Pyrimidine compound as well as preparation method and medical application thereof

Abstract

The invention relates to a pyrimidine compound as well as a preparation method and medical application thereof. Specifically, the invention relates to a compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as an ATR kinase inhibitor for treating ATR kinase mediated diseases. The definition of each group in the general formula (I) is the same as that in the specification. # imgabs0 #

Description

A pyrimidine compound and its preparation method and medical use Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a pyrimidine compound used as an ATR inhibitor, a preparation method thereof, a pharmaceutical composition containing the pyrimidine compound, and its use in treating ATR kinase-mediated diseases, such as cancer. Background Art

[0002] DNA can be continuously damaged by various factors in the external environment or inside the cell. If not repaired or repaired abnormally, these lesions may lead to cell death or even harmful gene mutations. In order to ensure the stability and integrity of the cell genome, cells have formed a complex network of signaling pathways, collectively known as the DNA damage response (DDR). The DDR is responsible for coordinating the early detection of DNA damage and sending signals to cell cycle checkpoints and DNA repair pathways to pause the cell cycle to initiate repairs, or to initiate cell death when the damage is too severe. Studies have found that healthy cells have multiple DDR mechanisms, and these repair mechanisms can compensate for each other during the DNA repair process. However, many cancer cells have defects in multiple DNA repair pathways and therefore show a greater dependence on intact DNA repair pathways.

[0003] The ataxia telangiectasia mutated gene, Rad3-related kinase (ATR), belongs to the serine-threonine kinase family of phosphatidylinositol 3-kinase (PIKK)s. Upon activation in response to DNA damage, ATR kinase regulates various cellular processes through signaling, including cell cycle arrest, inhibition of replication origins, promotion of deoxynucleotide synthesis, initiation of replication forks, and repair of DNA double-strand breaks, thereby preventing apoptosis. Most tumor cells harbor abnormal DNA damage repair systems, often lacking specific repair pathways (e.g., mutations in p53 or ATM), making them more dependent on ATR for survival. In contrast, in normal cells, due to their robust and intact repair pathways, inhibition of ATR kinase alone has little significant effect. Therefore, inhibiting ATR may have a more pronounced therapeutic effect on cancer while minimizing interference with normal cells, making ATR a promising target for cancer therapy.

[0004] ATR inhibitors can be used alone or as sensitizers for DNA-damaging chemotherapy or radiotherapy, other DDR inhibitors, and immune checkpoint inhibitors. Widely used combination therapy drugs include antimetabolites (such as gemcitabine), DNA cross-linking agents (such as cisplatin, carboplatin), alkylating agents (such as temozolomide), topoisomerase inhibitors (such as camptothecin, topotecan, irinotecan), and other DDR inhibitors (PARP inhibitors). Combination therapy inhibits ATR under elevated levels of replication stress, thereby inhibiting the ability of cancer cells to repair damaged DNA, greatly enhancing the therapeutic effect of cancer.

[0005] Although a variety of ATR kinase inhibitors have been disclosed (e.g., M6620, WO2011154737, WO2016020320, WO2010071837, WO2014089379, WO 2020087170, WO 2020049017, etc.), no ATR inhibitors are currently available on the market. Therefore, it is still necessary to discover more effective and safe ATR inhibitors.

[0006] Summary of the Invention

[0007] After intensive research, the present invention has designed and synthesized a new class of pyrimidine compounds, which can be used as ATR kinase inhibitors for treating diseases such as cancers that are linked to ATR kinase.

[0008] Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0009] in:

[0010] R 1 is selected from hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkoxy, halohydroxyalkyl, alkenyl, and alkynyl;

[0011] Or, R 1 for

[0012] in:

[0013] L is selected from a bond, alkylene, alkenylene, alkynylene, -C(O)-, -S(O)-, -S(O)2-, -C(O)NH-, -S(O)NH-, -S(O)2NH-, -C(O)O-;

[0014] Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclyl, and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with one or more Q groups;

[0015] Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、 -(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c (O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) qC(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-C(O)NR c (CH2) q NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c (O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c is substituted by one or more substituents;

[0016] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, and alkynyl;

[0017] Or, R 1 and R 2 The nitrogen atom to which it is attached forms a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2) q NR a R b is substituted by one or more substituents;

[0018] R 3 Selected from alkyl, haloalkyl or cycloalkyl;

[0019] Each R 4 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkoxy, halohydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2)q NR d C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in;

[0021] Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、 -C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R fwherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

[0022] R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0023] R d and R e each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, and haloalkyl;

[0025] R fselected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0026] m is 0, 1, 2, or 3;

[0027] p is 0, 1, or 2;

[0028] q is an integer from 0 to 6.

[0029] In one embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0030] R 1 for

[0031] in:

[0032] L is selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, -C(O)-, -S(O)-, -S(O)2-, -C(O)NH-, -S(O)NH-, -S(O)2NH-, -C(O)O-; preferably, a bond, an alkylene group, -C(O)-;

[0033] Ring A is selected from aryl, heteroaryl, preferably C 6-10 Aryl or 5-10 membered heteroaryl; the aryl or heteroaryl is optionally substituted with one or more Q groups;

[0034] Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) qC(O)NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-C(O)NR c (CH2) q NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c is substituted by one or more substituents;

[0035] R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NRd C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in;

[0036] Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R fwherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

[0037] R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0038] R d and R e each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0039] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, and haloalkyl;

[0040] R fselected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0041] p is 0, 1, or 2;

[0042] q is an integer from 0 to 6.

[0043] In a specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: Preferably Ring A is optionally further substituted by Q, wherein Q is as defined in the general formula (I).

