (540 mg, 3.3 mmol) was added. The resulting mixture was stirred at room temperature overnight. Ice water (50 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 3 / 1) to obtain compound 1-2 (700 mg, 67% yield, as a yellow solid).

[0306] LC-MS (ESI+): 316.0 m / z [M+H] + .

[0307] Step 2: Preparation of 6-thioureidonic acid (1-3)

[0308] Compound 1-2 (700 mg, 2.22 mmol) was dissolved in a single-necked flask containing THF (7 mL). Aqueous NaOH (1.1 mL, 4 M) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filter cake was washed with THF. The filter cake was vacuum-dried to yield the crude product 6-thioureidonicotinic acid (400 mg, 93% yield, as a white solid).

[0309] LC-MS (ESI+): 198.0 m / z [M+H] + .

[0310] Step 3: Preparation of 6-((amino(methylthio)methylene)amino)nicotinic acid (1-4)

[0311] Compound 1-3 (55 mg, 0.28 mmol) was dissolved in a single-necked flask containing acetone (2 mL). Methyl iodide (60 mg, 0.42 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the filter cake was vacuum-dried to obtain crude compound 1-4 (60 mg, 99% yield, as a white solid).

[0312] LC-MS (ESI+): 211.95 m / z [M+H] + .

[0313] Step 4: Preparation of 6-((amino(methylamino)methylene)amino)nicotinic acid (1-5)

[0314] Compound 1-4 (1.0 g, 4.73 mmol) was dissolved in a sealed tube containing isopropanol (10 mL). Methylamine tetrahydrofuran solution (2 M, 2.6 mL, 5.21 mmol) was added, and the resulting mixture was stirred at 80°C for 18 hours. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to obtain compound 1-5 (0.2 g, 22% yield, as a white solid).

[0315] LC-MS (ESI+): 195.0 m / z [M+H] + .

[0316] Step 5: Preparation of 6-((amino(methylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (1)

[0317] Compound 1-5 (40 mg, 0.21 mmol) was dissolved in a single-necked bottle containing DMF (2 mL), and 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (1-6) (70 mg, 0.25 mmol) (prepared according to the synthesis method of intermediate 139 on page 93 / 311 of patent application WO2021163344A1) and TEA (68 mg, 0.67 mmol) were added sequentially. The resulting mixture was cooled to 0 ° C under a nitrogen atmosphere, and BOPCl (0.13 g, 0.53 mmol) was added, and the mixture was naturally warmed to room temperature and stirred for 18 hours. EtOAc (50 mL) was added to the reaction solution and washed with saturated brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O=5-95%) and freeze-dried to give Compound 1 (11.1 mg, yield 22%, white solid).

[0318] LC-MS (ESI+): 459.1m / z[M+H] + .

[0319] 1 H NMR(400MHz,CH3OH-d4)δ8.80–8.46(m,4H),8.12–7.98(m,2H),7.53(d,J=8.9Hz,1H),7.32(t,J=4.9Hz,1H),7.15 –6.89(m,1H),5.46–5.28(m,1H),4.98(d,J=17.0Hz,1H),4.68(d,J=16.9Hz,1H),3.01(s,3H),1.74–1.63(m,3H).

[0320] The following compounds were obtained by the synthesis method of Example 1 using the corresponding raw materials:

[0321] Example 4: Synthesis of 4-((amino(methylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide (4)

[0322] Step 1: Preparation of methyl 4-(3-benzoylthioureido)benzoate (4-2)

[0323] Methyl 4-aminobenzoate (5.0 g, 33 mmol) was dissolved in a single-necked flask containing THF (50 mL) and benzoyl isothiocyanate (5.4 g, 33 mmol) was added. The resulting mixture was stirred at room temperature overnight. Ice water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 3 / 1) to obtain compound 4-2 (6.5 g, 63% yield, light yellow solid).

[0324] LC-MS (ESI+): 315.0 m / z [M+H] + .

[0325] Step 2: Preparation of 4-thioureidobenzoic acid (4-3)

[0326] Compound 4-2 (6.5 g, 20.7 mmol) was dissolved in a single-necked flask containing THF (70 mL). Aqueous NaOH (4 M, 10.5 mL) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filter cake was washed with THF. The filter cake was collected and vacuum-dried to obtain compound 4-3 (4.2 g, 95% yield, white solid). The crude product was used directly in the next reaction.

[0327] LC-MS (ESI+): 197.0 m / z [M+H] + .

[0328] Step 3: Preparation of 4-((amino(methylthio)methylene)amino)benzoic acid (4-4)

[0329] Compound 4-3 (2.1 g, 10.7 mmol) was dissolved in a single-necked flask containing acetone (42 mL), and iodomethane (2.28 g, 16.07 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the filter cake was collected and dried under vacuum to obtain compound 4-4 (1.8 g, yield 80%), as a white solid.

[0330] LC-MS (ESI+): 211.0 m / z [M+H] + .

[0331] Step 4: Preparation of (Z)-N'-(4-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)phenyl)carbamoylthiocarboxylate (4-5)

[0332] Compound 4-4 (107 mg, 0.5 mmol) was dissolved in a single-necked flask containing DMF (2 mL), and compound 1-6 (120 mg, 0.43 mmol) and TEA (129 mg, 1.3 mmol) were added sequentially. The resulting mixture was cooled to 0°C under a nitrogen atmosphere, and BOPCl (151 mg, 0.60 mmol) was added. The mixture was naturally warmed to room temperature and stirred for 18 hours. EtOAc (50 mL) was added to the reaction solution, and the mixture was washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to obtain compound 4-5 (40 mg, 20% yield, as a white solid).

[0333] LC-MS (ESI+): 475.1m / z[M+H] + .

[0334] Step 5: Preparation of 4-((amino(methylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide (4)

[0335] Compound 4-5 (40 mg, 0.21 mmol) was dissolved in isopropanol (3 mL) in a microwave tube. Methylamine tetrahydrofuran solution (2.8 M, 0.06 mL, 0.17 mmol) was added, and the resulting mixture was heated to 80°C and stirred for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to yield compound 4 (5.4 mg, 22% yield, as a white solid).

[0336] LC-MS (ESI+): 458.0 m / z [M+H] + .

[0337] 1 H NMR (400MHz, CH3OH-d4) δ8.81–8.66(m,3H),8.51(s,1H),8.01(d,J=8.3Hz,1H),7.67(d,J=8.0Hz,1H),7.55(d,J=8.4Hz,1H),7.40–7.15(m,3H),5.46 –5.32(m,1H),5.03(d,J=17.0Hz,1H),4.69(d,J=16.7Hz,1H),2.91(s,3H),1.72–1.57(m,3H).

[0338] The following compounds can be obtained by using the corresponding raw materials according to the synthesis method of Example 4:

[0339] Example 7: Synthesis of 6-(diaminoethylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (7)

[0340] Step 1: Preparation of N'-(5-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-ylcarbamoylthio)methyl ester (7-1)

[0341] Compound 1-4 (0.27 g, 1.3 mmol) was dissolved in a single-necked flask containing DMF (6 mL), and compound 1-6 (0.3 g, 1.1 mmol) and TEA (0.28 g, 2.8 mmol) were added sequentially. The resulting mixture was cooled to 0°C under a nitrogen atmosphere, and BOPCl (0.33 g, 1.3 mmol) was added. The mixture was naturally warmed to room temperature and stirred for 12 hours. Water (25 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (25 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / EtOAc = 1 / 1) to obtain compound 7-1 (0.2 g, 39% yield, yellow liquid).

[0342] LC-MS (ESI+): 476.2 m / z [M+H] + .

[0343] Step 2: Preparation of 6-(diaminoethylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (7)

[0344] Compound 7-1 (25 mg, 0.05 mmol) was dissolved in a sealed tube containing isopropanol (2 mL). Ammonium chloride (12 mg, 0.2 mmol) was added, and the resulting mixture was heated to 90°C and stirred for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to yield compound 7 (12.6 mg, 52% yield, as a white solid).

[0345] LC-MS (ESI+): 445.0 m / z [M+H] + .

[0346] 1 H NMR(400MHz,CH3OH-d4)δ8.87–8.53(m,4H),8.29–8.05(m,1H),8.03–7.92(m,1H),7.58–7.46(m,1H),7.38–7. 06(m,2H),5.47–5.23(m,1H),4.98(d,J=17.4Hz,1H),4.69(d,J=17.5Hz,1H),2.77(s,3H),1.76–1.60(m,3H).

[0347] The following compounds can be obtained by using the corresponding raw materials according to the synthesis method of Example 7:

[0348] Example 16: Synthesis of N-(1-(pyrimidin-2-yl)ethyl)-6-thioureido-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (16)

[0349] Compound 1-3 (45 mg, 0.21 mmol) was dissolved in a single-necked flask containing DMF (2 mL), and compound 1-6 (50 mg, 0.18 mmol) and TEA (55 mg, 0.54 mmol) were added sequentially. The resulting mixture was cooled to 0°C under a nitrogen atmosphere, and BOPCl (68 mg, 0.27 mmol) was added. The mixture was warmed to room temperature and stirred for 18 hours. EtOAc (25 mL) was added to the reaction solution, which was then washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to obtain compound 16 (14.9 mg, 15% yield, as a white solid).

[0350] LC-MS (ESI+): 462.0 m / z [M+H] + .

[0351] 1 H NMR(400MHz,CH3OH-d4)δ8.76–8.66(m,3H),8.56(s,1H),8.06–7.96(m,2H),7.52(d,J=8.4Hz,1H),7.31(t,J=4 .9Hz,1H),7.12–7.02(m,1H),5.47–5.35(m,1H),4.97(d,J=17.0Hz,1H),4.73–4.60(m,1H),1.77–1.56(m,3H).

[0352] Example 17: Synthesis of 6-((amino(methoxyformylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (17)

[0353] Compound 7 (20 mg, 0.04 mmol) was dissolved in a single-necked flask containing DCM (4 mL), and TEA (15 mg, 0.12 mmol) was added. The resulting mixture was cooled to 0°C in an ice bath, and methyl chloroformate (5 mg, 0.04 mmol) was added. The mixture was naturally warmed to room temperature and stirred for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to obtain compound 17 (3 mg, 13% yield, as a white solid).

[0354] LC-MS (ESI+): 503.5 m / z [M+H] + .

[0355] 1 H NMR(400MHz,CH3OH-d4)δ8.76–8.65(m,4H),8.60–8.50(m,1H),8.04–7.95(m,2H),7.52(d,J=8.3Hz,1H),7.31( t,J=4.9Hz,1H),5.44–5.42(m,1H),4.97(d,J=16.9Hz,1H),4.72–4.53(m,1H),3.67(s,3H),1.70–1.65(m,3H).

[0356] Example 18: Synthesis of (N'-(5-(1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-ylcarbamoyl)glycine tert-butyl ester (18)

[0357] Step 1: Preparation of (N'-(5-(1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-ylcarbamoyl)glycine tert-butyl ester (18-1)

[0358] Compound 7-1 (60 mg, 0.12 mmol) was dissolved in a sealed tube containing isopropanol (2 mL). T-butyl glycine (66 mg, 0.5 mmol) was added, and the resulting mixture was heated to 90°C and stirred for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / EtOAc = 1 / 1) to obtain compound 18-1 (22 mg, 62% yield, as a white solid).

[0359] LC-MS (ESI+): 559.2 m / z [M+H] + .

[0360] Step 2: Preparation of (N'-(5-(1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-ylcarbamoyl)glycine tert-butyl ester (18)

[0361] Compound 18-1 (22 mg, 0.04 mmol) was dissolved in a single-necked bottle containing DCM (2 mL), TFA (1 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (ACN / H2O=5-95%) and freeze-dried to obtain compound 18 (3.7 mg, yield 19%, white solid).

[0362] LC-MS (ESI+): 503.0 m / z [M+H] + .

[0363] 1 H NMR (400MHz, CH3OH-d4) δ8.81–8.53(m,4H),8.20–8.07(m,1H),7.99(d,J=8.1Hz,1H),7.62–7.44(m,1H),7.32(t,J=4.9Hz, 1H),7.19–6.98(m,1H),5.50–5.27(m,1H),4.98(d,J=17.1Hz,1H),4.69(d,J=17.6Hz,1H),4.19(s,2H),1.73–1.57(m,3H).

[0364] Example 19: Synthesis of 6-((amino((2-hydroxyethyl)amino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (19)

[0365] Step 1: Preparation of 6-((amino((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl ester)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (19-1)

[0366] Compound 7-1 (61.8 mg, 0.13 mmol) was dissolved in isopropanol (3 mL) in a microwave tube. 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (46 mg, 0.26 mmol) was added, and the resulting mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 19-1 (15.2 mg, 19% yield, as a white solid).

[0367] LC-MS (ESI+): 603.3 m / z [M+H] + .

[0368] Step 2: Preparation of (Z)-6-((amino((2-hydroxyethyl)amino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (19)

[0369] Compound 19-1 (25 mg, 0.04 mmol) was dissolved in a single-necked flask containing THF (6 mL), and triethylamine trihydrofluoride (65 mg, 0.4 mmol) was added, and the resulting mixture was stirred at room temperature overnight. Water (10 mL) and saturated NaHCO3 aqueous solution (10 mL) were added to the reaction solution, and the mixture was extracted with EtOAc (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O=5-95%) and freeze-dried to obtain compound 19 (4.3 mg, yield 21%, purity 99%, brown solid).

[0370] LC-MS (ESI+): 489.15 m / z [M+H] + .

