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 novel class of protein arginase methyltransferase-5 inhibitors, pharmaceutical compositions containing the same, preparation methods thereof, and uses thereof as PRMT5 (protein arginase methyltransferase-5) inhibitors 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 include: WO2021163344, WO2022115377, WO2022132914, WO2022169948, WO2022192745, WO2021050915, WO2023278564 and WO2022026892.

[0007] Summary of the Invention

[0008] After intensive research, the present inventors designed and synthesized a series of carbohydrazide compounds, which showed inhibitory activity against PRMT5 (protein arginase methyltransferase-5) and can be developed as drugs for preventing or treating diseases related to PRMT5 activity.

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

[0010] in:

[0011] X is CR 6 or N;

[0012] R 1 、R 2 are each independently selected from hydrogen, -(CH2) p -R 7 、-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, -NR a R b 、-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(OH)2、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-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;

[0013] R 3 Selected from hydrogen, -(CH2) p -R 7 、-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, -NR a R b 、-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 、-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;

[0014] Or, R 1 With R 2 , or R 1 With R 3 , together with the nitrogen atom to which it is connected, form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group, wherein the nitrogen-containing heterocyclic group or the nitrogen-containing heteroaryl group is optionally further selected from halogen, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, oxo, methylene, -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 、-(CH2) q -OR a , alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0015] R 4 、R 5 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, 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 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-CH2-R 7 、-NR a R b , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, amide, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0016] Or, R 4 With R 5 Together with the atoms to which it is attached, it forms a heteroaryl, heterocyclyl, aryl or cycloalkyl group, wherein the heteroaryl, heterocyclyl, aryl or cycloalkyl 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;

[0017] R 6 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, -NR a R b, 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 deuterated, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0018] R 7 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, oxo, -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, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, oxo, -NR a R b 、-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 、-(CH2) q -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0019] R a and R b 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, -NR c R d 、-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, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0020] 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;

[0021] R c and R deach 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;

[0022] 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;

[0023] p is an integer from 1 to 6;

[0024] q is an integer from 1 to 6.

[0025] In a 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 its nitrogen oxide, or its pharmaceutically acceptable salt, wherein:

[0026] X is CR 6 or N;

[0027] R 1 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0028] R 2 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-S(=O)2R a 、-P(=O)R a R b 、-B(OH)2、C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, one or more groups substituted, wherein C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0029] R 3 Selected from hydrogen, -(CH2) p -R 7 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group may be further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0030] Or, R1 With R 2 The nitrogen atom to which it is connected forms a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group, wherein the 5- to 10-membered nitrogen-containing heterocyclic group or the 5- to 10-membered nitrogen-containing heteroaryl group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0031] Or, R 1 With R 3 Together with the nitrogen atom to which it is connected, it forms a 5-10 membered nitrogen-containing heterocyclic group, wherein the 5-10 membered nitrogen-containing heterocyclic group is optionally selected from halogen, hydroxyl, nitro, cyano, hydroxyl, mercapto, carboxyl, oxo, methylene, -(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 6-10 substituted by one or more groups of aryl or 5-10 membered heteroaryl;

[0032] R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0033] R 5 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy;

[0034] Among them, R 4 、R 5 Not at the same time H;

[0035] Or, R 4 With R 5 The atoms to which it is attached together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclyl, a phenyl group or a 5-6 membered cycloalkyl group, wherein the 5-6 membered heteroaryl, the 5-6 membered heterocyclyl, the phenyl group or the 5-6 membered cycloalkyl group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 One or more groups of the alkynyl group are substituted;

[0036] R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1- 6-deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl;

[0037] R 7 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, the C 6- 10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group are optionally further selected from deuterated, halogen, -NR a R b , cyano, hydroxy, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, or one or more groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further selected from deuterated, halogen, cyano, hydroxy, oxo, -NR a R b 、-(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more cycloalkyl groups or 4-6 membered heterocyclic groups;

[0038] R a and R b are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl is optionally further selected from halogen, amino, nitro, cyano, hydroxy, -NR c R d 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 One or more groups of the alkynyl group are substituted;

[0039] or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by halogen, oxo, C 1-6 Alkyl substitution;

[0040] R c and R d Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0041] p is an integer from 1 to 6;

[0042] q is an integer from 1 to 6.

[0043] In a 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 its nitrogen oxide, or its pharmaceutically acceptable salt, wherein:

[0044] X is CR 6 ;

[0045] R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, C 1-6 Alkoxy, C 1-6 One or more haloalkoxy groups are substituted;

[0046] R 2 Selected from 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, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-S(=O)2R a 、-P(=O)R a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, one or more groups substituted, wherein C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0047] R 3 Selected from -(CH2) p -R 7 , where R 7 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, the C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6Cycloalkyl, 4 to 10 membered heterocyclic group are optionally further selected from deuterated, halogen, -NR a R b , cyano, hydroxy, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, or one or more groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further selected from deuterated, halogen, cyano, hydroxy, oxo, -NR a R b 、-(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more cycloalkyl groups or 4-6 membered heterocyclic groups;

[0048] Or, R 1 With R 2 The nitrogen atom to which it is connected forms a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group, wherein the 5- to 10-membered nitrogen-containing heterocyclic group or the 5- to 10-membered nitrogen-containing heteroaryl group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0049] Or, R 1 With R 3 Together with the nitrogen atom to which it is connected, it forms a 5-10 membered nitrogen-containing heterocyclic group, wherein the 5-10 membered nitrogen-containing heterocyclic group is optionally selected from halogen, hydroxyl, nitro, cyano, hydroxyl, mercapto, oxo, methylene, -(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 6-10 One or more groups of aryl groups are substituted;

[0050] R 4 is hydrogen;

[0051] R 5 C 1-6 alkyl;

[0052] Or, R 4 With R 5 Together with the atoms to which it is attached, it forms a 5-6 membered heteroaryl, a 5-6 membered heterocyclyl, a phenyl group or a 5-6 membered cycloalkyl group, wherein the 5-6 membered heteroaryl, the 5-6 membered heterocyclyl, the phenyl group or the 5-6 membered cycloalkyl group is optionally further selected from halogen, C 1-6 One or more groups are substituted on the alkyl group;

[0053] R 6 Selected from hydrogen, halogen, C 1-6 alkyl;

[0054] R a and R b are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl is optionally further selected from halogen, amino, -NR c R d 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 One or more groups of the alkynyl group are substituted;

[0055] or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by halogen, oxo, C 1-6 Alkyl substitution;

[0056] R c and R d Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C2-6 Alkenyl, C 2-6 Alkynyl;

[0057] p is an integer from 1 to 6;

[0058] q is an integer from 1 to 6.

[0059] In a preferred embodiment, the compound represented by general formula (I) according to the present invention, or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, is a compound represented by general formula (II), or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt,

[0060] wherein Ring A is selected from heteroaryl, heterocyclyl, aryl or cycloalkyl;

[0061] Each R 8 are each independently selected from hydrogen, halogen, -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, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0062] m is an integer from 0 to 4;

[0063] X, R 1 ~R 3 、R a 、R b As defined in general formula (I).

[0064] 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 its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0065] 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 its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 5 Selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-6 alkenyl, the C 1-6 The alkyl group is optionally deuterated, halogenated, hydroxyl or C 1-6 Alkoxy substituted.

[0066] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1- 6 alkoxy, C 1-6 Halogenated alkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

[0067] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally replaced by C 1-6 Alkoxy substituted.

[0068] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, -S(=O)2R a 、-S(=O)R a 、-C(=O)R a 、-P(=O)R a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 One or more groups of the alkynyl group are substituted;

[0069] R a and R b Each independently selected from hydroxyl or C 1-6 alkyl.

[0070] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 2 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

[0071] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 2 Selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

[0072] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 2 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, cyano, carboxyl, -S(=O)2R a 、-S(=O)R a 、-C(=O)R a 、-P(=O)R a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0073] R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or

[0074] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution.

[0075] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, which is optionally further substituted by one or more groups selected from halogen.

[0076] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 1 With R 2 The nitrogen atom to which it is connected forms a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group, wherein the 5- to 10-membered nitrogen-containing heterocyclic group or the 5- to 10-membered nitrogen-containing heteroaryl group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

[0077] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 1 With R 2Together with the nitrogen atom to which it is attached, it forms a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridopyrrolone, pyridoimidazolyl, pyridoimidazolone, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridopiperidone, pyridomorpholinone, pyrimidopyrrolone, pyrimidoimidazolyl, pyrimidoimidazolone, pyrimidopyrrolone, pyridinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidopiperidone, pyrimidomorpholinone, pyridazinopyrrolone, pyridazinoimidazolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, pyridazinopiperidone, pyridazinomorpholinone, benzopyrrolyl, which is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

[0078] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 3 Selected from hydrogen, -(CH2) p -R 7 、-NR a R b 、-C(=O)R a 、-S(=O)2R a 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered 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)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 、C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0079] R 7 Selected from 5-6 membered heteroaryl, C 6-10 Aryl, the 5-6 membered heteroaryl, C 6-10 Aryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxy, 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1- 6-haloalkoxy substituted with one or more groups;

[0080] p is an integer from 1 to 6;

[0081] R a 、R b As defined in general formula (I).

[0082] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 3Selected from -CH2-R 7 , R 7 Selected from 5-6 membered heteroaryl, C 6-10 Aryl, the 5-6 membered heteroaryl, C 6-10 Aryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; preferably, R 7 is selected from phenyl or pyridinyl, which is optionally substituted by C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0083] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 3 Selected from -(CH2) p -R 7 ; R 7 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, the C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group are optionally further selected from deuterated, halogen, -NR a R b , cyano, hydroxy, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, or one or more groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further selected from deuterated, halogen, cyano, hydroxy, oxo, -NR a R b 、-(CH2) q-OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more cycloalkyl groups or 4-6 membered heterocyclic groups;

[0084] R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with halogen, hydroxy, C 1-6 Alkoxy, -NR c R d Replace; or

[0085] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by halogen, oxo, C 1-6 Alkyl substitution;

[0086] R c and R d are each independently selected from hydrogen, C 1-6 Alkyl and hydroxy-substituted C 1-6 alkyl;

[0087] p is 1;

[0088] q is 1 or 2.

[0089] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 1 With R 3 , together with the nitrogen atom to which it is connected, form a 5-10 membered nitrogen-containing heterocyclic group, wherein the 5-10 membered nitrogen-containing heterocyclic group is optionally selected from halogen, hydroxyl, mercapto, oxo, methylene, -(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 6-10 substituted by one or more groups of aryl or 5-10 membered heteroaryl;

[0090] R a is hydrogen or C 1-6 alkyl;

[0091] q is 1 or 2.

[0092] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein:

[0093] R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0094] R 2 phenyl or 5-6 membered heterocyclic group, preferably phenyl or 6 membered heterocyclic group, which is optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0095] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group.

[0096] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein:

[0097] R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0098] R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 1-6 The alkyl group is optionally substituted with a hydroxyl group, a C 1-6 Alkoxy substitution;

[0099] R 3 Selected from -(CH2) p -R 7 ;

[0100] R 7is selected from 5-6 membered heteroaryl or phenyl, preferably 6 membered heteroaryl or phenyl, which is optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0101] p is 1.

[0102] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt, is a compound represented by general formula (IA) or (IIA), or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt,

[0103] in,

[0104] A1, A2, A3, A4 are each independently selected from CH or N, preferably one of them is N and the others are CH, or two of them are N and the others are CH;

[0105] Y1, Y2, Y3, and Y4 are each independently selected from CH or N, preferably one of them is N and the others are CH, or two of them are N and the others are CH;

[0106] Ring A is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclyl, phenyl or 5-6 membered cycloalkyl;

[0107] R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0108] R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0109] R 5 Selected from halogen, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-6 alkenyl, the C 1- 6 alkyl is optionally deuterated, halogenated, hydroxyl or C 1-6 substituted with alkoxy;

[0110] Each R 11 are each independently selected from hydrogen, deuterated, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(=O)2R a 、-S(=O)R a 、-C(=O)R a 、-P(=O)R a R b 、-B(OH)2、C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 or one or more haloalkoxy groups; or

[0111] Any two adjacent R 11 Together with the atoms to which it is attached, it forms a phenyl group, a 5-6 membered heteroaryl group, a 5-6 membered heterocyclyl group or a 4-6 membered cycloalkyl group, wherein the phenyl group, the 5-6 membered heteroaryl group, the 5-6 membered heterocyclyl group or the 4-6 membered cycloalkyl group is optionally selected from halogen and C 1-6 Alkyl radical substitution;

[0112] Each R 12 are each independently selected from hydrogen, deuterium, halogen, -NR a R b , cyano, hydroxy, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further selected from deuterated, halogen, cyano, hydroxy, amino, oxo, -NR a R b 、-(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more groups of cycloalkyl or 4-6 membered heterocyclic groups; or

[0113] Any two adjacent R 12 Together with the atoms to which it is attached, it forms a phenyl group, a 5-6 membered heteroaryl group, a 5-6 membered heterocyclyl group or a 4-6 membered cycloalkyl group, wherein the phenyl group, the 5-6 membered heteroaryl group, the 5-6 membered heterocyclyl group or the 4-6 membered cycloalkyl group is optionally selected from halogen, C 1-6 Alkyl, 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution;

[0114] Each R 8 are each independently selected from hydrogen, halogen, -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、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0115] R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with halogen, hydroxy, C 1-6 Alkoxy, -NR c R d Replace; or

[0116] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally selected from halogen, oxo, C 1-6 One or more groups are substituted on the alkyl group;

[0117] R c and R d are each independently selected from hydrogen, C 1-6 Alkyl and hydroxy-substituted C 1-6 alkyl;

[0118] m is an integer from 0 to 4;

[0119] q is 1 or 2.

[0120] s is an integer from 1 to 4; preferably 1 or 2;

[0121] t is an integer from 1 to 4, preferably 1, 2 or 3;

[0122] X is as defined in the general formula (I).

[0123] In another preferred embodiment, the compound represented by general formula (IA) or (IIA) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: pyrimidinyl, pyridinyl, phenyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, isoindolyl, naphthyl, naphthyridinyl, pyridofuranyl, pyridothiphenyl, pyridothiazolyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridopyrazolyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyrimidine pyrimidopyrrolyl, pyrimidothiphenylyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, benzopyrrolyl, benzopyrimidinyl, benzopyridinyl, benzopyridazinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, preferably, selected from More preferred

[0124] In another preferred embodiment, the compound represented by general formula (IA) or (IIA) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: selected from pyridyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, isoindolyl, naphthyl, naphthyridinyl, pyridofuranyl, pyridothiphenyl, pyridothiazolyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridopyrazolyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyrimidofuryl, pyrimidopyrrolyl, pyrimidothiphenyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, benzopyrrolyl, benzopyrimidinyl, benzopyridinyl, benzopyridazinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, preferably More preferred

[0125] In another preferred embodiment, the compound represented by general formula (IA) or (IIA) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl is optionally selected from deuterated, halogen, C 1-6The alkoxy group is substituted with one or more groups.

[0126] In another preferred embodiment, the compound represented by general formula (IA) or (IIA) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein each R 11 are independently selected from hydrogen, deuterated, halogen, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -P(=O)R a R b , -B(OH)2;

[0127] R a and R b are each independently selected from hydrogen, C 1-6 alkyl;

[0128] s is 1 or 2.

[0129] In another preferred embodiment, the compound represented by general formula (IA) or (IIA) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein each R 12 are each independently selected from hydrogen, deuterium, halogen, -NR a R b , cyano, -C(=O)R a 、-P(=O)R a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, hydroxyl, C 1-6 One or more alkoxy groups are substituted;

[0130] R a and R b are each independently selected from hydrogen, C 1-6Alkyl; or

[0131] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, said 4-6 membered heterocyclic group being optionally substituted by halogen;

[0132] t is 1, 2, or 3;

[0133] Preferably, R 12 C 1-6 Halogenated alkyl, t is 1.

[0134] In another preferred embodiment, the compound represented by general formula (IA) or (IIA) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein for

[0135] in,

[0136] Y1, Y2, Y3 are each independently selected from CH or N;

[0137] Ring E is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl; preferably pyridyl, dihydropyridyl, tetrahydropyridyl, phenyl, pyrazinyl, pyrimidinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyridopyrazolyl, quinolinyl;

[0138] R 12a is selected from hydrogen or halogen, preferably hydrogen;

[0139] Each R 13 are each independently selected from hydrogen, deuterated, halogen, cyano, hydroxyl, oxo, -NR a R b 、-(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more cycloalkyl groups or 4-6 membered heterocyclic groups;

[0140] R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6Alkyl is optionally selected from halogen, hydroxy, C 1-6 Alkoxy, -NR c R d Replace, or

[0141] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally selected from halogen, oxo, C 1-6 Alkyl substitution;

[0142] R c and R d are each independently selected from hydrogen and C 1-6 alkyl;

[0143] q is 1 or 2, preferably 1;

[0144] t is 1, 2, or 3;

[0145] v is 1 or 2.

[0146] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt, is a compound represented by general formula (IIIA) or general formula (IIIB), or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt,

[0147] in,

[0148] Ring B is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group;

[0149] Each R 9 are each independently selected from hydrogen, halogen, -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、-(CH2) q -OR a , oxo, methylene, alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0150] n is an integer from 0 to 4;

[0151] q is 1 or 2;

[0152] R 2 Selected from hydrogen, -(CH2) p -R 7 、-NR a R b 、-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, -NR a R b 、-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(OH)2、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, one or more groups substituted, the alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-C(=O)OR a 、-C(=O)R a 、-C(=O)NR aR 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;

[0153] X, R 4 、R 5 、R 7 、R a 、R b , p is as defined in general formula (I);

[0154] Ring A, R 8 , m are as defined in the general formula (II).

[0155] In another preferred embodiment, the compound represented by general formula (IIIA) or general formula (IIIB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt, wherein ring B is selected from a 5- to 10-membered nitrogen-containing heterocyclic group;

[0156] Each R 9 Each is independently selected from halogen, hydroxyl, mercapto, oxo, methylene, -(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, phenyl;

[0157] n is an integer from 0 to 4;

[0158] q is 1 or 2;

[0159] R 2 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, one or more groups, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0160] R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or

[0161] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution;

[0162] X, R 4 、R 5 As defined in the above general formula (I) or (II);

[0163] Ring A, R 8 , m are as defined in the above general formula (I) or (II).

[0164] In another preferred embodiment, the compound represented by general formula (IIIA) or general formula (IIIB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein ring B is a 5-10 membered nitrogen-containing heterocyclic group, preferably

[0165] Each R9 Each is independently selected from halogen, hydroxyl, mercapto, oxo, methylene, -(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, phenyl;

[0166] R a is hydrogen or C 1-6 alkyl;

[0167] q is 1 or 2; preferably 1;

[0168] n is 1 or 2.

[0169] In another preferred embodiment, the compound represented by general formula (IIIA) or general formula (IIIB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 2 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, isoindolyl, naphthyl, naphthyridinyl, pyridofuranyl, pyridothiphenyl, pyridothiazolyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridopyrazolyl, pyridopiperidinyl, pyridomorpholinyl, pyridopiperazine phenyl, pyrimidinofuryl, pyrimidopyrrolyl, pyrimidothiphenyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidopyridinyl, pyrimidomorpholinyl, pyrimidopyrazinyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, benzopyrrolyl, benzopyrimidinyl, benzopyridinyl, benzopyridazinyl, benzofuranyl, benzothiophenyl, benzothiazolyl; more preferably phenyl, pyridinyl;

[0170] It is optionally further selected from deuterated, halogen, cyano, -NR a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10aryl, 5 to 10 membered heteroaryl, one or more groups substituted, said C 2-6 Alkenyl, C 2- 6 alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0171] R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or

[0172] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution.

[0173] In another preferred embodiment, the compound represented by general formula (IIIA) or general formula (IIIB) according to the present invention, or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, is a compound represented by general formula (IIIAa) or general formula (IIIBa), or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt,

[0174] in,

[0175] G1, G2, G3, G4 are each independently selected from CH or N; preferably, G1, G2, G3, G4 are all CH; or one of G1, G2, G3, G4 is N and the others are CH, or two of G1, G2, G3, G4 are N and the others are CH;

[0176] Each R 13 are each independently selected from hydrogen, deuterated, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, one or more groups substituted, said C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0177] R a and R b are each independently selected from hydrogen and C 1-6 Alkyl; or

[0178] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution;

[0179] u is 1 or 2;

[0180] Ring B, Ring A, X, R 4 、R 5 、R 8 、R 9 , n, and m are as defined in formula (IIIA) or formula (IIIB).

[0181] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt, is a compound represented by general formula (IVA) or general formula (IVB), or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt,

[0182] in,

[0183] Ring D is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group;

[0184] Each R 10 are each independently selected from hydrogen, halogen, -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 , oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0185] s is an integer from 0 to 4;

[0186] R 3 Selected from hydrogen - (CH2) p -R 7 、-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;

[0187] X, R 4 、R 5 、R7 、R a 、R b , p is as defined in general formula (I);

[0188] Ring A, R 8 , m are as defined in the general formula (II).

[0189] In another preferred embodiment, the compound represented by general formula (IVA) or general formula (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt, wherein ring D is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group;

[0190] Each R 10 are each independently selected from hydrogen, halogen, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0191] s is an integer from 0 to 4;

[0192] R 3 Selected from hydrogen, -(CH2) p -R 7 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group; R 7 Selected from C 6- 10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, the C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group are optionally further selected from deuterated, halogen, -NR a R b , cyano, hydroxy, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl is substituted with one or more groups, the C 1-6 alkyl is optionally further selected from deuterated, halogen, cyano, hydroxy, -NR a R b 、-(CH2) q -OR a 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0193] R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with halogen, hydroxy, C 1-6 Alkoxy, -NR c R d Replace; or

[0194] R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by halogen, oxo, C 1-6 Alkyl substitution;

[0195] R c and R d are each independently selected from hydrogen, C 1-6 Alkyl and hydroxy-substituted C 1-6 alkyl;

[0196] p is 1;

[0197] q is 1 or 2;

[0198] X, R 4 、R 5 As defined in the above general formula (I) or general formula (II);

[0199] Ring A, R 8 , m are as defined in the above general formula (I) or (II).

[0200] In another preferred embodiment, the compound represented by general formula (IVA) or general formula (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt, wherein ring D is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group;

[0201] Each R 10 are each independently selected from hydrogen, halogen, -NR a Rb , nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0202] s is an integer from 0 to 4;

[0203] R 3 Selected from hydrogen, -(CH2) p -R 7 、C 1-6 Alkyl; R 7 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, cyano, hydroxy, oxo, -C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 One or more groups of the alkynyl group are substituted;

[0204] p is 1;

[0205] X, R 4 、R 5 As defined in the above general formula (I) or general formula (II);

[0206] Ring A, R 8 , m are as defined in the above general formula (I) or (II).

[0207] In another preferred embodiment, the compound represented by general formula (IVA) or general formula (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt,

[0208] wherein ring D is selected from

[0209] Each R 10 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0210] s is 0 or 1.

[0211] In another preferred embodiment, the compound represented by general formula (IVA) or general formula (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein:

[0212] R 3 Selected from hydrogen, -(CH2) p -R 7 、C 1-6 alkyl;

[0213] R 7 is selected from 5-6 membered heteroaryl or phenyl, preferably 6 membered heteroaryl or phenyl, which is optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

[0214] In another preferred embodiment, the compound represented by general formula (II), general formula (IIA), general formula (IIIB), general formula (IIIBa), general formula (IVB) or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt according to the present invention, wherein ring A is selected from 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic group; each R 8 are each independently selected from hydrogen, C 1-6 Alkyl; m is 1 or 2, preferably 1.

[0215] In another preferred embodiment, the compound represented by general formula (II), general formula (IIA), general formula (IIIB), general formula (IIIBa), general formula (IVB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt according to the present invention, wherein ring A is selected from 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic group; preferably pyrazolyl or tetrahydrofuranyl; in particular,

[0216] Each R 8 are each independently selected from hydrogen, C 1-6 alkyl;

[0217] m is 1 or 2, preferably 1.

[0218] In a preferred embodiment, ring A is selected from a pyrazole ring.

[0219] In another preferred embodiment, ring A is replaced by C 1-6 Alkyl substitution.

[0220] In another preferred embodiment, X is CR 6 or N, R 6 Selected from hydrogen, halogen, C 1-6 alkyl.

[0221] In another preferred embodiment, the compound represented by general formula (II), general formula (IIA), general formula (IIIB), general formula (IIIBa), general formula (IVB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt thereof according to the present invention, wherein X is CR 6 or N, R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl.