[0044] In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0045] R 1 for

[0046] R 2 is hydrogen or C 1-6 alkyl;

[0047] L is selected from -CH2-, -C(O)-;

[0048] Ring A is selected from phenyl or 5- to 6-membered heteroaryl, preferably phenyl; Ring A is optionally further substituted by -(CH2) q NR a R b ;

[0049] q is 1 or 2, preferably 1;

[0050] R a and R b Each independently selected from hydrogen or C 1-6 alkyl.

[0051] In another embodiment, the compound represented by general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is a compound represented by general formula (II) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0052] in:

[0053] L is selected from a bond, an alkylene group, -C(O)-; preferably a bond;

[0054] X1, X2, X3, X4 are each independently selected from CH or N;

[0055] Q1 is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R cThe alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-C(O)NR c (CH2) q NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c is substituted by one or more substituents;

[0056] Each Q2 is independently selected from hydrogen, halogen, alkyl, haloalkyl, -(CH2) q C(O)NR a R b , the alkyl group is optionally further NR a R b replace;

[0057] R aand R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in;

[0058] Or, R a and R bTogether with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

[0059] R cselected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0060] R d and R e each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0061] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, and haloalkyl;

[0062] R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0063] n is 0, 1, or 2;

[0064] R 2 、R 3 、R 4 , m, p, q are as defined in the general formula (I).

[0065] In another embodiment, the compound represented by the general formula (II) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

[0066] Q1 is -NR a R b ;

[0067] R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR d (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2)q NR d S(O) p R f is substituted by one or more substituents in;

[0068] Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-10 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R fwherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

[0069] R d and R e Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl;

[0070] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic group are optionally further substituted by one or more groups selected from halogen, alkyl, haloalkyl;

[0071] R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0072] p is 1 or 2;

[0073] q is an integer of 0-6, preferably an integer of 1-6, more preferably an integer of 1-4.

[0074] In another embodiment, the compound represented by general formula (I) or general formula (II) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is a compound represented by general formula (III) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0075] in:

[0076] X1, X2, X3, X4 are each independently selected from CH or N; preferably, X1 is N and X2, X3, X4 are CH, or X2 is N and X1, X3, X4 are CH, or X1, X2, X3, X4 are all CH;

[0077] Y is selected from NR 5 , CR 5 R 6 or SO2;

[0078] R 5 Selected from hydrogen, halogen, amino, oxo, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、C(O)R f 、C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-S(O) p R f 、-S(O) p NR d R e 、-NR d C(O)R f ; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents in a haloalkyl group;

[0079] R 6 Selected from hydrogen, halogen, amino and C 1-6 alkyl;

[0080] Or, R 5 and R 6 The carbon atom to which it is attached forms a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, or heteroaryl;

[0081] R d and R e Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl;

[0082] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic group are optionally further substituted by one or more groups selected from halogen, alkyl, haloalkyl;

[0083] R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0084] p is 1 or 2;

[0085] q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;

[0086] n is 0, 1, or 2;

[0087] s is 1 or 2; preferably 1;

[0088] t is 1 or 2; preferably 1;

[0089] R 2 、R 3 、R 4 , m are as defined in general formula (I); Q2 is as defined in general formula (II).

[0090] In a preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: X1 is N; X2, X3, X4 are CH.

[0091] In a preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from NR 5 ;

[0092] R 5 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group (e.g., oxetane, azetidine, pyrrolidinyl, furyl, piperidinyl, piperazinyl, pyranyl), phenyl, 5-6 membered heteroaryl (e.g., pyridinyl, oxazolyl), -C(O)R f ; the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents in a haloalkyl group;

[0093] R f Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0094] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from CR 5 R 6 ;

[0095] R 5 Selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl (e.g., imidazolyl), -(CH2) q NR d R e 、-C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-S(O) p NR d R e 、-NR d C(O)R f ;

[0096] R 6 Selected from hydrogen, halogen, amino and C 1-6 alkyl;

[0097] R d Selected from hydrogen, C 1-6 alkyl;

[0098] R e Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group (eg, pyranyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl), phenyl, 5-6 membered heteroaryl, said C 3-6 Cycloalkyl, 4 to 6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (eg pyridyl, thiazolyl, imidazolyl, pyrazolyl) optionally further selected from halogen, C 1-6 substituted with one or more groups of an alkyl group;

[0099] R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group (e.g., azetidine, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, azoctane), wherein the 3-8 membered heterocyclic group is optionally further selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, C 3-6 The C3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally further substituted by one or more groups selected from halogen, alkyl, and haloalkyl;

[0100] R f is hydrogen or C 1-6 alkyl;

[0101] p is 1 or 2, preferably 2;

[0102] q is 0, 1, or 2.

[0103] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from CR 5 R 6 ;

[0104] R 5 Selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) q NR d R e 、-NR d C(O)R f 、-S(O) p NR d R e ;

[0105] R 6 Selected from hydrogen, halogen, amino and C 1-6 alkyl;

[0106] R d Selected from hydrogen, C 1-6 alkyl;

[0107] R e Selected from hydrogen, C 1-6 alkyl;

[0108] R f is hydrogen or C 1-6 alkyl;

[0109] p is 2;

[0110] q is 0 or 1;

[0111] In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from CR 5 R6 ;

[0112] R 5 Selected from cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) q NR d R e 、-NR d C(O)R f 、-S(O) p NR d R e ;

[0113] R 6 selected from hydrogen;

[0114] R d Selected from hydrogen, C 1-6 alkyl;

[0115] R e Selected from hydrogen, C 1-6 alkyl;

[0116] R f is hydrogen or C 1-6 alkyl;

[0117] p is 2;

[0118] q is 0 or 1;

[0119] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from SO2.