[0371] 1 H NMR (400MHz, CH3OH-d4): δ8.85–8.41(m,5H),8.12(d,J=8.2Hz,1H),7.99(dd,J=8.3,2.2Hz,1H),7.52(d,J=8.2Hz,1H),7.31(t,J=4.9Hz,1H), 7.18–6.93(m,1H),5.46–5.32(m,1H),4.97(d,J=17.1Hz,1H),4.67(d,J =16.8Hz,1H),3.85–3.70(m,2H),3.55–3.40(m,2H),1.77–1.56(m,3H).

[0372] Example 20: Synthesis of N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-6-ureidonicotinamide (20)

[0373] Step 1: Preparation of 6-ureidonic acid (20-2)

[0374] 6-Aminonicotinic acid (300 mg, 2.17 mmol) was dissolved in a three-necked flask containing THF (10 mL). After cooling to 0°C in an ice bath, NaH (347 mg, 8.68 mmol) was slowly added portionwise. The resulting mixture was stirred at 0°C for 1 hour, and trichloroacetyl isocyanate (613 mg, 3.26 mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the mixture was allowed to warm to room temperature and stirred overnight. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL x 3). The aqueous phase was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to yield compound 20-2 (96.0 mg, 24% yield, colorless oil).

[0375] LC-MS (ESI+): 182.0 m / z [M+H] + .

[0376] Step 2: Preparation of N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-6-ureidonicotinamide (20)

[0377] 6-Ureidonic acid (50 mg, 0.28 mmol) was dissolved in a single-necked flask containing DMF (5 mL). Compound 1-6 (77.8 mg, 0.28 mmol) and DIEA (71 mg, 0.55 mmol) were added sequentially. The resulting mixture was cooled to 0°C in an ice bath, and BOPCl (105 mg, 0.41 mmol) was slowly added. After addition, the mixture was allowed to warm to room temperature and stirred overnight. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to yield Compound 20 (14 mg, 11.4% yield, as a white solid).

[0378] LC-MS (ESI+): 446.2 m / z [M+H] + .

[0379] 1H NMR (400MHz, CH3OH-d4) δ8.77–8.65(m,3H),8.60–8.50(m,1H),8.13–8.04(m,1H),8.03–7.91(m,1H),7.52(d,J= 8.3Hz,1H),7.35–7.21(m,2H),5.50–5.37(m,1H),4.96(d,J=16.2Hz,1H),4.75–4.63(m,1H),1.74–1.60(m,3H).

[0380] Example 21: Synthesis of 6-((bis(methyl-amino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (21)

[0381] Step 1: Preparation of 6-(3-methylthioureido)nicotinate (21-1)

[0382] Compound 1-1 (2.0 g, 13.1 mmol) was dissolved in a single-necked flask containing toluene (20 mL). Methyl isothiocyanate (1.1 g, 15.8 mmol) was added, and the resulting mixture was heated to 110°C and stirred for 48 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was purified by silica gel column chromatography (DCM / EtOAc = 1 / 1) to obtain compound 21-1 (1.3 g, 40% yield, as a white solid).

[0383] LC-MS (ESI+): 225.9 m / z [M+H] + .

[0384] Step 2: Preparation of 6-(bis(methylamino)methylene)amino)nicotinate (21-2)

[0385] Compound 21-1 (260 mg, 1.1 mmol) was dissolved in ethanol (5 mL) in a sealed tube. MeNH2 (3 M in THF, 0.57 mL, 1.5 mmol) and HgO (0.25 g, 1.1 mmol) were added sequentially. The resulting mixture was heated to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 21-2 (110 mg, 43% yield, as a white solid).

[0386] LC-MS (ESI+): 223.0 m / z [M+H] + .

[0387] Step 3: Preparation of 6-(bis(methylamino)methylene)amino)nicotinic acid (21-3)

[0388] Compound 21-2 (0.11 g, 0.5 mmol) was dissolved in a single-necked flask containing MeOH (2 mL). Aqueous LiOH (4 M, 0.5 mL, 2.0 mmol) was slowly added, and the resulting mixture was stirred at room temperature for 18 hours. Dilute hydrochloric acid (0.5 M) was added to the reaction solution to adjust the pH to approximately 5. The resulting solution was directly purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to afford compound 21-3 (100 mg, 96% yield, as a white solid).

[0389] LC-MS (ESI+): 209.0 m / z [M+H] + .

[0390] Step 4: Preparation of 6-((bis(methyl-amino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (21)

[0391] Compound 21-3 (100 mg, 0.48 mmol) was dissolved in a single-necked flask containing DMF (2 mL). TEA (97 mg, 0.96 mmol) and compound 1-6 (140 mg, 0.48 mmol) were added sequentially. The resulting mixture was cooled to 0°C in an ice bath, and BOPCl (0.13 g, 0.53 mmol) was slowly added. The mixture was naturally warmed to room temperature and stirred for 18 hours. EtOAc (50 mL) was added to the reaction solution, and the mixture was washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to obtain compound 21 (23.5 mg, 10% yield, as a white solid).

[0392] LC-MS (ESI+): 473.15 m / z [M+H] + .

[0393] 1H NMR(400MHz,CH3OH-d4)δ8.75–8.66(m,2H),8.64–8.58(m,1H),8.54–8.43(m,1H),8.19–8.10(m,1H),8.00(d,J=7.2Hz,1H),7.53(d,J=7.6Hz,1H) ,7.42(d,J=8.0Hz,1H),7.32(t,J=4.9Hz,1H),5.45–5.30(m,1H),4.98(d ,J=17.2Hz,1H),4.68(d,J=16.7Hz,1H),3.04(s,6H),1.74–1.57(m,3H).

[0394] Example 22: Synthesis of 6-((amino(nitroamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (22)

[0395] Step 1: Preparation of 6-fluoro-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (22-2)

[0396] Compound 1-6 (200 mg, 0.71 mmol) was dissolved in a single-necked flask containing DMF (5 mL). 6-Fluoronicotinic acid (100 mg, 0.71 mmol), HATU (324 mg, 0.85 mmol), and DIEA (275 mg, 2.13 mmol) were added sequentially. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / EtOAc = 1 / 1) to obtain compound 22-2 (0.14 g, 49% yield, as a light yellow solid).

[0397] LC-MS (ESI+): 406.1m / z[M+H] + .

[0398] Step 2: Preparation of 6-((amino(nitroamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (22)

[0399] Compound 22-2 (75 mg, 0.18 mmol) was dissolved in a single-necked flask containing DMF (2 mL). 1-Nitroguanidine (23 mg, 0.22 mmol) and Cs2CO3 (181 mg, 0.55 mmol) were added sequentially. The resulting mixture was heated to 40°C and stirred for 18 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to obtain compound 22 (17.8 mg, 20% yield, as a white solid).

[0400] LC-MS (ESI+): 490.1m / z[M+H] + .

[0401] 1 H NMR(400MHz,CH3OH-d4)δ8.85–8.42(m,4H),8.17–7.86(m,2H),7.59–7.47(m,1H),7.31(t,J=4.9Hz,1H ),7.21–6.94(m,1H),5.45–5.37(m,1H),4.97(d,J=16.9Hz,1H),4.77–4.56(m,1H),1.71–1.60(m,3H).

[0402] The following compounds were obtained by the synthesis method of Example 22 using the corresponding raw materials:

[0403] Example 29: Synthesis of 6-((isobutyramido(methylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (29)

[0404] Step 1: Preparation of N-isobutyryl-N'-(5-((1-(pyrimidin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-yl)carbamoylthiomethyl ester (29-1)

[0405] A solution of compound 7-1 (200 mg, 0.42 mmol) in DCM (5.0 mL) was cooled to 0°C in an ice bath. Isobutyryl chloride (59.4 mg, 0.56 mmol) and triethylamine (200 μL, 1.42 mmol) were slowly added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (30.0 mL) and extracted with DCM (30.0 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 29-1 (200 mg, 87% yield).

[0406] Step 2: Preparation of 6-((isobutyramido(methylamino)methylene)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (29)

[0407] The crude product of compound 29-1 (200 mg, 0.36 mmol) and a 2M solution of methylamine in tetrahydrofuran (100 μL) were added sequentially to isopropanol (10.0 mL) at room temperature. The resulting mixture was reacted in a microwave oven at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was separated by Prep-HPLC (ACN / H₂O = 5-95%) to afford compound 29 (16 mg, 31% yield).

[0408] LC-MS (ESI+): 528.2 m / z [M+H] + .

[0409] Example 30: Synthesis of 6-((1H-imidazol-2-yl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (30)

[0410] Step 1: Preparation of 6-bromo-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (30-2)

[0411] At room temperature, 6-bromonicotinic acid (100 mg, 0.50 mmol) and compound 1-6 (140 mg, 0.60 mmol) were added to N,N-dimethylacetamide (2.0 mL), followed by tripyrrolidinylphosphonium bromide hexafluorophosphate (278 mg, 0.60 mmol) and N,N-diisopropylethylamine (248 uL, 1.50 mmol). The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into EtOAc (20.0 mL) and washed three times with saturated brine (10.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to afford compound 30-2 (231 mg, 62% yield).

[0412] Step 2: Preparation of 6-((1H-imidazol-2-yl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (30)

[0413] Compound 30-2 (130 mg, 0.28 mmol), tert-butyl 2-amino-1H-imidazole-1-carboxylate (51.3 mg, 0.28 mmol), chloro[2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (20.6 mg, 0.03 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (25.5 mg, 0.06 mmol), and sodium tert-butoxide (24 mg, 0.25 mmol) were added to tert-butanol (5.0 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours and then cooled to room temperature. The cooled reaction mixture was poured into water (50.0 mL) and extracted with EtOAc (20.0 mL x 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was separated by Prep-HPLC (ACN / H2O=5-95%) to give compound 30 (20 mg, yield 20%).

[0414] LC-MS (ESI+): 468.2 m / z [M+H] + .

[0415] Example 31: Synthesis of 6-((amino(methylamino)methylene)amino)-N-(1-(m-tolyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (31)

[0416] Step 1: Preparation of N-methoxy-N,3-dimethylbenzamide (31-2)

[0417] 3-Methylbenzoic acid (1.00 g, 7.34 mmol) was dissolved in DCM (10 mL) at 0°C. A solution of N,N'-carbonyldiimidazole (1.19 g, 7.34 mmol) in DCM (3.0 mL) was added and stirred at this temperature for 0.5 hours. N,O-Dimethylhydroxylamine hydrochloride (716 mg, 7.34 mmol) and triethylamine (743 mg, 7.34 mmol) were added sequentially at 0°C. After stirring at this temperature for 1 hour, the mixture was stirred at room temperature overnight. The reaction mixture was washed sequentially with 1N aqueous hydrochloric acid (50.0 mL), saturated aqueous sodium carbonate (50.0 mL), and saturated brine (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1) to obtain compound 31-2 (1.2 g, crude yield 91%).

[0418] Step 2: Preparation of 1-(m-tolyl)ethan-1-one (31-3)

[0419] Compound 31-2 (500 mg, 2.79 mmol) was dissolved in tetrahydrofuran (3.0 mL) at room temperature, and methylmagnesium bromide (3 M in THF) (1.86 mL, 5.58 mmol) was added at 0°C. The mixture was stirred at 0°C for 3 hours. The mixture was quenched with saturated aqueous ammonium chloride (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The organic phase was collected and washed once with saturated brine (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 31-3 (300 mg, crude yield 80%).

[0420] Step 3: Preparation of 1-(m-tolyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (31-4)

[0421] At room temperature, (5-(trifluoromethyl)pyridin-2-yl)methanamine (360 mg, 2.04 mmol) and compound 31-3 (300 mg, 2.25 mmol) were dissolved in DCM (10 mL). Potassium acetate (240 mg, 2.45 mmol), acetic acid (122 mg, 2.04 mmol), and 4A molecular sieves (3.0 g) were added sequentially. The resulting mixture was stirred at room temperature for 0.5 hours under a nitrogen atmosphere, then cooled to 0°C and sodium acetate borohydride (1.23 g, 6.13 mmol) was added in three portions. After addition, the temperature was naturally warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (10.0 mL) and washed with saturated aqueous ammonium bicarbonate (20.0 mL). The resulting mixture was extracted with DCM (10.0 mL x 3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain compound 31-4 (164 mg, yield 27%).

[0422] Step 4: Preparation of (Z)-N'-(5-((1-(m-tolyl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-ylcarbamoylthio)methyl ester (31-5)

[0423] At room temperature, compound 1-4 (120 mg, 0.57 mmol) was dissolved in N,N-dimethylacetamide (5.0 mL). Compound 31-4 (167 mg, 0.57 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (318 mg, 0.68 mmol), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were added sequentially. After stirring at room temperature for 2 hours, the reaction solution was diluted with water (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound (31-5) (300 mg, crude yield >100%).

[0424] Step 5: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(1-(m-tolyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (31)

[0425] Compound 31-5 (300 mg, 0.41 mmol) was dissolved in isopropanol (3.0 mL) at room temperature, and ethanolic methylamine (30%, 2.0 mL) was added. The mixture was microwaved at 80°C for 1 hour. Prep-HPLC (ACN / H2O = 5-95%) was used to separate and purify compound 31 (32 mg, 11% yield).

[0426] LC-MS (ESI+): 471.2 m / z [M+H] + .

[0427] 1 H NMR(400MHz,DMSO-d6)δ10.9(s,1H),9.29(s,1H),8.85(s,1H),8.57–8.51(m,2H),8.10–8.00(m,1H),7.56(s,1H),7.2 2(s,2H),7.10(s,3H),5.14(s,1H),4.78–4.74(m,1H),4.41–4.35(m,1H),2.95(s,3H),2.27(s,3H),1.83–1.62(m,3H).

[0428] The following compounds were synthesized according to the method of Example 31 using the corresponding raw materials. In Example 35, cyclobutanone (purchased from Shanghai Titan Technology Exploration Platform) was used instead of compound 31-3. In Example 36, benzaldehyde (purchased from Shanghai Titan Technology Exploration Platform) was used instead of compound 31-3. In Example 44, 6,7-dihydro-5H-quinolin-8-one (purchased from Bidex Pharmaceuticals) was used instead of compound 31-3.