[0222] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (IIIA), general formula (IIIAa), general formula (IVA) or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt according to the present invention, wherein R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0223] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (IIIA), general formula (IIIAa), general formula (IVA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt according to the present invention, wherein R 5 Selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-6 alkenyl, the C 1-6 The alkyl group is optionally deuterated, halogenated, hydroxyl or C 1-6 Alkoxy substituted.

[0224] In another preferred embodiment, the compound represented by general formula (I), general formula (IA), general formula (IIIA), general formula (IIIAa), general formula (IVA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or pharmaceutically acceptable salt thereof according to the present invention, wherein X is CR 6 , R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl;

[0225] In another preferred embodiment, X, R 1 、R 2 、R 3 、R 4 、R 5 Each is independently the corresponding group in Example Compounds 1-512.

[0226] In another preferred embodiment, the present invention provides a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0227] (I)

[0228] in:

[0229] X is CR 6 or N;

[0230] R 1 、R 2 are each independently selected from hydrogen, -(CH2) p -R 7 、-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)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;

[0231] R 3 Selected from hydrogen, -(CH2) p -R 7 、-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;

[0232] Or, R 1 With R 2 , or R 1 With R3 , together with the nitrogen atom to which it is connected, form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group, wherein the nitrogen-containing heterocyclic group or the nitrogen-containing heteroaryl group is optionally further selected from halogen, -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;

[0233] R 4 、R 5 are each independently selected from hydrogen, 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 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-CH2-R 7 、-NR a R b , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, amide, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0234] Or, R 4 With R 5 Together with the atoms to which it is attached, it forms a heteroaryl, heterocyclyl, aryl or cycloalkyl group, wherein the heteroaryl, heterocyclyl, aryl or cycloalkyl 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;

[0235] R 6 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, -NR a R b , 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 deuterated, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0236] R 7 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)2Rb 、-S(=O)2NR a R b 、-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;

[0237] 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, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups;

[0238] 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;

[0239] R c and R deach 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;

[0240] 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;

[0241] p is an integer from 1 to 6.

[0242] Typical compounds of the present invention include, but are not limited to:

[0243] or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or its pharmaceutically acceptable salt.

[0244] 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.

[0245] The method can be prepared, for example, using the method shown in Scheme 1: Under a nitrogen atmosphere, A, B, and a condensing agent are added to a reaction solvent to obtain C through a condensation reaction. Under a nitrogen atmosphere, C, D, and a base are added to a reaction solvent to obtain the final product E through a substitution reaction. The route of Scheme 1 is as follows:

[0246] The method can be prepared, for example, using the method shown in Scheme 2: under a nitrogen atmosphere, F, G and a base are added to a reaction solvent to obtain product H through a condensation reaction. The route of Scheme 2 is as follows:

[0247] Wherein, in the above preparation method, the definitions of the substituents in the compounds shown are as described above.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] The present invention further relates to a method for preventing and / or treating diseases associated with PRMT5 activity, comprising administering to a patient in need thereof a preventive or therapeutically 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. In a preferred embodiment, the cancer and tumor-related disease according to the present invention is bladder cancer.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] Terminology

[0266] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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:

[0272] 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:

[0273] 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:

[0274] 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.

[0275] 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.

[0276] 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:

[0277] 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:

[0278] 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:

[0279] 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:

[0280] 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.

[0281] 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. Phenyl is more preferred. 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:

[0282] 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.

[0283] 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 group can be oxidized, for example, C atoms are oxidized to C=O, S atoms are oxidized to S=O or SO2, and N atoms are oxidized to N + -O - The heteroaryl ring may 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:

[0284] 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.

[0285] 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.

[0286] 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.

[0287] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0288] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0289] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0290] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above.

[0291] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0292] The term "hydroxy" refers to an -OH group.

[0293] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0294] The term "amino" refers to -NH2.

[0295] The term "cyano" refers to -CN.

[0296] The term "nitro" refers to -NO2.

[0297] The term "oxo" refers to =0.

[0298] The term "thio" refers to =S.

[0299] The term "carboxy" refers to -C(O)OH.

[0300] The term "mercapto" refers to -SH.

[0301] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0302] 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.

[0303] "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.

[0304] "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.

[0305] 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.

[0306] "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

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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 0.20–0.25 mm silica gel plates, while separation and purification used 0.5 mm silica gel plates.

[0313] 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.

[0314] 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.

[0315] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] Example 1: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (1)

[0323] Step 1: Preparation of 2-(bromomethyl)-5-(trifluoromethyl)pyridine (1-2)

[0324] (5-(Trifluoromethyl)pyridin-2-yl)methanol (1-1) (500 mg, 2.82 mmol) was dissolved in DCM (5 mL) and cooled to 0°C in an ice bath under a nitrogen atmosphere. Phosphorus tribromide (0.76 g, 2.82 mmol) was then added. After the addition was complete, the resulting mixture was naturally warmed to room temperature and stirred for 2 hours. After the reaction solution was cooled to 0°C, ice water (10 mL) was added and extracted with DCM (10 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 (DCM / MeOH=20 / 1) to give compound 1-2 (0.32 g, yield 47%, purity 90%, brown liquid).

[0325] LC-MS (ESI+): 240.1 m / z [M+H] + .

[0326] Step 2: Preparation of 2-(1-methylhydrazinyl)pyrimidine (1-4)

[0327] 2-Chloropyrimidine (1-3, 500 mg, 4.36 mmol) was dissolved in EtOH (10 mL), methylhydrazine (350 mg, 7.68 mmol) was added, and the resulting mixture was stirred at 65 ° C overnight. Water (20 mL) was 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-TLC (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 1-4 (0.2 g, yield 37%, purity 95%, white solid).

[0328] LC-MS (ESI+): 125.1 m / z [M+H] + .

[0329] Step 3: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (1-5)

[0330] 2-Amino-3-methylquinoline-6-carboxylic acid (922 mg, 4.56 mmol) was dissolved in DMF (5 mL). Compound 1-4 (566 mg, 4.56 mmol), HATU (2.08 g, 5.47 mmol), and DIEA (1.77 g, 13.68 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 18 hours. Water (10 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 (DCM / MeOH = 15 / 1) to obtain compound 1-5 (760 mg, 54% yield, 90% purity, as a light yellow solid).

[0331] LC-MS (ESI+): 309.0 m / z [M+H] + .

[0332] Step 4: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (1)

[0333] Compound 1-5 (231 mg, 0.75 mmol) was dissolved in DMF (6 mL), and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (1-2) (180 mg, 0.75 mmol) and K2CO3 (312 mg, 2.26 mmol) were added sequentially. The resulting mixture was stirred at room temperature overnight. Water (20 mL) was 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 high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 1 (35.4 mg, yield 10%, purity 99%, white solid).

[0334] LC-MS (ESI+): 468.0 m / z [M+H] + .

[0335] 1H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.42–8.31(m,2H),8.23–8.10(m,1H),7.82(d,J=8.2Hz,1H),7.75–7.61(m,2H),7.44(d,J=8.3Hz ,1H),7.26(d,J=8.6Hz,1H),6.79–6.69(m,1H),6.47(s,2H),5.36(d,J=15.6Hz,1H),4.56(d,J=15.6Hz,1H),3.25(s,3H),2.13(s,3H).

[0336] Example 2: Preparation of 2-amino-3-methyl-N'-(methyl-d3)-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (2)

[0337] Step 1: Preparation of tert-butyl (E)-2-benzylidenehydrazine-1-carboxylate (2-2)

[0338] Benzaldehyde (2-1, 1.00 g, 9.42 mmol) was dissolved in THF (10 mL), and BocN2H3 (1.25 g, 9.42 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product compound 2-2 (2.1 g, yield 101%, white solid).

[0339] Step 2: Preparation of tert-butyl (E)-2-benzylidene-1-(methyl-d3)hydrazine-1-carboxylate (2-3)

[0340] Compound 2-2 (2.10 g, 9.56 mmol) was dissolved in THF (10 mL), and t-BuOK (1.29 g, 11.46 mmol) was added. After nitrogen substitution, CD3I (1.6 g, 11.46 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 2-3 (2.0 g, 22% yield, as a yellow oil).

[0341] 1 H NMR (400MHz, DMSO-d6): δ7.80 (s, 1H), 7.69 (dt, J = 6.1, 1.4Hz, 2H), 7.45–7.39 (m, 2H), 7.39–7.33 (m, 1H), 1.51–1.48 (m, 9H).

[0342] Step 3: Preparation of tert-butyl 1-(methyl-d3)hydrazine-1-carboxylate (2-4)

[0343] Compound 2-3 (500 mg, 2.11 mmol) was dissolved in MeOH (5 mL). Pd / C (250 mg, 50% wt) was added under a nitrogen atmosphere. The resulting mixture was replaced with hydrogen and stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 2-4 (260 mg, 82% yield, as a colorless oil).

[0344] 1 H NMR (400MHz, DMSO-d6): δ4.48 (s, 2H), 1.40 (s, 9H).

[0345] Step 4: Preparation of (methyl-d3)hydrazine hydrochloride (2-5)

[0346] Compound 2-4 (260 mg, 1.74 mmol) was dissolved in EtOAc / HCl (4 M, 5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was directly filtered and the filter cake was vacuum dried to obtain compound 2-5 (167 mg, yield 112%, white solid).

[0347] 1 H NMR (400MHz, DMSO-d6): δ4.23 (s, 2H), 3.80 (s, 1H).

[0348] Step 5: Preparation of 2-(1-(methyl-d3)hydrazino)pyrimidine (2-6)

[0349] Compound 2-5 (167 mg, 3.66 mmol) was dissolved in EtOH (10 mL), and 2-chloropyrimidine (420 mg, 3.66 mmol) and Na2CO3 (1165 mg, 10.99 mmol) were added sequentially. The resulting mixture was heated to 75°C and stirred for 16 hours. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and water (10 mL) were added. The organic phase was 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 = 2 / 1) to obtain compound 2-6 (50 mg, yield 11%), as a yellow solid.

[0350] LC-MS (ESI+): m / z 128.1[M+1] + .

[0351] Step 6: Preparation of 2-amino-3-methyl-N-methyl-d3-pyrimidin-2-ylquinoline-6-carbohydrazide (2-7)

[0352] Compound 2-6 (93 mg, 0.46 mmol) was dissolved in DMF (2 mL). HATU (227 mg, 0.60 mmol), 2-(1-(methyl-d3)hydrazino)pyrimidine (57 mg, 0.46 mmol), and DIEA (178 mg, 1.38 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution. The organic phase was 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 = 10 / 1) to obtain compound 2-7 (28 mg, 20% yield, as a yellow solid).

[0353] LC-MS (ESI+): m / z 312.2 [M+1] + .

[0354] Step 7: Preparation of 2-amino-3-methyl-N'-(methyl-d3)-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (2)

[0355] Compound 2-7 (28 mg, 0.09 mmol) was dissolved in DMF (2 mL), and K2CO3 (37 mg, 0.27 mmol) and 2-bromomethyl-5-trifluoromethylpyridine (22 mg, 0.09 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 16 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution, and the organic phase was 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 = 10 / 1) to obtain compound 2 (12.2 mg, yield 28%, white solid).

[0356] LC-MS (ESI+): m / z 471.2 [M+1] + .

[0357] 1 H NMR (400MHz, DMSO-d6): δ8.90(s,1H),8.43–8.35(m,2H),8.21(d,J=8.2Hz,1H),7.85(d,J=8.4Hz,1H),7.71(d,J=19 .5Hz,2H),7.47(d,J=8.6Hz,1H),7.30(d,J=8.7Hz,1H),6.78(s,1H),6.48(s,2H),5.40(d,J=15.5Hz,1H),4.59(d,J= 15.8Hz,1H),2.17(s,3H).

[0358] The following compounds were obtained by the synthesis method of Example 2 using the corresponding raw materials:

[0359] Example 20: Preparation of 4-amino-N',1-dimethyl-N'-(pyrimidin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide (20)

[0360] Step 1: Preparation of 3-bromo-N'-methyl-4-nitro-N-(pyrimidin-2-yl)benzohydrazide (20-2)

[0361] At room temperature, 3-bromo-4-nitrobenzoic acid (20-1, 400 mg, 1.6 mmol) was dissolved in 6 mL of DMF, and PyBroP (1.1 g, 2.4 mmol), 2-(1-methylhydrazinyl)pyrimidine (201 mg, 1.6 mmol), and DIEA (629 mg, 4.8 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (30.0 mL), stirred for 10 minutes, and then extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, washed with 5% aqueous sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100%-50%) to obtain compound 20-2 (300 mg, yield 52%).

[0362] Step 2: Preparation of 3-bromo-N'-methyl-4-nitro-N-pyrimidin-2-yl-N-(4-trifluoromethylbenzyl)benzohydrazide (20-3)

[0363] At room temperature, compound 20-2 (300 mg, 0.8 mmol) was dissolved in 3 mL of DMF, 1-bromomethyl-4-trifluoromethylbenzene (407 mg, 1.6 mmol) and cesium carbonate (830 mg, 2.5 mmol) were added, and the mixture was reacted at 60° C. overnight. The reaction mixture was cooled to room temperature and poured into water (30.0 mL), stirred for 10 minutes, and then extracted with ethyl acetate (50.0 mL×2). The organic phases were combined, washed with 5% aqueous sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100%-50%) to obtain compound 20-3 (230 mg, 53% yield).

[0364] Step 3: Preparation of 4-amino-3-bromo-N'-methyl-N-pyrimidin-2-yl-N-(4-trifluoromethyl)benzylbenzohydrazide (20-4)

[0365] At room temperature, compound 20-3 (230 mg, 0.4 mmol) was dissolved in 3 mL of ethanol and 3 mL of saturated ammonium chloride solution, and iron powder (109 mg, 2 mmol) was added. The reaction was allowed to react at 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered under reduced pressure, poured into water (30.0 mL), stirred for 10 minutes, and extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-5%) to give compound 20-4 (140 mg, yield 74%).

[0366] Step 4: Preparation of 4-amino-N'-methyl-N'-(pyrimidin-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)benzyl)benzohydrazide (20-5)

[0367] Compound 20-4 (140 mg, 0.3 mmol) was dissolved in 3 mL of dioxane at room temperature. 4,4,4,5,5,5,5-octamethyl-2,2-bis(1,3,2-dioxaborolane) (370 mg, 1.5 mmol), potassium acetate (85 mg, 0.9 mmol), and Pd(dppf)Cl2 (21 mg, 0.03 mmol) were added. The reaction was continued at 90°C overnight under a nitrogen atmosphere. The reaction mixture was used directly in the next step.

[0368] Step 5: Preparation of 4-amino-N',1-dimethyl-N'-(pyrimidin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide (20)

[0369] At room temperature, 0.5 mL of water was added to the reaction mixture from the previous step, followed by 5-bromo-1-methylpyrazole-4-carbonitrile (60 mg, 0.3 mmol) and potassium carbonate (120 mg, 0.9 mmol). The mixture was allowed to react overnight at 90°C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by HPLC (water / acetonitrile = 95% / 5% to 10% / 90%) to afford compound 20 (1.7 mg, 0.003 mmol, 1% yield).

[0370] LC-MS (ESI+): m / z 507.2[M+1] + .

[0371] Example 21: Preparation of 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (21)

[0372] Step 1: Preparation of 1H-pyrrolo[2,3-b]pyridin-1-amine (21-2)

[0373] NH4Cl (300 mg) was added to diethyl ether (10 mL), cooled to -5°C in an ice-salt bath, and aqueous ammonia (0.5 mL) was added. After stirring for 5 minutes, a 10% aqueous NaClO solution (7.5 mL) was added, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was allowed to stand, and the ether layer was separated and dried over CaCl2 to obtain an NH2Cl ether solution. 1H-Pyrrolo[2,3-b]pyridine (21-1, 750 mg, 6.35 mmol) was dissolved in DMF (20 mL), and t-BuOK (750 mg, 12.70 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. NH2Cl was added to the above mixture at 0°C, and the resulting mixture was stirred at room temperature overnight. Saturated aqueous Na2SO3 solution (20 mL) was added to the reaction mixture, and the mixture was extracted with diethyl ether (25 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 give compound 21-2 (500 mg, yield 59%, yellow solid).

[0374] LC-MS (ESI+): 134.1 m / z [M+H] + .

[0375] Step 2: Preparation of 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)quinoline-6-carboxamide (21-3)

[0376] Compound 21-2 (500 mg, 3.75 mmol) was dissolved in DMF (10 mL), and 2-amino-3-methylquinoline-6-carboxylic acid (prepared by the synthetic method of intermediate 1 (page 58 / 311) in reference patent WO2021163344A1) (760 mg, 3.75 mmol) and triethylamine (1.14 g, 11.2 mmol) were added. The resulting mixture was cooled to 0 ° C and BOPCl (1.14 g, 4.5 mmol) was added, and the mixture was naturally warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-TLC (DCM / MeOH=15 / 1) to give compound 21-3 (20 mg, yield 5%, white solid).

[0377] LC-MS (ESI+): 318.1m / z[M+H] + .

[0378] Step 3: Preparation of 2-amino-3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (21)

[0379] Compound 21-3 (20 mg, 0.06 mmol) was dissolved in DMF (4 mL), and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (15 mg, 0.06 mmol) and K2CO3 (26 mg, 0.18 mmol) were added sequentially. The resulting mixture was heated to 40°C and stirred overnight. The reaction solution was cooled to room temperature, H2O (25 mL) was added, and extracted with EtOAc (25 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 HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 21 (4.2 mg, 13% yield, 99% purity, yellow solid).

[0380] LC-MS (ESI+): 477.2 m / z [M+H] + .

[0381] 1 H NMR(400MHz,CHCl3-d)δ10.98(s,1H),8.83(s,1H),8.36(s,1H),8.00–7.80(m,3H),7.79–7.68(m,1H),7.65– 7.35(m,3H),7.21–7.16(m,2H),6.30(s,1H),6.05(s,1H),5.85–5.68(m,1H),5.01–4.85(m,1H),2.29(s,3H).

[0382] Example 22: Preparation of 2-amino-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (22)

[0383] Step 1: Preparation of 1-nitroso-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (22-2)

[0384] 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (22-1, 550 mg, 4.58 mmol) was dissolved in AcOH / H₂O (10 mL / 2 mL). A solution of NaNO₂ (230 mg, 5.04 mmol) in water (2 mL) was slowly added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with EtOAc (20 mL × 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 (DCM / EtOAc = 1 / 1) to obtain compound 22-2 (560 mg, 82% yield, colorless oil).

[0385] LC-MS (ESI+): 150.1m / z[M+H] + .

[0386] Step 2: Preparation of 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-amine (22-3)

[0387] Compound 22-2 (560 mg, 3.30 mmol) was dissolved in MeOH (10 mL). Zinc powder (882 mg, 13.5 mmol) and AcOH (2 mL) were added to the mixture after cooling to 0°C in an ice bath. The resulting mixture was stirred at room temperature for 4 hours. Water (20 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 HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 22-3 (350 mg, 76% yield, as a white solid).

[0388] LC-MS (ESI+): 136.1m / z[M+H] + .

[0389] Step 3: Preparation of 2-amino-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methylquinoline-6-carboxamide (22-4)

[0390] Compound 22-3 (350 mg, 2.59 mmol) was dissolved in DMF (4 mL), and 2-amino-3-methylquinoline-6-carboxylic acid (523 mg, 2.59 mmol) and triethylamine (785 mg, 7.77 mmol) were added sequentially. The resulting mixture was cooled to 0°C, and BOPCl (790 mg, 3.10 mmol) was added. The mixture was naturally warmed to room temperature and stirred for 2 hours. HO (25 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (25 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 HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to afford compound 22-4 (130 mg, 15% yield, as a white solid).

[0391] LC-MS (ESI + ):320.2m / z[M+H] + .

[0392] Step 4: Preparation of 2-amino-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (22)

[0393] Compound 22-4 (50 mg, 0.15 mmol) was dissolved in DMF (4 mL), and (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (50 mg, 0.19 mmol) and KCO (65 mg, 0.47 mmol) were added sequentially. The resulting mixture was heated to 40°C and stirred overnight. The reaction solution was cooled to room temperature, H2O (25 mL) was added, and the mixture was extracted with EtOAc (25 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 HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 22 (28.3 mg, 37% yield, as a white solid).

[0394] LC-MS (ESI+): 479.2 m / z [M+H] + .

[0395] 1H NMR(400MHz,CHCl3-d)δ8.84–8.66(m,1H),8.61(s,1H),8.05–7.98(m,2H),7.96–7 .90(m,1H),7.89–7.84(m,2H),7.73(s,1H),7.63(d,J=8.9Hz,1H),7.34(d,J=8.2Hz ,1H),7.29(d,J=7.0Hz,1H),6.75–6.66(m,1H),5.32(d,J=16.4Hz,1H),4.67(d,J= 15.6Hz,1H),3.70–3.41(m,2H),2.98–2.80(m,1H),2.80–2.62(m,1H),2.28(s,3H).

[0396] The following compounds were obtained by the synthesis method of Example 22 using the corresponding raw materials:

[0397] Example 23: Preparation of 2-amino-N'-cyclohexyl-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (23)

[0398] Step 1: Preparation of tert-butyl 2-cyclohexyl-2-methylhydrazine-1-carboxylate (23-2)

[0399] At room temperature, tert-butyl 2-cyclohexylhydrazine-1-carboxylate (23-1, 300 mg, 1.4 mmol) and potassium carbonate (387 mg, 2.8 mmol) were dissolved in dry DMF (3 mL), and iodomethane (0.1 mL) was added. The reaction solution was stirred at 25 ° C for 4 hours. After completion of the reaction, water (20 mL) was added to the reaction solution to quench the mixture, and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 23-2 (250 mg, yield 78%).

[0400] LC-MS (ESI+): 229.0 m / z [M+H] + .

[0401] Step 2: Preparation of 1-cyclohexyl-1-methylhydrazine trifluoroacetate (23-3)

[0402] Compound 23-2 (200 mg, 0.87 mmol) was dissolved in dry dichloromethane (1 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. 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 obtain compound 23-3 (100 mg, yield 89%).

[0403] LC-MS (ESI+): 128.8 m / z [M+H] + .

[0404] Step 3: Preparation of 2-amino-N'-cyclohexyl-N',3-dimethylquinoline-6-carbohydrazide (23-4)

[0405] At room temperature, compound 23-3 (80 mg, 0.62 mmol) and 2-amino-3-methylquinoline-6-carboxylic acid (126 mg, 0.62 mmol) were dissolved in dry DMF (3 mL). Carter condensation agent (552 mg, 1.25 mmol) and DIEA (0.5 mL) were added sequentially. The reaction solution was stirred at 25°C for 12 hours. Water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (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 (methanol / dichloromethane = 1 / 10) to obtain compound 23-4 (60 mg, 31% yield).

[0406] LC-MS (ESI+): 313.2 m / z [M+H] + .

[0407] Step 4: Preparation of 2-amino-N'-cyclohexyl-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (23)

[0408] At room temperature, compound 23-4 (55 mg, 0.17 mmol) and (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (135 mg, 0.53 mmol) were dissolved in dry DMF (2 mL), and potassium carbonate (73 mg, 0.53 mmol) was added. The reaction solution was stirred at 50°C for 12 hours. Water (20 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (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 high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to obtain compound 23 (1.4 mg, yield 1.7%).

[0409] LCMS measured: LC-MS (ESI+): 472.2m / z[M+H] + .

[0410] The following compounds were synthesized using the corresponding raw materials according to the method of Example 23:

[0411] Example 25: Preparation of 2-amino-3-cyclopropyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (25)

[0412] Step 1: Preparation of diethyl (bromo(cyano)methyl)phosphate (25-2)

[0413] Diethyl cyanomethylphosphonate (25-1, 4.00 g, 22.6 mmol) was dissolved in tetrahydrofuran (50.0 mL) at room temperature. Lithium bistrimethylsilylamide (24.8 mmol, 2 M) was added dropwise at 0°C and allowed to react for 0.5 hours. N-bromosuccinimide (NBS) (4.42 g, 24.8 mmol) was added portionwise at -78°C and allowed to react at 0°C for 1 hour. The reaction mixture was quenched by pouring into ice water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed five times with water (200 mL), then with 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 = 4 / 1) to afford compound 25-2 (4.2 g, 72% yield).

[0414] Step 2: Preparation of methyl 2-amino-3-bromoquinoline-6-carboxylate (25-3)

[0415] Sodium hydroxide (1.92 g, 48.0 mmol, 60%) was dissolved in anhydrous tetrahydrofuran (20.0 mL) at room temperature. Compound 25-2 (4.1 g, 16.1 mmol) was added at 0°C under a nitrogen atmosphere and reacted for 0.5 hours. Methyl 4-amino-3-formylbenzoate (2.87 g, 16.1 mmol) was then added and reacted at room temperature for 4 hours. Water (50 mL) was added at 0°C to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine (60.0 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 = 1 / 1) to give compound 25-3 (1.6 g, 36% yield).