[0120] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0121] Y is selected from CR 5 R 6 ;

[0122] R 5 and R 6 Together with the carbon atom to which it is attached, it forms an azetidinyl group, a pyrrolidinyl group, or a tetrahydroimidazolyl group; the azetidinyl group, the pyrrolidinyl group, or the tetrahydroimidazolyl group is optionally further substituted by an oxo group.

[0123] In another embodiment, the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is a compound represented by general formula (IIIA) or (IIIB) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0124] in:

[0125] X1 and X2 are each independently selected from CH or N;

[0126] Y1 is selected from N or CR 6 ;

[0127] R 6 Selected from hydrogen, halogen, amino and C 1-6 alkyl;

[0128] R 7 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further selected from halogen, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 substituted by one or more substituents of a haloalkyl group or a 3- to 6-membered heterocyclic group;

[0129] R 8 Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0130] Or, R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, preferably a 6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, wherein the C 3-6Cycloalkyl, 3-8 membered heterocyclic group may be further selected from halogen, C 1-6 Alkyl, C 1-6 substituted with one or more haloalkyl groups;

[0131] R d and R e are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclyl are optionally further substituted with one or more substituents selected from halogen;

[0132] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents of a haloalkyl group;

[0133] R 10 Selected from C 1-6 Alkyl, C 1-6 alkyl halide;

[0134] q is an integer from 1 to 4, preferably 1 or 2;

[0135] n is 0, 1, or 2;

[0136] R 2 、R 3 、R 4 , m are as defined in general formula (I); Q2 is as defined in general formula (II).

[0137] In a preferred embodiment, the compound represented by general formula (IIIA) or (IIIB) according to the present invention, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: X1 is N, X2 is CH.

[0138] In another preferred embodiment, the compound represented by general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0139] Y1 is selected from CR 6 ;

[0140] R 6 Selected from hydrogen, halogen, amino and C 1-6alkyl.

[0141] In another preferred embodiment, the compound represented by general formula (IIIA) or (IIIB) according to the present invention, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0142] Y1 is selected from N.

[0143] In another preferred embodiment, the compound represented by general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0144] R 7 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group (e.g., oxetanyl, azetidinyl, pyranyl, furanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), phenyl, 5- to 6-membered heteroaryl (e.g., thiazolyl, imidazolyl, pyrazolyl, pyridinyl), -(CH2) q NR d R e , wherein the C 3-6 Cycloalkyl, 3 to 6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 The alkyl group is substituted with one or more substituents;

[0145] R 8 Selected from hydrogen, C 1-6 alkyl;

[0146] R d Selected from C 1-6 alkyl;

[0147] R e Selected from C 1-6 alkyl;

[0148] Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);

[0149] q is 2.

[0150] In another preferred embodiment, the compound represented by general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0151] R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group (e.g., azetidinyl, azocanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), preferably a 6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-6 The C 3-6 Cycloalkyl, 3-8 membered heterocyclic group may be further selected from halogen, C 1-6 Alkyl, C 1-6 The alkyl group is substituted with one or more haloalkyl groups.

[0152] In another preferred embodiment, the compound represented by general formula (IIIB) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0153] R 10 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0154] In another embodiment, the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is a compound represented by general formula (IIIC) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0155] in:

[0156] X1 and X2 are each independently selected from CH or N;

[0157] Y2 is selected from NR 11 , CR 11 R 12 , SO2;

[0158] R 12 Selected from hydrogen, halogen, amino and C 1-6 alkyl;

[0159] R 11 Selected from hydrogen, halogen, oxo, thio, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、-C(O)NR d R e 、-S(O) p NR d R e and -NR d C(O)R f is substituted by one or more substituents; said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents in a haloalkyl group;

[0160] Or, R 11 and R 12 The carbon atom to which it is attached forms a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, or heteroaryl;

[0161] R d and R e are each independently selected from hydrogen and C 1-6 alkyl;

[0162] R f Selected from C 1-6 alkyl;

[0163] p is 1 or 2;

[0164] q is an integer from 0 to 4, preferably an integer from 0 to 2;

[0165] R 2 、R 3 、R 4, m are as defined in general formula (I); Q2, n are as defined in general formula (II).

[0166] In another embodiment, the compound represented by the general formula (II) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

[0167] Q1 is selected from NR a R b ;

[0168] R a Selected from hydrogen and C 1-6 alkyl;

[0169] R b Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further selected from -NR d R e 、-NR d C(O)R f 、-C(O)NR d R e substituted by a substituent;

[0170] R d and R e are each independently selected from hydrogen and C 1-6 alkyl;

[0171] or R d and R e Together with the nitrogen atom to which it is attached, it forms a 5-6 membered heterocyclic group (e.g., pyrrolidinyl), wherein the 5-6 membered heterocyclic group is optionally further selected from halogen, amino, oxo, C 1-6 substituted by an alkyl substituent;

[0172] R f Selected from C 1-6 alkyl.

[0173] In another embodiment, the compound represented by the general formula (II) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

[0174] L is a bond;

[0175] Q1 is selected from NR a R b ;

[0176] R a Selected from hydrogen and C 1-6 alkyl;

[0177] R b Selected from C 1-6 Alkyl, preferably C 1-4 Alkyl, said alkyl being optionally further selected from -NR d R e 、-NR d C(O)R f 、-C(O)NR d R e substituted by a substituent;

[0178] R d and R e are each independently selected from hydrogen and C 1-6 alkyl;

[0179] or R d and R e Together with the nitrogen atom to which it is attached, it forms a 5-6 membered heterocyclic group (e.g., pyrrolidinyl), wherein the 5-6 membered heterocyclic group is optionally further selected from halogen, amino, oxo, C 1-6 The alkyl group is substituted by a substituent, preferably substituted by an oxo group;

[0180] R f Selected from C 1-6 alkyl.