[0429] Example 45: Synthesis of 6-((amino(methylamino)methylene)amino)-N-(quinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (45)

[0430] Step 1: Preparation of 6-fluoro-N-(quinolin-8-yl)nicotinamide (45-2)

[0431] At room temperature, 6-fluoronicotinic acid (500 mg, 3.54 mmol) was dissolved in N,N-dimethylacetamide (10.0 mL). Quinolin-8-amine (511 mg, 3.54 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (2.48 g, 5.31 mmol), and N,N-diisopropylethylamine (1.08 g, 10.6 mmol) were added sequentially. After stirring overnight at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 45-2 (900 mg, crude yield 95%).

[0432] Step 2: Preparation of 6-fluoro-N-(quinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (45-3)

[0433] At room temperature, compound 45-2 (300 mg, 1.12 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (573 mg, 2.24 mmol) and potassium carbonate (465 mg, 3.36 mmol) were added sequentially. After stirring at 50°C overnight, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 45-3 (300 mg, crude yield 55%).

[0434] Step 3: Preparation of 6-((amino(methylamino)methylene)amino)-N-(quinolin-8-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (45)

[0435] Compound 45-3 (300 mg, 0.70 mmol) was dissolved in N,N-dimethylacetamide (5.0 mL) at room temperature, and 1-methylguanidine hydrochloride (153 mg, 1.40 mmol) and cesium carbonate (153 mg, 2.80 mmol) were added sequentially. After stirring at 100°C overnight, the mixture was separated and purified by Prep-HPLC (ACN / H2O = 5-95%) to obtain compound 45 (23.8 mg, 7% yield).

[0436] LC-MS (ESI+): 480.4 m / z [M+H] + .

[0437] 1 HNMR (400MHz, DMSO-d6) δ8.91(d,J=3.6Hz,1H),8.83(s,1H),8.34(d,J=8.8Hz,1H),8.29(s,1H),8.17(dd,J=8.2,2.4 Hz,1H),8.02(s,1H),7.96(d,J=8.3Hz,1H),7.88(d,J=8.5Hz,1H),7.80(d,J=7.3Hz,1H),7.56–7.51(m,3H),6.50(s, 1H),5.59(s,1H),5.08(s,1H),2.71(s,3H).

[0438] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 45:

[0439] Example 54: Synthesis of 6-((amino(methylamino)methylene)amino)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)nicotinamide (54)

[0440] Step 1: Preparation of 2-((methylimino)methyl)-5-(trifluoromethyl)phenol (54-2)

[0441] 2-Hydroxy-4-(trifluoromethyl)benzaldehyde (0.5 g, 2.6 mmol) was dissolved in DCM (5 mL) in a single-necked flask. MgSO (1.2 g, 10.5 mmol) and NH Me (2 M in THF, 2.6 mL, 5.2 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filter cake was dried under vacuum to yield compound 54-2 (0.2 g, 37% yield, as a yellow solid).

[0442] LC-MS (ESI+): 204.0 m / z [M+H] + .

[0443] Step 2: Preparation of N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (54-3)

[0444] Potassium tert-butoxide (1 M in THF, 2.4 mL, 2.4 mmol) was added to a solution of trimethylsulfoxide iodide (0.5 g, 2.4 mmol) in THF (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 hour, and then a solution of (E)-2-((methylimino)methyl)-5-(trifluoromethyl)phenol (0.2 g, 0.9 mmol) in THF (2 mL) was slowly added dropwise. Stirring was continued at room temperature for 1 hour, then the temperature was raised to 50°C and stirred for 3 hours. The reaction solution was cooled to room temperature, and the insoluble solid was removed by filtration. H2O (20 mL) was added to the filtrate, and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / EtOAc=1 / 1) to obtain compound 54-3 (92 mg, yield 43%, colorless oil).

[0445] LC-MS (ESI+): 218.0 m / z [M+H] + .

[0446] Step 3: Preparation of N'-(5-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)pyridin-2-yl)carbamoylthiomethyl ester (54-4) N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (92 mg, 0.4 mmol) was dissolved in a single-necked bottle containing DMF (2 mL), and triethylamine (110 mg, 1.0 mmol) and compound 1-4 (90 mg, 0.4 mmol) were added in sequence. mol). The resulting mixture was cooled to 0°C and BOPCl (0.13 g, 0.5 mmol) was slowly added. The mixture was naturally warmed to room temperature and stirred for 18 hours. EtOAc (50 mL) was added to the reaction solution, and the mixture was washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to obtain compound 54-4 (100 mg, 58% yield, colorless oil).

[0447] LC-MS (ESI+): 411.0 m / z [M+H] + .

[0448] Step 4: Preparation of 6-((amino(methylamino)methylene)amino)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)nicotinamide (54)

[0449] Compound 54-4 (50 mg, 0.1 mmol) was dissolved in isopropanol (2 mL) in a sealed tube. NH2Me (2 M in THF, 0.3 mL, 0.6 mmol) was added, and the resulting mixture was stirred at 90°C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to afford compound 54 (40.3 mg, 85% yield, as a white solid).

[0450] LC-MS (ESI+): 394.1m / z[M+H] + .

[0451] 1 H NMR(400MHz,CH3OH-d4)δ8.49(s,1H),7.99(dd,J=8.5,1.9Hz,1H),7.55(s,1H),7.27(d,J=7.9Hz,1 H),7.16–7.01(m,1H),6.41(s,0.6H),5.76(s,0.4H),4.83–4.60(m,2H),3.01(s,3H),2.74(s,3H).

[0452] Example 55: Synthesis of 6-((amino(methylamino)methylene)amino)-N-methyl-N-(6-(pyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)nicotinamide (55)

[0453] Step 1: Preparation of 2-hydroxy-4-(pyridin-4-yl)benzaldehyde (55-2)

[0454] 4-Bromo-2-hydroxybenzaldehyde (50 mg, 0.2 mmol) was dissolved in a single-necked flask containing dioxane / H₂O (2 mL / 0.5 mL). K₂CO₃ (66 mg, 0.6 mmol) and pyridin-4-ylboronic acid (30 mg, 0.6 mmol) were added sequentially at room temperature. The resulting mixture was purged with nitrogen, and Pd(PPh₃)₄ (14 mg, 0.01 mmol) was added. After further nitrogen purging, the mixture was heated to 90°C and stirred for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc = 3 / 1) to give compound 55-2 (30 mg, 61% yield, as a yellow solid).

[0455] LC-MS (ESI+): 200.0 m / z [M+H] + .

[0456] Step 2: Preparation of 2-((methylimino)methyl)-5-(pyridin-4-yl)phenol (55-3)

[0457] Compound 55-2 (0.2 g, 1.0 mmol) was dissolved in a single-necked flask containing DCM (2 mL). Magnesium sulfate (0.48 g, 4.0 mmol) and methylamine (2 M in THF, 1 mL, 2 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 55-3 (0.2 g, 99% yield, yellow solid), which was used directly in the next reaction without further treatment.

[0458] LC-MS (ESI+): 213.1m / z[M+H] + .

[0459] Step 3: Preparation of N-methyl-6-(pyridin-4-yl)-2,3-dihydrobenzofuran-3-amine (55-4)

[0460] Trimethylsulfoxide iodide (0.5 g, 2.4 mmol) was dissolved in a three-necked flask containing THF (2 mL). t-BuOK (0.26 g, 2.36 mmol) was slowly added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 hours, and then a solution of compound 55-3 (0.2 g, 0.9 mmol) in THF (2 mL) was slowly added dropwise. Stirring was continued at room temperature for 1 hour, and then heated to 50°C and stirred for 2 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extracted with EtOAc (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 55-4 (90 mg, 42% yield, colorless oil).

[0461] LC-MS (ESI+): 227.1m / z[M+H] + .

[0462] Step 4: Preparation of N'-(5-(methyl(6-(pyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)pyridin-2-yl)carbamoylthiomethyl ester (55-5)

[0463] Compound 55-4 (90 mg, 0.3 mmol) was dissolved in a single-necked flask containing DMF (2 mL), and compound 1-4 (0.1 g, 0.4 mmol) and TEA (0.1 g, 0.9 mmol) were added sequentially. The resulting mixture was cooled to 0°C, and BOPCl (0.1 g, 0.4 mmol) was added, followed by stirring at room temperature for 18 hours. EtOAc (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 55-5 (80 mg, 48% yield, as a white solid).

[0464] LC-MS (ESI+): 420.2 m / z [M+H] + .

[0465] Step 5: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-methyl-N-(6-(pyridin-4-yl)-2,3-dihydrobenzofuran-3-yl)nicotinamide (55)

[0466] Compound 55-5 (80 mg, 0.2 mmol) was dissolved in isopropanol (2 mL) in a sealed tube. Methylamine (2 M in THF, 0.3 mL, 0.7 mmol) was added, and the resulting mixture was stirred at 90°C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to afford compound 55 (13 mg, 17% yield, as a white solid).

[0467] LC-MS (ESI+): 403.2 m / z [M+H] + .

[0468] 1 H NMR (400MHz, CH3OH-d4) δ8.56(d,J=4.9Hz,2H),8.47(dd,J=15.5,2.1Hz,1H),8.01–7.83(m,1H),7.68(d,J=5.8Hz,2H),7.50(s,1H),7.36(d, J=7.6Hz,1H),7.25(s,1H),7.12–7.04(m,1H),6.40(s,0.6H),5.76(s, 0.4H),4.82–4.58(m,2H),3.00(s,1.2H),2.77(s,3H),2.50(s,1.7H).

[0469] Example 56: Synthesis of 6-((amino(methylamino)methylene)amino)-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)-N-[(5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (56)

[0470] Step 1: Preparation of 1H-pyrrolo[2,3-b]pyridin-1-amine (56-2)

[0471] 1H-Pyrrolo[2,3-b]pyridine (1.0 g, 8.47 mmol) was dissolved in a single-necked flask containing DMF (60 mL). Potassium tert-butoxide (1.9 g, 16.9 mmol) was slowly added. The resulting mixture was stirred at room temperature for 2 hours, then cooled to approximately 0°C and a solution of NH2Cl in diethyl ether (0.15 mol / L, 84.7 mL, 12.7 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was naturally warmed to room temperature and stirred overnight. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with methyl tert-butyl ether (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc = 1 / 1) to afford compound 56-2 (322 mg, 26% yield, as a white solid).

[0472] LC-MS (ESI+): 134.1m / z[M+H] + .

[0473] Step 2: Preparation of N'-(5-((1H-pyrrolo[2,3-b]pyridin-1-yl)carbamoyl)pyridin-2-yl)aminoiminothiomethyl ester (56-3)

[0474] Compound 56-2 (260 mg, 1.96 mmol) was dissolved in a single-necked flask containing DMF (15 mL), and compound 1-4 (416 mg, 1.96 mmol), DIEA (504 mg, 3.91 mmol), and PyBrOP (1.0 g, 2.15 mmol) were added. The resulting mixture was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 56-3 (500 mg, 78% yield, light yellow oil).

[0475] LC-MS (ESI+): 327.1m / z[M+H] + .

[0476] Step 3: Preparation of N'-(5-((1H-pyrrolo[2,3-b]pyridin-1-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-ylcarbamoylthiomethyl ester (56-4)

[0477] Compound 56-3 (500 mg, 1.54 mmol) and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (391 mg, 1.54 mmol) were dissolved in a single-necked flask containing DMF (10 mL). KCO (638 mg, 4.62 mmol) was added, and the resulting mixture was heated to 40°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 10 / 1) to obtain compound 56-4 (155 mg, 21% yield, as a pale yellow solid).

[0478] LC-MS (ESI+): 486.1m / z[M+H] + .

[0479] Step 4: Preparation of 6-((amino(methylamino)methylene)amino)-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)-N-[(5-(trifluoromethyl)pyridin-2-yl)methyl]nicotinamide (56)

[0480] Compound 56-4 (50 mg, 0.11 mmol) was dissolved in isopropanol (3 mL) in a microwave tube. Methylamine (3N in THF, 0.5 mL, 0.43 mmol) was added. The resulting mixture was purged with nitrogen and heated to 80°C with stirring overnight. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to yield compound 56 (5.82 mg, 12% yield, as a white solid).

[0481] LC-MS (ESI+): 469.2 m / z [M+H] + .

[0482] 1H NMR (400MHz, CH3Cl-d) δ8.79 (s, 1H), 8.34–8.27 (m, 2H), 7.89 (dd, J = 8.1, 2. 3Hz,1H),7.83(dd,J=7.8,1.5Hz,1H),7.56(d,J=8.2Hz,1H),7.50–7.42(m,1 H),7.16(d,J=3.8Hz,1H),7.14–7.09(m,1H),6.82(d,J=8.7Hz,1H),6.32(d ,J=3.8Hz,1H),5.77(d,J=15.6Hz,1H),4.89(d,J=15.6Hz,1H),2.95(s,3H).

[0483] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 56:

[0484] Example 57: Synthesis of 2-(5-((2R,5S)-2-(4-fluorophenyl)-5-methylpiperidine-1-carbonyl)pyridin-2-yl)-1-methylguanidine (57)

[0485] Step 1: Synthesis of 6-(((tert-Butoxycarbonyl)amino)(methylamino)methylene)amino)nicotinic acid (57-1)

[0486] Compound 1-5 (130 mg, 0.67 mmol) was dissolved in a single-necked flask containing THF (5 mL). Boc2O (294 mg, 1.36 mmol), TEA (275 mg, 2.7 mmol), and DMAP (8.5 mg, 0.07 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 57-1 (26 mg, 13% yield, brown liquid).