[0416] Step 3: Preparation of methyl 2-amino-3-cyclopropylquinoline-6-carboxylate (25-4)

[0417] Compound 25-3 (200 mg, 0.71 mmol), cyclopropyl borate (144 mg, 0.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51.7 mg, 0.07 mmol), and sodium carbonate (151 mg, 1.42 mmol) were dissolved in a solution of 1,4-dioxane (4 mL) and water (1 mL) at room temperature. The mixture was reacted at 110°C under a nitrogen atmosphere for 12 hours. Water (15.0 mL) was added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (15.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 25-4 (90.0 mg, 52% yield).

[0418] Step 4: Preparation of 2-amino-3-cyclopropylquinoline-6-carboxylic acid lithium salt (25-5)

[0419] At room temperature, compound 25-4 (60.0 mg, 0.25 mmol) and lithium hydroxide (23.8 mg, 0.99 mmol) were dissolved in methanol (4 mL) and water (1 mL) solution, reacted at 50 ° C for 12 hours, and concentrated under reduced pressure to obtain the crude product of compound 25-5 (50.0 mg, crude yield 89%).

[0420] Step 5: Preparation of 2-amino-3-cyclopropyl-N'-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (25-6)

[0421] Compound 25-5 (50.0 mg, 0.22 mmol), 2-(1-methylhydrazine)pyrimidine (27.0 mg, 0.22 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (153.2 mg, 0.33 mmol), and triethylamine (44.4 mg, 0.44 mmol) were dissolved in DMF (2 mL) at room temperature and reacted at room temperature for 12 hours. Water (20.0 mL) was added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (20.0 mL × 3), and the combined organic phases were washed with saturated brine (20.0 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 = 1 / 1) to give compound 25-6 (50.0 mg, yield 68%).

[0422] Step 6: Preparation of 2-amino-3-cyclopropyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (25)

[0423] Compound 25-6 (20.0 mg, 0.06 mmol), (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (30.5 mg, 0.12 mmol), and potassium carbonate (41.3 mg, 0.3 mmol) were dissolved in DMF (2 mL) at room temperature and reacted at 70°C for 12 hours. The mixture was filtered through celite, and the filter cake was washed with a mixture of dichloromethane and methanol (dichloromethane / methanol = 20 / 1) (10.0 mL x 2). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford compound 25 (10.2 mg, 34.5% yield).

[0424] LC-MS (ESI+): 494.2 m / z [M+H] + .

[0425] 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.38(d,J=4.0Hz,2H),8.20(d,J=8.0Hz,1H ),7.84(d,J=8.0Hz,1H),7.78(s,1H),7.60(s,1H),7.46(d,J=8.0Hz,1H),7.28(d ,J=8.0Hz,1H),6.78(t,J=4.0Hz,1H),6.58(s,2H),5.40(d,J=16.0Hz,1H),4.58 (d,J=16.0Hz,1H),3.29(s,3H),1.77(s,1H),0.93(d,J=8.0Hz,2H),0.62(s,2H).

[0426] Example 26: Preparation of 2-amino-3-isopropyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (26)

[0427] Step 1: Preparation of methyl 2-amino-3-isopropenylquinoline-6-carboxylate (26-1)

[0428] Methyl 2-amino-3-bromoquinoline-6-carboxylate (25-3, 200 mg, 0.71 mmol), isopropyl borate (179 mg, 1.07 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51.7 mg, 0.07 mmol), and sodium carbonate (151 mg, 1.42 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature and reacted at 110°C for 12 hours under a nitrogen atmosphere. Water (20.0 mL) was added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 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 = 1 / 1) to give compound 26-1 (100 mg, 58% yield).

[0429] Step 2: Preparation of methyl 2-amino-3-isopropylquinoline-6-carboxylate (26-2)

[0430] At room temperature, compound 26-1 (100 mg, 0.41 mmol) and palladium carbon (875 mg, 0.82 mmol, 10% wt%) were dissolved in ethanol (5 mL). The reaction solution was stirred at 25 ° C. under a hydrogen atmosphere for 2 hours and concentrated under reduced pressure to obtain compound 26-2 (100 mg, yield 99%).

[0431] Step 3: Preparation of 2-amino-3-cyclopropylquinoline-6-carboxylic acid lithium salt (26-3)

[0432] At room temperature, compound 26-2 (100 mg, 0.41 mmol) and lithium hydroxide (39.3 mg, 1.64 mmol) were dissolved in methanol (4 mL) and water (1 mL), reacted at 50°C for 12 hours, and concentrated under reduced pressure to obtain a crude product of compound 26-3 (50.0 mg, crude yield 89%).

[0433] Step 4: Preparation of 2-amino-3-isopropyl-N'-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (26-4)

[0434] Compound 26-3 (100 mg, 0.43 mmol), 2-(1-methylhydrazine)pyrimidine (64.7 mg, 0.52 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (304 mg, 0.65 mmol), and triethylamine (112 mg, 0.87 mmol) were dissolved in N,N-dimethylacetamide (2 mL) at room temperature and reacted for 12 hours. Water (20.0 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 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 = 1 / 1) to give compound 26-4 (100 mg, 68% yield).

[0435] Step 5: Preparation of 2-amino-3-isopropyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (26)

[0436] Compound 26-4 (100 mg, 0.30 mmol), (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (152 mg, 0.60 mmol), and potassium carbonate (123 mg, 0.90 mmol) were dissolved in DMF (2 mL) at room temperature and reacted at 70°C for 12 hours. The mixture was then diluted with water (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 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 provide compound 26 (11.0 mg, 7.5% yield).

[0437] LC-MS (ESI+): 496.4 m / z [M+H] + .

[0438] 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 8.39 (d, J = 4.0Hz, 2H), 8.21 (d, J = 4.0 Hz,1H),7.86–7.83(m,2H),7.76(s,1H),7.46(d,J=8.0Hz,1H),7.27(d,J=8 .0Hz,1H),6.79(t,J=4.0Hz,1H),6.52(s,2H),5.41(d,J=16.0Hz,1H),4.5 7(d,J=16.0Hz,1H),3.31(s,3H),3.01–2.65(m,1H),1.20(d,J=4.0Hz,6H).

[0439] Example 27: Preparation of 2-amino-N-(3H-imidazo[4,5-b]pyridin-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (27)

[0440] Step 1: Preparation of 2-hydrazine-3-nitropyridine (27-2)

[0441] At room temperature, 2-chloro-3-nitropyridine (27-1, 1.0 g, 6.3 mmol) was dissolved in ethanol (10.0 mL), and hydrazine hydrate (742 mg, 12.6 mmol) was added at 0°C. The reaction solution was reacted at 80°C for 2 hours and concentrated under reduced pressure to obtain the crude product compound 27-2 (1.2 g, crude yield>100%).

[0442] Step 2: Preparation of tert-butyl 2-(3-nitropyridin-2-yl)hydrazine-1-carboxylate (27-3)

[0443] Compound 27-2 (400 mg, 2.6 mmol) and potassium carbonate (1.07 g, 7.78 mmol) were dissolved in 1,4-dioxane (8 mL) at room temperature. Di-tert-butyl dicarbonate (622 mg, 2.85 mmol) was slowly added dropwise at 0°C. The mixture was allowed to react for 12 hours at room temperature. Water (15.0 mL) was then added to dilute the mixture, followed by extraction with ethyl acetate (20.0 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 27-3 (500 mg, 76% yield).

[0444] Step 3: Preparation of tert-butyl 2-(3-aminopyridin-2-yl)hydrazine-1-carboxylate (27-4)

[0445] At room temperature, compound 27-3 (500 mg, 1.97 mmol) and palladium carbon (3.1 g, 2.95 mmol, 10% wt%) were dissolved in methanol (6 mL). The reaction solution was reacted at 25°C under a hydrogen atmosphere for 2 hours and concentrated under reduced pressure to obtain the crude product compound 27-4 (480 mg, crude yield >100%).

[0446] Step 4: Preparation of tert-butyl (3H-imidazo[4,5-b]pyridin-3-yl)carbamate (27-5)

[0447] Compound 27-4 (480 mg, 2.1 mmol) was dissolved in triethoxymethane (4 mL) at room temperature and reacted at 130°C for 3 hours. Water (20.0 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 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 afford compound 27-5 (210 mg, 42% yield).

[0448] Step 5: Preparation of 3H-imidazo[4,5-b]pyridin-3-amine (27-6)

[0449] At room temperature, compound 27-5 (210 mg, 0.89 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction solution was reacted at 25°C for 2 hours and concentrated to dryness under reduced pressure to obtain the crude product compound 27-6 (480 mg, crude yield 100%).

[0450] Step 6: Preparation of 2-amino-N-(3H-imidazo[4,5-b]pyridin-3-yl)-3-methylquinoline-6-carboxamide (27-7)

[0451] Compound 27-6 (50.0 mg, 0.37 mmol), 2-amino-3-methylquinoline-6-carbonyl chloride (82.2 mg, 0.37 mmol), and triethylamine (226 mg, 2.2 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and reacted for 12 hours. Water (20.0 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 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 27-7 (50.0 mg, 42% yield).

[0452] Step 7: Preparation of 2-amino-N-(3H-imidazo[4,5-b]pyridin-3-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (27)

[0453] Compound 27-7 (50.0 mg, 0.16 mmol), (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (60.1 mg, 0.23 mmol), and potassium carbonate (43.4 mg, 0.31 mmol) were dissolved in DMF (2 mL) at room temperature and reacted at 50°C for 12 hours. Water (20.0 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 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 afford compound 27 (0.5 mg, 0.67% yield).

[0454] LC-MS (ESI+): 478.2 m / z [M+H] + .

[0455] Example 28: Preparation of 2-amino-N-(1H-indol-1-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (28)

[0456] Step 1: Preparation of 1H-indole-1-amine (28-2)

[0457] At room temperature, 1H-indole (28-1, 2.00 g, 17 mmol) was dissolved in 40 mL of DMF, potassium hydroxide powder (9.60 g, 170 mmol) was added, and hydroxylaminesulfonic acid (3.90 g, 34 mmol) was slowly added under ice-cooling, with the temperature controlled below 10°C throughout. The reaction mixture was poured into water (200 mL), stirred for 10 minutes, and then extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 100%-50%) to obtain compound 28-2 (1.00 g, yield 44%).

[0458] Step 2: Preparation of 2-amino-N-(1H-indol-1-yl)-3-methylquinoline-6-carboxamide (28-3): Compound 28-2 (200 mg, 1.5 mmol) was dissolved in 3 mL of DMF at room temperature. PyBroP (297 mg, 0.6 mmol), 2-amino-3-methylquinoline-6-carboxylic acid (197 mg, 1.0 mmol), and DIEA (598 mg, 4.6 mmol) were added and allowed to react overnight at room temperature. The reaction mixture was poured into water (30.0 mL), stirred for 10 minutes, and extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100% to 50%) to afford compound 28-3 (320 mg, 67% yield).

[0459] Step 3: Preparation of 2-amino-N-(1H-indol-1-yl)-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (28)

[0460] At room temperature, compound 28-3 (200 mg, 0.6 mmol) was dissolved in 3 mL of DMF, and (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (323 mg, 1.3 mmol) and potassium carbonate (610 mg, 4.4 mmol) were added. The mixture was reacted at 60°C overnight. The reaction mixture was filtered and purified by HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to obtain compound 28 (8.5 mg, 0.018 mmol, 3% yield).

[0461] LC-MS (ESI+): 476.2 m / z [M+H] + .

[0462] 1 H NMR (400MHz, DMSO-d6) δ8.95(d,J=2.3Hz,1H),8.19(dd,J=8.3,2.4Hz,1H),7.72(d,J=7.6Hz,2H),7.52(s,1H),7.48–7.45(m,2H),7.40(d,J=8.0H z,2H),7.18–7.14(m,2H),7.04(t,J=7.5Hz,1H),6.51(s,2H),6.36(d,J= 3.4Hz, 1H), 5.54 (d, J = 16.0Hz, 1H), 5.03 (d, J = 15.6Hz, 1H), 2.15 (s, 4H).

[0463] Example 29: Preparation of 2-amino-4-cyclopropyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (29)

[0464] Step 1: Preparation of 4-bromo-6-carboxyquinoline 1-oxide (29-2)

[0465] 4-Bromoquinoline-6-carboxylic acid (29-1, 3.0 g, 7.9 mmol) and m-CPBA (2.7 g, 15.6 mmol) were added to dichloromethane (20.0 mL) at room temperature, and the resulting mixture was stirred at 25°C overnight. After completion of the reaction, the reaction solution was filtered, and the filter cake was dried under reduced pressure to obtain crude compound 29-2 (2.3 g, crude yield 75%).

[0466] Step 2: Preparation of 4-bromo-2-tert-butylaminoquinoline-6-carboxylic acid (29-3)

[0467] At room temperature, crude compound 29-2 (2.3 g, 8.6 mmol) was dissolved in 25 mL of dichloromethane. Tert-butylamine (3.2 g, 42.9 mmol) and p-toluenesulfonic anhydride (5.6 g, 17.2 mmol) were added under an ice bath and reacted at room temperature for 4 hours. The reaction mixture was poured into water (100 mL), stirred for 10 minutes, and then extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100%-50%) to obtain compound 29-3 (750 mg, yield 27%).

[0468] Step 3: Preparation of 4-bromo-2-(tert-butylamino)-N'-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (29-4)

[0469] At room temperature, compound 29-3 (600 mg, 1.4 mmol) was dissolved in 6 mL of DMF, and PyBroP (1.60 g, 3.5 mmol), 2-(1-methylhydrazinyl)pyrimidine (288 mg, 2.3 mmol), and DIEA (898 mg, 6.9 mmol) were added. The mixture was allowed to react overnight at room temperature. Water (30.0 mL) was poured into the reaction mixture, stirred for 10 minutes, and then extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100% to 50%) to obtain compound 29-4 (600 mg, 60% yield).

[0470] Step 4: Preparation of 4-bromo-2-(tert-butylamino)-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (29-5)

[0471] At room temperature, compound 29-4 (600 mg, 2.3 mmol) was dissolved in 7 mL of DMF, and (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (713 mg, 2.8 mmol) and potassium carbonate (578 mg, 4.2 mmol) were added. The reaction mixture was allowed to react at 60° C. overnight. The reaction mixture was cooled to room temperature and poured into water (30.0 mL), stirred for 10 minutes, and then extracted with ethyl acetate (50.0 mL×2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100%-50%) to give compound 29-5 (350 mg, 42% yield).

[0472] Step 5: Preparation of 2-amino-4-bromo-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (29-6)

[0473] At room temperature, compound 29-5 (350 mg, 0.59 mmol) was dissolved in 4 mL of trifluoroacetic acid and reacted at 80°C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, poured into water (30.0 mL), stirred for 10 minutes, and extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, 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 29-6 (110 mg, yield 26%).

[0474] Step 6: Preparation of 2-amino-4-cyclopropyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (29)

[0475] At room temperature, compound 29-6 (110 mg, 1.4 mmol) was dissolved in 3 mL of dioxane and 0.5 mL of water. 2-Cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57 mg, 0.4 mmol), potassium carbonate (70 mg, 0.5 mmol), and Pd(dppf)Cl2 (13 mg, 0.02 mmol) were added, and the mixture was reacted at 100°C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, dissolved in methanol / dichloromethane (10:1), filtered through celite, and concentrated under reduced pressure again. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to afford compound 29 (42 mg, 0.085 mmol, 6% yield).

[0476] LC-MS (ESI+): 494.2 m / z [M+H] + .

[0477] 1 H NMR (400MHz, DMSO-d6) δ8.92 (s, 1H), 8.46 (d, J = 4.7Hz, 2H), 8.24 (dd, J = 8.3, 2.4Hz, 1H) ,8.16(s,1H),7.90(d,J=8.1Hz,1H),7.60(d,J=8.7Hz,1H),7.36(d,J=8.7Hz,1H),6.83( s,1H),6.52(s,2H),6.44(s,1H),5.42(d,J=15.6Hz,1H),4.68(d,J=15.6Hz,1H),3.27( s,3H),2.15–1.93(m,1H),1.14(d,J=35.3Hz,1H),1.02–0.91(m,2H),0.60–0.52(m,2H).

[0478] The following compounds were obtained by the synthesis method of Example 29 using the corresponding raw materials:

[0479] Example 31: Preparation of 4-amino-7-fluoro-N,1-dimethyl-N-(5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (31)

[0480] Step 1: Preparation of 1-nitroso-5-(trifluoromethyl)indoline (31-2)

[0481] At room temperature, 5-trifluoromethylindoline (31-1, 400 mg, 2.10 mmol) was dissolved in 3 mL of acetic acid and 2 mL of water. The mixture was cooled to 0°C, and sodium nitrite (162 mg, 2.30 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 hours. The reaction mixture was poured into water (100 mL) and diluted. The mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed once with water (200 mL) and once with 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 = 4 / 1) to afford compound 31-2 (496 mg, 87% yield).

[0482] Step 2: Preparation of 5-(trifluoromethyl)indoline-1-amino (31-3)

[0483] At room temperature, compound 31-2 (430 mg, 1.80 mmol) was dissolved in 3 mL of methanol and cooled to 0°C. Zinc powder (481 mg, 7.20 mmol) and 3 mL of acetic acid were added. The mixture was reacted at room temperature for 4 hours and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (60.0 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 = 4 / 1) to obtain compound 31-3 (376 mg, 53% yield).

[0484] Step 3: Preparation of 4-amino-7-fluoro-1-methyl-N-(5-(trifluoromethyl)indolin-1-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (31-4)

[0485] At room temperature, compound 31-3 (80.0 mg, 0.30 mmol) and 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (60.0 mg, 0.30 mmol) were dissolved in 2 mL of DMF. Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (172 mg, 0.36 mmol) and N,N-diisopropylethylamine (79.0 mg, 0.6 mmol) were added. The reaction mixture was allowed to react at 25°C for 12 hours and then diluted with water (40.0 mL). The resulting mixture was extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with saturated brine (50.0 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 afford compound 31-4 (30.0 mg, 22% yield).

[0486] Step 4: Preparation of 4-amino-7-fluoro-N,1-dimethyl-N-(5-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (31)

[0487] At room temperature, compound 31-4 (20.0 mg, 0.04 mmol) was dissolved in 2 mL of tetrahydrofuran, and potassium carbonate (20.0 mg, 0.12 mmol) and iodomethane (7.60 mg, 0.05 mmol) were added. The reaction solution was reacted at 50°C for 12 hours and diluted with water (40.0 mL). The resulting mixture was extracted with ethyl acetate (30.0 mL × 3). The combined organic phases were washed with saturated brine (50.0 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 31 (13.7 mg, yield 66%).

[0488] LC-MS (ESI+): 459.2 m / z [M+H] + .

[0489] 1 H NMR (400MHz, DMSO-d6) δ8.28-8.21(m,2H),7.48(d,J=8.0Hz,1H),7.39(s,1H),7.23-7.20(m ,3H),6.98(d,J=8.0Hz,1H),4.28(s,3H),3.65–3.60(m,2H),3.07(s,3H),3.05–2.99(m,2H).

[0490] Example 32: Preparation of 4-amino-N-(5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (32)

[0491] Step 1: Preparation of tert-butyl 1H-pyrrolo[3,2-b]pyridine-1-carboxylate (32-2)

[0492] 1H-pyrrolo[3,2-b]pyridine (32-1, 4.50 g, 38 mmol) was dissolved in DCM (20 mL), and triethylamine (9.60 g, 95 mmol), DMAP (0.470 g, 3.8 mmol), and Boc2O (9.90 g, 45 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with DCM (100 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 (petroleum ether / ethyl acetate = 4 / 1) to give compound 32-2 (5.2 g, yield 99%, white solid).

[0493] LC-MS (ESI+): 219.1 m / z [M+H] + .

[0494] Step 2: Preparation of tert-butyl 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (32-3)

[0495] Compound 32-2 (0.25 g, 1.15 mmol) was dissolved in methanol (2 mL). Pd(OH)2 (0.25 g) was added under a nitrogen atmosphere. The resulting mixture was replaced with hydrogen and stirred at room temperature for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 32-3 (20 mg, 8% yield, as a yellow oil).

[0496] LC-MS (ESI+): 221.1m / z[M+H] + .

[0497] Step 3: Preparation of tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (32-4)

[0498] Compound 32-3 (0.98 g, 4.4 mmol) was dissolved in acetonitrile (10 mL), and NBS (1.19 g, 6.6 mmol) was slowly added at 0°C. The resulting mixture was stirred at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, 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 (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 32-4 (0.78 g, 58% yield, as a yellow solid).

[0499] LC-MS(ESI+):299.0,301.0m / z[M+H] + .

[0500] Step 4: Preparation of 5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (32-5)

[0501] Compound 32-4 (0.78 g, 2.6 mmol) was dissolved in ethyl acetate (2 mL), and EtOAc / HCl (2 M, 6.5 mL, 13 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 32-5 (0.55 g, 89% yield, as a white solid).

[0502] LC-MS (ESI+): 199.0 m / z [M+H] + .

[0503] Step 5: Preparation of 5-bromo-1-nitroso-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (32-6)

[0504] Compound 32-5 (0.1 g, 0.4 mmol) was dissolved in AcOH / H₂O (3 mL / 1 mL), and an aqueous solution of NaNO₂ (32 mg, 0.6 mL of water) was slowly added. The resulting mixture was stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 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 (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 32-6 (0.1 g, 99% yield, as a white solid).

[0505] LC-MS(ESI-):226.0, 228.0m / z[MH] - .

[0506] Step 6: Preparation of 5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-amine (32-7)

[0507] Compound 32-6 (0.100 g, 0.4 mmol) was dissolved in MeOH (1 mL), and zinc powder (105 mg, 1.6 mmol) and AcOH (0.5 mL) were added. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the filtrate was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (10 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 (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 32-7 (20 mg, 21% yield, as a yellow solid).

[0508] LC-MS(ESI+):214.0,216.0m / z[M+H] + .

[0509] Step 7: Preparation of 4-amino-N-(5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (32-8)

[0510] Compound 32-7 (80 mg, 0.3 mmol) was dissolved in DMF (2 mL), and 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (97 mg, 0.3 mmol) and TEA (93 mg, 0.93 mmol) were added sequentially. The resulting mixture was cooled to 0°C, BOPCl (0.11 g, 0.44 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 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 under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 32-8 (20 mg, 12% yield, as a white solid).

[0511] LC-MS(ESI+):456.0,458.0m / z[M+H] + .

[0512] Step 8: Preparation of 4-amino-N-(5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (32)

[0513] Compound 32-8 (20.0 mg, 0.04 mmol) was dissolved in a sealed tube containing DMF (2 mL). K2CO3 (9.00 mg, 0.06 mmol) and iodomethane (5 mg, 0.03 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. EtOAc (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 32 (10 mg, 50% yield, white solid).

[0514] LC-MS(ESI+):470.0,472.0m / z[M+H] + .

[0515] 1H NMR (400MHz, CH3OH-d4) δ8.35(d,J=7.0Hz,1H),8.21(s,1H),7.33(d,J=8.2Hz,1H),7.26(d,J=11.4Hz,1H),7.17(d, J=6.3Hz,1H),4.36(s,3H),3.70–3.59(m,1H),3.52–3.48(m,1H),3.15(s,3H),3.08–2.95(m,1H),2.88–2.72(m,1H).

[0516] The following compounds were obtained by the synthesis method of Example 32 using the corresponding starting materials:

[0517] Example 115: Preparation of 4-amino-N-ethyl-N-methyl-N-(4-(trifluoromethyl)phenyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide (115)

[0518] Step 1: Preparation of (diphenylmethylene)-2-(4-(trifluoromethyl)phenyl)hydrazine (115-2)

[0519] At room temperature, 4-(trifluoromethyl)phenylhydrazine (1.0 g, 5.68 mmol), benzophenone (1.03 g, 5.68 mmol) and acetic acid (974 μL, 17.0 mmol) were dissolved in ethanol (30 mL). The mixture was heated to 80°C, the reaction was continued for 4 hours, and then cooled to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed once with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and the filtrate was collected by filtration. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (eluent: PE / EA = 10 / 1) to obtain compound 115-2 (1.2 g, yield 62%). LC-MS (ESI+): 341.1 m / z [M+H] + .