[0181] In another embodiment, the compound represented by the general formula (I) or the general formula (II) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is a compound represented by the general formula (IV) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein,

[0182] in:

[0183] X1 and X2 are each independently selected from CH or N;

[0184] Y3, Y4, Y5, and Y6 are each independently selected from CH or N, preferably all CH, or one of them is N and the others are CH, or two of them are N and the others are CH;

[0185] Each R 13a are each independently selected from hydrogen, halogen, C 1-6 Alkyl; s is 0, 1, 2, 3 or 4, preferably 0, 1 or 2;

[0186] R 13b Selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 3-6Cycloalkyl, 3-8 membered heterocyclic group, -C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e ;

[0187] R d and R e are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, as described;

[0188] or R d and R e Together with the nitrogen atom to which it is attached, it forms a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally further selected from halogen, amino, oxo, C 1-6 substituted by an alkyl group or a 5-6-membered heterocyclic group;

[0189] R f Selected from hydrogen and C 1-6 alkyl;

[0190] q is an integer from 1 to 4, preferably 1 or 2;

[0191] R 2 、R 3 、R 4 , m are as defined in general formula (I); Q2, n are as defined in general formula (II).

[0192] In a preferred embodiment, according to the compound represented by general formula (IV) of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Y3, Y4, Y5, and Y6 are CH.

[0193] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X1 is N and X2 is CH.

[0194] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 13b Selected from -C(O)NR d R e

[0195] Rd Selected from hydrogen, C 1-6 alkyl;

[0196] R e Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally further substituted with halogen;

[0197] or R d and R e Together with the nitrogen atom to which it is attached, it forms a 5-6 membered heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), which is optionally further substituted by a 5-6 membered heterocyclic group (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl).

[0198] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 13b Selected from -C(O)NR f (CH2) q NR d R e ;

[0199] R d Selected from hydrogen, C 1-6 Alkyl, preferably C 1-6 alkyl;

[0200] R e Selected from C 1-6 alkyl;

[0201] or R d and R e Together with the nitrogen atom to which it is attached, it forms a 5-6 membered heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);

[0202] R f Selected from hydrogen and C 1-6 Alkyl, preferably hydrogen;

[0203] q is an integer from 1 to 4, preferably 2.

[0204] In another embodiment, the compound represented by the general formula (I) or the general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Q1 is selected from an 8-10 membered fused heterocyclic group, preferably It is optionally further selected from C1-6 Alkyl and C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0205] In another embodiment, the compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0206] in:

[0207] R 1 for

[0208] L is selected from a bond, an alkylene group, or -C(O)-;

[0209] Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, preferably phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyridopyrrolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, which are optionally substituted with one or more Q groups;

[0210] Q is selected from halogen, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) q NR a R b ;

[0211] R a and R b are each independently selected from hydrogen and C 1-6 alkyl;

[0212] q is an integer of 0-4, preferably an integer of 0-2.

[0213] In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0214] Among them, R 2 Selected from hydrogen and C 1-6 alkyl.

[0215] In another embodiment, the compound represented by the general formula (I) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 and R2 Together with the nitrogen atom to which it is connected, it forms a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, preferably an 8-10 membered heterocyclic group, more preferably It is optionally further selected from halogen, amino, cyano, hydroxy, mercapto, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) q NR a R b is substituted by one or more substituents;

[0216] q is an integer from 1 to 4, preferably 1 or 2;

[0217] R a and R b Each independently selected from hydrogen or C 1-6 alkyl.

[0218] In another embodiment, the compound represented by the general formula (I) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group selected from: Preferably The heterocyclic group is optionally further selected from halogen, amino, cyano, hydroxy, mercapto, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) q NR a R b is substituted by one or more substituents;

[0219] q is an integer from 1 to 4, preferably 1 or 2;

[0220] R a and R b Each independently selected from hydrogen or C 1-6 alkyl.

[0221] In another embodiment, the compound represented by the general formula (I) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 and R 2Together with the nitrogen atom to which it is attached, it forms a heterocyclic group selected from: The heterocyclic group is optionally further selected from C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) q NR a R b is substituted by one or more substituents;

[0222] q is 1 or 2;

[0223] R a and R b Each independently selected from hydrogen or C 1-6 alkyl.

[0224] In another specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0225] R 1 for

[0226] R 2 is hydrogen;

[0227] in:

[0228] L is selected from -CH2-, -C(O)-;

[0229] Ring A is selected from phenyl, said phenyl being optionally further substituted with -(CH2) q NR a R b replaced by;

[0230] R a and R b Each independently selected from hydrogen or C 1-6 alkyl;

[0231] q is 1.

[0232] In another specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0233] R 1 for

[0234] R 2 is hydrogen;

[0235] in:

[0236] L is a bond;

[0237] Ring A is selected from C 6-10 Aryl or 5- to 10-membered heteroaryl, preferably 5- to 10-membered heteroaryl; the C 6-10 Aryl or 5 to 10 membered heteroaryl is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 Halogen alkyl, -(CH2) q NR a R b is substituted by one or more groups;

[0238] R a and R b Each independently selected from hydrogen or C 1-6 alkyl;

[0239] q is 1.

[0240] In another specific embodiment, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0241] R 1 for

[0242] R 2 is hydrogen;

[0243] in:

[0244] L is a bond;

[0245] Ring A is selected from Ring A is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 Halogen alkyl, -(CH2) q NR a R b is substituted by one or more groups;

[0246] R a and R b Each independently selected from hydrogen or C 1-6 alkyl;

[0247] q is 1.