[0487] LC-MS (ESI+): 295.2 m / z [M+H] + .

[0488] Step 2: Synthesis of 2-(5-((2R,5S)-2-(4-fluorophenyl)-5-methylpiperidine-1-carbonyl)pyridin-2-yl)-N-methyl-N'-tert-butyloxycarbonylguanidine (57-3)

[0489] Compound 57-1 (26 mg, 0.09 mmol) was dissolved in a single-necked bottle containing DMF (5 mL), and (2R, 5S)-2-(4-fluorophenyl)-5-methylpiperidine (17 mg, 0.09 mmol) (57-2, for the synthesis method, refer to step 4A on page 655 of the specification of WO2022026892A1), HATU (40 mg, 0.11 mmol) and DIEA (46 mg, 0.35 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. Water (40 mL) was added to the reaction solution and extracted with EtOAc (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=15 / 1) to give compound 57-3 (7 mg, yield 17%, white solid).

[0490] LC-MS (ESI+): 470.2 m / z [M+H] + .

[0491] Step 3: Synthesis of 2-(5-((2R,5S)-2-(4-fluorophenyl)-5-methylpiperidine-1-carbonyl)pyridin-2-yl)-1-methylguanidine (57)

[0492] Compound 57-3 (7 mg, 0.015 mmol) was dissolved in a single-necked flask containing DCM (2 mL). TFA (17 mg, 0.15 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water (10 mL) and a NaHCO3 aqueous solution (10 mL), and extracted with EtOAc (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by Prep-HPLC (ACN / H2O = 5-95%) and freeze-dried to yield compound 57 (5.9 mg, 99% yield, as a white solid).

[0493] LC-MS (ESI+): 370.10 m / z [M+H] + .

[0494] 1H NMR(400MHz,CH3OH-d4)δ8.43–8.35(m,1H),7.90(dd,J=8.5,2.3Hz,1H),7.40–7.29(m,2H),7.18–7.02(m,3H),5.57–5.38(m,1H), 3.88–3.66(m,1H),3.29–3.24(m,2H),3.00(s,3H),2.27–2.15(m,2H),1.97–1.73(m,2H),1.46–1.35(m,1H),1.04(d,J=6.9Hz,3H).

[0495] Examples 65 and 66: Preparation of rel-(S,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (65) and rel-(R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (66)

[0496] Compound 58 was subjected to chiral separation (chiral column: AD-3, 0.46 cm × 5 cm; mobile phase: CO2: EtOH (0.05% DEA) = 80:20; flow rate: 2.5 mL / min; column temperature: 25°C) to give compound (retention time: 2.11 minutes), arbitrarily designated as rel-(S,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (65) and compound (retention time: 2.39 minutes), arbitrarily designated as rel-(R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(3-fluoropyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (66).

[0497] Compound 65:

[0498] LC-MS (ESI+): 476.2 m / z [M+H] + .

[0499] 1H NMR(400MHz, DMSO-d6)δ8.78(s,1H),8.33(d,J=3.2Hz,1H),8.27(s,1H)8.04(d,J=7.2Hz,1H),7.74-7 .22(m,6H),6.67(s,1H),5.85-5.36(m,1H),4.93-4.55(m,2H),2.77(s,3H),1.62(s,3H),1.25(s,1H).

[0500] Compound 66:

[0501] LC-MS (ESI+): 476.2 m / z [M+H] + .

[0502] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.33(d,J=3.2Hz,1H),8.28(s,1H),8.04(d,J=7.6Hz,1H),7.81-7.47(m,4H ),7.43-7.32(m,2H),6.70(s,1H),5.85-5.49(m,1H),4.83-4.56(m,2H),2.78(s,3H),1.63(s,3H),1.25(s,1H).

[0503] Example 67: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((6'-morpholinyl-[3,3'-bipyridyl]-6-yl)methyl)nicotinamide (67)

[0504] Step 1: Preparation of tert-butyl (R)-(1-(2-fluorophenyl)ethyl)carbamate (67-2)

[0505] At room temperature, (R)-1-(2-fluorophenyl)ethanamine (67-1, 3.2 g, 23 mmol) and di-tert-butyl dicarbonate (7.5 mL) were dissolved in dichloromethane (30 mL), and diisopropylethylamine (6.5 mL) was added. The reaction solution was stirred at 25°C for 12 hours. Water (30 mL) was added to the reaction solution to quench the reaction solution, and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 4) to obtain compound 67-2 (4.4 g, yield: 80%).

[0506] LC-MS (ESI+): 240.2 m / z [M+H] + .

[0507] Step 2: Preparation of tert-butyl (R)-((5-bromopyridin-2-yl)methyl)(1-(2-fluorophenyl)ethyl)carbamate (67-3)

[0508] Compound 67-2 (1.2 g, 5 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (240 mg, 10 mmol) was added at 0°C, and the reaction mixture was stirred for 30 minutes. Methyl (5-bromopyridin-2-yl)methanesulfonate (1.3 g, 5 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, water (20 mL) was added to the reaction mixture to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain compound 67-3 (1.6 g, yield 78%).

[0509] LC-MS (ESI+): 409.2 m / z [M+H] + .

[0510] Step 3: Preparation of tert-butyl (R)-(1-(2-fluorophenyl)ethyl)((6'-morpholinyl-[3,3'-bipyridyl]-6-yl)methyl)carbamate (67-4)

[0511] At room temperature, tert-butyl (R)-((5-bromopyridin-2-yl)methyl)(1-(2-fluorophenyl)ethyl)carbamate (67-3, 100 mg, 0.24 mmol) / 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (141 mg, 0.48 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, 0.02 mmol) were dissolved in a mixture of dioxane (2 mL) and water (0.5 mL). Potassium carbonate (102 mg, 0.73 mmol) was added. The reaction mixture was heated to 100°C under a nitrogen atmosphere and stirred for 12 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 67-4 (100 mg, yield 83%).

[0512] LC-MS (ESI+): 493.2 m / z [M+H] + .

[0513] Step 4: Preparation of (R)-1-(2-fluorophenyl)-N-((6'-morpholinyl-[3,3'-bipyridyl]-6-yl)methyl)ethanamine (67-5)

[0514] Compound 67-4 (100 mg, 0.2 mmol) was dissolved in dry dichloromethane (2 mL) at room temperature, and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 67-5 (hydrochloride salt, 60 mg, yield 75%).

[0515] LC-MS (ESI+): 393.2 m / z [M+H] + .

[0516] The remaining steps were the same as in Example 4, except that compound 67-5 was used instead of compound 1-6 to synthesize compound 67.

[0517] LC-MS (ESI+): 569.4 m / z [M+H] + .

[0518] The following compounds were obtained by the synthesis method of Example 67 using the corresponding starting materials:

[0519] Example 74: Preparation of 6-((Z)-(amino(methylamino)methylene)amino)-N-((5-(1-fluoroethyl)pyridin-2-yl)methyl)-N-((R)-1-(2-fluorophenyl)ethyl)nicotinamide (74)

[0520] Step 1: Preparation of tert-butyl (R)-((5-acetylpyridin-2-yl)methyl)(1-(2-fluorophenyl)ethyl)carbamate (74-1)

[0521] At room temperature, compound 67-3 (1.6 g, 3.9 mmol) and tributyl(1-ethoxyvinyl)tin (2 mL) were dissolved in dry 1,4-dioxane (20 mL), and tetrakistriphenylphosphine palladium (451 mg, 0.39 mmol) was added. The reaction mixture was heated to 100°C and stirred under a nitrogen atmosphere for 12 hours. After completion of the reaction, 1N hydrochloric acid (40 mL) was added to the reaction mixture for quenching, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain compound 74-1 (1.3 g, yield: 89%).

[0522] LC-MS (ESI+): 373.2 m / z [M+H] + .

[0523] Step 2: Preparation of tert-butyl ((R)-1-(2-fluorophenyl)ethyl)((5-(1-hydroxyethyl)pyridin-2-yl)methyl)carbamate (74-2)

[0524] Compound 74-1 (150 mg, 0.4 mmol) was dissolved in methanol (2 mL) at room temperature, and sodium borohydride (30 mg, 0.8 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 74-2 (150 mg, 99% yield).

[0525] LC-MS (ESI+): 375.2 m / z [M+H] + .

[0526] Step 3: Preparation of tert-butyl ((5-(1-fluoroethyl)pyridin-2-yl)methyl)((R)-1-(2-fluorophenyl)ethyl)carbamate (74-3)

[0527] At room temperature, compound 74-2 (150 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL) and diethylaminosulfur trifluoride (0.2 mL) was added. The reaction solution was stirred at 25 ° C for 1 hour. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution to quench the mixture, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound 74-3 (120 mg, yield 80%).

[0528] LC-MS (ESI+): 377.4 m / z [M+H] + .

[0529] The remaining steps were the same as in Example 67, except that compound 74-3 was used instead of compound 67-4 to obtain compound 74.

[0530] LC-MS (ESI+): 453.4 m / z [M+H] + .

[0531] 1H NMR (400MHz, DMSO-d6) δ8.38(s,2H),7.88(s,1H),7.61(d,J=7.2Hz,1H),7.43(t,J=7.2Hz,1H),7.26-7.0(m,5H ),5.75-5.58(m,1H),4.53-4.59(m,1H),4.35-4.21(m,1H),3.15-3.10(m,1H),2.82(s,3H),1.55-1.47(m,6H).

[0532] Example 75: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((5-(2-fluoropropan-2-yl)pyridin-2-yl)methyl)nicotinamide (75)

[0533] Step 1: Preparation of tert-butyl ((R)-1-(2-fluorophenyl)ethyl)((5-(2-methyloxiran-2-yl)pyridin-2-yl)methyl)carbamate (75-1)

[0534] At room temperature, trimethylsulfoxide iodide (709 mg, 3.2 mmol) and potassium tert-butoxide (361 mg, 3.2 mmol) were dissolved in dry tetrahydrofuran (10 mL), heated to 50°C, and stirred for 0.5 hours. Compound 74-1 (300 mg, 0.8 mmol) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction mixture was stirred at 50°C for 12 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then quenched and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 75-1 (250 mg, 80% yield).

[0535] LC-MS (ESI+): 387.4 m / z [M+H] + .

[0536] Step 2: Preparation of tert-butyl (R)-(1-(2-fluorophenyl)ethyl)((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)carbamate (75-2)

[0537] At room temperature, compound 75-1 (250 mg, 0.64 mmol) was dissolved in ethanol (2 mL) and sodium borohydride (49 mg, 1.3 mmol) was added. The reaction solution was stirred at 25 ° C for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 75-2 (150 mg, yield 60%). LC-MS (ESI+): 389.4m / z[M+H] + .

[0538] The remaining steps were the same as in Example 67, except that compound 75-2 was used instead of compound 67-4 to obtain compound 75.

[0539] LC-MS (ESI+): 467.4 m / z [M+H] + .

[0540] Example 76: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-((5-(1,1-difluoroethyl)pyridin-2-yl)methyl)-N-(1-(2-fluorophenyl)ethyl)nicotinamide (76)

[0541] Step 1: Preparation of tert-butyl (R)-((5-(1,1-difluoroethyl)pyridin-2-yl)methyl)(1-(2-fluorophenyl)ethyl)carbamate (76-1)

[0542] Compound 74-1 (200 mg, 0.54 mmol) and diethylaminosulfur trifluoride (173 mg, 1.07 mmol) were dissolved in 1,2-dichloroethane (3 mL) and heated to 50°C for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 76-1 (150 mg, 72% yield).

[0543] LC-MS (ESI+): 395.0 m / z [M+H] + .

[0544] Step 2: Preparation of (R)-N-((5-(1,1-difluoroethyl)pyridin-2-yl)methyl)-1-(2-fluorophenyl)ethan-1-amine (76-2)

[0545] Compound 76-1 (140 mg, 0.35 mmol) was dissolved in trifluoroacetic acid (2 mL), reacted at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 76-2 (117.0 mg, yield 99.67%).

[0546] LC-MS (ESI+): 295.0 m / z [M+H] + .

[0547] The remaining steps were the same as in Example 67, except that compound 76-2 was used instead of compound 67-5 to obtain compound 76.

[0548] LC-MS (ESI+): 471.0 m / z [M+H] + .

[0549] Example 77: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((5-(trifluoromethoxy)pyridin-2-yl)methyl)nicotinamide (77)

[0550] Step 1: Preparation of methyl (5-(trifluoromethoxy)pyridin-2-yl)methanesulfonate (77-2)

[0551] At room temperature, (5-(trifluoromethoxy)pyridin-2-yl)methanol (77-1, 300 mg, 1.5 mmol) and diisopropylethylamine (0.8 mL) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (0.4 mL) was added. The reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution to quench the mixture, and then extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to give compound 77-2 (300 mg, yield 71%).

[0552] LC-MS (ESI+): 272.1m / z[M+H] + .

[0553] Step 2: Preparation of tert-butyl (R)-(1-(2-fluorophenyl)ethyl)((5-(trifluoromethoxy)pyridin-2-yl)methyl)carbamate (77-3)

[0554] Under an ice-water bath, sodium hydride (60%, 80 mg, 2 mmol) was added to a solution of tert-butyl (R)-(1-(2-fluorophenyl)ethyl)carbamate (250 mg, 1 mmol) in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at 0°C for 30 minutes. Compound 77-2 (283 mg, 1 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution to quench the reaction solution, and the solution was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 77-3 (400 mg, yield 92%).

[0555] LC-MS (ESI+): 414.3 m / z [M+H] + .