[0520] Step 2: Preparation of 2-(diphenylmethylene)-1-methyl-1-(4-(trifluoromethyl)phenyl)hydrazine (115-3)

[0521] At room temperature, compound 115-2 (1.0 g, 2.94 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0°C in an ice-water bath, and sodium hydride (60%, 141 mg, 3.52 mmol) was slowly added. The reaction was maintained at 0°C for 15 minutes, followed by the slow addition of iodomethane (220 μL, 3.52 mmol). The temperature was raised to room temperature and the reaction was continued for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was collected by filtration. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (eluent: PE / EA = 5 / 1) to obtain compound 115-3 (800 mg, 77% yield). LC-MS (ESI+): 355.2 m / z [M+H] + .

[0522] Step 3: Preparation of 1-methyl-1-(4-(trifluoromethyl)phenyl)hydrazine (115-4)

[0523] At room temperature, compound X-3 (700 mg, 1.98 mmol) was dissolved in 10 mL of concentrated hydrochloric acid / 1 mL of ethanol and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a solid, which was washed with petroleum ether (10 mL x 3) to obtain compound 115-4 (300 mg, yield 80%). LC-MS (ESI+): 191.1 m / z [M+H] + .

[0524] Compound 115-4 was synthesized according to the route of Example 1 to obtain 4-amino-N-ethyl-N-methyl-N-(4-(trifluoromethyl)phenyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carbohydrazide.

[0525] LC-MS (ESI+): 431.0 m / z [M+H] + .

[0526] The following compounds were obtained by the synthesis method of Example 115 using the corresponding starting materials:

[0527] Example 117: Preparation of 2-amino-N'-(3-(difluoromethyl)pyridin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (117)

[0528] Step 1: Preparation of 2-chloro-3-(difluoromethyl)pyridine (117-2)

[0529] Diethylaminosulfur trifluoride (2.27 g, 14.1 mmol) was added to 2-chloronicotinic acid (117-1, 2 g, 14.1 mmol) in dichloromethane (15 mL) at 0°C. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (45 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 4) to obtain compound 117-2 (1.35 g, yield 58%).

[0530] LC-MS (ESI+): 164.1m / z[M+H] + .

[0531] The remaining steps were the same as the synthetic method of Example 1, except that compound 117-2 was used instead of compound 1-3 to obtain 2-amino-N'-(3-(difluoromethyl)pyridin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0532] LC-MS (ESI+): 517.1m / z[M+H] + .

[0533] Example 118: Preparation of 2-amino-3-methyl-N-(1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide (118)

[0534] Step 1: Preparation of N3-methylpyridine-2,3-diamine (118-2)

[0535] 2-Nitro-3-methylamino-pyridine (118-1, 1.0 g, 6.53 mmol) and palladium on carbon (300 mg, 5%) were dissolved in dry methanol (15 mL) at room temperature. The reaction mixture was stirred at 40°C under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered, concentrated, and dried to afford compound 118-2 (700 mg, 87% yield).

[0536] LC-MS (ESI+): 124.1m / z[M+H] + .

[0537] Step 2: Preparation of 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (118-3)

[0538] At room temperature, N,N'-carbonyldiimidazole (1.18 g, 7.31 mmol) was added to tetrahydrofuran (10 mL) containing 118-2 (600 mg, 4.88 mmol). The reaction mixture was stirred at 25°C for 12 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain compound 118-3 (700 mg, yield 96.3%).

[0539] LC-MS (ESI+): 150.1m / z[M+H] + .

[0540] Step 3: Preparation of 3-amino-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (118-4)

[0541] At 0°C, sodium hydroxide (60%, 241 mg, 6 mmol) was added to tetrahydrofuran (10 mL) containing 118-3 (600 mg, 4.0 mmol). After 20 minutes, (aminooxy)diphenylphosphine oxide (1125 mg, 4.8 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was quenched by adding water (25 mL) and then extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 118-4 (400 mg, yield 61%).

[0542] LC-MS (ESI+): 165.1m / z[M+H] + .

[0543] The remaining steps were the same as the synthetic method of Example 1, except that compound 118-4 was used instead of compound 1-3 to obtain 2-amino-3-methyl-N-(1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carboxamide.

[0544] LC-MS (ESI+): 508.0 m / z [M+H] + .

[0545] Example 119: Preparation of 2-amino-N',3-dimethyl-N'-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (119)

[0546] Step 1: Preparation of 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (119-2)

[0547] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine (119-1, 1.0 g, 6.51 mmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (60%, 390 mg, 9.77 mmol) was added at 0°C and stirring continued for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (2.18 g, 13.0 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) to afford compound 119-2 (800 mg, 43% yield).

[0548] LC-MS (ESI+): 284.2 m / z [M+H] + .

[0549] Step 2: Preparation of 2-(1-methylhydrazinyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (119-3)

[0550] 119-2 (200 mg, 0.71 mmol), methylhydrazine (206 mg, 1.41 mmol), and potassium carbonate (292 mg, 2.11 mmol) were dissolved in dioxane (4 mL), and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (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 crude product was purified by C18 reverse phase chromatography (eluent: water / acetonitrile = 1.5 / 1) to obtain compound 119-3 (130 mg, yield 63%). LC-MS (ESI+): 294.2 m / z [M+H] + .

[0551] Step 3: Preparation of 2-amino-N',3-dimethyl-N'-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)quinoline-6-carbohydrazide (119-4)

[0552] Compound 119-3 (130 mg, 0.44 mmol), 2-amino-3-methylquinoline-6-carboxylic acid (134 mg, 0.66 mmol), and N,N-diisopropylethylamine (171 mg, 1.33 mmol) were dissolved in N,N-dimethylacetamide (2 mL). The reaction mixture was stirred at 25°C for 10 minutes. Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (268 mg, 0.58 mmol) was then added, and the reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (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 crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford compound 119-4 (100 mg, 47% yield).

[0553] LC-MS (ESI+): 478.2 m / z [M+H] + .

[0554] Step 4: Preparation of 2-amino-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-N'-(7-((2-(trimethylsilyl)ethoxy)methyl) (119-5)

[0555] 119-4 (90 mg, 0.18 mmol) and potassium carbonate (78 mg, 0.57 mmol) were dissolved in dimethyl sulfoxide (2 mL) solution, and the reaction solution was stirred at 25°C for 1 hour. Subsequently, (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (96 mg, 0.38 mmol) was added. The reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (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 crude product was purified by C18 reverse phase chromatography (eluent: water / acetonitrile = 4 / 1) to obtain compound 119-5 (20 mg, yield 17%).

[0556] LC-MS (ESI+): 637.2 m / z [M+H] + .

[0557] Step 5: Preparation of 2-amino-N',3-dimethyl-N'-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (119)

[0558] At room temperature, 119-5 (20 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (1.5 mL). The reaction solution was stirred at 25 ° C for 2 hours until the starting material disappeared. The reaction solution was concentrated to dryness under reduced pressure. The crude product was diluted with tetrahydrofuran (2 mL), and ammonia water (2 mL) was added to adjust the pH to 9. The reaction solution was stirred at 25 ° C for 16 hours. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 119 (1.3 mg, yield 8%).

[0559] LC-MS (ESI+): 507.1m / z[M+H] + .

[0560] The following compounds were prepared according to the synthesis method of Example 119 using the corresponding starting materials:

[0561] Example 121: Preparation of 2-amino-N'-(bicyclo[1.1.1]pentan-1-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (121)

[0562] Step 1: Preparation of tert-butyl bicyclo[1.1.1]pentan-1-ylcarbamate (121-2)

[0563] Bicyclo[1.1.1]pentane-1-amine (121-1, 2.0 g, 16.8 mmol) was dissolved in THF (20 mL). Sodium hydroxide (60%, 806 mg, 33.6 mmol) and Boc2O (4.03 g, 18.5 mmol) were added at 0°C, and the resulting mixture was stirred at room temperature for 24 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 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 (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 121-2 (1.5 g, 49% yield, as a white solid).

[0564] LC-MS (ESI+): 184.2 m / z [M+H] + .

[0565] Step 2: Preparation of tert-butyl bicyclo[1.1.1]pentan-1-yl(methyl)carbamate (121-3)

[0566] Compound 121-2 (1.5 g, 8.2 mmol) was dissolved in DMF (2 mL). Sodium hydroxide (60%, 393 mg, 16.3 mmol) was added at 0°C. The reaction mixture was stirred for 5 minutes, followed by the addition of iodomethane (2.3 g, 16.4 mmol). The resulting mixture was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction mixture, 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 to afford compound 121-3 (700 mg, 43% yield, as a colorless oil).

[0567] LC-MS (ESI+): 198.3 m / z [M+H] + .

[0568] Step 3: Preparation of N-methylbicyclo[1.1.1]pentan-1-amine (121-4)

[0569] Compound 121-3 (1.3 g, 6.6 mmol) was dissolved in 4 M HCl in ethyl acetate (20 mL), and the resulting mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated to give compound 121-4 (hydrochloride salt, 600 mg, 94% yield, white solid). LC-MS (ESI+): 98.1 m / z [M+H] + .

[0570] The remaining steps were the same as the synthetic method of Example 22, except that compound 121-4 was used instead of compound 22-3 to obtain 2-amino-N'-(bicyclo[1.1.1]pentan-1-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0571] LC-MS (ESI+): 456.2 m / z [M+H] + .

[0572] Example 122: Preparation of 2-amino-6-(2-(5-carboxypyrimidin-2-yl)-2-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carbonyl)-3-methylquinolin-4-yl (122)

[0573] Step 1: Preparation of 2-amino-6-(2-(5-carboxypyrimidin-2-yl)-2-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carbonyl)-3-methylquinolin-4-yl (122)

[0574] Methyl 2-(2-(2-amino-3-methylquinoline-6-carbonyl)-1-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine)pyrimidine-5-carboxylate (122-1, synthesized according to the method of Example 1) (100 mg, 0.19 mmol) was dissolved in THF / MeOH / H₂O (3 mL / 2 mL / 1 mL). Lithium hydroxide (23 mg, 0.57 mmol) was added, and the resulting mixture was stirred at 25°C for 3 hours. 1N HCl was added to the reaction solution to adjust the pH to ~3, and then EtOAc (20 mL) was added for extraction. The organic phase was washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to afford compound 122 (37 mg, 38% yield, as a white solid).

[0575] LC-MS (ESI+): 512.2 m / z [M+H] + .

[0576] Example 123: Preparation of 2-amino-N-((8-fluoroisoquinolin-3-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (123)

[0577] Step 1: Preparation of 2-(2-fluoro-6-iodobenzene)-1,3-dioxane (123-2)

[0578] 2-Fluoro-6-(p-iodobenzaldehyde) (123-1, 1.00 g, 3.99 mmol), propane-1,3-diol (456 mg, 5.99 mmol), and p-toluenesulfonic acid (69 mg, 0.40 mmol) were dissolved in toluene (10 mL) at room temperature and reacted at 110°C for 2 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 (100 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 = 1 / 1) to give compound 123-2 (1.20 g, 97% yield).

[0579] LC-MS (ESI+): 309.2 m / z [M+H] + .

[0580] Step 2: Preparation of (Z)-3-(2-(1,3-dioxane-2-yl)-3-fluorophenyl)-2-acetamidoacrylate (123-3)

[0581] Compound 123-2 (1.00 g, 3.25 mmol), methyl 2-acetamidoacrylate (511 mg, 3.57 mmol), sodium bicarbonate (619 mg, 8.11 mmol), palladium acetate (73.5 mg, 0.32 mmol), and 3,3-dimethylbutyryl chloride (721 mg, 2.59 mmol) were added to toluene (10 mL) at room temperature and reacted at 90°C for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 123-3 (1.00 g, 95% yield).

[0582] LC-MS (ESI+): 324.2 m / z [M+H] + .

[0583] Step 3: Preparation of 8-fluoroisoquinoline-3-carboxylic acid methyl ester (123-4)

[0584] Compound 123-3 (800 mg, 2.47 mmol) and 4-methylbenzenesulfonate pyridinium (PPTS, 155 mg, 0.68 mmol) were dissolved in acetic acid (10 mL) and water (2 mL) at room temperature and reacted at 80°C for 12 hours. Water (100 mL) was 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 (100 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 = 1 / 1) to obtain compound 123-4 (400 mg, 78% yield).

[0585] LC-MS (ESI+): 206.1m / z[M+H] + .

[0586] Step 4: Preparation of (8-fluoroisoquinolin-3-yl)methanol (123-5)

[0587] Compound 123-4 (250 mg, 1.20 mmol) was dissolved in methanol (5 mL) at room temperature, and sodium borohydride (53 mg, 2.43 mmol) was added at 0°C. The reaction was allowed to proceed at 0°C for 2 hours. Water (50 mL) was added to quench the mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). 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 (eluent: petroleum ether / ethyl acetate = 0 / 1) to afford compound 123-5 (230 mg, 100% yield).

[0588] LC-MS (ESI+): 178.1m / z[M+H] + .

[0589] Step 5: Preparation of (8-fluoroisoquinolin-3-yl)methyl methanesulfonate (123-6)

[0590] Compound 123-5 (230 mg, 1.29 mmol), methanesulfonyl chloride (178 mg, 1.56 mmol), and triethylamine (159 mg, 1.56 mmol) were dissolved in dichloromethane (4 mL) at room temperature and allowed to react for 12 hours. Water (60 mL) was added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain compound 123-6 (210 mg, yield 63%).

[0591] LC-MS (ESI+): 256.0 m / z [M+H] + .

[0592] The remaining steps were the same as the synthetic method of Example 1, except that compound 123-6 was used instead of compound 1-2 to obtain compound 2-amino-N-((8-fluoroisoquinolin-3-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0593] LC-MS (ESI+): 468.2 m / z [M+H] + .

[0594] 1H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.40(s,2H),7.87(d,J=8.3Hz,1H),7.83–7.76(m,2H),7.73(s,1H),7.69(s,1H),7.50-7.45( m,2H),7.29(d,J=8.4Hz,1H),6.78(s,1H),6.46(s,2H),5.61(d,J=15.7Hz,1H),4.57(d,J=15.1Hz,1H),3.19(s,3H),2.16(s,3H).

[0595] Example 124: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)quinoline-6-carbohydrazide (124)

[0596] According to the synthesis method of Example 123, 6-(trifluoromethyl)pyridazine-3-carboxylic acid methyl ester was used to replace 8-fluoroisoquinoline-3-carboxylic acid methyl ester (123-4) to obtain 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((6-(trifluoromethyl)pyridazin-3-yl)methyl)quinoline-6-carbohydrazide.

[0597] LC-MS (ESI+): 469.2 m / z [M+H] + .

[0598] Example 125: Preparation of 2-amino-N'-(6-fluoroquinoxalin-5-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (125)

[0599] Step 1: Preparation of 5,6-difluoroquinoxaline (125-2)

[0600] At room temperature, 3,4-difluorobenzene-1,2-diaminobenzene (125-1, 2.00 g, 13.9 mmol) and glyoxal (4.0 mg, 27.8 mmol) were dissolved in ethanol (10 mL) and reacted at 80°C for 12 hours. Water (100 mL) was 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 125-2 (2.00 g, yield 86%).

[0601] LC-MS (ESI+): 167.0 m / z [M+H]+ .

[0602] The remaining steps were the same as the synthetic method of Example 1, except that 125-2 was used instead of compound 1-3 to obtain 2-amino-N'-(6-fluoroquinoxaline-5-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0603] LC-MS (ESI+): 536.2 m / z [M+H] + .

[0604] Example 126: Preparation of 2-amino-N',3-dimethyl-N'-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (126)

[0605] Step 1: Preparation of 6-bromo-3-trifluoromethylquinoline (126-2)

[0606] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine (126-1, 500 mg, 3.26 mmol) was dissolved in acetonitrile (6 mL) at room temperature, and sodium hydride (60%, 160 mg, 3.91 mmol) was added to the reaction solution at 0°C. The reaction solution was stirred at 25°C for 1 hour. Subsequently, iodomethane (1020 mg, 7.16 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 4) to obtain compound 126-2 (300 mg, yield 55%).

[0607] LC-MS (ESI+): 168.2 m / z [M+H] + .

[0608] The remaining steps were the same as the synthetic method of Example 1, except that 126-1 was used instead of 1-3 to obtain the compound 2-amino-N',3-dimethyl-N'-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0609] LC-MS (ESI+): 521.2 m / z [M+H] + .

[0610] 1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.61(s,1H),8.25–8.19(m,1H),7.93( d,J=8.0Hz,1H),7.83(s,1H),7.71(s,1H),7.57(d,J=8.6Hz,1H),7.30(d,J= 8.4Hz,1H),7.26–7.21(m,1H),6.46(s,2H),6.42–6.36(m,1H),5.36(d,J=1 5.6Hz, 1H), 4.66 (d, J = 15.6Hz, 1H), 3.63 (s, 3H), 3.44 (s, 3H), 2.18 (s, 3H).

[0611] The following compounds were obtained by the synthesis method of Example 126 using the corresponding starting materials:

[0612] Example 128: Preparation of 2-amino-N'-ethyl-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (128)

[0613] Step 1: Preparation of tert-butyl 2-(2-amino-3-methylquinoline-6-carbonyl)-1-methylhydrazinecarboxylate (128-2)

[0614] At room temperature, 2-amino-3-methylquinoline-6-carboxylic acid (500 mg, 2.47 mmol) and tert-butyl 1-methylhydrazinecarboxylate (128-1, 542 mg, 3.7 mmol) were dissolved in N,N-dimethylformamide (10 mL). Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (1729 mg, 3.7 mmol) and diisopropylethylamine (1 mL) were added sequentially. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (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 crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 10 / 1) to obtain compound 128-2 (800 mg, 98% yield).

[0615] LC-MS (ESI+): 331.2 m / z [M+H] + .

[0616] Step 2: Preparation of 2-amino-N',3-dimethylquinoline-6-hydrazide (128-3)

[0617] At room temperature, 128-2 (300 mg, 0.91 mmol) was dissolved in dry dichloromethane (2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at 25°C for 1 hour until the starting material disappeared. The reaction mixture was concentrated to dryness under reduced pressure to obtain compound 128-3 (200 mg, yield 99%).

[0618] LC-MS (ESI+): 231.2 m / z [M+H] + .

[0619] Step 3: Preparation of 2-amino-N'-ethyl-N',3-dimethylquinoline-6-hydrazide (128-4)

[0620] At room temperature, 128-3 (150 mg, 0.65 mmol) and iodoethane (221 mg, 1.3 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (269 mg, 1.9 mmol) was added. The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (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 crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 10 / 1) to obtain compound 128-4 (50 mg, 30% yield).

[0621] LC-MS (ESI+): 259.2 m / z [M+H] + .

[0622] The remaining steps were the same as the synthetic method of Example 1, except that compound 128-4 was used instead of compound 1-5 to obtain 2-amino-N'-ethyl-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0623] LC-MS (ESI+): 418.2 m / z [M+H] + .

[0624] The following compounds were obtained by the synthesis method of Example 128 using the corresponding starting materials:

[0625] Example 132: Preparation of 2-amino-N'-(2-hydroxyethyl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (132)

[0626] Step 1: Preparation of 2-amino-N'-(2-hydroxyethyl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (132)

[0627] Compound 132-1 (synthesized according to the method of Example 128) (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, and 1N hydrochloric acid (0.1 mL) was added. The reaction solution was stirred at 25°C for 1 hour. After completion of the reaction, the crude product was separated by reverse-phase high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to obtain compound 132 (2 mg, 6% yield).

[0628] LC-MS (ESI+): 434.3 m / z [M+H] + .

[0629] Example 133: Preparation of 2-amino-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-N'-(3-vinylpyridin-2-yl)quinoline-6-carbohydrazide (133) and 2-amino-N'-(3-ethylpyridin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (134)

[0630] Step 1: Preparation of 2-amino-N',3-dimethyl-N'-(3-vinylpyridin-2-yl)quinoline-6-hydrazide (133-2)

[0631] At room temperature, 2-amino-N'-(3-bromopyridin-2-yl)-N',3-dimethylquinoline-6-hydrazide (133-1, synthesized according to the method of Example 1) (100 mg, 0.26 mmol), potassium vinyl trifluoroborate (347 mg, 2.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (19 mg, 0.025 mmol), and cesium carbonate (422 mg, 1.3 mmol) were added to 1,4-dioxane (3 mL) and water (0.4 mL). The reaction mixture was 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, and the mixture was extracted with ethyl acetate (25 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain compound 133-2 (80 mg, yield 93%).

[0632] LC-MS (ESI+): 334.1m / z[M+H] + .

[0633] Step 2: Preparation of 2-amino-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-N'-(3-vinylpyridin-2-yl)quinoline-6-carbohydrazide (133)

[0634] At room temperature, 133-2 (70 mg, 0.21 mmol), (5-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate (107 mg, 0.43 mmol), and potassium carbonate (87 mg, 0.63 mmol) were added to dimethyl sulfoxide (2 mL). The reaction solution was stirred at 50°C for 4 hours. After the reaction was completed, water (25 mL) was added to the reaction solution, and then extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain compound 133 (30 mg, yield 29%).

[0635] LC-MS (ESI+): 493.1m / z[M+H] + .

[0636] Step 3: Preparation of 2-amino-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-N'-(3-ethylpyridin-2-yl)quinoline-6-hydrazide (134)

[0637] At room temperature, 133 (20 mg, 0.04 mmol) and palladium on carbon (40 mg, 10%) were added to methanol (2 mL). The reaction mixture was stirred at 25°C under a hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was separated by reverse-phase HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to obtain compound 134 (1.9 mg, 10% yield).

[0638] LC-MS (ESI+): 495.1m / z[M+H] + .

[0639] The following compounds were prepared according to the synthesis method of Example 133 using the corresponding starting materials:

[0640] Example 137: Preparation of 2-amino-N-((2'-methoxy-6'-methyl-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (137)

[0641] Step 1: Preparation of methyl (5-bromopyridin-2-yl)methanesulfonate (137-2)

[0642] At room temperature, (5-bromopyridin-2-yl)methanol (137-1) (20 g, 106 mmol) was dissolved in 200 mL of dichloromethane, triethylamine (32 g, 319 mmol) was added, and the mixture was stirred for 5 minutes under an ice bath. Trifluoromethanesulfonic anhydride (28 g, 159 mmol) was slowly added. After the addition was completed, the mixture was reacted for 1 hour under an ice bath. The reaction mixture was poured into water (300 mL), stirred for 10 minutes, and then extracted with ethyl acetate (500 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to give compound 137-2 (21 g, yield 74%).

[0643] LC-MS (ESI+): 266.0 m / z [M+H] + .

[0644] Step 2: Preparation of tert-butyl 2-methyl-2-(pyrimidin-2-yl)hydrazine-1-carboxylate (137-3)

[0645] At room temperature, compound 1-4 (20 g, 161 mmol) was dissolved in 200 mL of tetrahydrofuran and 200 mL of water, and di-tert-butyl dicarbonate (53 g, 242 mmol) and sodium carbonate (51 g, 483 mmol) were added. The reaction was allowed to react overnight at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure, and the resulting mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to give compound 137-3 (31 g, yield 86%).

[0646] LC-MS (ESI+): 225.1m / z[M+H] + .

[0647] Step 3: Preparation of tert-butyl 1-((5-bromopyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazine-1-carboxylate (137-4)

[0648] At room temperature, 137-3 (15 g, 67 mmol) was dissolved in 150 mL of DMF, and potassium carbonate (28 g, 201 mmol) and 137-2 (20 g, 77 mmol) were added. The reaction was allowed to react at 65° C. under a nitrogen atmosphere overnight. 200 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to give compound 137-4 (10 g, yield 25%).

[0649] LC-MS (ESI+): 394.1m / z[M+H] + .

[0650] Step 4: Preparation of 2-(2-((5-bromopyridin-2-yl)methyl)-1-methylhydrazinyl)pyrimidine (137-5)

[0651] At room temperature, 137-4 (10 g, 25 mmol) was dissolved in 100 mL of dichloromethane, 4 M hydrochloric acid solution in dioxane (50 mL) was added, and the mixture was reacted at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give compound 137-5 (hydrochloride salt, 6.5 g, yield 87%).

[0652] LC-MS (ESI+): 294.1m / z[M+H] + .

[0653] Step 5: Preparation of 2-amino-N-((5-bromopyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (137-6)

[0654] At room temperature, 137-5 (hydrochloride, 6.5 g, 22 mmol) was dissolved in 70 mL of dichloromethane and N,N-diisopropylethylamine (8.55 g, 66 mmol) was added. After stirring in an ice bath for 5 minutes, 2-amino-3-methylquinoline-6-carbonyl chloride (4.88 g, 22 mmol) was added, and 1 mL of DMF was added to the reaction solution to promote dissolution. The reaction was allowed to proceed under a nitrogen atmosphere for 1 hour. The reaction mixture was directly concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-10%) to obtain compound 137-6 (10 g, yield 95%).

[0655] LC-MS (ESI+): 478.1m / z[M+H] + .