[0248] In another embodiment, the compound represented by general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, is a compound represented by general formula (V) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

[0249] in:

[0250] Ring M is selected from 5-6 membered heterocyclic groups, preferably 6 membered heterocyclic groups;

[0251] Y7 is selected from NR 13 , CR 13 R 14 , SO2;

[0252] R 14 Selected from hydrogen, halogen, amino and C 1-6 alkyl;

[0253] R 13 Selected from hydrogen, halogen, oxo, thio, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、-C(O)NR d R e 、-S(O) p NR d R e and -NR d C(O)R f is substituted by one or more substituents; said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents in a haloalkyl group;

[0254] Or, R 13 and R 14 The carbon atom to which it is attached forms a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, or heteroaryl;

[0255] R d and R e are each independently selected from hydrogen and C 1-6 alkyl;

[0256] R f Selected from C 1-6 alkyl;

[0257] p is 1 or 2;

[0258] q is an integer from 0 to 4, preferably an integer from 0 to 2;

[0259] R 2 、R 3 、R 4 , m are as defined in general formula (I); Q2, n are as defined in general formula (II).

[0260] In a preferred embodiment, the compound represented by the general formula (V) according to the present invention or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring M is

[0261] In a preferred embodiment, the compound represented by the general formula (V) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Y7 is CR 13 R 14 ;

[0262] R 14 Selected from hydrogen or C 1-6 Alkyl, preferably hydrogen;

[0263] R 13 Selected from -C(O)NR d R e ;

[0264] R d and R e are each independently selected from hydrogen and C 1-6 alkyl.

[0265] In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV), general formula (V) or its stereoisomers, tautomers, meso-forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R3 Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl, in particular methyl, ethyl, n-propyl, isopropyl.

[0266] In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each R 4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl; m is 0 or 1.

[0267] In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 2 is hydrogen or C 1-6 Alkyl, preferably hydrogen.

[0268] In another embodiment, the compound represented by the general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each Q2 is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, oxo, cyano, (CH2) q C(O)NR a R b , the C 1-6 The alkyl group is optionally further substituted with NR a R b replace;

[0269] R a and R b Each independently selected from hydrogen or C 1-6 alkyl;

[0270] q is an integer from 0 to 6;

[0271] n is an integer of 0 to 4, preferably an integer of 0 to 2.

[0272] In another embodiment, the compound represented by the general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each Q2 is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, oxo, cyano, -C(O)NR a R b 、-CH2-NR a R b ;

[0273] R a and R b Each independently selected from hydrogen or C 1-6 alkyl.

[0274] In another embodiment, the compound represented by the general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein n is 1 or 2, preferably 1.

[0275] Typical compounds of the present invention include, but are not limited to:

[0276] The present invention also relates to a method for preparing the compound represented by general formula (I) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which comprises the following steps:

[0277] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) reacts with the compound of general formula (IB) to obtain a compound represented by general formula (I);

[0278] The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, or DIPEA (diisopropylethylamine);

[0279] The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

[0280] The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

[0281] Where: R 1 、R 2 、R 3 、R 4 , m are as defined in the general formula (I).

[0282] The present invention also relates to a method for preparing the compound represented by general formula (II) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which comprises the following steps:

[0283] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IIB) to obtain a compound represented by general formula (II);

[0284] The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, or DIPEA (diisopropylethylamine);

[0285] The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

[0286] The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

[0287] Where: R 2 、R 3 、R 4 , L, X1~X4, Q1, Q2, m, and n are as defined in the general formula (II).

[0288] The present invention also relates to a method for preparing the compound represented by general formula (III) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which comprises the following steps:

[0289] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IIIb) to obtain a compound represented by general formula (III);

[0290] The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, or DIPEA (diisopropylethylamine);

[0291] The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

[0292] The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

[0293] Where: R 2 、R 3 、R 4 , X1~X4, Y, Q2, m, and n are as defined in the general formula (III).

[0294] The present invention also relates to a method for preparing a compound represented by general formula (IIIA) according to the present invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0295] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IIIAa) undergoes a condensation reaction with the compound of general formula (IIIAb) to obtain a compound represented by general formula (IIIA);

[0296] The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, or DIPEA (diisopropylethylamine);

[0297] The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

[0298] The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

[0299] Where: R 2 、R 3 、R 4 、R 7 、R 8 , X1, X2, Y1, Q2, m, and n are as defined in the general formula (IIIA).

[0300] The present invention also relates to a method for preparing the compound represented by general formula (IIIC) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0301] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) reacts with the compound of general formula (IIICb) to obtain a compound represented by general formula (IIIC);

[0302] The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, or DIPEA (diisopropylethylamine);

[0303] The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

[0304] The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

[0305] Where: R 2 、R 3 、R 4 , X1, X2, Y2, Q2, m, and n are as defined in the general formula (IIIC).

[0306] The present invention also relates to a method for preparing the compound represented by general formula (IV) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0307] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) reacts with the compound of general formula (IVb) to obtain a compound represented by general formula (IV);

[0308] The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, or DIPEA (diisopropylethylamine);

[0309] The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

[0310] The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

[0311] Where: R 2 、R 3 、R 4 、R 13a 、R 13b , X1, X2, Y3~Y6, Q2, m, n, s are as defined in the general formula (IV).

[0312] The present invention further relates to a pharmaceutical composition comprising a compound according to the present invention or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0313] The present invention further relates to the use of the compound according to the present invention or its stereoisomers, tautomers, meso-racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of ATR kinase inhibitors.

[0314] The present invention further relates to the use of the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for treating ATR kinase-mediated diseases, preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

[0315] The present invention also relates to the compounds according to the invention or their stereoisomers, tautomers, meso-, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or to pharmaceutical compositions comprising them, for use as ATR kinase inhibitors.

[0316] The present invention also relates to the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating ATR kinase-mediated diseases, preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

[0317] The present invention also relates to a method for inhibiting ATR kinase, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0318] The present invention also relates to a method for treating an ATR kinase-mediated disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, wherein the disease is preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

[0319] The compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids according to conventional methods in the field of the present invention. The acids include inorganic acids and organic acids, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like being particularly preferred.