[0556] Step 3: Preparation of (R)-(1-(2-fluorophenyl)-N-((5-(trifluoromethoxy)pyridin-2-yl)methyl)ethanamine (77-4)

[0557] To a solution of compound 77-3 (100 mg, 0.24 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at room temperature. The reaction mixture was stirred at 25°C for 1 hour until the starting material disappeared. The reaction mixture was concentrated under reduced pressure to afford compound 77-4 (TFA salt, 70 mg, 92% yield).

[0558] LC-MS (ESI+): 314.2 m / z [M+H] + .

[0559] The remaining steps were the same as in Example 4, except that compound 77-4 was used instead of compound 1-6 to obtain compound 77.

[0560] LC-MS (ESI+): 491.3 m / z [M+H] + .

[0561] Example 78: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((2-methylbenzo[d]thiazol-6-yl)methyl)nicotinamide (78)

[0562] Step 1: Preparation of methyl 2-methylbenzothiazole-6-carboxylate (78-2)

[0563] At room temperature, 6-bromo-2-methylbenzothiazole (78-1, 1.0 g, 4.38 mmol) was dissolved in 10 mL of ethanol. Hexacarbonyl molybdenum (2.89 g, 11.0 mmol), triethylamine (2.66 g, 26.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.27 g, 2.19 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (801 mg, 1.10 mmol) were added. The mixture was reacted at 100°C overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-5%) to obtain compound 78-2 (400 mg, 44% yield).

[0564] LC-MS (ESI+): 208.2 m / z [M+H] + .

[0565] Step 2: Preparation of (2-methylbenzothiazol-6-yl)methanol (78-3)

[0566] Compound 78-2 (300 mg, 0.48 mmol) was dissolved in 6 mL of tetrahydrofuran at room temperature. Diisobutylaluminum hydride (172 mg, 1.21 mmol) was added dropwise under an ice bath. The mixture was allowed to react under an ice bath for 2 hours under a nitrogen atmosphere. The reaction mixture was added to water to quench the reaction and then extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to afford compound 78-3 (300 mg, 92% yield).

[0567] LC-MS (ESI+): 180.2 m / z [M+H] + .

[0568] Step 3: Preparation of 2-methylbenzothiazole-6-carbaldehyde (78-4)

[0569] At room temperature, compound 78-3 (300 mg, 1.67 mmol) was dissolved in 5 mL of dichloromethane, and manganese dioxide (437 mg, 5.02 mmol) was added. The mixture was reacted at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 78-4 (150 mg, 50% yield).

[0570] LC-MS (ESI+): 178.2 m / z [M+H] + .

[0571] Step 4: Preparation of (R)-1-(2-fluorophenyl)-N-((2-methylbenzo[d]thiazol-6-yl)methyl)ethan-1-amine (78-5)

[0572] At room temperature, compound 78-4 (100 mg, 0.56 mmol) was dissolved in 3 mL of dichloromethane, and (R)-1-(2-fluorophenyl)ethan-1-amine (94 mg, 0.68 mmol), potassium acetate (55 mg, 0.56 mmol), and acetic acid (40 mg, 0.67 mmol) were added. After reacting in an ice bath for half an hour, sodium acetate borohydride (359 mg, 1.68 mg) was added, and the mixture was allowed to react overnight at room temperature under a nitrogen atmosphere. The reaction solution was quenched with water and extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-5%) to obtain compound 78-5 (80 mg, 47% yield).

[0573] LC-MS (ESI+): 301.2 m / z [M+H] + .

[0574] Step 5: Preparation of (R,Z)-N'-(5-((1-(2-fluorophenyl)ethyl)((2-methylbenzo[d]thiazol-6-yl)methyl)carbamoyl)pyridin-2-yl)carbamoylthiomethyl ester (78-6)

[0575] At room temperature, compound 1-4 (56 mg, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphine chloride (101 mg, 0.40 mmol), and N,N-diisopropylethylamine (103 mg, 0.80 mmol) were added to compound 78-5 (80 mg, 0.27 mmol), and the mixture was reacted at room temperature overnight under a nitrogen atmosphere. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL×2). The organic phases were combined and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-5%) to give compound 78-6 (50 mg, yield, 38%).

[0576] LC-MS (ESI+): 494.2 m / z [M+H] + .

[0577] Step 6: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((2-methylbenzo[d]thiazol-6-yl)methyl)nicotinamide (78)

[0578] At room temperature, compound 78-6 (50 mg, 0.10 mmol) was dissolved in 3 mL of dimethyl sulfoxide, and methylamine ethanol solution (1 mL) and N,N-diisopropylethylamine (103 mg, 0.80 mmol) were added. The mixture was reacted at 100 ° C. under microwave for 2 hours. The reaction solution was filtered and purified by high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%). After freeze-drying, the target compound 78 (12.3 mg, yield 25%) was obtained.

[0579] LC-MS (ESI+): 477.2 m / z [M+H] + .

[0580] Example 79: Preparation of (R,Z)-6-((amino(aminomethyl)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((2-(1-methylpiperidin-4-yl)benzothiazol-5-yl)methyl)nicotinamide (79)

[0581] Step 1: Preparation of 2-amino-4-bromobenzenethiol (79-2)

[0582] 5-Bromobenzothiazol-2-amine (79-1, 10.0 g, 43.6 mmol) and a 50% aqueous sodium hydroxide solution (50 mL) were dissolved in ethylene glycol (50 mL) at room temperature and allowed to react for 2 hours. Water (100 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to afford compound 79-2 (5.00 g, 56% yield).

[0583] LC-MS (ESI+): 203.8 m / z [M+H] + .

[0584] Step 2: Preparation of 5-bromo-2-(1-methylpiperidin-4-yl)benzothiazole (79-3)

[0585] 2-Amino-4-bromobenzenethiol (2.00 g, 869 mmol) and 1-methylpiperidine-4-carboxylic acid (2.11 g, 1.30 mol) were dissolved in phosphorus oxychloride (20 mL) at room temperature and reacted at 90°C for 12 hours. The mixture was then diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to obtain compound 79-3 (2.00 g, 67% yield).

[0586] LC-MS (ESI+): 310.8 m / z [M+H] + .

[0587] According to the synthesis method of Example 78, compound 79 was obtained by replacing compound 78-1 with compound 79-3.

[0588] LC-MS (ESI+): 560.2 m / z [M+H] + .

[0589] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,3H),7.88(d,J=8.0Hz,2H),7.67(s,1H),7.55(s,1H),7.30(s,1H),7.19(t,J=8.0Hz,2H),7.07(s,2H),5. 32(s,1H),4.61(d,J=16.0Hz,1H),4.39(s,1H),3.05(s,1H),2.87(s,5H),2.21(s,3H),2.10-2.05(m,5H),1.81-1.78(m,2H),1.64(s,2H).

[0590] Example 80: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((2-(methylaminobenzothiazol-5-yl)methyl)nicotinamide (80)

[0591] Step 1: Preparation of methyl 2-bromobenzothiazole-5-carboxylate (80-2)

[0592] Benzothiazole-5-carboxylic acid methyl ester (80-1, 1.40 g, 7.25 mmol), carbon tetrabromide (2.64 g, 7.97 mmol), and sodium tert-butoxide (1.39 g, 14.49 mmol) were dissolved in tetrahydrofuran (20 mL) at room temperature and reacted for 2 hours. Water (100 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to give compound 80-2 (650 mg, 33% yield).

[0593] LC-MS (ESI+): 271.8 m / z [M+H] + .

[0594] Compound 80 was synthesized according to the method of Example 78, using compound 80-2 instead of 78-2.

[0595] 1 H NMR(400MHz, DMSO-d6)δ8.38(s,2H),7.91(s,1H),7.55-7.48(m,3H),7.34–7.31(m,1H),7.20(t,J=8.0Hz,2H),7.14-7.12(m,2H),7.0 1(s,1H),6.79(s,1H),5.45(s,1H),4.55(d,J=16.0Hz,1H),4.21(s,1H),2.91(d,J=4.0Hz,3H),2.85(s,3H),2.54(s,1H),1.60(s,3H).

[0596] LC-MS (ESI+): 492.2 m / z [M+H] + .

[0597] Example 81: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(benzothiazole-5-methylene)-N-(1-(2-fluorophenyl)ethyl)nicotinamide (81)

[0598] Step 1: Preparation of (R)-N-(benzothiazol-5-methylene)-1-(2-fluorophenyl)ethan-1-amine (81-2)

[0599] At room temperature, (R)-N-((2-bromobenzothiazol-5-yl)methyl)-1-(2-fluorophenyl)ethan-1-amine (synthesized according to the method of Step 2-4 of Example 78, substituting 80-2 for 78-2) (81-1, 100 mg, 0.27 mmol) and palladium on carbon (29 mg, 2.27 mmol) were added to methanol (5 mL) and reacted at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 81-2 (70 mg, 89% yield).

[0600] LC-MS (ESI+): 287.0 m / z [M+H] + .

[0601] According to the method of Example 7, compound 81 was synthesized by replacing compound 1-6 with compound 81-2.

[0602] LC-MS (ESI+): 463.2 m / z [M+H] + .

[0603] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.39(s,2H),7.99(d,J=8.0Hz,1H),7.89(s,1H),7.77(s,1H),7.55(t,J=8.0Hz,1H),7.28–7.25(m ,2H),7.19-7.15(m,1H),7.04(s,2H),5.40(s,1H),4.62(d,J=16.0Hz,1H),4.46(d,J=16.0Hz,1H),2.85(s,3H),1.65(d,J=4.0Hz,3H).

[0604] Example 82: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2,4-difluorophenyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (82)

[0605] Step 1: Preparation of (R)-1-(2,4-difluorophenyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (82-2)

[0606] At room temperature, (R)-1-(2,4-difluorophenyl)ethane-1-amine (82-1, 100 mg, 0.64 mmol) and 5-(trifluoromethyl)picolinaldehyde (134 mg, 0.76 mmol) were dissolved in a mixed solution of dichloromethane (2 mL) and acetic acid (1 mL), and the reaction solution was stirred at 25°C for 1 hour. Sodium acetate borohydride (60 mg, 0.95 mmol) was then added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. After completion of the reaction, water (20 mL) was added to the reaction solution to quench the reaction solution, and the solution was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 8%) to obtain compound 82-2 (120 mg, yield 59%).

[0607] LC-MS (ESI+): 317.2 m / z [M+H] + .

[0608] Step 2: Preparation of (R,Z)-N'-(5-((1-(2,4-difluorophenyl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)carbamoyl)pyridin-2-yl)carbamoylthiomethyl ester (82-3)

[0609] At room temperature, compound 82-2 (120 mg, 0.38 mmol), compound 1-4 (160 mg, 0.76 mmol), N,N-diisopropylethylamine (147 mg, 1.14 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (145 mg, 0.57 mmol) were dissolved in N,N-dimethylacetamide (2 mL). The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 10%) to obtain compound 82-3 (50 mg, yield 26%).

[0610] LC-MS (ESI+): 510.2 m / z [M+H] + .

[0611] Step 3: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2,4-difluorophenyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (82)

[0612] At room temperature, compound 82-3 (50 mg, 0.09 mmol), methylamine hydrochloride (13 mg, 0.20 mmol) and N,N-diisopropylethylamine (38 mg, 0.29 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction solution was stirred at 90 ° C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench it and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 82 (21.2 mg, yield 44%).

[0613] LC-MS (ESI+): 493.2 m / z [M+H] + .

[0614] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.51–8.31(m,2H),8.03(d,J=8.2Hz,1H),7.54(dd,J=15.6,8. 4Hz,1H),7.37(s,1H),7.16–6.89(m,3H),5.35(s,1H),4.79–4.36(m,2H),2.86(s,3H),1.63(s,3H).

[0615] The following compounds were obtained by the synthesis method of Example 82 using the corresponding starting materials:

[0616] Example 92: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (92)

[0617] Step 1: Preparation of (Z)-5H-cyclopenta[b]pyridine-7(6H)-one oxime (92-2)

[0618] At room temperature, 5H-cyclopenta[b]pyridin-7(6H)-one (92-1, 800 mg, 6 mmol) and hydroxylamine hydrochloride (835 mg, 12 mmol) were dissolved in methanol (20 mL), and diisopropylethylamine (4 mL) was added. The reaction mixture was heated to 60°C and stirred for 12 hours. After completion of the reaction, water (20 mL) was added to quench the reaction mixture and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 92-2 (700 mg, 78% yield).

[0619] LC-MS (ESI+): 149.2 m / z [M+H] + .

[0620] Step 2: Preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine (92-3)

[0621] Compound 92-2 (100 mg, 0.67 mmol) was dissolved in acetic acid (2 mL) at room temperature, and zinc powder (87 mg, 1.3 mmol) was added. The reaction mixture was heated to 70°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was directly filtered hot, and the filtrate was concentrated under reduced pressure to obtain compound 92-3 (90 mg, 99% yield).

[0622] LC-MS (ESI+): 135.2 m / z [M+H] + .

[0623] According to the method of Example 82, compound 92-3 was used instead of compound 82-1 to obtain compound 92.

[0624] LC-MS (ESI+): 470.4 m / z [M+H] + .

[0625] The following compounds were obtained by the synthesis method of Example 92 using the corresponding starting materials:

[0626] Example 94: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(cyclopropyl(2-fluorophenyl)methyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (94)

[0627] Step 1: Preparation of cyclopropyl(2-fluorophenyl)methanone (94-2)

[0628] Under a nitrogen atmosphere, 1-bromo-2-fluorobenzene (94-1, 3000 mg, 17 mmol) was dissolved in THF (30 mL) in a dry 100 mL three-necked flask. The reaction solution was cooled to -78°C, and n-butyllithium solution (7.2 mL, 18 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes, followed by the addition of N-methoxy-N-methylcyclopropanecarboxamide (2325 mg, 18.0 mmol). The reaction solution was heated to room temperature and stirred at this temperature for another 2 hours. After completion of the reaction, water (50 mL) and saturated NH4Cl solution (50 mL) were added to quench the reaction, and the mixture was extracted with ethyl acetate (150 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to obtain compound 94-2 (1600 mg, 57% yield).