[0656] Step 6: Preparation of 2-amino-N-((2'-methoxy-6'-methyl-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (137)

[0657] At room temperature, 137-6 (100 mg, 0.28 mmol) was dissolved in 3 mL of dioxane, and (2-methoxy-6-methylpyridin-3-yl)boronic acid (150 mg, 0.90 mmol), potassium carbonate (298 mg, 2.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.31 mg, 0.02 mmol), and water (0.6 mL) were added. The reaction was allowed to proceed at 100°C overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to afford compound 137 (2.1 mg, 1.4% yield).

[0658] LC-MS (ESI+): 521.2 m / z [M+H] + .

[0659] 1 H NMR(400MHz, DMSO-d6)δ8.67(s,1H),8.43(d,J=4.8Hz,2H),8.28(s,1H),7.98(dd,J=8 .1,2.3Hz,1H),7.77–7.72(m,2H),7.65(d,J=8.2Hz,1H),7.50(d,J=8.7Hz,1H),7.32( d,J=8.8Hz,1H),7.00(d,J=7.5Hz,1H),6.90–6.78(m,1H),6.51(s,2H),5.44(d,J=15. 2Hz, 1H), 4.46 (d, J = 15.3Hz, 1H), 3.90 (s, 3H), 3.29 (s, 3H), 2.47 (s, 3H), 2.19 (s, 3H).

[0660] The following compounds were prepared according to the synthesis method of Example 137 using the corresponding starting materials:

[0661] Example 217: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(tetrahydrofuran-3-yl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (217)

[0662] Step 1: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(tetrahydrofuran-3-yl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (217)

[0663] Compound 186 (80 mg, 0.17 mmol) was dissolved in methanol (2 mL) at room temperature, and palladium on carbon (20 mg, 0.19 mmol) was added. The resulting mixture was replaced with hydrogen and stirred at room temperature for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 217 (2.1 mg, 2.6% yield).

[0664] LC-MS (ESI+): 470.3 m / z [M+H] + .

[0665] The following compounds were prepared according to the synthesis method of Example 217 using the corresponding starting materials:

[0666] Example 220: Preparation of 2-amino-N',3-dimethyl-N-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (220)

[0667] Step 1: Preparation of 2-amino-N',3-dimethyl-N-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (220)

[0668] 137-6 (50 mg, 0.10 mmol) was dissolved in toluene (2 mL) in a sealed tube, and 4-(tributyltinyl)pyridazine (57.80 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and lithium chloride (4.4 mg, 0.10 mmol) were added sequentially. After replacing the nitrogen, the resulting mixture was stirred at 100°C for 12 hours. EtOAc (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 220 (6.7 mg, 13% yield, as a white solid).

[0669] LC-MS (ESI+): 478.2 m / z [M+H] + .

[0670] 1 H NMR (400MHz, DMSO-d6) δ9.72 (d, J=2.4Hz, 1H), 9.33 (dd, J=5.6, 1.2Hz, 1H), 9. 07(s,1H),8.45–8.23(m,3H),8.11(dd,J=5.6,2.4Hz,1H),7.85–7.64(m,3H), 7.48(d,J=8.8Hz,1H),7.31(d,J=8.8Hz,1H),6.79(t,J=4.8Hz,1H),6.46(s,2 H), 5.46 (d, J = 15.2Hz, 1H), 4.53 (d, J = 15.6Hz, 1H), 3.27 (s, 3H), 2.18 (s, 3H).

[0671] The following compounds were prepared according to the synthesis method of Example 220 using the corresponding starting materials:

[0672] Example 224: Preparation of 2-amino-N-((5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (224)

[0673] Step 1: Preparation of 2-amino-N-((5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (224)

[0674] Compound 137-6 (100 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2 mL) in a sealed tube. 3,3-Difluoropyrrolidine (45.00 mg, 0.31 mmol), Brettphos Pd G3 (19.0 mg, 0.02 mmol), and cesium carbonate (204 mg, 0.63 mmol) were added sequentially. After replacing the nitrogen atmosphere, the resulting mixture was stirred at 100°C for 12 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 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 preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 224 (0.8 mg, 1% yield) as a white solid.

[0675] LC-MS (ESI+): 505.2 m / z [M+H] + .

[0676] The following compounds were obtained by the synthesis method of Example 224 using the corresponding starting materials:

[0677] Example 226: Preparation of 2-amino-N-((5-(4-(methoxymethyl)thiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (226)

[0678] Step 1: Preparation of 5-bromo-4-methoxymethylthiazole (226-2)

[0679] At room temperature, (5-bromothiazol-4-yl)methanol (226-1) (60 mg, 0.31 mmol) was dissolved in 5 mL of tetrahydrofuran, and sodium hydride (60%, 12 mg, 0.46 mmol) was added. After reacting in an ice bath for 30 minutes, iodomethane (88 mg, 0.62 mmol) was slowly added and reacted at room temperature for 1 hour. The reaction mixture was poured into water (20 mL) to quench, and then extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 226-2 (60 mg, 94% yield). It was used directly in the next step without purification.

[0680] LC-MS (ESI+): 208.2 m / z [M+H] + .

[0681] Step 2: Preparation of (6-((1-(2-amino-3-methylquinoline-6-carbonyl)-2-methyl-2-(pyrimidin-2-yl)hydrazine)methyl)pyridin-3-yl)boronic acid (226-3)

[0682] At room temperature, 137-6 (200 mg, 0.42 mmol) was dissolved in 5 mL of dioxane. Bis(2,1-bis(diphenylphosphino)ferrocene)-1,1'-dichloropalladium dichloromethane complex (30 mg, 0.04 mmol) was added. The mixture was allowed to react at 90°C overnight. The reaction mixture was cooled to room temperature and used directly in the next step without further treatment.

[0683] LC-MS (ESI+): 444.2 m / z [M+H] + .

[0684] Step 3: Preparation of 2-amino-N-((5-(4-(methoxymethyl)thiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (226)

[0685] To the reaction mixture from the previous step were added cesium carbonate (300 mg, 0.92 mmol), compound 226-2 (60 mg, 0.29 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30 mg, 0.04 mmol), and 0.5 mL of water at room temperature. The mixture was allowed to react at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to afford compound 226 (1.6 mg, 1.1% yield).

[0686] LC-MS (ESI+): 527.2 m / z [M+H] + .

[0687] 1H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.68 (s, 1H), 8.40 (d, J = 4.8Hz, 2H), 7. 98(dd,J=9.2,2.4Hz,1H),7.78–7.73(m,3H),7.50(d,J=8.8Hz,1H),7.33(d ,J=8.4Hz,1H),6.79(t,J=4.8Hz,1H),6.51(s,2H),5.42(d,J=15.2Hz,1H), 4.56(d,J=15.2Hz,1H),4.49(s,2H),3.32(s,3H),3.28(s,3H),2.19(s,3H).

[0688] The following compounds were obtained by the synthesis method of Example 226 using the corresponding starting materials:

[0689] Example 237: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(4-(trifluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (237)

[0690] Step 1: Preparation of 5-bromo-4-trifluoromethylthiazole (237-2)

[0691] At room temperature, 5-bromo-4-(trifluoromethyl)thiazol-2-amine (237-1) (60 mg, 0.24 mmol) was dissolved in 5 mL of tetrahydrofuran and tert-butyl nitrite (50 mg, 0.49 mmol) was added. The reaction mixture was reacted at 70 ° C overnight under a nitrogen atmosphere. Water (20.0 mL) was poured into the reaction mixture to quench it, and then extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product 237-2 was used directly in the next step without purification. LC-MS (ESI+): 232.2 m / z [M+H] + .

[0692] According to the procedure of step 3 of Example 226, 237-2 was used instead of 226-2 to obtain 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(4-(trifluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0693] LC-MS (ESI+): 551.2 m / z [M+H] + .

[0694] Example 238: Preparation of 2-amino-N'-cyclopropyl-3-methyl-N-((5-(4-methylthiazol-5-yl-2d)pyridin-2-yl)methyl)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (238)

[0695] Step 1: Preparation of 4-methylthiazole-2d (238-2)

[0696] 2-Bromo-4-methylthiazole (238-1) (1500 mg, 8.42 mmol) was dissolved in THF (6 mL). n-Butyl lithium (647 mg, 10.1 mmol) was added at -78°C. The mixture was reacted at -78°C for 1 hour. Deuterated methanol (6 mL) was added to the reaction solution, and the temperature was slowly raised to room temperature for 1 hour. After the reaction was completed, water (25 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (40 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. Due to the low boiling point of 238-2, the filtrate was used directly in the next step.

[0697] LC-MS (ESI+): 101.1m / z[M+H] + 。

[0698] Step 2: Preparation of 5-bromo-4-methylthiazole-2d (238-3)

[0699] To the filtrate from the previous step, NBS (1332 mg, 7.5 mmol) and AcOH (10 mL) were added and allowed to react at room temperature 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 (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain 238-3 (500 mg, 33% yield) as a yellow oil. LC-MS (ESI+): 179.1 m / z [M+H] + .

[0700] According to the procedure of step 3 of Example 226, 238-3 was used instead of 226-2 to obtain 2-amino-N'-cyclopropyl-3-methyl-N-((5-(4-methylthiazol-5-yl-2d)pyridin-2-yl)methyl)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0701] LC-MS (ESI+): 524.1m / z[M+H] + 。

[0702] 1H NMR(400MHz,DMSO-d6)δ8.60-8.52(m,3H),7.98-8.92(m,1H),7.84–7.78(m,2H), 7.75(d,J=8.0Hz,1H),7.56-8.50(m,1H),7.39(d,J=8.8Hz,1H),7.23(s,2H),7.04 -6.96(m,1H),5.34(d,J=15.2Hz,1H),4.66(d,J=15.2Hz,1H),2.82-2.74(m,1H),2 .47(s,3H),2.22(s,3H),0.79-0.72(m,1H),0.58–0.40(m,2H),0.15-0.10(m,1H).

[0703] Example 239: Preparation of 2-amino-N'-cyclopropyl-N-((5-(4-(difluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)-3-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (239)

[0704] Step 1: Preparation of 5-bromo-4-difluoromethylthiazol-2-amine (239-2)

[0705] At room temperature, tert-butyl (4-(difluoromethyl)thiazol-2-yl)carbamate (239-1) (250 mg, 1.00 mmol) and N-bromosuccinimide (213 mg, 1.20 mmol) were dissolved in acetic acid (2 mL). The mixture was heated to 80°C and stirred for 6 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (10 mL) and washed with dichloromethane (3 x 20 mL). The combined organic phases were washed with brine (10 mL) and dried over anhydrous sodium sulfate. The filtrate was collected by filtration, concentrated under reduced pressure, and passed through a silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain compound 239-2 (200 mg, 61% yield).

[0706] LC-MS (ESI+): 229.0 m / z [M+H] + .

[0707] Step 2: Preparation of 5-bromo-4-difluoromethylthiazol-2-amine (239-3)

[0708] At room temperature, 239-2 (100 mg, 0.44 mmol) and isoamyl nitrite (153 mg, 1.31 mmol) were dissolved in 2 mL of 1,4-dioxane (2 mL). The mixture was heated to 100°C with stirring for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (20 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 239-3 (14.5 mg, 15% yield).

[0709] LC-MS (ESI+): 214.0 m / z [M+H] + .

[0710] According to the procedure of step 3 of Example 226, 239-3 was used instead of 226-2 to obtain 2-amino-N'-cyclopropyl-N-((5-(4-(difluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)-3-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0711] LC-MS (ESI+): 559.0 m / z [M+H] + 。

[0712] 1 H NMR(400MHz,DMSO-d6)δ9.36–9.26(m,1H),8.67–8.54(m,3H),8.00–7.94(m,1H),7.87–7.80 (m,1H),7.72(d,J=1.7Hz,1H),7.61(s,1H),7.46–7.40(m,1H),7.34–7.23(m,1H),7.11(t,J= 53.2Hz,1H),7.03(t,J=4.8Hz,1H),6.52(s,2H),5.39(d,J=15.4Hz,1H),4.63(d,J=15.4Hz,1 H),2.80–2.72(m,1H),2.18(s,3H),0.82–0.65(m,1H),0.57–0.36(m,2H),0.20–0.06(m,1H).

[0713] Example 240: Preparation of 2-amino-N'-cyclopropyl-N-((5-(4-cyclopropylthiazol-5-yl)pyridin-2-yl)methyl)-3-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (240)

[0714] Step 1: Preparation of 5-bromo-4-cyclopropylthiazole (240-2)

[0715] At room temperature, 4-cyclopropylthiazole (240-1, 200 mg, 1.59 mmol) and NBS (369 mg, 2.07 mmol) were dissolved in N,N-dimethylformamide (10 mL), reacted at room temperature for 1 hour, and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 240-2 (300 mg, yield 92%). LC-MS (ESI+): 204.0 m / z [M+H] + .

[0716] According to the procedure of step 3 of Example 226, 240-2 was used instead of 226-2 to obtain 2-amino-N'-cyclopropyl-N-((5-(4-cyclopropylthiazol-5-yl)pyridin-2-yl)methyl)-3-methyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0717] LC-MS (ESI+): 549.2 m / z [M+H] + .

[0718] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.59(d,J=1.6Hz,1H),8.56(d,J=4.0Hz,2H),7.96-7.99(m ,1H),7.76(d,J=8.0Hz,1H),7.69(s,1H),7.58(s,1H),7.40(d,J=8.0Hz,1H),7.25(d,J=8.0Hz,1 H),6.97-6.99(m,1H),6.48(s,2H),5.32(d,J=16.0Hz,1H),4.63(d,J=16.0Hz,1H),2.76(s,1H), 2.15(s,3H),2.01-2.02(m,1H),0.93-0.97(m,4H),0.71(s,1H),0.42-0.48(m,2H),0.10(s,1H).

[0719] Example 241: Preparation of 2-amino-N-((5-(4-ethylthiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (241)

[0720] Step 1: Preparation of 5-bromo-4-ethylthiazol-2-amino (241-2)

[0721] 4-Ethylthiazol-2-amine (241-1, 500 mg, 3.90 mmol) and NBS (833 mg, 4.68 mmol) were dissolved in acetic acid (10 mL) at room temperature and reacted for 12 hours. Water (50 mL) was then added to dilute the mixture. The resulting mixture was extracted with ethyl acetate (50 mL x 3). 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 241-2 (800 mg, 99% yield).

[0722] LC-MS (ESI+): 207.0 m / z [M+H] + .

[0723] Step 2: Preparation of 5-bromo-4-ethylthiazole (241-3)

[0724] 241-2 (800 mg, 3.86 mmol) and tert-butyl nitrite (800 mg, 11.6 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature and reacted at 60°C for 12 hours. The mixture was then diluted with water (60 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to provide compound 241-3 (500 mg, 67% yield).

[0725] LC-MS (ESI+): 192.0 m / z [M+H] + .

[0726] According to the method of step 3 of Example 226, 241-3 was used instead of 226-2 to obtain 2-amino-N-((5-(4-ethylthiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide

[0727] LC-MS (ESI+): 511.2 m / z [M+H] + .

[0728] 1H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.57 (s, 1H), 8.38 (d, J = 4.0Hz, 2H), 7.88 (d,J=4.0Hz,1H),7.74(s,1H),7.69(s,2H),7.47(d,J=8.0Hz,1H),7.29(d,J=8 .0Hz,1H),6.77(s,1H),6.47(s,2H),5.37(d,J=16.0Hz,1H),4.54(d,J=16.0H z, 1H), 3.27 (s, 3H), 2.74 (q, J = 8.0Hz, 2H), 2.17 (s, 3H), 1.24 (t, J = 8.0Hz, 3H).

[0729] Example 242: Preparation of 2-amino-N-((5-(4-(fluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (242)

[0730] Step 1: Preparation of 5-bromo-4-(fluoromethyl)thiazole (242-1)

[0731] (5-Bromothiazol-4-yl)methanol (226-1, 100 mg, 0.515 mmol) was dissolved in DCM (5 mL) and DAST (249 mg, 1.54 mmol) was slowly added at -20°C. The reaction was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (3 x 10 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product 242-1, which was used directly in the next step.

[0732] LC-MS (ESI+): 196.2 m / z [M+H] + 。

[0733] According to the procedure of step 3 of Example 226, 242-1 was used instead of 226-2 to obtain 2-amino-N-((5-(4-(fluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0734] LC-MS (ESI+): 515.6 m / z [M+H] + .

[0735] 1H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.64(s,1H),8.39(d,J=4.8Hz,2H),8.17(s,1H),7.96(dd,J=8.1,2.4Hz,1H),7.77–7.67(m,2H),7.48(d,J=8. 8Hz,1H),7.30(d,J=8.6Hz,1H),6.76-6.79(m,1H),6.45(s,2H),5.52(s, 1H), 5.43–5.37 (m, 2H), 4.55 (d, J = 15.5Hz, 1H), 3.28 (s, 3H), 2.17 (s, 3H).

[0736] Example 243: Preparation of 2-amino-N-((5-(4-cyanothiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (243)

[0737] Step 1: Preparation of 5-bromothiazole-4-carboxamide (243-2)

[0738] Ethyl 5-bromothiazole-4-carboxylate (243-1, 2 g, 8.47 mmol) was dissolved in 20 mL of aqueous ammonia (20 mL) and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude product 243-2, which was used directly in the next step.

[0739] LC-MS (ESI+): 207.2 m / z [M+H] + 。

[0740] Step 2: Preparation of 5-bromothiazole-4-carbonitrile (243-3)

[0741] 243-2 (500 mg, 2.44 mmol) was dissolved in DCM (5 mL). TEA (1.24 g, 12.2 mmol) was added at 0°C, followed by the slow addition of TFAA (2.57 g, 12.2 mmol). The reaction was stirred at 0°C for 2 h. After completion of the reaction, the reaction mixture was diluted with an appropriate amount of water and extracted with DCM (3 x 20 mL). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude 243-3, which was used directly in the next step.

[0742] LC-MS (ESI+): 189.3 m / z [M+H] + .

[0743] According to the procedure of step 3 of Example 226, 243-3 was used instead of 226-2 to obtain 2-amino-N-((5-(4-cyanothiazol-5-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0744] LC-MS (ESI+): 508.6 m / z [M+H] + .

[0745] 1 H NMR (400MHz, DMSO-d6) δ9.35(s,1H),8.88(s,1H),8.40(d,J=4.7Hz,2H),8.21(dd,J=8.2,2.5Hz,1H),8.13(s,1H),7.86–7.79(m,3H),7. 55(d,J=8.6Hz,1H),7.37(d,J=8.6Hz,1H),6.86–6.76(m,2H),5.41(d,J=15.5Hz,1H),4.57(d,J=15.7Hz,1H),3.30(s,3H),2.20(s,3H).

[0746] Example 244: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(2-(trifluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (244)

[0747] Step 1: Preparation of 5-bromo-2-iodothiazole (244-2)

[0748] 5-Bromothiazol-2-amine (244-1, 1.0 g, 3.8 mmol) was dissolved in THF (10 mL), and diiodomethane (1.2 g, 4.6 mmol) and 3-methylbutyl nitrite (0.675 g, 5.76 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1) to obtain compound 244-2 (700 mg, 63% yield, yellow oil).

[0749] LC-MS (ESI+): 289.8 m / z [M+H] + .

[0750] Step 2: Preparation of 5-bromo-2-(trifluoromethyl)thiazole (244-3)

[0751] Compound 244-2 (0.2 g, 0.69 mmol) was dissolved in DMF (2 mL). Cuprous iodide (0.2 g, 1.03 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.2 g, 1.03 mmol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 70°C for 12 hours. Water (20 mL) was added to the reaction solution, 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 to obtain compound 244-3 (100 mg, 62% yield, as a yellow oil).

[0752] According to the procedure of step 3 of Example 226, 244-3 was used instead of 226-2 to obtain 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(2-(trifluoromethyl)thiazol-5-yl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0753] LC-MS (ESI+): 551.3 m / z [M+H] + .

[0754] Example 245: Preparation of N-((5-(2H-tetrazol-5-yl)pyridin-2-yl)methyl)-2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (245)

[0755] Step 1: Preparation of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole (245-2)

[0756] 5-Bromo-2H-tetrazole (245-1, 0.2 g, 1.34 mmol) was dissolved in DMF (5 mL). Sodium hydroxide (60%, 80 mg, 2.01 mmol) was added at 0°C. After stirring for half an hour, 2-(trimethylsilyl)ethoxymethyl chloride (0.22 g, 1.34 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. Water (100 mL) was added to the reaction solution, 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 to obtain compound 245-2 (mixture of isomers, 200 mg, 53% yield, as a yellow oil).

[0757] LC-MS (ESI+): 279.1m / z[M+H] + .

[0758] The remaining steps were carried out according to the method of step 3 of Example 226 and step 5 of Example 119 to synthesize the compound N-((5-(2H-tetrazol-5-yl)pyridin-2-yl)methyl)-2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0759] LC-MS (ESI+): 468.3 m / z [M+H] + .

[0760] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.41(d,J=4.8Hz,2H),8.36(dd,J=8.0,2.4Hz,1H),7.82(d,J=10.8Hz,2H),7.76(d,J=8.0Hz,1H),7.55(d,J =8.8Hz,1H),7.38(d,J=8.8Hz,1H),6.95(s,2H),6.79(t,J=4.8Hz,1H),5 .45(d,J=15.2Hz,1H), 4.52(d,J=15.2Hz,1H), 3.22(s,3H), 2.20(s,3H).

[0761] Example 246: Preparation of 2-amino-N-((6'-((2-hydroxyethyl)(methyl)amino)-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (246)

[0762] Step 1: Preparation of 2-amino-N-((6'-((2-hydroxyethyl)(methyl)amino)-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (246)

[0763] At room temperature, 2-amino-N-((6'-fluoro-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (246-1, synthesized according to Example 137) (80 mg, 0.16 mmol) and 2-(methylamino)ethanol (0.05 mL) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (45 mg, 0.32 mmol) was added. The reaction mixture was heated to 80°C and stirred for 22 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (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 preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to afford compound 246 (24 mg, 26% yield). LC-MS (ESI+): 550.3 m / z [M+H] + .

[0764] The following compounds were prepared according to the synthesis method of Example 246 using the corresponding starting materials:

[0765] Example 248: Preparation of 4-amino-N',1-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide (248)

[0766] Step 1: Preparation of tert-butyl 2-methyl-2-(pyrimidin-2-yl)-1-((5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)hydrazine-1-carboxylate (248-1)

[0767] Compound 137-5 (700 mg, 1.78 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (930 mg, 3.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (114 mg, 0.18 mmol), and potassium carbonate (490 mg, 3.55 mmol) were dissolved in dioxane (10 mL) and water (2 mL) at room temperature. The mixture was 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). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 248-1 (670 mg, yield 84%).

[0768] LC-MS (ESI+): 450.2 m / z [M+H] + .

[0769] According to steps 4-5 of Example 137, 248-1 was used instead of 137-4 to synthesize 4-amino-N', 1-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide.

[0770] LC-MS (ESI+): 574.2 m / z [M+H] + .

[0771] 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.93(s,1H),8.57(s,1H),8.48(s,2H),8.22(m,1H),8.16-8.14(m,2H),7.65(s, 2H), 7.50 (s, 1H), 7.18 (s, 2H), 6.85 (s, 1H), 5.44 (d, J = 16.0Hz, 1H), 4.53 (d, J = 16.0Hz, 1H), 4.12 (s, 3H), 3.17 (s, 3H).

[0772] The following compounds were prepared according to the synthesis method of Example 248 using the corresponding starting materials:

[0773] Example 254: Preparation of 2-amino-N-((6'-((2-methoxyethyl)(methyl)amino)-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (254)

[0774] Step 1: Preparation of N-(2-methoxyethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (254-2)

[0775] 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (254-1, 500 mg, 2.25 mmol), 2-methoxy-N-methylethane-1-amine (401 mg, 4.50 mmol), and potassium carbonate (939 mg, 6.76 mmol) were dissolved in N,N-dimethylformamide (8 mL), and the reaction mixture was stirred at 100°C for 10 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) to obtain compound 254-2 (300 mg, 45% yield).

[0776] LC-MS (ESI+): 293.2 m / z [M+H] + .

[0777] According to step 7 of Example 137, 2-amino-N-((6'-((2-methoxyethyl)(methyl)amino)-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide was synthesized by replacing 2-methoxy-6-methylpyridin-3-yl)boronic acid with 254-2.

[0778] LC-MS (ESI+): 564.3 m / z [M+H] + .