[0320] The compound of the present invention can be reacted with a base to form a pharmaceutically acceptable base addition salt according to conventional methods in the art. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, and the like.

[0321] 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.

[0322] 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.

[0323] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0324] 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.

[0325] Dispersible powders and granules suitable for preparing aqueous suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent, or one or more preservatives for mixing by the addition of water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavorings, and coloring agents may also be added. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] The present invention may contain a compound of the general formula and a pharmaceutically acceptable salt, hydrate, or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to form a composition, and then prepared into a clinically acceptable dosage form. The derivatives of the present invention may 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 may be used as the sole active ingredient or in combination with other therapeutic agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.

[0332] Terminology

[0333] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0334] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0335] 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, an alkyl group containing 1 to 4 carbon atoms or an alkyl group containing 1 to 3 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 and may be 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.

[0336] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), further preferably an alkylene containing 1 to 4 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH—), 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and 1,4-butylene (—CHCHCHCHCH—). Alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0337] The term "alkenyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be 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.

[0338] The term "alkynyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent may be 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.

[0339] 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.

[0340] 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 7 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:

[0341] 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 7 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:

[0342] 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 7-10 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:

[0343] 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 may be optionally substituted or unsubstituted, and when substituted, the substituent may be 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.

[0344] 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 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 7 to 12 ring atoms, of which 1 to 4 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.

[0345] 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 7 to 12 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral 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 single spiral heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0346] 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 7 to 12 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:

[0347] 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 7 to 12 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:

[0348] 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:

[0349] wait.

[0350] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be 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.

[0351] 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. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0352] The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be 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.

[0353] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0354] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be 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.

[0355] The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl 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, substituents can be one or more following groups 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.

[0356] The alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived by removing one hydrogen atom from a parent ring atom, or residues derived by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely, "alkenylene", "alkynylene", "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0357] The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

[0358] The term "heterocycloalkoxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

[0359] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0360] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0361] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0362] The term "hydroxy" refers to -OH.

[0363] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0364] The term "amino" refers to -NH2.

[0365] The term "cyano" refers to -CN.

[0366] The term "nitro" refers to -NO2.

[0367] The term "oxo" refers to =0.

[0368] The term "thio" refers to =S.

[0369] The term "carboxy" refers to -C(O)OH.

[0370] The term "mercapto" refers to -SH.

[0371] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0372] The term "acyl" refers to a compound of the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0373] "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.

[0374] "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.

[0375] 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.

[0376] "Pharmaceutically acceptable salts" or "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.

[0377] "Carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. DETAILED DESCRIPTION

[0378] 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 understood that these examples do not limit the present invention. Variations of the present invention now known or further developed are considered to fall within the scope of the invention described herein and claimed.

[0379] 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.

[0380] 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's "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.

[0381] 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.

[0382] 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 a WNMR-I-400 MHz nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0383] MS was measured using an LC (Agilent 1260 Infinity) / MS (G6125B) mass spectrometer (manufacturer: Agilent).

[0384] The preparative liquid chromatography method used a GX-281 high performance liquid chromatograph (manufacturer: GILSON). 5 μm EVO C18 100 (100 mm × 30.0 mm), mobile phase: acetonitrile / water.

[0385] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0386] 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.

[0387] 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, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.

[0388] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0389] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0390] 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, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] Preparation Example 1: Synthesis of 4-bromo-3-fluoro-5-nitropyridine (Intermediate A1)

[0396] Step 1: Preparation of 3-fluoro-5-nitropyridin-4-amine (A1-2)

[0397] 3-Fluoropyridin-4-amine (A1-1) (30 g, 268 mmol, 1.0 eq.) was dissolved in cold concentrated sulfuric acid (180 mL). Concentrated HNO3 (42.2 g, 402 mmol, 1.5 eq.) was added dropwise in an ice bath. The mixture was heated to 60°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and added to 1000 mL of ice water. 400 mL of 10 mol / L aqueous KOH solution was added to a pH of 12. 500 mL of ethyl acetate was then added and extracted three times with ethyl acetate. The organic phases were combined, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to afford compound A1-2 as a yellow solid (15.0 g, yield 33.8%).

[0398] Step 2: Preparation of 4-bromo-3-fluoro-5-nitropyridine (A1)

[0399] Compound A1-2 (15 g, 98.5 mmol, 1.0 eq.) was dissolved in anhydrous ACN (150 mL), followed by the addition of CuBr (21.5 g, 150 mmol, 1.5 eq.). Tert-butyl nitrite (16 g, 150 mmol, 1.5 eq.) was added dropwise with stirring at 70°C, and the mixture was stirred at 70°C for 4 hours. The reaction mixture was added with 300 mL of water, followed by 300 mL of ethyl acetate. Extraction was performed three times with ethyl acetate. The combined organic phases were washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether / ethyl acetate = 5:2) to afford 7.0 g of compound A1 as a yellow solid in an 85.7% yield.

[0400] Preparation Example 2: Synthesis of 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylic acid (Intermediate A2)

[0401] Step 1: Preparation of methyl 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylate (A2-3)

[0402] Methyl 3-amino-6-bromopyrazine-2-carboxylate (A2-1) (10.0 g, 43.3 mmol, 1.0 eq.), (4-(isopropylsulfonyl)phenyl)boronic acid (A2-2) (11.9 g, 52 mmol, 1.2 eq.), Cs2CO3 (42.4 g, 130 mmol, 3.0 eq.), and Pd(dppf)Cl2 (800 mg, 8%) were dissolved in dioxane (90 mL), and 10 mL of water was added. The mixture was stirred at 80°C under a nitrogen atmosphere for 8 hours. 300 mL of water was added to the reaction mixture, followed by washing with 300 mL of ethyl acetate and extraction with ethyl acetate three times. 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 to obtain 11.0 g of compound A2-3 as a yellow solid in a yield of 75.8%.