[0629] LC-MS (ESI+): 165.2 m / z [M+H] + .

[0630] Step 2: Preparation of (Z)-N-(cyclopropyl(2-fluorophenyl)methylene)-2-methylpropane-2-sulfamide (94-3)

[0631] Compound 94-2 (1000 mg, 6.09 mmol) and 2-methylpropane-2-sulfamide (960 mg, 7.90 mmol) were dissolved in toluene (10 mL) at room temperature, and tetraisopropyl titanate (5.2 mL) was added to the reaction mixture. The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with acetonitrile (100 mL). Water (50 mL) was added dropwise to the mixture at this temperature, and the mixture was stirred for 30 minutes. The solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain compound 94-3 (1000 mg, 61% yield).

[0632] LC-MS (ESI+): 268.2 m / z [M+H] + .

[0633] Step 3: Preparation of N-(cyclopropyl(2-fluorophenyl)methyl)-2-methylpropane-2-sulfamide (94-4)

[0634] At room temperature, compound 94-3 (1000 mg, 3.76 mmol) was dissolved in a mixed solution of methanol (10 mL) and acetic acid (1 mL). Sodium cyanoborohydride (471 mg, 7.50 mmol) was then added to the reaction solution, and the reaction solution was stirred at 50 ° C for 16 hours. After the reaction was completed, methanol was removed under reduced pressure, water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (40 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60%) to obtain compound 94-4 (600 mg, yield 59%).

[0635] LC-MS (ESI+): 270.2 m / z [M+H] + .

[0636] Step 4: Preparation of cyclopropyl(2-fluorophenyl)methanamine (94-5)

[0637] Compound 94-4 (600 mg, 2.23 mmol) was dissolved in methanol (10 mL) at room temperature, and dioxane hydrochloride solution (2 mL) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound 94-5 (300 mg, 81% yield).

[0638] LC-MS (ESI+): 166.2 m / z [M+H] + .

[0639] According to the method of Example 82, compound 94-5 was used instead of compound 82-1 to obtain compound 94.

[0640] LC-MS (ESI+): 501.2 m / z [M+H] + .

[0641] Example 95: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (95)

[0642] Step 1: Preparation of 6-bromo-2,3-dihydrobenzofuran-3-ol (95-2)

[0643] 4-Bromo-2-hydroxybenzaldehyde (95-1, 9.0 g, 44.8 mmol) and trimethylsulfonium iodide (14.8 g, 67.2 mmol) were dissolved in DMSO (90 mL). Potassium tert-butoxide (7.5 g, 67.2 mmol) was added at 0°C and stirred at 25°C for 12 hours. After completion of the reaction, water (150 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (3 x 80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 3 / 10) to afford compound 95-2 (5.0 g, 52% yield) as a white solid.

[0644] LCMS (ESI+): 215.1m / z[M+H] + .

[0645] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.33(m,1H),7.11-7.09(m,2H),5.69(d,J=5.6Hz,1H),5.28-5.24(m,1H),4.59-4.57(m,1H),4.31-4.27(m,1H).

[0646] Step 2: Preparation of 3-azido-6-bromo-2,3-dihydrobenzofuran (95-3)

[0647] Compound 95-2 (3.0 g, 13.9 mmol) and diphenylphosphoryl azide (4.6 g, 16.7 mmol) were dissolved in toluene (50 mL). DBU (2.5 g, 16.7 mmol) was added at 0°C, and stirring was continued at 25°C for 12 hours. After completion of the reaction, water (60 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine (2 x 60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to afford compound 95-3 (1.6 g, 48% yield) as a yellow solid.

[0648] 1 H NMR (400MHz, DMSO-d6) δ7.48(d,J=8.0Hz,1H),7.25–7.16(m,2H),5.37-5.35(m,1H),4.66-4.62(m,1H),4.55-4.51(m,1H).

[0649] Step 3: Preparation of 6-bromo-2,3-dihydrobenzofuran-3-amine (95-4)

[0650] Compound 95-3 (1.6 g, 6.7 mmol) and triphenylphosphine (2.6 g, 10.0 mmol) were dissolved in THF (40 mL) and stirred at 25°C for 1 hour. Potassium hydroxide (1.1 g, 20.0 mmol) and water (15 mL) were added, and stirring continued for 12 hours. After completion of the reaction, water (60 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to afford compound 95-4 (1.2 g, 84% yield) as a yellow solid.

[0651] LCMS (ESI+): 214.1 m / z [M+H] + .

[0652] According to the steps of Example 56, Compound 95 was synthesized by replacing Compound 56-2 with Compound 95-4.

[0653] LCMS (ESI + ):549.1m / z[M+H] + .

[0654] 1 HNMR(400MHz,DMSO-d6)δ8.99(d,J=2.4Hz,1H),8.90(d,J=2.4Hz,1H),8.47(s,1H ),8.37-8.31(m,1H),8.29-8.24(m,1H),7.82(d,J=8.4Hz,1H),7.53(d,J=8.8Hz, 1H),7.40(d,J=2.0Hz,1H),7.28(d,J=8.0Hz,1H),7.24-7.20(m,1H),5.68-5.60( m,1H),5.41(d,J=3.2Hz,2H),4.96-4.90(m,1H),4.28-4.24(m,1H),3.43(s,3H).

[0655] Example 96: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (96)

[0656] Step 1: Preparation of (R)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (96-2)

[0657] (R)-1,2,3,4-Tetrahydronaphthalen-1-amine (96-1, 600 mg, 4.08 mmol) was dissolved in methanol / acetic acid (2.5 mL / 0.5 mL). 5-(Trifluoromethyl)picolinaldehyde (714 mg, 4.08 mmol) was added at room temperature. After stirring for 10 minutes, 2-methylpyridine borane (873 mg, 8.16 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 5) to obtain compound 96-2 (600 mg, 48% yield, as a yellow solid).

[0658] LC-MS (ESI+): 307.2 m / z [M+H] + .

[0659] According to the synthesis method of Example 7, compound 96 was obtained by replacing compound 1-6 with compound 96-2.

[0660] LC-MS (ESI+): 483.2 m / z [M+H] +, .

[0661] Example 97: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((2-methyl-2H-indazol-5-yl)methyl)nicotinamide (97)

[0662] Step 1: Preparation of (R)-1-(2-fluorophenyl)-N-((2-methyl-2H-indazol-5-yl)methyl)ethan-1-amine (97-2)

[0663] 2-Methyl-2H-indazole-5-carbaldehyde (97-1, 100 mg, 0.624 mmol) was dissolved in DCM (5 mL), and (R)-1-(2-fluorophenyl)ethan-1-amine (87 mg, 0.624 mmol) and acetic acid (0.1 mL) were added. The resulting mixture was stirred at room temperature for half an hour. Sodium triacetoxyborohydride (226 mg, 0.93 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Aqueous sodium bicarbonate was added to the reaction mixture to adjust the pH to >7, and the mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This afforded compound 97-2 (160 mg, 90% yield, as a yellow oil).

[0664] LC-MS (ESI+): 284.2 m / z [M+H] + .

[0665] According to the synthesis method of Example 7, compound 97 was obtained by replacing compound 1-6 with compound 97-2.

[0666] LC-MS (ESI+): 460.2 m / z [M+H] + .

[0667] The following compounds were obtained by the synthesis method of Example 97 using the corresponding starting materials:

[0668] Example 114: Preparation of (S,Z)-6-((amino(methylamino)methylene)amino)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (114)

[0669] Step 1: Preparation of (S)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (114-2)

[0670] (S)-1,2,3,4-Tetrahydronaphthalen-1-amine (114-1, 600 mg, 4.08 mmol) was dissolved in DMSO (2 mL). (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (1.56 g, 6.12 mmol) and potassium carbonate (1.68 g, 12.2 mmol) were added at room temperature. The resulting mixture was stirred at 55°C for 10 hours. After completion of the reaction, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 5) to obtain compound 114-2 (400 mg, 32% yield, as a yellow solid).

[0671] LC-MS (ESI+): 307.2 m / z [M+H] + .

[0672] According to the synthetic method of Example 31, except using compound 114-2 instead of compound 31-4, compound 114 was obtained.

[0673] LC-MS (ESI+): 483.2 m / z [M+H] + .

[0674] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 114:

[0675] Example 118: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(1-(4-fluorophenyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (118)

[0676] Step 1: Preparation of 1-(4-fluorophenyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethanamine (118-2).

[0677] At room temperature, (5-(trifluoromethyl)pyridin-2-yl)methanamine (118-1, 500 mg, 3.62 mmol), 1-(4-fluorophenyl)ethanone (765 mg, 4.34 mmol), potassium acetate (532 mg, 5.43 mmol), and acetic acid (1 mL) were dissolved in dichloromethane (10 mL) and stirred for 0.5 hours. Sodium triacetylborohydride (1.53 g, 7.24 mmol) was added portionwise at 0°C. The mixture was reacted at room temperature for 4 hours and diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to provide compound 118-2 (270 mg, 25% yield).

[0678] LC-MS (ESI+): 298.8 m / z [M+H] + .

[0679] Step 2: Preparation of 6-fluoro-N-(1-(4-fluorophenyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (118-3)

[0680] At room temperature, compound 118-2 (211 mg, 0.71 mmol), 6-fluoronicotinic acid (100 mg, 0.71 mmol), triethylamine (144 mg, 1.42 mmol), and tripyrrolidinylphosphonium bromide hexafluorophosphate (495 mg, 1.06 mmol) were dissolved in N,N-dimethylacetamide (3 mL) and reacted at room temperature for 12 hours. Water (100 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 118-3 (250 mg, 71% yield).

[0681] LC-MS (ESI+): 422.0 m / z [M+H] + .

[0682] Step 3: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(1-(4-fluorophenyl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (118)

[0683] At room temperature, compound 118-3 (250 mg, 0.59 mmol), 1-methylguanidine (86 mg, 1.19 mmol), and cesium carbonate (771 mg, 2.37 mmol) were dissolved in N,N-dimethylacetamide (6 mL), reacted at 100°C for 12 hours, and diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 118 (8.7 mg, yield 3%).

[0684] LC-MS (ESI+): 475.2 m / z [M+H] + .

[0685] 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.36(s,1H),8.81(s,1H),8.53(s,3H),8.05( s,2H),7.50-7.11(m,4H),5.14(s,1H),4.69-4.41(m,2H),2.92(s,3H),1.56(s,3H).

[0686] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 118:

[0687] Example 120: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(1-(quinoxalin-5-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (120)

[0688] Step 1: Preparation of 1-(quinoxalin-5-yl)ethan-1-one (120-2)

[0689] A solution of 5-bromoquinoxaline (120-1, 1.50 g, 7.18 mmol), tributyl(1-ethoxyethylene)tin (5.18 g, 14.3 mmol), bistriphenylphosphine palladium dichloride (504 mg, 0.72 mmol), and triethylamine (2.99 mL, 21.5 mmol) in dioxane (6 mL) / DMF (2 mL) was heated to 120°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, and a 1N aqueous hydrochloric acid solution (3 mL) was added and stirred for 30 minutes. The reaction mixture was poured into ethyl acetate (50 mL) for extraction. The organic phase was washed five times with water (50 mL). The combined organic phases were washed with brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 120-2 (1.00 g, 83% yield).

[0690] LC-MS (ESI+): 173.0 m / z [M+H] + .

[0691] According to the synthesis method of Example 118, compound 120 was obtained by replacing 1-(4-fluorophenyl)ethanone with compound 120-2.

[0692] LC-MS (ESI+): 509.0 m / z [M+H] + .

[0693] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 120:

[0694] Example 122: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (122)

[0695] Step 1: Preparation of 5,6,7,8-tetrahydroquinoxaline-1-oxide (122-2)

[0696] 5,6,7,8-Tetrahydroquinoxaline (122-1, 3.00 g, 22.4 mmol) and m-CPBA (4.87 g, 21.2 mmol) were dissolved in DCM (15 mL) and reacted at room temperature for 16 h. After completion of the reaction, the reaction solution was poured into a saturated sodium sulfite solution (20 mL) and extracted with ethyl acetate (3x30 mL). The organic phases were combined, washed with sodium sulfite (3x30 mL) and then with saturated sodium carbonate (3x30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.

[0697] LC-MS (ESI+): 151.2 m / z [M+H] + .

[0698] Step 2: Preparation of 5,6,7,8-tetrahydroquinoxalin-5-yl acetate (122-3)

[0699] Compound 122-2 (240 mg, 1.60 mmol) was dissolved in acetic acid (2 mL) and acetic anhydride (2 mL) and reacted at 120°C for 16 h. After completion of the reaction, the reaction solution was poured into saturated sodium carbonate solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined and washed sequentially with water (3 x 20 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step.

[0700] LC-MS (ESI+): 193.2 m / z [M+H] + .

[0701] Step 3: Preparation of 5,6,7,8-tetrahydroquinoxalin-5-ol (122-4)

[0702] Compound 122-3 (306 mg, 1.59 mmol) was dissolved in MeOH (2 mL), and 4 M aqueous sodium hydroxide solution (1 mL) was added to the reaction mixture. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 122-4 (134 mg, 56% yield).

[0703] LC-MS (ESI+): 151.2 m / z [M+H] + .

[0704] Step 4: Preparation of 7,8-dihydroquinoxalin-5(6H)-one (122-5)

[0705] Compound 122-4 (134 mg, 0.89 mmol) was dissolved in DCM (2 mL) and DMP (756 mg, 1.78 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 1 h. After completion, the reaction mixture was poured into saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to provide compound 122-5 (80 mg, 60% yield).