[0779] 1 H NMR(400MHz,DMSO-d6)δ8.82–8.70(m,1H),8.47(s,1H),8.45–8.37(m,2H),8.27(s,1H),8.04–7.97(m, 1H),7.92–7.84(m,1H),7.73(s,1H),7.69(s,1H),7.62–7.54(m,1H),7.50–7.41(m,1H),7.30(d,J=8.6 Hz,1H),6.80–6.76(m,1H),6.76–6.71(m,1H),6.45(s,2H),5.43(d,J=14.8Hz,1H),4.43(d,J=14.8Hz, 1H),3.74(t,J=5.6Hz,2H),3.52(t,J=5.8Hz,2H),3.26(s,3H),3.20(s,3H),3.07(s,3H),2.17(s,3H).

[0780] The following compounds were prepared according to the synthesis method of Example 254 using the corresponding starting materials:

[0781] Example 260: Preparation of 2-amino-N-((6'-((2-(dimethylamino)ethyl)(methyl)amino)-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (260)

[0782] Step 1: Preparation of 2-amino-N-((6'-((2-(dimethylamino)ethyl)(methyl)amino)-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (260)

[0783] At room temperature, 2-amino-N-((6'-fluoro-[3,3'-bipyridyl]-6-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-hydrazide (260-1, synthesized according to the method of Example 137) (100 mg, 0.20 mmol), N 1 ,N 1 ,N 2 -Trimethylethane-1,2-diamine (55 mg, 0.61 mmol) and potassium carbonate (75 mg, 0.61 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction solution was stirred at 80 ° C for 12 hours. Water (20 mL) was added to the reaction solution to quench it, and then extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by high-performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 260 (27.5 mg, yield 26%).

[0784] LC-MS (ESI+): 577.2 m / z [M+H] + .

[0785] 1H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.50–8.38(m,3H),8.01(d,J=8.4Hz,1H),7.92–7.85(m ,1H),7.71(d,J=14.8Hz,2H),7.58(d,J=8.0Hz,1H),7.46(d,J=8.8Hz,1H),7.30(d,J=8.8Hz ,1H),6.80–6.70(m,2H),6.46(s,2H),5.43(d,J=15.2Hz,1H),4.43(d,J=15.2Hz,1H),3.70( t,J=6.8Hz,2H),3.20(s,3H),3.05(s,3H),2.53(d,J=7.2Hz,2H),2.26(s,6H),2.17(s,3H).

[0786] The following compounds were prepared according to the synthesis method of Example 260 using the corresponding starting materials:

[0787] Example 262: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl)methyl)quinoline-6-carbohydrazide (262)

[0788] Step 1: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl)methyl)quinoline-6-carbohydrazide (262)

[0789] At room temperature, tert-butyl 6-((1-(2-amino-3-methylquinoline-6-carbonyl)-2-methyl-2-(pyrimidin-2-yl)hydrazine)methyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (262-1, synthesized according to the route of Example 137) (50 mg, 0.09 mmol) was dissolved in 3 mL of dichloromethane. 4 M hydrochloric acid solution in dioxane (1 mL) was added, and the mixture was reacted at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to obtain compound 262 (10 mg, 24% yield).

[0790] LC-MS (ESI+): 481.2 m / z [M+H] + .

[0791] Example 263: Preparation of 2-amino-N-((5-iodopyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (263)

[0792] Step 1: Preparation of (5-iodopyridin-2-yl)methanol (263-2)

[0793] Methyl 5-iodopicolinate (262-1, 900 mg, 3.42 mmol) was dissolved in methanol (10 mL) at room temperature, and sodium borohydride (195 mg, 5.1 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours. 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, and filtered. The organic phase was concentrated to dryness under reduced pressure to obtain compound 263-2 (800 mg, 99% yield).

[0794] LC-MS (ESI+): 236.0 m / z [M+H] + .

[0795] Step 2: Preparation of (5-iodopyridin-2-yl)methylmethanesulfonic acid (263-3)

[0796] At room temperature, 263-2 (800 mg, 3.4 mmol) and diisopropylethylamine (0.8 mL) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (0.4 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound 263-3 (800 mg, yield 75%).

[0797] LC-MS (ESI+): 314.1m / z[M+H] + .

[0798] Step 3: Preparation of tert-butyl 1-((5-iodopyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazinecarboxylate (263-4)

[0799] 137-3 (573 mg, 2.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (122 mg, 5.1 mmol) was added at 0°C, and the mixture was stirred for 0.5 hours. Compound 263-3 (800 mg, 2.5 mmol) was added to the reaction solution. 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 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain compound 263-4 (1100 mg, yield 97%).

[0800] LC-MS (ESI+): 442.2 m / z [M+H] + .

[0801] According to steps 4 and 5 of Example 137, 2-amino-N-((5-iodopyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide was obtained by substituting compound 263-4 for compound 137-4.

[0802] LC-MS (ESI+): 526.2 m / z [M+H] + .

[0803] 1 H NMR(400MHz, DMSO-d6)δ8.73(s,1H),8.39(d,J=3.6Hz,2H),8.18-8.15(m,1H),7.69(d,J=12.0Hz,2H),7.44(d,J=7.2Hz,2H),7 .29(d,J=8.4Hz,1H),6.82-6.75(m,1H),6.45(s,2H),5.31(d,J=15.2Hz,1H),4.39(d,J=15.2Hz,1H),3.19(s,3H),2.17(s,3H).

[0804] The following compounds were prepared according to the synthesis method of Example 263 using the corresponding starting materials:

[0805] Example 282: 2-Amino-N-((5-bromopyrazin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (282)

[0806] Step 1: Preparation of 2-bromo-5-(bromomethyl)pyrazine (282-2)

[0807] 2-Bromo-5-methylpyrazine (282-1, 500 mg, 2.89 mmol) was dissolved in carbon tetrachloride (10 mL). NBS (566 mg, 3.18 mmol) and AIBN (24 mg, 0.14 mmol) were added sequentially. After replacing the nitrogen atmosphere, the resulting mixture was stirred at 75°C for 16 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 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 silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound 282-2 (100 mg, 14% yield, as a yellow oil).

[0808] LC-MS(ESI+):250.9, 252.9m / z[M+H] + .

[0809] Compound 282 was synthesized according to the method of Example 263, using compound 282-2 instead of 263-3 to obtain 2-amino-N-((5-bromopyrazin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0810] LC-MS (ESI+): 479.1m / z[M+H] + .

[0811] The following compounds were prepared according to the synthesis method of Example 282 using the corresponding starting materials:

[0812] Example 284: Synthesis of 2-amino-N-((5-(3-methoxyoxetane-3-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (284)

[0813] Step 1: Preparation of 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (284-1)

[0814] At room temperature, (5-bromopyridin-2-yl)methanol (137-1, 5 g, 26.6 mmol) and imidazole (3.62 g, 53.2 mmol) were dissolved in dichloromethane (100 mL), and tert-butyldimethylsilyl chloride (4.2 g, 27.9 mmol) was added. The reaction solution was stirred at 25 ° C for 2 hours. Water (20 mL) was added to the reaction solution to quench it, and then extracted with dichloromethane (50 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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound 284-1 (8 g, yield 99%).

[0815] LC-MS (ESI+): 302.1m / z[M+H] + .

[0816] Step 2: Preparation of 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxetane-3-ol (284-2)

[0817] 284-1 (4 g, 13.2 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). The reaction solution was cooled to -78°C and n-butyllithium (8 mL, 2.5 M) was added dropwise. The reaction solution was stirred at -78°C for 1 hour. Oxetane-3-one (1.43 g dissolved in 5 mL tetrahydrofuran) was added to the reaction solution. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride (50 mL) and then extracted with dichloromethane (50 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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound 284-2 (1.2 g, yield 30%).

[0818] LC-MS (ESI+): 296.1m / z[M+H] + .

[0819] Step 3: Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(3-methoxyoxetan-3-yl)pyridine (284-3)

[0820] 284-2 (1.2 g, 4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (60%, 195 mg, 8 mmol) was added at 0°C and stirred for 0.5 hours. Iodomethane (0.5 mL) was added to the reaction solution. The reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution to quench it, and then extracted with ethyl acetate (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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain compound 284-3 (900 mg, yield 71%).

[0821] LC-MS (ESI+): 310.2 m / z [M+H] + .

[0822] Step 4: Preparation of (5-(3-methoxyoxetane-3-yl)pyridin-2-yl)methanol (284-4)

[0823] At room temperature, compound 284-3 (900 mg, 2.9 mmol) was dissolved in dichloromethane (10 mL), and tetrabutylammonium fluoride (5 mL, 1 M) 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 dichloromethane (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 crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to afford compound 284-4 (500 mg, 88% yield).

[0824] LC-MS (ESI+): 196.1m / z[M+H] + .

[0825] According to the method of Example 263, compound 284-4 was used instead of compound 263-2 to obtain 2-amino-N-((5-(3-methoxyoxetan-3-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0826] LC-MS (ESI+): 486.2 m / z [M+H] + .

[0827] Example 285: Preparation of 2-amino-N-((5-(3-hydroxyoxetane-3-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (285)

[0828] Step 1: Preparation of 3-(6-(hydroxymethyl)pyridin-3-yl)oxetane-3-ol (285-1)

[0829] Compound 284-2 (400 mg, 1.3 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and tetrabutylammonium fluoride (1.6 mL, 1 M THF solution) was added. The reaction mixture was stirred at 25°C for 1 hour. The resulting crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to afford compound 285-1 (200 mg, 81% yield).

[0830] LC-MS (ESI+): 182.1m / z[M+H] + .

[0831] According to the method of Example 263, compound 285-1 was used instead of compound 263-2 to obtain 2-amino-N-((5-(3-hydroxyoxetan-3-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0832] LC-MS (ESI+): 472.2 m / z [M+H] + .

[0833] Example 286: Preparation of 2-amino-N-((5-(3-fluorooxetane-3-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (286)

[0834] Step 1: Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(3-fluorooxetan-3-yl)pyridine (286-1)

[0835] Compound 284-2 (300 mg, 1 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and diethylaminosulfur trifluoride (0.2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated to dryness under reduced pressure to provide compound 286-1 (300 mg, 99% yield).

[0836] LC-MS (ESI+): 298.2 m / z [M+H] + .

[0837] According to the method of Example 285, 286-1 was used instead of 284-2 to synthesize 2-amino-N-((5-(3-fluorooxetane-3-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0838] LC-MS (ESI+): 474.2 m / z [M+H] + .

[0839] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.42(d,J=4.0Hz,2H),8.00(d,J=7.2Hz,1H),7.75-7.71(m,3H),7.48(d,J=8.4Hz,1H),7.32(d,J=8.4Hz ,1H),6.80(t,J=4.4Hz,1H),6.51(s,2H),5.43(d,J=15.2Hz,1H),5.03 (s,2H),4.98(s,2H),4.50(d,J=15.2Hz,1H),3.24(s,3H),2.19(s,3H).

[0840] The following compounds were prepared according to the synthesis method of Example 286 using the corresponding starting materials:

[0841] Example 289: Preparation of 2-amino-N-((5-cyclobutylpyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (289)

[0842] Step 1: Preparation of (5-(cyclobut-1-en-1-yl)pyridin-2-yl)methanol (289-2)

[0843] At room temperature, compound 289-1 (synthesized according to the method of Example 284) (300 mg, 1 mmol) was dissolved in toluene (5 mL), and p-toluenesulfonic acid (352 mg, 2 mmol) was added. The reaction solution was heated to 100°C and stirred for 2 hours. Water (20 mL) was added to the reaction solution, which was then quenched and extracted with dichloromethane (50 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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain compound 289-2 (60 mg, 36% yield).

[0844] LC-MS (ESI+): 162.1m / z[M+H] + .

[0845] Step 2: Preparation of (5-cyclobutylpyridin-2-yl)methanol (289-3)

[0846] Palladium on carbon (20 mg, 5%) was added to 289-2 (5 mL) at room temperature, and the reaction solution was replaced with hydrogen three times. The reaction solution was stirred at 25°C under a hydrogen atmosphere for 2 hours. After the reaction was completed, the palladium on carbon was filtered, and the organic phase was concentrated to dryness under reduced pressure to obtain compound 289-3 (240 mg, 99% yield).

[0847] LC-MS (ESI+): 164.2 m / z [M+H] + .

[0848] According to the method of Example 263, 289-3 was used instead of 263-2 to synthesize 2-amino-N-((5-cyclobutylpyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0849] LC-MS (ESI+): 454.2 m / z [M+H] + .

[0850] 1 H NMR (400MHz, DMSO-d6) δ8.49–8.36(m,3H),7.71(m,3H),7.57–7.24(m,3H),6.79(t,J=4.4Hz,1H),6.50(s,2H),5.4 1(d,J=14.8Hz,1H),4.38(d,J=14.8Hz,1H),3.15(s,3H),2.35-2.29(m,2H),2.23–1.95(m,7H),1.89–1.79(m,1H).

[0851] Example 290: Preparation of 2-amino-N-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (290)

[0852] Step 1: Preparation of tert-butyl 1-((5-acetylpyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazinecarboxylate (290-1)

[0853] At room temperature, 137-4 (500 mg, 1.2 mmol) and tributyl(1-ethoxyvinyl)tin (0.8 mL) were dissolved in dry 1,4-dioxane (10 mL), and tetrakistriphenylphosphine palladium (146 mg, 0.12 mmol) was added. The reaction mixture was purged with nitrogen three times and then heated to 100°C under a nitrogen atmosphere and stirred for 12 hours. After completion of the reaction, the mixture was quenched with 1N hydrochloric acid (5 mL) and extracted with ethyl acetate (30 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 crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to afford compound 290-1 (400 mg, 88% yield).

[0854] LC-MS (ESI+): 358.2 m / z [M+H] + .

[0855] Step 2: Preparation of tert-butyl 2-methyl-1-((5-(2-methoxy-2-yl)pyridin-2-yl)methyl)-2-(pyrimidin-2-yl)hydrazinecarboxylate (290-2)

[0856] At room temperature, trimethylsulfoxide iodide (492 mg, 2.2 mmol) and potassium tert-butoxide (251 mg, 2.2 mmol) were dissolved in dry tetrahydrofuran (10 mL), heated to 50°C, and stirred for 0.5 hours. Compound 290-1 (200 mg, 0.56 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 extracted with ethyl acetate (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 crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 290-2 (100 mg, 48% yield).

[0857] LC-MS (ESI+): 372.2 m / z [M+H] + .

[0858] Step 3: Preparation of tert-butyl 1-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazinecarboxylate (290-3)

[0859] At room temperature, 290-2 (90 mg, 0.24 mmol) was dissolved in ethanol (2 mL) and sodium borohydride (18 mg, 0.48 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 it, 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 290-3 (70 mg, yield 77%).

[0860] LC-MS (ESI+): 374.4 m / z [M+H] + .

[0861] Step 4: Preparation of 2-(6-((2-methyl-2-(pyrimidin-2-yl)hydrazine)methyl)pyridin-3-yl)propan-2-ol (290-4)

[0862] At room temperature, 290-3 (70 mg, 0.18 mmol) was dissolved in dry dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour until the starting material disappeared. The reaction mixture was concentrated to dryness under reduced pressure to give compound 290-4 (50 mg, yield 97%).

[0863] LC-MS (ESI+): 274.2 m / z [M+H] + .

[0864] Step 5: Preparation of 6-bromo-3-trifluoromethylquinoline (290-5)

[0865] At room temperature, 290-4 (20 mg, 0.07 mmol) and 2-amino-3-methylquinoline-6-carbonyl chloride (16 mg, 0.07 mmol) were dissolved in dry N,N-dimethylacetamide (1 mL), and diisopropylethylamine (0.1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The crude product was separated by HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 290 (2.9 mg, 8% yield).

[0866] LC-MS (ESI+): 458.3 m / z [M+H] + .

[0867] Example 291: Preparation of 2-amino-N-((5-(1,1-difluoroethyl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (291)

[0868] Step 1: Preparation of tert-butyl 1-((5-(1,1-difluoroethyl)pyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazinecarboxylate (291-1)

[0869] At room temperature, 290-1 (300 mg, 0.84 mmol) was dissolved in dichloromethane (5 mL) and diethylaminosulfur trifluoride (0.4 mL) was added. The reaction solution was stirred at 25 ° C for 36 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution to quench it, 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound 291-1 (100 mg, yield 31%).

[0870] LC-MS (ESI+): 380.4 m / z [M+H] + .

[0871] According to steps 4 and 5 of Example 290, 291-1 was used instead of 290-3 to synthesize 2-amino-N-((5-(1,1-difluoroethyl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0872] LC-MS (ESI+): 464.2 m / z [M+H] + .

[0873] 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.41(d,J=4.4Hz,2H),8.01(d,J=6.4Hz,1H),7.81–7.67(m,3H),7.48(d,J=8.0Hz,1H),7.32(d,J=8.8H z,1H),6.81(t,J=4.4Hz,1H),6.51(s,2H),5.42(d,J=15.2Hz,1H),4.53(d,J=15.2Hz,1H),3.27(s,3H),2.19(s,3H),2.04(t,J=19.2Hz,3H).

[0874] Example 292: Preparation of 2-amino-N-((5-(1-fluoroethyl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (292)

[0875] Step 1: Preparation of tert-butyl 1-((5-(1-hydroxyethyl)pyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazinecarboxylate (292-1)

[0876] At room temperature, compound 290-1 (200 mg, 0.56 mmol) was dissolved in methanol (2 mL), and sodium borohydride (42 mg, 1.1 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, and filtered. The organic phase was concentrated to dryness under reduced pressure to obtain compound 292-1 (200 mg, 99% yield).

[0877] LC-MS (ESI+): 360.2 m / z [M+H] + .

[0878] Step 2: Preparation of tert-butyl 1-((5-(1-fluoroethyl)pyridin-2-yl)methyl)-2-methyl-2-(pyrimidin-2-yl)hydrazinecarboxylate (292-2)

[0879] At room temperature, 292-1 (200 mg, 0.55 mmol) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (0.2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, which was 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound 292-2 (100 mg, yield 49%).

[0880] LC-MS (ESI+): 362.4 m / z [M+H] + .

[0881] According to steps 4 and 5 of Example 290, 292-2 was used instead of 290-3 to synthesize 2-amino-N-((5-(1-fluoroethyl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0882] LC-MS (ESI+): 446.2 m / z [M+H] + .

[0883] 1H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.39(d,J=4.0Hz,2H),7.84(d,J=8.0Hz,1H),7.70(d,J=13 .6Hz,2H),7.61(d,J=8.0Hz,1H),7.45(d,J=8.4Hz,1H),7.29(d,J=8.4Hz,1H),6.78(t,J=4.0Hz 1H), 6.47 (s, 2H), 5.88-5.72 (m, 1H), 5.40 (d, J = 15.2Hz, 1H), 4.44 (d, J = 15.2Hz, 1H), 3.19 (s, 3H), 2.17 (s, 3H), 1.62 (dd, J = 24.0, 6.4Hz, 3H).

[0884] Example 293: Preparation of 2-amino-N',3-dimethyl-N-((5-(perfluoroethyl)pyridin-2-yl)methyl)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (293)

[0885] Step 1: Preparation of tert-butyl 2-methyl-1-((5-(perfluoroethyl)pyridin-2-yl)methyl)-2-(pyrimidin-2-yl)hydrazinecarboxylate (293-1)

[0886] Compound 263-4 (100 mg, 0.22 mmol), cuprous iodide (86 mg, 0.45 mmol), and (pentafluoroethyl)trimethylsilane (0.1 mL) were dissolved in dry N,N-dimethylformamide (1 mL) at room temperature, and potassium fluoride (39.4 mg, 0.67 mmol) was added. The reaction mixture was purged with nitrogen three times and then heated to 80°C under a nitrogen atmosphere and stirred for 12 hours. After completion of the reaction, the mixture was quenched with water (10 mL) 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 to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to afford compound 293-1 (60 mg, 61% yield).

[0887] LC-MS (ESI+): 434.2 m / z [M+H] + .

[0888] Following steps 4 and 5 of Example 290, substituting 293-1 for 290-3, 2-amino-N',3-dimethyl-N-((5-(perfluoroethyl)pyridin-2-yl)methyl)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide was obtained.

[0889] LC-MS (ESI+): 518.2 m / z [M+H] +.

[0890] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.37(d,J=4.0Hz,2H),8.17(d,J=6.8Hz,1H),7.89(d,J=8.0Hz,1H),7.75(s,1H),7.69(s,1H),7.48(d,J=8 .4Hz,1H),7.30(d,J=8.4Hz,1H),6.76(t,J=8.4Hz,1H),6.47(s,2H),5.36(d,J=15.6Hz,1H),4.67(d,J=15.6Hz,1H),3.31(s,3H),2.18(s,3H).

[0891] Example 294: Preparation of N-((5-acetylpyridin-2-yl)methyl)-2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (294)

[0892] Compound 290-1 was synthesized according to steps 4 and 5 of Example 137, replacing 137-4 with compound 290-1 to obtain N-((5-acetylpyridin-2-yl)methyl)-2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0893] LC-MS (ESI+): 442.2 m / z [M+H] + .

[0894] Example 295: Preparation of 2-amino-N-((5-(1-hydroxyethyl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (295)

[0895] Step 1: Preparation of 2-amino-N-((5-(1-hydroxyethyl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (295)

[0896] 294 (50 mg, 0.11 mmol) was dissolved in methanol (1 mL) and sodium borohydride (4 mg, 0.11 mmol) was added. The reaction solution was stirred at 0°C for 1 hour. Water (10 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The crude product was separated by reverse-phase high-performance liquid chromatography (mobile phase: water / acetonitrile = 95% / 5%-10% / 90%) to give compound 295 (2.2 mg, yield 4%).

[0897] LC-MS (ESI+): 444.3 m / z [M+H] + .

[0898] Example 296: Preparation of 2-amino-N'-(5-(dimethylphosphoryl)pyrimidin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (296)

[0899] Step 1: Preparation of 2-amino-N'-(5-(dimethylphosphoryl)pyrimidin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (296)

[0900] Compound 267 (50.0 mg, 0.08 mmol) was dissolved in 1,4-dioxane (2 mL) in a sealed tube. Dimethylphosphine oxide (7.00 mg, 0.08 mmol), Pd2(dba)3 (8 mg, 0.008 mmol), Xantphos (10 mg, 0.016 mmol), and potassium phosphate (36 mg, 0.17 mmol) were added sequentially. After replacing the nitrogen atmosphere, the resulting mixture was stirred at 100°C for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 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 preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to afford compound 296 (7.8 mg, 17% yield, as a white solid).

[0901] LC-MS (ESI+): 544.3m / z[M+H] + .

[0902] Example 297: Preparation of 2-amino-N-((5-(dimethylphosphoryl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (297)

[0903] According to the method of step 1 of Example 296, 137-6 was used to replace 267 to synthesize 2-amino-N-((5-(dimethylphosphoryl)pyridin-2-yl)methyl)-N',3-dimethyl-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide.

[0904] LC-MS (ESI+): 476.6 m / z [M+H] + .

[0905] Example 298: Preparation of 2-amino-N'-(3-cyanopyridin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (298)

[0906] Step 1: Preparation of tert-butyl 2-(3-cyanopyridin-2-yl)-2-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carboxylate (298-2)

[0907] Compound 298-1 (synthesized according to the method of Example 263) (90 mg, 0.19 mmol), zinc hydride (46 mg, 0.39 mmol), and di(tri-tert-butylphosphine)palladium (10 mg, 0.02 mmol) were dissolved in N-methylpyrrolidone (5 mL) at room temperature and reacted at 130°C for 12 hours. The mixture was then diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). 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 (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide compound 298-2 (80 mg, 100% yield).

[0908] LC-MS (ESI+): 408.2 m / z [M+H] + .

[0909] According to steps 4 and 5 of Example 290, 298-2 was used instead of 290-3 to synthesize 2-amino-N'-(3-cyanopyridin-2-yl)-N',3-dimethyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0910] LC-MS (ESI+): 492.2 m / z [M+H] + .

[0911] Example 299: Preparation of (2-(2-(2-amino-3-methylquinoline-6-carbonyl)-1-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazino)pyrimidin-5-yl)boronic acid (299)

[0912] According to the method of step 2 of Example 226, compound 267 was used instead of 137-6 to synthesize 2-(2-(-2-amino-3-methylquinoline-6-carbonyl)-1-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazino)pyrimidin-5-yl)boronic acid.