[0403] Step 2: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylic acid (A2)

[0404] Compound A2-3 (11 g, 32.8 mmol, 1.0 eq.) was dissolved in MeOH / THF / H₂O (3:2:1, 100 mL). LiOH.H₂O (4.2 g, 98.4 mmol, 3.0 eq.) was added and stirred at 25°C for 8 hours. 1 mol / L HCl was added dropwise to the reaction mixture until no solid precipitated. The resulting solid was filtered to afford 7.4 g of compound A2 as a yellow solid in a 74.0% yield.

[0405] Preparation Example 3: Synthesis of 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (Intermediate A3)

[0406] Step 1: Preparation of methyl 1-(3-fluoro-5-nitropyridin-4-yl)piperidine-4-carboxylate (A3-2)

[0407] Compound A1 (3.1 g, 14.1 mmol, 1.0 eq.), methyl piperidine-4-carboxylate (A3-1) (2.44 g, 17 mmol, 1.2 eq.), and TEA (2.9 g, 28.2 mmol, 2.0 eq.) were dissolved in DMF (20 mL) and stirred at 25°C for 3 hours. The reaction mixture was added with 100 mL of water and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain 3.4 g of compound A3-2 as a yellow solid in a yield of 82.5%.

[0408] Step 2: Preparation of methyl 1-(3-fluoro-5-nitropyridin-4-yl)piperidine-4-carboxylate (A3-3)

[0409] Compound A3-2 (3.4 g, 12 mmol, 1.0 eq.) was dissolved in anhydrous methanol (40 mL), and Pd / C (680 mg, 20%) was added. The mixture was stirred at 25°C under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through celite, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to afford 3.0 g of compound A3-3 as a yellow solid, in a yield of 96.5%.

[0410] Step 3: Preparation of methyl 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylate (A3-4)

[0411] Compound A2 (4.3 g, 13.4 mmol, 1.0 eq.), compound A3-3 (4.1 g, 16.1 mmol, 1.2 eq.), DIEA (4.2 g, 32.2 mmol, 2.5 eq.), and HATU (6.6 g, 17.4 mmol, 1.3 eq.) were dissolved in DMF (30 mL) and stirred at 25°C for 3 hours. 30 mL of water was added to the reaction mixture, and stirring continued for 8 minutes. 10 mL of water was then added and stirring continued for 5 minutes. A solid precipitated, and the reaction mixture was filtered. The filter cake was washed with 8 mL of methanol and then with 8 mL of ethyl acetate. The filter cake was dried to afford 4.9 g of compound A3-4 as a yellow solid, in a 66.2% yield.

[0412] Step 4: Preparation of 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (A3)

[0413] Compound A3-4 (4.9 g, 8.8 mmol, 1.0 eq.) was dissolved in MeOH / DCM / H₂O (3:2:1, 50 mL). LiOH.H₂O (11.1 g, 26.4 mmol, 3.0 eq.) was added and stirred at 40°C for 6 hours. 1 mol / L HCl was added dropwise to the reaction mixture until no solid precipitated. The mixture was filtered to obtain 4.1 g of compound A3 as a yellow solid in an 84.3% yield.

[0414] Example 1: Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazole-2-carboxamide (1)

[0415] Step 1: Preparation of methyl 3-amino-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxylate (1-3)

[0416] Methyl 3-amino-6-bromopyrazine-2-carboxylate (1-1) (500 mg, 2.16 mmol, 1.00 eq), (4-(methylsulfonyl)phenyl)boronic acid (1-2) (476 mg, 2.38 mmol, 1.1 eq), 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (354 mg, 0.43 mmol, 0.2 eq), and sodium carbonate (459 mg, 4.3 mmol, 2.00 eq) were dissolved in dioxane (10 mL) and water (1 mL) and reacted at 100°C under a nitrogen atmosphere for 1.5 hours. The reaction solution was then concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: 100% ethyl acetate / petroleum ether) to afford compound 1-3 as a black solid (544 mg, 84% yield, 93% purity).

[0417] LCMS (ESI) m / z 308, (M+H) + .

[0418] Step 2: Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxylic acid (1-4)

[0419] Compound 1-3 (544 mg, 1.77 mmol, 1.0 eq.) and lithium hydroxide (212 mg, 8.85 mmol, 5.0 eq.) were dissolved in methanol (5 mL) and water (5 mL) and heated to 90°C for 2 hours. The reaction mixture was cooled and 1N dilute hydrochloric acid was added. A solid precipitated, which was filtered to obtain a filter cake. The mixture was then concentrated in vacuo to afford crude compound 1-4 as a black solid (375 mg, 72% yield, 95% purity).

[0420] LCMS (ESI) m / z 294, (M+H) + .

[0421] Step 3: Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazole-2-carboxamide (1)

[0422] Compound 1-4 (100 mg, 0.34 mmol, 1.00 eq), 1H-pyrrolo[2,3-b]pyridin-4-amine (1-5) (45 mg, 0.34 mmol, 1.0 eq), HATU (156 mg, 0.42 mmol, 1.2 eq), and DIPEA (132 mg, 1.02 mmol, 3.00 eq) were dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. The reaction solution was purified by reverse-phase preparative HPLC (mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume percentage, flow rate 20.0 mL / min) to obtain compound 1 as a yellow solid (30.5 mg, yield 22%, purity 98%).

[0423] LCMS (ESI) m / z 409, (M+H) + .