[0706] LC-MS (ESI+): 149.2 m / z [M+H] + .

[0707] According to the synthesis method of Example 120, compound 122-5 was used instead of compound 120-2 to obtain compound 122.

[0708] LC-MS (ESI+): 485.2 m / z [M+H] + .

[0709] Example 123: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(1-(pyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyridine-3-sulfonamide (123)

[0710] Step 1: Preparation of 6-fluoro-N-(1-(pyridin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyridine-3-sulfonamide (123-2)

[0711] At room temperature, 6-fluoropyridine-3-sulfonyl chloride (200 mg, 0.94 mmol), 1-(pyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (123-1, synthesized according to the method of Example 118) (265 mg, 0.94 mmol) and triethylamine (390 μL, 2.83 mmol) were dissolved in dichloromethane (3 mL). The reaction was continued at room temperature for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 123-2 (100 mg, yield 23%).

[0712] LC-MS (ESI+): 441.0 m / z [M+H] + .

[0713] According to the synthesis method of Example 118, compound 123 was obtained by replacing compound 118-3 with compound 123-2.

[0714] LC-MS (ESI+): 494.0 m / z [M+H] + .

[0715] Example 124: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(1,5-naphthyridin-4-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (124)

[0716] Step 1: Preparation of 4-chloro-1,5-naphthyridine (124-2)

[0717] 1,5-naphthyridin-4-ol (124-1, 1.0 g, 6.84 mmol) was dissolved in phosphorus oxychloride (10 mL), and the resulting mixture was stirred at 110 ° C for half an hour. After adding ice water (10 mL) to the reaction solution and stirring for 10 minutes, sodium bicarbonate aqueous solution was added to adjust the pH>7, and extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give compound 124-2 (0.7 g, yield 62%, yellow oil).

[0718] LC-MS (ESI+): 165.2 m / z [M+H] + .

[0719] Step 2: Preparation of N-(4-methoxybenzyl)-1,5-naphthyridin-4-amine (124-3)

[0720] Compound 124-2 (0.7 g, 4.25 mmol) was dissolved in n-butanol (10 mL), and 4-methoxybenzylamine (1.75 g, 12.7 mmol) was added. The resulting mixture was stirred at 110°C for 18 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 2) to obtain compound 124-3 (800 mg, 71% yield, yellow oil).

[0721] LC-MS (ESI+): 266.1 m / z [M+H] + .

[0722] Step 3: Preparation of 1,5-naphthyridin-4-amine (124-4)

[0723] Compound 124-3 (0.8 g, 3.01 mmol) was dissolved in hydrobromic acid solution (10 mL), and the resulting mixture was stirred at 80°C for 2 hours. Water (10 mL) was added to the reaction solution and stirred for 10 minutes. Then, aqueous sodium bicarbonate solution was added to adjust the pH to >7, and the mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol / ammonia water = 97 / 2 / 1) to obtain compound 124-4 (0.4 g, 90% yield, yellow oil).

[0724] LC-MS (ESI+): 146.2 m / z [M+H] + .

[0725] According to the synthesis method of Example 45, compound 124-4 was used instead of compound 45-1 to obtain compound 124.

[0726] LC-MS (ESI+): 481.2 m / z [M+H] + .

[0727] Example 125: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (125)

[0728] Step 1: Preparation of N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-6-fluoronicotinamide (125-2)

[0729] 6-Bromo-2,3-dihydrobenzofuran-3-amine (125-1, 300 mg, 1.40 mmol), 6-fluoronicotinic acid (300 mg, 2.10 mmol), BOPCl (535 mg, 2.10 mmol), and DIEA (362 mg, 2.80 mmol) were dissolved in DMA (8 mL) and stirred at 25°C for 12 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 5 / 10) to afford Compound 125-2 (350 mg, 74% yield) as a yellow solid.

[0730] LCMS (ESI+): 337.1m / z[M+H] + .

[0731] Step 2: Preparation of N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-6-fluoro-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (125-3)

[0732] Compound 125-2 (250 mg, 0.74 mmol), (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (284 mg, 1.11 mmol), and potassium carbonate (205 mg, 1.48 mmol) were added to DMSO (5 mL) and stirred at 50°C for 4 hours. After completion of the reaction, water (25 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 3 / 10) to afford Compound 125-3 (150 mg, 41% yield) as a yellow solid.

[0733] LCMS (ESI+): 496.1m / z[M+H] + .

[0734] Step 3: Preparation of 6-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (125-4)

[0735] Compound 125-3 (100 mg, 0.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.24 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and cesium carbonate (200 mg, 0.60 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.5 mL) and stirred at 90°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, water (25 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 8 / 10) to obtain yellow solid compound 125-4 (70 mg, yield 70%).

[0736] LCMS (ESI+): 498.1 m / z [M+H] + .

[0737] Step 4: Preparation of (Z)-6-((amino(methylamino)methylene)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)-N-)((5-(trifluoromethyl)pyridin-2-yl)methyl)nicotinamide (125)

[0738] Compound 125-4 (70 mg, 0.14 mmol), 1-methylguanidine (50 mg, 0.70 mmol), and potassium phosphate (97 mg, 0.70 mmol) were dissolved in DMSO (2 mL) and stirred at 90°C for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by reverse-phase high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to obtain 125 (3.0 mg, 3.9% yield) as a white solid.

[0739] LCMS (ESI+): 551.1 m / z [M+H] + .

[0740] The following compounds were obtained by the synthesis method of Example 125 using the corresponding starting materials:

[0741] Example 127: Preparation of ((R,Z)-N-([3,4'-bipyridyl]-6-ylmethyl)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)nicotinamide (127)

[0742] Step 1: Preparation of tert-butyl (R)-([3,4'-bipyridyl]-6-ylmethyl)(1-(2-fluorophenyl)ethyl)carbamate (127-1)

[0743] Compound 67-3 (120 mg, 0.29 mmol), pyridin-4-ylboronic acid (72 mg, 0.59 mmol), potassium carbonate (121 mg, 0.88 mmol), and Pd(dppf)Cl2 (21 mg, 0.03 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL) and stirred at 90°C for 6 hours. After completion of the reaction, water (15 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 7 / 10) to afford compound 127-1 (110 mg, 92% yield) as a white solid.

[0744] LCMS (ESI+): 408.1m / z[M+H] + .

[0745] Step 2: Preparation of (R)-N-([3,4'-bipyridyl]-6-ylmethyl)-1-(2-fluorophenyl)ethan-1-amine (127-2)

[0746] Compound 127-1 (110 mg, 0.27 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1 mL) and stirred at 25° C. for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a yellow liquid 127-2 (80 mg, yield 96%).

[0747] LCMS (ESI+): 308.1m / z[M+H] + .

[0748] Step 3: Preparation of (R)-N-([3,4'-bipyridyl]-6-ylmethyl)-6-fluoro-N-(1-(2-fluorophenyl)ethyl)nicotinamide (127-3)

[0749] Compound 127-2 (100 mg, 0.33 mmol), 6-fluoronicotinic acid (69 mg, 0.49 mmol), BOPCl (125 mg, 0.49 mmol), and DIEA (84 mg, 0.66 mmol) were dissolved in DMA (2 mL) and stirred at 25°C for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to afford 127-3 (80 mg, 57% yield) as a yellow liquid.

[0750] LCMS (ESI+): 431.1 m / z [M+H] + .

[0751] Step 4: Preparation of ((R,Z)-N-([3,4'-bipyridyl]-6-ylmethyl)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)nicotinamide (127)

[0752] Compound 127-3 (70 mg, 0.16 mmol), 1-methylguanidine (59 mg, 0.81 mmol), and potassium carbonate (112 mg, 0.81 mmol) were dissolved in DMSO (1 mL) and stirred at 85°C for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 20 mL). 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. The residue was isolated and purified by reverse-phase high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to obtain Compound 127 (3.6 mg, 4.6% yield) as a white solid.

[0753] LCMS (ESI+): 484.1m / z[M+H] + .

[0754] 1 H NMR(400MHz, DMSO-d6)δ8.91(d,J=27.8Hz,1H),8.70–8.67(m,3H),8.47(s,2H),8.12(s,1H),7.78–7.75(m,2H),7.56–7.52(m,1H),7.42 –7.31(m,3H),7.23–7.10(m,3H),5.35(d,J=8.0Hz,1H),4.64(d,J=15.6Hz,1H),4.43(d,J=16.4Hz,1H),3.35–3.25(m,3H),1.25(s,3H).

[0755] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 127:

[0756] Example 130: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((6'-(4-methylpiperazin-1-yl)-[3,3'-bipyridyl]-6-yl)methyl)nicotinamide (130)

[0757] Step 1: Preparation of (R)-N-((5-bromopyridin-2-yl)methyl)-1-(2-fluorophenyl)ethan-1-amine (130-1)

[0758] Compound 67-3 (120 mg, 0.29 mmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1 mL) and stirred at 25° C. for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a yellow liquid 130-1 (80 mg, yield 88%).

[0759] LCMS (ESI+): 309.1m / z[M+H] + .

[0760] Step 2: Preparation of (R)-N-([3,4'-bipyridyl]-6-ylmethyl)-6-fluoro-N-(1-(2-fluorophenyl)ethyl)nicotinamide (130-2)

[0761] Compound 130-1 (80 mg, 0.26 mmol), (Z)-6-((amino(methylthio)methylene)amino)nicotinic acid (82 mg, 0.39 mmol), BOPCl (100 mg, 0.39 mmol), and DIEA (67 mg, 0.52 mmol) were dissolved in DMA (4 mL) and stirred at 25°C for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to afford 130-2 (80 mg, 62% yield) as a yellow liquid.

[0762] LCMS (ESI+): 502.1m / z[M+H] + .

[0763] Step 3: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-((5-bromopyridin-2-yl)methyl)-N-(1-(2-fluorophenyl)ethyl)nicotinamide (130-3)

[0764] Compound 130-2 (80 mg, 0.16 mmol), 1-methylguanidine (58 mg, 0.80 mmol), and potassium phosphate (169 mg, 0.80 mmol) were dissolved in DMSO (2 mL) and stirred at 85°C for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 x 20 mL). 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 afford crude product 130-3 (40 mg, 52% yield) as a yellow solid.

[0765] LCMS (ESI+): 485.1m / z[M+H] + .

[0766] Step 4: Preparation of (R,Z)-6-((amino(methylamino)methylene)amino)-N-(1-(2-fluorophenyl)ethyl)-N-((6'-(4-methylpiperazin-1-yl)-[3,3'-bipyridyl]-6-yl)methyl)nicotinamide (130)

[0767] Compound 130-3 (40 mg, 0.08 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (37 mg, 0.12 mmol), Pd(dppf)Cl2 (12 mg, 0.02 mmol), and potassium carbonate (23 mg, 0.16 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL) and stirred at 90°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, water (15 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give Compound 130 (3.3 mg, yield 6.9%) as a white solid.

[0768] LCMS (ESI+): 582.1m / z[M+H] + .

[0769] 1H NMR(400MHz, DMSO-d6)δ8.70(s,1H),8.48–8.30(m,3H),8.08–7.81(m,3H),7.54-7.48(m,1H),7.36-7.29(m,1H),7.26–7.04(m,3H),6.93(d, J=8.8Hz,1H),5.37(s,1H),4.61(d,J=16.8Hz,1H),4.34(s,1H),3.57- 3.51(m,4H),2.86(s,3H),2.43-2.37(m,4H),2.22(s,3H),1.62(s,3H).

[0770] Biological tests

[0771] Test Example 1: PRMT5-MTA enzyme inhibition activity test method of the compound:

[0772] The AlphaScreen assay was used to assess the inhibitory activity of compounds against PRMT5-MTA. 1× Methyltransferase Assay Buffer IV (Signalchem) was prepared as a dilution solution for each component of the enzymatic reaction. PRMT5 / MET50 protein was mixed at a final concentration of 1 nM, 5′-deoxy-5′-adenosine (Sigma) at a final concentration of 1 μM, and S-(5′-adenosyl)-L-methionine chloride dihydrochloride (Sigma) at a final concentration of 2.5 μM. The mixture was incubated at room temperature for 30 minutes and transferred to an OptiPlate-384-well plate (PerkinElmer) at a volume of 6 μL per well. Control wells were left without PRMT5 / MET50 protein. Using a Tecan D300e, test compounds were diluted three-fold starting at 1000 nM and added to all wells of the plate except the control wells. The mixture was centrifuged at 1000 rpm for 1 minute and incubated at 23°C for 15 minutes. A histone H4 substrate with a final concentration of 5 nM was added to the well plate, 4 μL per well, centrifuged at 1000 rpm for 1 minute, and then placed in a 23°C incubator for 45 minutes. Anti-histone H4 (symmetrical dimethyl R3) antibody (abcam) was pre-incubated with 50 μg / mL AlphaScreen Protein A Acceptor beads (PerkinElmer) at room temperature for 10 minutes, added to the well plate at a volume of 10 μL per well, and reacted at room temperature for 1 hour. 10 uL of 50 ug / mL AlphaScreen Streptavidin Donor beads (PerkinElmer) was added to each well and reacted at room temperature for 1 hour. The signal value in the well plate was detected using the Envision multi-function microplate reader Alpha method, and the IC value of the compound for inhibition of PRMT5 / MET50 enzyme activity was calculated using Xlfit 5.0 software.50 value.

[0773] Table 1. IC of compounds for inhibition of PRMT5+MTA enzyme activity 50 value

[0774] Conclusion: As shown in the table above, the compounds of the present invention exhibit excellent PRMT5 enzyme activity inhibition activity, and the enzyme inhibition IC of most compounds is 50 The measured value was less than 10 nM.