[0913] LC-MS (ESI+): 512.2 m / z [M+H]+

[0914] Example 300: Preparation of 4-amino-N',1-dimethyl-N'-(pyrimidin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide (300)

[0915] Step 1: Preparation of 3-bromo-N'-methyl-4-nitro-N'-(pyrimidin-2-yl)benzohydrazide (300-2)

[0916] At room temperature, 3-bromo-4-nitrobenzoic acid (300-1) (400 mg, 1.63 mmol) was dissolved in 6 mL of dimethylacetamide, and 1-4 (202 mg, 1.63 mmol), N,N-diisopropylethylamine (494 mg, 4.89 mmol), and tripyrrolidinylphosphonium bromide hexafluorophosphate (1.14 g, 2.45 mmol) were added. The reaction was allowed to react at room temperature overnight 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-5%). Concentration under reduced pressure gave compound 300-2 (300 mg, yield 58.4%).

[0917] LC-MS (ESI+): 352.0 m / z [M+H] + .

[0918] Step 2: Preparation of 3-bromo-N'-methyl-4-nitro-N'-(pyrimidin-2-yl)-N-(4-(trifluoromethyl)benzyl)benzohydrazide (300-3)

[0919] At room temperature, 300-2 (270 mg, 0.77 mmol) was dissolved in 6 mL of DMF, and cesium carbonate (747 mg, 2.30 mmol) and 1-bromomethyl-4-trifluoromethylbenzene (366 mg, 1.53 mmol) were added. Under a nitrogen atmosphere, the reaction was allowed to proceed at 50°C overnight. The reaction mixture was added to water to quench the reaction, and then extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-5%). Concentration under reduced pressure gave compound 300-3 (240 mg, 44% yield).

[0920] LC-MS (ESI+): 510.0 m / z [M+H] + .

[0921] Step 3: Preparation of 4-amino-3-bromo-N'-methyl-N'-(pyrimidin-2-yl)-N-(4-(trifluoromethyl)benzyl)benzohydrazide (300-4)

[0922] At room temperature, 300-3 (240 mg, 0.47 mmol) was dissolved in 3 mL of ethanol and 3 mL of saturated aqueous ammonium chloride solution, and iron powder (132 mg, 2.35 mmol) was added. The reaction was allowed to react at 80°C for 2 hours. The reaction mixture was filtered through celite, rinsed with ethanol, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-5%). Concentration under reduced pressure afforded compound 300-4 (220 mg, 97% yield).

[0923] LC-MS (ESI+): 480.0 m / z [M+H] + .

[0924] Step 4: Preparation of 4-amino-N'-methyl-N'-(pyrimidin-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)benzyl)benzohydrazide (300-5)

[0925] At room temperature, 300-4 (140 mg, 0.47 mmol) was dissolved in 3 mL of dioxane, and bis-pinacol boronate (370 mg, 1.46 mmol), potassium acetate (85.70 mg, 0.87 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (21 mg, 0.03 mmol) were added. The reaction was allowed to proceed at 90°C overnight under a nitrogen atmosphere. The reaction was cooled to room temperature and used directly in the next step without treatment. LC-MS (ESI+): 528.2 m / z [M+H] + .

[0926] Step 5: Preparation of 4-amino-N',1-dimethyl-N'-(pyrimidin-2-yl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazolo[4,3-c]quinoline-8-carbohydrazide (300)

[0927] To the reaction mixture from the previous step were added 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (59 mg, 0.32 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (21 mg, 0.03 mmol), 0.5 mL of water, and potassium carbonate (108 mg, 0.78 mmol) at room temperature. The reaction was allowed to proceed overnight at 90°C under a nitrogen atmosphere. The reaction mixture was filtered through celite and extracted with ethyl acetate (30 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to afford compound 300 (1.2 mg, 2.1% yield).

[0928] LC-MS (ESI+): 507.2 m / z [M+H] + .

[0929] Example 301: Preparation of 2-amino-3-methyl-6-(2-methyl-2-(pyrimidin-2-yl)-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carbonyl)quinoline 1-oxide (301)

[0930] Step 1: Preparation of 2-amino-3-methyl-6-(2-methyl-2-(pyrimidin-2-yl)-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carbonyl)quinoline 1-oxide (301)

[0931] Compound 1 (100 mg, 0.21 mmol) was dissolved in DCM (10 mL), and m-chloroperbenzoic acid (51 mg, 0.11 mmol) was added, and the resulting mixture was stirred at 20°C for 2 hours. DCM (20 mL) was added to the reaction solution, and the mixture was washed with aqueous sodium bicarbonate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 301 (38 mg, 37% yield, white solid).

[0932] LC-MS (ESI+): 484.2 m / z [M+H] + .

[0933] The following compounds were prepared according to the synthesis method of Example 301 using the corresponding starting materials:

[0934] Example 303: Preparation of 2-amino-3-bromo-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (303)

[0935] According to the method of step 3-5 of Example 26, 25-3 was used to replace 26-2 to synthesize 2-amino-3-bromo-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0936] LC-MS (ESI+): 532.0 m / z [M+H] + .

[0937] 1 H NMR(400MHz, DMSO-d6)δ8.90(s,1H),8.41–8.38(m,3H),8.21(d,J=8.0Hz,1H),7.87–7.80(m,2H),7.57(d,J=8.0Hz,1H ),7.35(d,J=12.0Hz,1H),6.86(s,2H),6.82–6.75(m,1H),5.39(d,J=16.0Hz,1H),4.60(d,J=16.0Hz,1H),3.30(s,3H).

[0938] Example 304: Preparation of 2-amino-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3-vinylquinoline-6-carbohydrazide (304)

[0939] According to the method of step 1 of Example 26, vinyl borate was used instead of isopropylene borate, and compound 303 was used to replace 25-3 to synthesize compound 304.

[0940] LC-MS (ESI+): 480.2 m / z [M+H] + .

[0941] Example 305: Preparation of 2-amino-3-ethyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (305)

[0942] According to the method of step 2 of Example 26, compound 304 was used to replace 26-1 to synthesize 2-amino-3-ethyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[0943] LC-MS (ESI+): 482.2 m / z [M+H] + .

[0944] 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.39(d,J=4.0Hz,2H),8.20(d,J=4.0H z,1H),7.85(d,J=8.0Hz,1H),7.79(s,1H),7.68(s,1H),7.46(d,J=8.0Hz,1H ),7.29(d,J=8.0Hz,1H),6.78(s,1H),6.44(s,2H),5.40(d,J=16.0Hz,1H), 4.58(d,J=16.0Hz,1H),,3.29(s,3H),2.58-2.52(m,2H),1.23-1.18(m,3H).

[0945] Example 306: Preparation of 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,7-naphthyridine-6-carbohydrazide (306)

[0946] Step 1: Preparation of (E)-methyl 4-(2-(dimethylamino)vinyl)-5-nitropyridinecarboxylate (306-2): Methyl 4-methyl-5-nitropyridinecarboxylate (306-1, 2.50 g, 12.74 mmol) and 1,1-dimethoxy-N,N-dimethylamine (3.04 g, 25.49 mmol) were dissolved in N-methylformamide (30 mL) at room temperature and reacted at 90°C for 6 hours. The mixture was then diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (300 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 = 1 / 1) to obtain compound 306-2 (2.50 g, yield 78%).

[0947] LC-MS (ESI+): 252.0 m / z [M+H] + .

[0948] Step 2: Preparation of methyl 4-formyl-5-nitropyridinecarboxylate (306-3)

[0949] 306-2 (3.50 g, 13.9 mmol) and sodium periodate (6.02 g, 27.9 mmol) were dissolved in tetrahydrofuran (30 mL) and water (10 mL) at room temperature. The mixture was reacted at room temperature for 12 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 (100 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 = 10 / 1) to give compound 306-3 (2.60 g, yield 88%).

[0950] LC-MS (ESI+): 211.0 m / z [M+H] + .

[0951] Step 3: Preparation of 5-amino-4-formaldehyde pyridinecarboxylic acid methyl ester (306-4)

[0952] At room temperature, 306-3 (2.00 g, 9.52 mmol), iron powder (1.06 g, 19.0 mmol), and hydrochloric acid (19.0 mmol) were dissolved in a solution of ethanol (20 mL) and water (10 mL). The mixture was reacted at 80°C for 12 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 (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford compound 306-4 (750 mg, 51% yield).

[0953] LC-MS (ESI+): 181.0 m / z [M+H] + .

[0954] The remaining steps were carried out according to the synthetic method of Example 25, except that compound 306-4 was used instead of 4-amino-3-formylbenzoic acid methyl ester to obtain compound 2-amino-N',3-dimethyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,7-naphthyridine-6-carbohydrazide.

[0955] LC-MS (ESI+): 469.2 m / z [M+H] + .

[0956] Example 307: Preparation of 2-amino-3-cyano-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (307)

[0957] Step 1: Preparation of N-(((3-bromo-6-(chlorocarbonyl)quinolin-2-yl)amino)methylene)-N-methylmethanium (307-2)

[0958] 2-Amino-3-bromoquinoline-6-carboxylic acid (307-1, obtained by hydrolysis of 25-3) (600 mg, 2.24 mmol) was dissolved in SOCl2 (15 mL), and DMF (0.5 mL) was added. The resulting mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 307-2 (600 mg, 93% yield, as a white solid).

[0959] LC-MS (ESI+): 341.1m / z[M+H] + .

[0960] Step 2: Preparation of N-(((3-bromo-6-(2-methyl-2-(pyrimidin-2-yl)-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carbonyl)quinolin-2-yl)amino)methylene)-N-methylmethanium (307-3)

[0961] Compound 307-2 (0.4 g, 1.41 mmol) was dissolved in DCM (5 mL), and DIEA (0.55 g, 4.23 mmol) and 2-(1-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazino)pyrimidine (synthesized according to the method for Intermediate 137-5 of Example 137) (0.4 g, 1.41 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (20 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 (DCM / MeOH = 92 / 8) to obtain compound 307-3 (400 mg, 53% yield, as a yellow solid).

[0962] LC-MS (ESI+): 588.1m / z[M+H] + .

[0963] Step 3: Preparation of N-(((3-cyano-6-(2-methyl-2-(pyrimidin-2-yl)-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carbonyl)quinolin-2-yl)amino)methylene)-N-methylmethanium (307-4)

[0964] Compound 307-3 (0.1 g, 0.188 mmol) was dissolved in 1,4-dioxane (3 mL) in a sealed tube. CuCN (50 mg, 0.56 mmol), Pd2(dba)3 (17 mg, 0.018 mmol), and DPPF (31 mg, 0.056 mmol) were added sequentially. After replacing the nitrogen atmosphere, the resulting mixture was stirred at 100°C for 12 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 307-4 (60 mg, 67% yield, as a yellow solid).

[0965] LC-MS (ESI+): 535.2 m / z [M+H] + .

[0966] Step 4: Preparation of 2-amino-3-cyano-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (307)

[0967] Compound 307-4 (0.1 g, 0.18 mmol) was dissolved in methanol (1 mL), and 1N HCl (1 mL) was added. The resulting mixture was stirred at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 307 (7.9 mg, 9% yield, as a white solid).

[0968] LC-MS (ESI+): 479.2 m / z [M+H] + .

[0969] 1 H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.70(s,1H),8.40(d,J=4.8Hz,2H),8.21(d,J=8.4Hz,1H),7.93(s,1H),7.85(d,J=8.4Hz, 1H),7.68(d,J=8.8Hz,1H),7.39(s,1H),7.15(s,2H),6.80(s,1H),5.39(d,J=15.6Hz,1H),4.62(d,J=15.6Hz,1H),3.32(s,3H).

[0970] Example 308: Preparation of 5-amino-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)benzo[c][2,7]naphthyridine-9-carbohydrazide (308)

[0971] Step 1: Preparation of ethyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (308-2)

[0972] Ethyl 4-amino-3-bromobenzoate (308-1, 1.0 g, 4.1 mmol), (BPin)2 (1.56 mg, 6.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.2 mmol), and potassium acetate (1204 mg, 12.3 mmol) were dissolved in 1,4-dioxane (30 mL) at room temperature. The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) to obtain compound 308-2 (900 mg, 75% yield).

[0973] LC-MS (ESI+): m / z 292.1[M+1] + .

[0974] Step 2: Preparation of ethyl 5-aminobenzo[c][2,7]naphthyridine-9-carboxylate (308-3)

[0975] At room temperature, 308-2 (800 mg, 2.7 mmol), 4-bromonicotinonitrile (553 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (158 mg, 0.14 mmol), and potassium carbonate (1138 mg, 8.24 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL). The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. After completion of the reaction, water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain compound 308-3 (250 mg, 34% yield).

[0976] LC-MS (ESI+): m / z 268.1[M+1] + .

[0977] Step 3: Preparation of 5-aminobenzo[c][2,7]naphthyridine-9-carboxylic acid (308-4)

[0978] 308-3 (250 mg, 0.94 mmol) and lithium hydroxide (112 mg, 4.68 mmol) were dissolved in methanol (5 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at 50°C for 12 hours. After completion of the reaction, the pH was adjusted to 5-6 with 2N hydrochloric acid and filtered to afford compound 308-4 (200 mg, 89% yield).

[0979] LC-MS (ESI+): m / z 240.2[M+1] + .

[0980] Step 4: Preparation of 5-aminobenzo[c][2,7]naphthyridine-9-carbonyl chloride (308-5)

[0981] 308-4 (200 mg, 2.24 mmol) was dissolved in SOCl2 (15 mL), and DMF (1 drop) was added. The resulting mixture was stirred at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 308-5 (crude product, 200 mg, white solid), which was used directly in the next step.

[0982] According to the method of Example 137, compound 308-5 was used instead of compound 2-amino-3-methylquinoline-6-carbonyl chloride, and (5-(trifluoromethyl)pyridin-2-yl)methanol was used instead of 137-1 to synthesize 5-amino-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)benzo[c][2,7]naphthypyridine-9-carbohydrazide.

[0983] LC-MS (ESI+): m / z 505.2[M+1] + .

[0984] 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.93 (s, 1H), 8.86 (d, J = 5.6Hz, 1H), 8.58 (s,1H),8.48–8.41(m,2H),8.37(d,J=5.6Hz,1H),8.28–8.22(m,1H),7.96(d, J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.58(s,2H),7.43(d,J=8.8Hz,1H),6.82 (t, J=4.8Hz, 1H), 5.45 (d, J=15.6Hz, 1H), 4.68 (d, J=15.6Hz, 1H), 3.33 (s, 3H).

[0985] Example 309: Preparation of 2-amino-N'-(3-fluoropyridin-2-yl)-N'-methyl-3-(methyl-D3)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (309)

[0986] Step 1: Preparation of 3-fluoro-2-(1-methylhydrazinyl)pyridine (309-2)

[0987] 2,3-Difluoropyridine (309-1) (10 g, 87 mmol) was dissolved in 100 mL of ethanol at room temperature, and methylhydrazine sulfate (12 g, 87 mmol) and sodium carbonate (28 g, 261 mmol) were added. The mixture was reacted at 85°C under a nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated under reduced pressure to afford compound 309-2 (7 g, 57% yield).

[0988] LC-MS (ESI+): 142.2 m / z [M+H] + .

[0989] Step 2: Preparation of tert-butyl 2-methyl-2-(pyrimidin-2-yl)hydrazine-1-carboxylate (309-3)

[0990] At room temperature, 309-2 (13 g, 92.10 mmol) was dissolved in 150 mL of tetrahydrofuran and 150 mL of water, and di-tert-butyl dicarbonate (30 g, 138 mmol) and sodium carbonate (29 g, 276 mmol) were added. The reaction was allowed to react overnight at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure, and the resulting mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to give compound 309-3 (19 g, yield 85%).

[0991] LC-MS (ESI+): 242.2 m / z [M+H] + .

[0992] Step 3: Preparation of tert-butyl 2-(3-fluoropyridin-2-yl)-2-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazine-1-carboxylate (309-4)

[0993] At room temperature, 309-3 (14 g, 58 mmol) was dissolved in 150 mL of DMF, and potassium carbonate (24 g, 174 mmol) and methyl (5-(trifluoromethyl)pyridin-2-yl)methanesulfonate (22 g, 87 mmol) were added. The reaction was allowed to proceed at 65° C. under a nitrogen atmosphere overnight. 200 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (200 ml x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to give compound 309-4 (14 g, 61% yield).

[0994] LC-MS (ESI+): 401.2 m / z [M+H] + .

[0995] Step 4: Preparation of 3-fluoro-2-(1-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)hydrazino)pyridine (309-5)

[0996] At room temperature, 309-4 (14 g, 34 mmol) was dissolved in 150 mL of dichloromethane, and a 4 M hydrochloric acid solution in dioxane (20 mL) was added. The mixture was reacted at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 309-5 (hydrochloride salt, 13 g, yield 87%).

[0997] LC-MS (ESI+): 301.2 m / z [M+H] + .

[0998] Step 5: Preparation of 6-bromo-3-(methyl-d3)quinoline (309-7)

[0999] 6-Bromo-3-iodoquinoline (309-6, 10 g, 29.9 mmol) was dissolved in THF (200 mL). n-Butyl lithium (13.2 mL, 33 mmol) was added at -78°C. After reacting at low temperature for half an hour, ICD3 (4.3 g, 29.9 mmol) was dissolved in THF (20 mL) and added dropwise to the reaction mixture. The reaction was continued at low temperature for half an hour, then returned to room temperature for 2 hours. Aqueous ammonium chloride (100 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was then extracted with ethyl acetate (300 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 = 5 / 1) to afford compound 309-7 (8 g, 80% yield, colorless oil).

[1000] LC-MS (ESI+): 225.1m / z[M+H] + .

[1001] Step 6: Preparation of ethyl 3-(methyl-d3)quinoline-6-carboxylate (309-8)

[1002] Compound 309-7 (25 g, 111.0 mmol) was dissolved in EtOH (250 mL), and hexacarbonyl molybdenum (14.6 g, 55.5 mmol), TEA (33.6 g, 333.2 mmol), Pd(dppf)Cl2 (9.0 g, 11.1 mmol), and Xantphos (12.8 g, 22.2 mmol) were added. The atmosphere was replaced with N2, and the reaction was carried out at 85°C for 6 hours. The reaction solution was filtered after adding MeOH and DCM, and then dried by spin drying. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) gave compound 309-8 (20 g, 88% yield, yellow oil).

[1003] LC-MS (ESI+): 219.1m / z[M+H] + .

[1004] Step 7: Preparation of 6-(ethoxycarbonyl)-3-(methyl-d3)quinoline 1-oxide (309-9)

[1005] Compound 309-8 (22.0 g, 101 mmol) was dissolved in DCM (250 mL), and m-chloroperbenzoic acid (26.0 g, 151 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. DCM (100 mL) and aqueous sodium bicarbonate solution (100 mL×3) were added to the reaction solution for extraction, and the mixture was spin-dried to obtain compound 309-9 (23 g, yield 97%, yellow solid).

[1006] LC-MS (ESI+): 234.2 m / z [M+H] + .

[1007] Step 8: Preparation of ethyl 2-(tert-butylamino)-3-(methyl-d3)quinoline-6-carboxylate (309-10)

[1008] Compound 309-9 (23 g, 104.4 mmol) was dissolved in DCM (250 mL). Tert-butylamine (34.3 g, 470 mmol) and 4-toluenesulfonic anhydride (59.5 g, 183 mmol) were added at 0°C, and the reaction solution was stirred at room temperature for 12 hours. DCM (100 mL) and aqueous sodium bicarbonate (100 mL x 3) were added to the reaction solution for extraction. The organic phase was 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 = 20 / 1) to obtain compound 309-10 (8.2 g, 30% yield, as a yellow solid).

[1009] LC-MS (ESI+): 290.4 m / z [M+H] + .

[1010] Step 9: Preparation of 2-(tert-butylamino)-3-(methyl-d3)quinoline-6-carboxylic acid (309-11)

[1011] Compound 309-10 (8.0 g, 34.3 mmol) was dissolved in THF / H2O / MeOH (50 / 50 / 50 mL), and lithium hydroxide monohydrate (4.3 g, 102.9 mmol) was added. The resulting mixture was stirred at 50°C for 2 hours. The solvent was partially evaporated, and 1N HCl was added to adjust the pH to ~3. A solid precipitated, which was filtered and lyophilized to afford compound 309-11 (6 g, 85% yield, as a white solid).

[1012] LC-MS (ESI-): 262.3m / z[MH] - .

[1013] Step 10: Preparation of 2-(tert-butylamino)-3-(methyl-D3)quinoline-6-carbonyl chloride (309-12)

[1014] At room temperature, 309-11 (300 mg, crude) was dissolved in 5 mL of dichloromethane, 1 mL of thionyl chloride was added, and the mixture was reacted at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain compound 309-12 (300 mg, crude).

[1015] Step 11: Preparation of 2-(tert-butylamino)-N'-(3-fluoropyridin-2-yl)-N'-methyl-3-(methyl-d3)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (309-13)

[1016] At room temperature, 309-5 (100 mg, 0.33 mmol) was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (129 mg, 1.0 mmol) was added, and 309-12 (crude product, 100 mg) was added under an ice bath. The reaction was allowed to react at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-10%) to give compound 309-13 (150 mg, yield 65%).

[1017] LC-MS (ESI+): 544.2 m / z [M+H] + .

[1018] Step 12: Preparation of 2-amino-N'-(3-fluoropyridin-2-yl)-N'-methyl-3-(methyl-d3)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (309)

[1019] At room temperature, 309-13 (150 mg, 0.28 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 309 (12 mg, 9% yield).

[1020] LC-MS (ESI+): 488.2 m / z [M+H] + .

[1021] 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=6.1Hz,2H),8.01(d,J=4.7Hz,1H),7.89–7.74(m,3H),7.61(d,J=8.7Hz,1H),7.49(dd,J=13.9,8.1Hz,1H),7.38(d,J =8.8Hz, 1H), 6.91 (ddd, J = 7.8, 4.7, 2.8Hz, 1H), 6.53 (s, 2H), 5.32 (d, J = 15.9Hz, 1H), 4.69 (d, J = 15.8Hz, 1H).

[1022] The following compounds were prepared according to the synthesis method of Example 309 using the corresponding starting materials:

[1023] Example 315: Preparation of N-((5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)methyl)-2-amino-N'-cyclopropyl-3-(methyl-d3)-N'-(pyrimidin-2-yl)quinoline-6-carbohydrazide (315)

[1024] Step 1: Preparation of (6-((1-(tert-Butoxycarbonyl)-2-cyclopropyl-2-(pyrimidin-2-yl)hydrazine)methyl)pyridin-3-yl)boronic acid (315-2)

[1025] Compound 315-1 (synthesized according to Example 137) (300 mg, 0.714 mmol) was dissolved in dioxane (5 mL). B2Pin2 (272 mg, 1.07 mmol), KOAc (140 mg, 1.43 mmol), and Pd(dppf)Cl2 (52 mg, 0.071 mmol) were added sequentially at room temperature. The reaction was stirred at 90°C under a N2 atmosphere overnight. After completion of the reaction, the crude reaction mixture (315-2) was used directly in the next step.

[1026] LC-MS (ESI+): 386.2 m / z [M+H] + .

[1027] Step 2: Preparation of tert-butyl 1-((5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)methyl)-2-cyclopropyl-2-(pyrimidin-2-yl)hydrazine-1-carboxylate (315-3)

[1028] 315-2 (275 mg, 0.714 mmol) was dissolved in dioxane (5 mL) and H2O (1 mL). 2-Bromo-1,3,4-thiadiazole (118 mg, 0.714 mmol), Pd(dppf)Cl2 (78 mg, 0.107 mmol), and K2CO3 (296 mg, 2.14 mmol) were added sequentially at room temperature. The reaction was stirred at 100°C under a N2 atmosphere overnight. After completion of the reaction, the reaction mixture was diluted with an appropriate amount of aqueous solution and washed with ethyl acetate (20 mL x 3). The organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 315-3.

[1029] LC-MS (ESI+): 426.5 m / z [M+H] + .

[1030] Step 3: Preparation of 2-(6-((2-cyclopropyl-2-(pyrimidin-2-yl)hydrazine)methyl)pyridin-3-yl)-1,3,4-thiadiazole (315-4)

[1031] 315-3 (100 mg, 0.515 mmol) was dissolved in 2.5 M HCl in ethyl acetate (5 mL) and the reaction was stirred at 40°C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude 315-4 (hydrochloride salt), which was used directly in the next step.

[1032] LC-MS (ESI+): 326.5 m / z [M+H] +

[1033] Step 4: Preparation of N-((5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)methyl)-2-(tert-butylamino)-N'-cyclopropyl-3-(methyl-d3)-N'-(pyrimidin-2-yl)quinoline-6-hydrazide (315-5)

[1034] 315-4 (60 mg, 0.184 mmol) was dissolved in DCM (5 mL) and DIPEA (119 mg, 0.922 mmol) was added at room temperature. The reaction was stirred at room temperature for 5 minutes before the addition of 309-12 (41 mg, 0.148 mmol). The reaction was stirred at 40°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the crude product (315-5), which was used directly in the next step.

[1035] LC-MS (ESI+): 596.5 m / z [M+H] + .

[1036] Step 5: Preparation of N-((5-(1,3,4-thiadiazol-2-yl)pyridin-2-yl)methyl)-2-amino-N'-cyclopropyl-3-(methyl-d3)-N'-(pyrimidin-2-yl)quinoline-6-hydrazide (315)

[1037] 315-5 (80 mg, 0.141 mmol) was dissolved in TFA (3 mL) and stirred at 70°C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to afford compound 315.

[1038] LC-MS (ESI+): 540.6 m / z [M+H] + .

[1039] 1 H NMR(400MHz,DMSO-d6)δ8.58(d,J=4.8Hz,2H),8.51(d,J=2.4Hz,1H),7.90-7.86(m,,1H),7.7 3(d,J=8.1Hz,1H),7.70(d,J=2.0Hz,1H),7.60(s,1H),7.43-7.40(m,1H),7.27(d,J=8.7Hz,1H ),7.00(t,J=4.8Hz,1H),6.49(s,2H),5.33(d,J=15.1Hz,1H),4.63(d,J=15.1Hz,1H),2.65(s, 3H),2.80–2.73(m,1H),2.38(s,3H),0.77–0.67(m,1H),0.55–0.39(m,2H),0.14–0.07(m,1H).

[1040] The following compounds were prepared according to the synthesis method of Example 315 using the corresponding starting materials:

[1041] Example 319: Preparation of 2-amino-3-methoxy-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (319)

[1042] Step 1: Preparation of methyl 3-iodoquinoline-6-carboxylate (319-2)

[1043] Under nitrogen atmosphere, 6-carboxyquinoline methyl ester (319-1, 1.0 g, 5.35 mmol) is added to a solution of AcOH (9.0 mL) / NIS (1.68 g, 7.49 mmol). The resulting mixture is stirred at 100° C. for 16 hours. The reaction mixture is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=5 / 1) to obtain 3-iodoquinoline-6-methyl formate (800 mg, 48% yield).

[1044] LC-MS (ESI+): 204.0 m / z [M+H] + .

[1045] Step 2: Preparation of 3-methoxyquinoline-6-carboxylic acid (319-3)

[1046] At room temperature, 319-2 (500 mg, 1.59 mmol), cuprous iodide (30 mg, 0.16 mmol), and a methanol solution of sodium methoxide (431 mg, 7.98 mmol) were dissolved in N-methylformamide (10 mL). The mixture was reacted at 90°C for 12 hours, and 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 (100 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 = 1 / 1) to provide compound 319-3 (200 mg, 61% yield).

[1047] LC-MS (ESI+): 204.0 m / z [M+H] + .

[1048] According to the route of Example 309, 319-3 was used instead of 309-8 to synthesize the compound 2-amino-3-methoxy-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide.

[1049] LC-MS (ESI+): 484.1m / z[M+H] + .

[1050] 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.39(d,J=8.0Hz,2H),8.21(d,J=8.0Hz,1H),7.93(s,1H),7.83(d,J=12.0Hz,1H),7.73(s,1H),7.58 (d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),6.80(t,J=4.0Hz,1H),5.39(d,J=16.0Hz,1H),4.60(d,J=16.0Hz,1H),3.97(s,3H),3.32(s,3H).

[1051] Example 320: Preparation of 2-amino-N'-cyclopropyl-3-(hydroxymethyl)-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (320)

[1052] Step 1: Preparation of 2-amino-N'-cyclopropyl-3-(hydroxymethyl)-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (320)

[1053] Compound 270 (200 mg, 0.358 mmol) was dissolved in 1,4-dioxane (2 mL) in a sealed tube. (tributyltin)methanol (115 mg, 0.358 mmol) and Pd(PPh3)4 (41 mg, 0.035 mmol) were added sequentially. After replacing the nitrogen atmosphere, the resulting mixture was stirred at 100°C for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 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 silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain a crude product, which was then purified by preparative HPLC (water / acetonitrile = 95% / 5% to 10% / 90%) and freeze-dried to afford compound 320 (8.0 mg, 5% yield, as a white solid).

[1054] LC-MS (ESI+): 510.2 m / z [M+H] + .

[1055] The following compounds were prepared according to the synthesis method of Example 320 using the corresponding starting materials:

[1056] Example 323: Preparation of 2-amino-N'-cyclopropyl-3-(fluoromethyl)-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (323)

[1057] Step 1: Preparation of 2-amino-N'-cyclopropyl-3-(fluoromethyl)-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (323)

[1058] Compound 320 (50 mg, 0.098 mmol) was dissolved in DCM (2 mL), diethylaminosulfur trifluoride (0.2 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. DCM (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 323 (6.1 mg, 12% yield, as a white solid).

[1059] LC-MS (ESI+): 512.2 m / z [M+H] + .

[1060] 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.41(d,J=4.8Hz,2H),8.05(dd,J=8.4,2.4Hz ,1H),7.75(d,J=8.0Hz,2H),7.64(s,1H),7.33(s,1H),7.15(d,J=8.8Hz,1H),6.85 (t,J=4.8Hz,1H),6.55(s,2H),5.28(d,J=48Hz,1H),5.18(d,J=15.6Hz,1H),4.52( d,J=15.6Hz,1H),2.61(s,1H),0.59(s,1H),0.41–0.22(m,2H),0.02–0.00(m,1H).

[1061] The following compounds were prepared according to the synthesis method of Example 323 using the corresponding starting materials:

[1062] Example 325: Preparation of 2-amino-3-hydroxymethyl-N'-methyl-N'-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-6-carbohydrazide (325)

[1063] Step 1: Preparation of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylate (325-1)

[1064] At room temperature, methyl 3-iodoquinoline-6-carboxylate (319-2) (500 mg, 1.60 mmol) was dissolved in 5 mL of toluene, and tert-butyldimethyl-(tributylstannylmethoxy)silane (1.39 g, 3.20 mmol), lithium chloride (206 mg, 4.80 mmol), and bistriphenylphosphine palladium dichloride (103 mg, 0.16 mmol) were added. The reaction was allowed to react at 100°C overnight under a nitrogen atmosphere. The reaction mixture was added with water, filtered through celite, and the filtrate was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to afford 325-1 (450 mg, 85% yield).

[1065] LC-MS (ESI+): 332.2 m / z [M+H] + .

[1066] Step 2: Preparation of 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(methoxycarbonyl)quinoline-1-oxide (325-2)

[1067] At room temperature, 325-1 (450 mg, 1.36 mmol) was dissolved in 5 mL of dichloromethane, and m-chloroperbenzoic acid (700 mg, 4.07 mmol) was added. The reaction mixture was reacted in an ice bath under a nitrogen atmosphere overnight. The reaction mixture was quenched with an aqueous sodium sulfite solution and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to obtain compound 325-2 (300 mg, yield 64%).

[1068] LC-MS (ESI+): 348.2 m / z [M+H] + .

[1069] Step 3: Preparation of methyl 2-(tert-butylamino)-3-(((tert-butyldimethylsilyl)oxy)methyl)quinoline-6-carboxylate (325-3)

[1070] At room temperature, 325-2 (450 mg, 1.36 mmol) was dissolved in 5 mL of dichloromethane. Tert-butylamine (315 mg, 4.32 mmol) was added under ice-bath. After stirring for 10 minutes, methanesulfonic anhydride (563 mg, 1.73 mmol) was added. The reaction was allowed to react overnight under a nitrogen atmosphere in an ice-bath. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100%-50%) to give compound 325-3 (280 mg, 85% yield).

[1071] LC-MS (ESI+): 403.2 m / z [M+H] + .

[1072] Step 4: Preparation of methyl 2-amino-3-hydroxymethylquinoline-6-carboxylate (325-4)

[1073] 325-3 (280 mg, 0.70 mmo...

Claims

1. A compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, in: X is CR 6 or N; R 1 , R 2 are each independently selected from hydrogen, -(CH2) p -R 7 、-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, -NR a R b 、-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(OH)2、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-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 3 Selected from hydrogen, -(CH2) p -R 7 、-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, -NR a R b 、-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 1 With R 2 , or R 1 With R 3 , together with the nitrogen atom to which it is connected, form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group, wherein the nitrogen-containing heterocyclic group or the nitrogen-containing heteroaryl group is optionally further selected from halogen, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, oxo, methylene, -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 、-(CH2) q -OR a , alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; R 4 , R 5 are each independently selected from hydrogen, 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 、-S(=O)R a 、-P(=O)R a R b 、-NR a S(=O)2R b 、-CH2-R 7 、-NR a R b , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated, halogen, amino, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, amide, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; Or, R 4 With R 5 Together with the atoms to which it is attached, it forms a heteroaryl, heterocyclyl, aryl or cycloalkyl group, wherein the heteroaryl, heterocyclyl, aryl or cycloalkyl 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; R 6 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, -NR a R b , 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 deuterated, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 7 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, oxo, -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, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, oxo, -NR a R b 、-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 、-(CH2) q -OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; 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, -NR c R d 、-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, alkoxy, 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 may be further selected from Substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, 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 from 1 to 6; q is an integer from 1 to 6.

2. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, which is the compound of the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, in, Ring A is selected from heteroaryl, heterocyclyl, aryl or cycloalkyl; Each R 8 are each independently selected from hydrogen, halogen, -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, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; m is an integer from 0 to 4; X, R 1 ~R 3 , R a , R b As defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

4. The compound of claim 1, wherein R 5 Selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-6 alkenyl, the C 1-6 The alkyl group is optionally deuterated, halogenated, hydroxyl or C 1-6 Alkoxy substituted.

5. A compound according to any one of claims 1 to 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

6. A compound of the general formula (I) according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, -S(=O)2R a 、-S(=O)R a 、-C(=O)R a 、-P(=O)R a R b 、-B(OH)2、C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl is substituted with one or more groups; R a and R b Each independently selected from hydroxyl or C 1-6 alkyl.

7. A compound of the general formula (I) according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, cyano, carboxyl, -S(=O)2R a 、-S(=O)R a 、-C(=O)R a 、-P(=O)R a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; 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 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution.

8. A compound represented by the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 1 With R 2 The nitrogen atom to which it is connected forms a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group, wherein the 5- to 10-membered nitrogen-containing heterocyclic group or the 5- to 10-membered nitrogen-containing heteroaryl group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

9. A compound represented by the general formula (I) according to any one of claims 1 to 8, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 3 Selected from hydrogen, -(CH2) p -R 7 、-NR a R b 、-C(=O)R a 、-S(=O)2R a , C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered 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 , C 1-6 Alkyl, -OR a , C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; R 7 is selected from 5-6 membered heteroaryl, C 6-10 Aryl, the 5-6 membered heteroaryl, C 6-10 Aryl is 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 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1- 6-haloalkoxy substituted with one or more groups; p is an integer from 1 to 6; R a , R b As defined in claim 1.

10. A compound represented by the general formula (I) according to any one of claims 1 to 8, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 3 Selected from -(CH2) p -R 7 ; R 7 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, the C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclyl optionally further selected from deuterated, halogen, -NR a R b , cyano, hydroxyl, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, or one or more groups, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further selected from deuterated, halogen, cyano, hydroxyl, oxo, -NR a R b 、-(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 One or more groups of cycloalkyl or 4-6 membered heterocyclic group are substituted; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy, -NR c R d replace; or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by halogen, oxo, C 1-6 Alkyl substitution; R c and R d are each independently selected from hydrogen, C 1-6 Alkyl and hydroxy-substituted C 1-6 alkyl; p is 1; q is 1 or 2.

11. The compound represented by the general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 1 With R 3 Together with the nitrogen atom to which it is connected, it forms a 5-10-membered nitrogen-containing heterocyclic group, wherein the 5-10-membered nitrogen-containing heterocyclic group is optionally selected from halogen, hydroxyl, thiol, oxo, methylene, -(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, or one or more substituents; R a is hydrogen or C 1-6 alkyl; q is 1 or 2.

12. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; R 2 is selected from phenyl or 5-6 membered heterocyclic group, preferably phenyl or 6 membered heterocyclic group, which is optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group.

13. The compound represented by the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 The alkyl group is optionally substituted with a hydroxyl group, a C 1-6 Alkoxy substitution; R 3 Selected from -(CH2) p -R 7 ; R 7 is selected from 5-6 membered heteroaryl or phenyl, preferably 6 membered heteroaryl or phenyl, which is optionally further selected from deuterated, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; p is 1.

14. The compound of the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, which is a compound of the general formula (IA) or (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, in, A1, A2, A3, A4 are each independently selected from CH or N, preferably one of them is N and the others are CH, or two of them are N and the others are CH; Y1, Y2, Y3, and Y4 are each independently selected from CH or N, preferably one of them is N and the others are CH, or two of them are N and the others are CH; Ring A is selected from 5-6 membered heteroaryl, 5-6 membered heterocyclyl, phenyl or 5-6 membered cycloalkyl; R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 5 Selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-6 alkenyl, the C 1- 6 alkyl is optionally deuterated, halogenated, hydroxyl or C 1-6 Alkoxy substituted; Each R 11 are each independently selected from hydrogen, deuterated, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(=O)2R a 、-S(=O)R a 、-C(=O)R a 、-P(=O)R a R b 、-B(OH)2、C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenation Alkyl, C 1-6 or one or more haloalkoxy groups; or Any two adjacent R 11 The atoms to which it is attached together form a phenyl group, a 5-6 membered heteroaryl group, a 5-6 membered heterocyclyl group or a 4-6 membered cycloalkyl group, wherein the phenyl group, the 5-6 membered heteroaryl group, the 5-6 membered heterocyclyl group or the 4-6 membered cycloalkyl group is optionally selected from halogen and C 1-6 Alkyl radical substitution; Each R 12 are each independently selected from hydrogen, deuterated, halogen, -NR a R b , cyano, hydroxyl, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further selected from deuterated, halogen, cyano, hydroxyl, amino, oxo, -NR a R b 、-(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclic group or one or more groups; or Any two adjacent R 12 The atoms to which it is attached together form a phenyl group, a 5-6 membered heteroaryl group, a 5-6 membered heterocyclyl group or a 4-6 membered cycloalkyl group, wherein the phenyl group, the 5-6 membered heteroaryl group, the 5-6 membered heterocyclyl group or the 4-6 membered cycloalkyl group is optionally selected from halogen, C 1-6 alkyl, 4-6 membered heterocyclic group, the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution; Each R 8 are each independently selected from hydrogen, halogen, -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 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy, -NR c R d replace; or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally selected from halogen, oxo, C 1-6 One or more groups of the alkyl group are substituted; R c and R d are each independently selected from hydrogen, C 1-6 Alkyl and hydroxy-substituted C 1-6 alkyl; m is an integer from 0 to 4; q is 1 or 2. s is an integer from 1 to 4; preferably 1 or 2; t is an integer from 1 to 4, preferably 1, 2 or 3; X is as defined in claim 1.

15. The compound represented by the general formula (I) according to claim 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: pyrimidinyl, pyridinyl, phenyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, isoindolyl, naphthyl, naphthyridinyl, pyridofuranyl, pyridothiphenyl, pyridothiazolyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyridinyl, pyridomorpholinyl, pyridopiperazinyl, pyrimidine pyrimidopyrrolyl, pyrimidothiphenylyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidopyridinyl, pyrimidomorpholinyl, pyrimidopyrazinyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, benzopyrrolyl, benzopyrimidinyl, benzopyridinyl, benzopyridazinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, preferably selected from More preferred 16. The compound of the general formula (I) according to claim 14 or 15, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein is selected from the group consisting of pyridyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, isoindolyl, naphthyl, naphthyridinyl, pyridofuranyl, pyridothiphenyl, pyridothiazolyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyridinyl, pyridomorpholinyl, pyridopiperazinyl, pyrimidofuranyl, pyrimidopyrrolyl, pyrimidothiphenylyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, benzopyrrolyl, benzopyrimidinyl, benzopyridinyl, benzopyridazinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, preferably More preferred 17. A compound of the general formula (I) according to any one of claims 1 to 10, 14 to 16, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally selected from deuterated, halogen, C 1-6 Alkoxy is substituted with one or more groups; Preferably, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, wherein the C 1-6 The alkyl group is optionally replaced by C 1-6 Alkoxy substituted.

18. A compound of the general formula (I) according to any one of claims 14 to 17, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: Each R 11 are each independently selected from hydrogen, deuterated, halogen, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -P(=O)R a R b , -B(OH)2; R a and R b are each independently selected from hydrogen, C 1-6 alkyl; s is 1 or 2.

19. A compound of the general formula (I) according to any one of claims 14 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: Each R 12 are each independently selected from hydrogen, deuterated, halogen, -NR a R b , cyano, -C(=O)R a 、-P(=O)R a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group may be further selected from deuterated, halogen, hydroxyl, C 1-6 Alkoxy is substituted with one or more groups; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl; or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, said 4-6 membered heterocyclic group being optionally substituted by halogen; t is 1, 2, or 3; Preferably, R 12 C 1-6 Halogenated alkyl, t is 1.

20. A compound of the general formula (I) according to any one of claims 14 to 19, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein for in, Y1, Y2, Y3 are each independently selected from CH or N; Ring E is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl; preferably pyridyl, dihydropyridyl, tetrahydropyridyl, phenyl, pyrazinyl, pyrimidinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyridopyrazolyl, quinolinyl; R 12a is selected from hydrogen or halogen, preferably hydrogen; Each R 13 are each independently selected from hydrogen, deuterated, halogen, cyano, hydroxyl, oxo, -NR a R b 、-(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 One or more groups of cycloalkyl or 4-6 membered heterocyclic group are substituted; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 Alkoxy, -NR c R d Replace, or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally selected from halogen, oxo, C 1-6 Alkyl substitution; R c and R d are each independently selected from hydrogen and C 1-6 alkyl; q is 1 or 2, preferably 1; t is 1, 2, or 3; v is 1 or 2.

21. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, which is a compound of the general formula (IIIA) or general formula (IIIB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, in, Ring B is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group; Each R 9 are each independently selected from hydrogen, halogen, -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 、-(CH2) q -OR a , oxo, methylene, alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; n is an integer from 0 to 4; q is 1 or 2; R 2 Selected from hydrogen, -(CH2) p -R 7 、-NR a R b 、-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, -NR a R b 、-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(OH)2、alkyl、-OR a , haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b 、-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; X, R 4 , R 5 , R 7 , R a , R b , p as defined in claim 1; Ring A, R 8 , m as defined in claim 2; Preferably, ring B is selected from a 5- to 10-membered nitrogen-containing heterocyclic group; Each R 9 Each is independently selected from halogen, hydroxyl, mercapto, oxo, methylene, -(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, phenyl; n is an integer from 0 to 4; q is 1 or 2; R 2 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, wherein the C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, -NR a R b , -B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; 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 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution; X, R 4 , R 5 As defined in claim 1; Ring A, R 8 , m as defined in claim 2.

22. The compound of the general formula (I) according to claim 21, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: Ring B is a 5-10 membered nitrogen-containing heterocyclic group, preferably Each R 9 Each is independently selected from halogen, hydroxyl, mercapto, oxo, methylene, -(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, phenyl; R a is hydrogen or C 1-6 alkyl; q is 1 or 2; preferably 1; n is 1 or 2.

23. The compound of the general formula (I) according to claim 21 or 22, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein: R 2 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indolyl, isoindolyl, naphthyl, naphthyridinyl, pyridofuranyl, pyridothiphenyl, pyridothiazolyl, pyridopyrrolyl, pyridopyrrolidinyl, pyridoimidazolyl, pyridopyrazolyl, pyridopyridinyl, pyridomorpholinyl, pyridopiperazine phenyl, pyrimidinyl, pyrimidinopyrrolyl, pyrimidothiphenylyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidopyridinyl, pyrimidomorpholinyl, pyrimidopyrazinyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinopiperidinyl, pyridazinomorpholinyl, pyridazinopiperazinyl, benzopyrrolyl, benzopyrimidinyl, benzopyridinyl, benzopyridazinyl, benzofuranyl, benzothiophenyl, benzothiazolyl; more preferably phenyl, pyridinyl; It is optionally further selected from deuterated, halogen, cyano, -NR a R b 、-B(OH)2、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl, 5 to 10 membered heteroaryl, one or more groups, said C 2-6 Alkenyl, C 2- 6 alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; 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 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution.

24. A compound of the general formula (I) according to any one of claims 21 to 23, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIIAa) or the general formula (IIIBa), or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof, in, G1, G2, G3, G4 are each independently selected from CH or N; preferably G1, G2, G3, G4 are all CH; or one of G1, G2, G3, G4 is N, and the others are CH, or two of G1, G2, G3, G4 are N, and the others are CH; Each R 13 are each independently selected from hydrogen, deuterated, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6- 10 aryl, 5 to 10 membered heteroaryl, one or more groups, said C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, hydroxyl, -NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; 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 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by C 1-6 Alkyl substitution; u is 1 or 2; Ring B, Ring A, X, R 4 , R 5 , R 8 , R 9 , n, m as defined in any one of claims 21 to 23.

25. A compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, which is a compound of the general formula (IVA) or general formula (IVB) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, in, Ring D is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group; Each R 10 are each independently selected from hydrogen, halogen, -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 , oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; s is an integer from 0 to 4; R 3 Selected from hydrogen, -(CH2) p -R 7 、-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; X, R 4 , R 5 , R 7 , R a , R b , p as defined in claim 1; Ring A, R 8 , m as defined in claim 2; Preferably, ring D is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group; Each R 10 are each independently selected from hydrogen, halogen, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy; s is an integer from 0 to 4; R 3 Selected from hydrogen, -(CH2) p -R 7 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 10-membered heterocyclic group; R 7 Selected from C 6- 10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclic group, the C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 4 to 10 membered heterocyclyl optionally further selected from deuterated, halogen, -NR a R b , cyano, hydroxyl, mercapto, oxo, -C(=O)R a 、-P(=O)R a R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl is substituted with one or more groups, the C 1- 6 alkyl is optionally further selected from deuterated, halogen, cyano, hydroxyl, -NR a R b 、-(CH2) q -OR a , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 One or more haloalkoxy groups are substituted; R a and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 The alkyl group is optionally substituted with halogen, hydroxyl, C 1-6 Alkoxy, -NR c R d replace; or R a and R b Together with the atoms to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally substituted by halogen, oxo, C 1-6 Alkyl substitution; R c and R d are each independently selected from hydrogen, C 1-6 Alkyl and hydroxy-substituted C 1-6 alkyl; p is 1; q is 1 or 2; X, R 4 , R 5 As defined in claim 1; Ring A, R 8 , m as defined in claim 2; More preferably, ring D is selected from a 5- to 10-membered nitrogen-containing heterocyclic group or a 5- to 10-membered nitrogen-containing heteroaryl group; Each R 10 are each independently selected from hydrogen, halogen, -NR a R b , nitro, cyano, hydroxyl, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy; s is an integer from 0 to 4; R 3 Selected from hydrogen, -(CH2) p -R 7 , C 1-6 Alkyl; R 7 Selected from C 6-10 Aryl, 5 to 10 membered heteroaryl, the C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further selected from deuterated, halogen, cyano, hydroxyl, oxo, -C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkyne One or more groups are substituted; p is 1; X, R 4 , R 5 As defined in claim 1; Ring A, R 8 , m as defined in claim 2.

26. The compound of claim 25, wherein ring D is selected from Each R 10 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl; s is 0 or 1.

27. The compound of the general formula (I) according to claim 25 or 26, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its nitrogen oxide, or its pharmaceutically acceptable salt, wherein R 3 Selected from hydrogen, -(CH2) p -R 7 , C 1-6 alkyl; R 7 is selected from 5-6 membered heteroaryl or phenyl, preferably 6 membered heteroaryl or phenyl, which is optionally further selected from deuterated, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The haloalkoxy group is substituted with one or more groups.

28. A compound of the general formula (I) according to any one of claims 2 to 27, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl; preferably pyrazolyl or tetrahydrofuranyl; in particular, Each R 8 are each independently selected from hydrogen, C 1-6 alkyl; m is 1 or 2, preferably 1.

29. A compound of the general formula (I) according to any one of claims 1 to 28, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X is CR 6 or N, R 6 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl.

30. A compound of the general formula (I) according to any one of claims 1 to 29, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

31. A pharmaceutical composition comprising a compound of the general formula (I) according to any one of claims 1 to 30 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

32. Use of a compound of formula (I) according to any one of claims 1 to 30 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31 in the preparation of a PRMT5 inhibitor.

33. Use of a compound of formula (I) according to any one of claims 1 to 30 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31 in the preparation of a medicament for preventing and / or treating a PRMT5-mediated disease, wherein the disease is preferably cancer and tumor-related diseases, and the disease is preferably bladder cancer.

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