[0775] Test Example 2: Cell proliferation inhibitory activity test of compounds

[0776] HCT116-WT (ATCC, CCL-247) and HCT116 MTAP KO (Nanjing Kebai, CBP75002) cells were seeded into white low-permeability 96-well sterile cell culture plates at a density of 250 cells per well. The culture medium was McCoy's 5A Medium + 10% FBS. The plates were cultured overnight at 37°C with 5% CO2. The cells were treated with a compound gradient of 8 concentration points using an initial concentration of 10,000 nM, 4-fold dilution, and the last two columns were control wells with only DMSO added. The drug-treated cells were cultured for 6 days, and 50 μL CellTiter was added to each well on the seventh day. After the reaction was stirred at room temperature for 10 minutes, the chemiluminescent signal in the well plate was detected using a BIOTEK H1 multifunctional microplate reader under the chemiluminescent detection method. The IC value of the compound for cell viability inhibition was calculated using Xlfit 5.0 software. 50 value.

[0777] Table 2. IC values ​​of compounds for HCT116 MTAP KO / WT cell growth inhibition 50 value

[0778] Conclusion: As shown in the table above, the compounds of the present invention exhibited excellent HCT116 MTAP KO cell growth inhibitory activity, and the cell growth inhibition IC of some compounds was 50 The measured value is less than 100 nM. At the same time, the compounds of the present invention show selectivity for HCT116-WT cells, and the selectivity of some compounds is greater than 20 times.

Claims

1. A compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: Z is selected from C(=O), S(=O), S(=O)2, A 1 Select from N or CR 7 ; A 2 Select from N or CR 8 ; X is selected from N or CR 9 ; R 1 Selected from: Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; in, E is selected from N or CR 16 ; Y is selected from O or S; Each R 10 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, Substitution with one or more groups of cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 11a and R 11b are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 12 Selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or, R 11a or R 11b With R 10 , or R 12 With R 10 , and the atoms to which they are attached together form a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 13 and R 14 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 13 With R 14 and the nitrogen atom to which they are attached together form a heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 16 Selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 2 , R 3 , R 7 , R 8 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 5 , R 6 , R 9 are each independently selected from hydrogen, -(CH2) p -R a 、-OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-NR a R b 、-(CH2) p -NR a R b 、-C(=O)R a 、-C(=O)OR a 、-S(=O)2R a , halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-B(OR a )2, alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 4 Selected from hydrogen, -(CH2) p -R 15 、-NR a R b 、-C(=O)R a 、-S(=O)2R a , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or R 4 , R 5 , R 6 , R 9 Any two of them together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b ,alkyl Base, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and one or more groups thereof, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl groups are optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 15 is selected from heteroaryl, aryl, heterocyclic group, cycloalkyl, wherein the heteroaryl, aryl, heterocyclic group, cycloalkyl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b Each is independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, -C(=O)OR c 、-C(=O)R c 、-C(=O)NR c R d 、-OC(=O)R c 、-NR c C(=O)R d 、-S(=O)2R c 、-NR c S(=O)2R d 、-S(=O)2NR c R d 、-S(=O)R c 、-P(=O)R c R d 、-NR c S(=O)2R d 、alkyl、-OR c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or R a and R b Together with the atoms to which they are attached, they form a heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; R c and R d each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R c and R d Together with the atoms to which they are attached, they form a heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; p is an integer of 1-6.

2. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II) or general formula (III), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, A 1 , A 2 ,X,R 1 ~R 6 As defined in claim 1.

3. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IV) or general formula (V) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, A 1 , A 2 ,X,R 2 ~R 6 , R 10 , R 11a , R 11b As defined in claim 1.

4. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIA) or general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: G is selected from N or CH; R 17 Selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably halogen, alkyl, cycloalkyl or haloalkyl; the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; m is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 ,X,R 1 ~R 3 , R 5 , R 6 , R a , R b As defined in claim 1.

5. The compound of the general formula (I) according to claim 1 or 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IVA) or the general formula (VA), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, G is selected from N or CH; R 17 Selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably halogen, alkyl, cycloalkyl, or haloalkyl; m is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 ,X,R 2 ~R 3 , R 5 , R 6 , R 10 , R 11a , R 11b , R a , R b As defined in claim 1.

6. A compound represented by the general formula (I) according to any one of claims 1 to 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: A 1 CR 7 And A 2 N; or A 1 CR 7 And A 2 CR 8 , or A 1 N and A 2 N; R 7 and R 8 As defined in claim 1, preferably, R 7 and R 8 are each independently selected from hydrogen, halogen or C 1-6 alkyl.

7. A compound represented by the general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X is selected from N or CR 9 ; R 5 and R 6 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, one or more groups substituted; R 9 Selected from hydrogen or C 1-6 alkyl.

8. A compound represented by the general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X is selected from N or CR 9 ; R 4 , R 5 , R 6 , R 9 Any two of them together with the atoms they are connected to form C 3-10 Cycloalkyl, 5- to 10-membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl, the C 3-10 Cycloalkyl, 5- to 10-membered heterocyclic group, C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-NR a C(=O)R b 、-OR a , halogenated alkoxy, C 3-6 Cycloalkyl, 5- to 10-membered heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or more groups; 6-10 Aryl, 5 to 10 membered heteroaryl optionally further substituted with C 1-6 Alkyl substitution; Where R a , R b As defined in claim 1.

9. A compound represented by the general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X is selected from N or CR 9 ; R 4 With R 5 , R 6 , R 9 One of them and the atoms to which it is attached together form a 5- to 10-membered heterocyclic group, a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heterocyclic group or the 5- to 10-membered heteroaryl is optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-NR a C(=O)R b 、-OR a , halogenated alkoxy, C 3-6 Cycloalkyl, 5- to 10-membered heterocyclic group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or more groups; 6-10 Aryl, 5 to 10 membered heteroaryl optionally further substituted with C 1-6 Alkyl substitution; Where R a , R b As defined in claim 1.

10. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of the general formula (IVB) or the general formula (VB), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, X is selected from N or CR 9 ; G is selected from N or CH; G 1 and G 2 are each independently selected from N or CH; R 5 Selected from hydrogen or C 1-6 alkyl; R 9 Selected from hydrogen or C 1-6 alkyl; R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the heterocyclic, aryl, heteroaryl may be further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or one or more groups; preferably halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl is optionally selected from -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl Halides Base, C 1-6 Substituted by one or more haloalkoxy groups or 5-6-membered heterocyclic groups; R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 Haloalkyl; Or, two adjacent R 18 The atoms to which it is attached together form a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 5-6 membered cycloalkyl, the 5-6 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-B(OR a )2, alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or R a and R b Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally further substituted with C 1-6 Alkyl substitution; m is an integer from 0 to 4, preferably 1 or 2; n is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 , R 2 , R 3 , R 10 , R 11a , R 11b As defined in claim 1.

11. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IVC) or the general formula (VC), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from 5- to 10-membered heteroaryl, C 6-10 aryl, 3 to 10 membered heterocyclyl or 3 to 10 membered cycloalkyl, the 5 to 10 membered heteroaryl, C 6-10 The aryl group, the 3- to 10-membered heterocyclic group or the 3- to 10-membered cycloalkyl group is preferably a 9- to 10-membered paracyclic heteroaryl group, a naphthyl group, a 9- to 10-membered paracyclic heterocyclic group, a 9- to 10-membered paracyclic cycloalkyl group or a C 3-6 Cycloalkyl; Each R 19 are each independently selected from hydrogen, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further selected from halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by C 1-6 Alkyl substitution; G is selected from N or CH; R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; m is an integer from 0 to 4, preferably 1 or 2; s is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 , R 2 , R 3 , R 10 , R 11a , R 11b , R a , R b As defined in claim 1.

12. The compound represented by the general formula (I) according to claim 11, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is Ring A 4 and Ring A 5 Each independently selected from C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl; in particular, ring A 4 Selected from C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and phenyl, and ring A 5 is selected from 5- to 6-membered heteroaryl and phenyl; Preferably, Ring A is selected from: Ring A is optionally substituted with one or more R 19 Replacement, R 19 As defined in claim 11.

13. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IVD) or the general formula (VD), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, X is selected from N or CR 9 ; Ring G is selected from 5-10 membered heteroaryl, C 6-10 Aryl, 5-10 membered heterocyclic group, preferably 5-10 membered heteroaryl, phenyl or 5-6 membered heterocyclic group; G 1 and G 2 are each independently selected from N or CH; R 5 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; R 9 Selected from hydrogen or C 1-6 alkyl; R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the heterocyclic, aryl, heteroaryl may be further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, alkyl-substituted heterocyclic, aryl, heteroaryl, or one or more groups; preferably halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl is optionally selected from -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituted by one or more haloalkoxy groups or 5-6-membered heterocyclic groups; R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 Haloalkyl; Or, two adjacent R 18 The atoms to which it is attached together form a 5-6 membered cycloalkyl, a 5-6 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 5-6 membered cycloalkyl, the 5-6 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl is optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, Carboxyl, alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or R a and R b Together with the atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally further substituted with C 1-6 Alkyl substitution; m is an integer from 0 to 4, preferably 1 or 2; n is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 , R 2 , R 3 , R 10 , R 11a , R 11b As defined in claim 1.

14. The compound of the general formula (I) according to claim 13, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring G is selected from 15. A compound of the general formula (I) according to any one of claims 1 to 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 10 Selected from hydrogen, -C(=O)R a , C 1-6 alkyl; R 11a Selected from hydrogen, -OR a 、-(CH2) p -OR a 、-(CH2) p -C(=O)OR a 、-(CH2) p -NR a R b 、-C(=O)OR a , nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl are optionally further substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 11b Selected from hydrogen and C 1-6 alkyl; R a and R b are each independently selected from hydrogen and C 1-6 alkyl; Or, R 11a , R 11b One of them is related to R 10 and the atoms to which they are attached form a 5- to 6-membered heterocyclic group, R 11a , R 11b wherein the other is hydrogen; the 5- to 6-membered heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; p is an integer of 1 to 6, preferably 1.

16. A compound of the general formula (I) according to any one of claims 1 to 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 10 Selected from hydrogen and C 1-6 alkyl; R 11a Selected from C 1-6 Alkyl and hydroxyl groups; R 11b Selected from hydrogen and C 1-6 alkyl; R a and R b are each independently selected from hydrogen and C 1-6 alkyl; Or, R 11a , R 11b One of them is related to R 10 and the atoms to which they are attached form a 5- to 6-membered heterocyclic group, R 11a , R 11b wherein the other is hydrogen; the 5- to 6-membered heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; p is an integer of 1 to 6, preferably 1, 2 or 3.

17. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (VIA) or general formula (VIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, Y is selected from O or S; X is selected from N or CR 9 ; G is selected from N or CH; G 1 and G 2 are each independently selected from N or CH; R 5 Selected from hydrogen or C 1-6 alkyl; R 9 Selected from hydrogen or C 1-6 alkyl; R 10 Selected from hydrogen or C 1-6 alkyl; R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl; R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 Haloalkyl; m is an integer from 0 to 4, preferably 1 or 2; n is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 , R 2 , R 3 As defined in claim 1.

18. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of the general formula (VIIA), the general formula (VIIB), the general formula (VIIC) or the general formula (VIID), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, E is selected from N or CR 16 ; X is selected from N or CR 9 ; G is selected from N or CH; G 1 and G 2 are each independently selected from N or CH; R 5 Selected from hydrogen or C 1-6 alkyl; R 9 Selected from hydrogen or C 1-6 alkyl; R 10 Selected from hydrogen or C 1-6 alkyl; R 11a C 1-6 alkyl; R 12 Selected from hydrogen or C 1-6 alkyl; R 16 Selected from hydrogen, C 1-6 Alkoxy, C 1-6 alkyl; R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl; the aryl and heteroaryl are optionally replaced by C 1-6 Alkyl substituted; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution; R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 Haloalkyl; m is an integer from 0 to 4, preferably 1 or 2; n is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 , R 2 , R 3 As defined in claim 1.

19. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of the general formula (VIIIA) or general formula (VIIIB), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, X is selected from N or CR 9 ; G is selected from N or CH; G 1 and G 2 are each independently selected from N or CH; R 5 Selected from hydrogen or C 1-6 alkyl; R 9 Selected from hydrogen or C 1-6 alkyl; R 13 Selected from hydrogen or C 1-6 alkyl; R 14 is selected from 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Or, R 13 With R 14 and the nitrogen atom to which they are attached together form a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 17 are each independently selected from hydrogen, deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl; R 18 are each independently selected from hydrogen, deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -C(=O)OR a 、-C(=O)R a 、-C(=O)NR a R b 、-OC(=O)R a 、-NR a C(=O)R b 、-S(=O)2R a 、-NR a S(=O)2R b 、-S(=O)2NR a R b 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b , C 1-6 Alkyl, -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; preferably hydrogen, deuterated, C 1-6 Alkyl, C 1-6 Haloalkyl; m is an integer from 0 to 4, preferably 1 or 2; n is an integer from 0 to 4, preferably 1 or 2; A 1 , A 2 , R 2 , R 3 As defined in claim 1.

20. A compound of the general formula (I) according to any one of claims 1 to 19, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 , R 3 , R 7 , R 8 are each independently selected from hydrogen, halogen, C 1-6 alkyl.

21. The compound of the general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are optionally further substituted by one or more groups selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

22. A compound of the general formula (I) according to any one of claims 1 to 21, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

23. A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 22 or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

24. Use of the compound represented by general formula (I) according to any one of claims 1 to 22 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 23 in the preparation of a PRMT5 inhibitor.

25. Use of a compound of general formula (I) according to any one of claims 1 to 22 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 in the preparation of a medicament for preventing and / or treating a PRMT5-mediated disease, wherein the disease is cancer or a tumor-related disease, preferably bladder cancer.

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