[0424] 1 H NMR(400MHz,DMSO-d6)δ11.2(s,1H),10.55(s,1H),9.03(s,1H),8.51(d,J=8.5Hz,2H),8 .33(s,1H),7.97–7.82(m,4H),7.63(d,J=8.4Hz,1H),6.95(d,J=8.7Hz,1H),3.23(s,3H).

[0425] Example 2: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-((methylamino)methyl)benzyl)pyrazole-2-carboxamide (2)

[0426] Step 1: Preparation of tert-butyl (4-((3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)methyl)benzyl)(methyl)carbamate (2-2)

[0427] To a solution of compound A2 (500 mg, 1.5 mmol, 1.0 eq.), HATU (709.9 mg, 1.87 mmol, 1.2 eq.), and DIPEA (401 mg, 3.1 mmol, 2.0 eq.) in DMF (6 ml) was added tert-butyl (4-(aminomethyl)benzyl)(methyl)carbamate (2-1) (467 mg, 1.87 mmol, 1.2 eq.), and stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO₃, washed with saturated brine, and concentrated under reduced pressure to afford compound 2-2 (800 mg, 92% yield, 95% purity) as a colorless, transparent liquid.

[0428] LCMS (ESI) m / z 554.69, (M+H) + .

[0429] Step 2: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-((methylamino)methyl)benzyl)pyrazole-2-carboxamide (2)

[0430] To a solution of compound 2-2 (800 mg, 1.44 mmol, 1.0 eq.) in DCM (10 ml) was added TFA (2 ml) and stirred at room temperature for 0.5 hours. The reaction mixture was adjusted to a pH of 10-11 with a 1 mol / L NaOH / H₂O solution, extracted with DCM, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: MeOH / DCM = 0% to 10%) to afford compound 2 (390 mg, 59% yield, 96% purity) as a yellow solid.

[0431] LCMS (ESI) m / z 454, (M+H) + .

[0432] 1H NMR (400MHz, DMSO) δ9.49(s,1H),8.99(s,1H),8.48(d,J=8.4Hz,2H),7.89(d,J=8.4Hz,4H),7.28(q,J=8.4H z, 4H), 4.53 (d, J = 6.4Hz, 2H), 3.61 (s, 2H), 3.46 (dt, J = 13.2, 6.6Hz, 2H), 2.24 (s, 3H), 1.18 (d, J = 6.8Hz, 6H). ).

[0433] The following compounds were prepared by referring to the synthesis method of Example 2:

[0434] Example 3: Preparation of (3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone (3)

[0435] Compound A2 (50 mg, 155.6 mmol, 1.0 eq.), 1,2,3,4-tetrahydroisoquinoline (3-1) (27 mg, 203 mmol, 1.3 eq.), HATU (77 mg, 203 mmol, 1.0 eq.), and DIPEA (41 mg, 318 mmol, 2.0 eq.) were dissolved in DMF (2 mL) and stirred at 25°C for 14 hours. The reaction mixture was added with 2 mL of water and stirred for 10 minutes. Then, 6 mL of water was added and stirring continued for 10 minutes. The mixture was filtered, and the filter cake was rinsed with 2 mL of methanol and then with 2 mL of ethyl acetate. The filter cake was collected and dried to afford 63 mg of compound 3 as a yellow solid (yield 92.6%, purity 96.2%).

[0436] LCMS (ESI) m / z 437, (M+H) + .

[0437] 1 H NMR (400MHz, DMSO) δ8.85(s,1H),8.22(d,J=8.4Hz,2H),7.90(d,J=8.8Hz,2H),7.25(d,J=28.6Hz,3H),6.98(s,2H),4.84(s ,1H),4.75(s,1H),3.91(s,1H),3.71(s,1H),3.44(s,1H),2.91(d,J=12.0Hz,2H),2.08–1.93(m,1H),1.18(d,J=6.8Hz,6H).

[0438] The following compounds were prepared by referring to the synthesis method of Example 3:

[0439] Example 5: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-((methylamino)methyl)benzoyl)pyrazole-2-carboxamide (5)

[0440] To a solution of H5IO6 (602.9 mg, 2.64 mmol, 6.0 eq.) and CrO3 (2.2 mg, 0.02 mmol, 5 mol%) in ACN (6 ml) was added Ac2O (270 mg, 2.64 mmol, 6.0 eq.), and the mixture was stirred at 0°C for 0.5 h. Compound 2 (200 mg, 0.44 mmol, 1.0 eq.) was then added to the reaction mixture. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO3, and then washed with saturated brine. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluent: MeOH / DCM = 0% to 10%) to obtain Compound 5 (3 mg, 1.5% yield, 96% purity) as a yellow solid.

[0441] LCMS (ESI) m / z 468, (M+H) + .

[0442] 1 H NMR (400MHz, DMSO) δ9.13 (s, 1H), 8.41 (d, J = 8.4Hz, 2H), 7.98 (d, J = 8.0Hz 1H), 7.92 (d, J = 7.8Hz 1H),7.63(d,J=8.0Hz,2H),4.36(s,1H),3.93(s,2H),3.53–3.45(m,1H),3.42(s,1H),2.40(s,3H),1.20(d,J=6.8Hz,6H).

[0443] Example 6: Preparation of 3-amino-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (6)

[0444] Step 1: Preparation of 1-(3-fluoro-5-nitropyridin-4-yl)-4-(oxetane-3-yl)piperazine (6-2)

[0445] Compound A1 (200 mg, 0.91 mmol, 1.0 eq.), 1-(oxetan-3-yl)piperazine (6-1) (129 mg, 0.91 mmol, 1.0 eq.), and TEA (235 mg, 1.82 mmol, 2.0 eq.) were dissolved in DMF (5 mL) and stirred at 25°C for 4 hours. The reaction mixture was added with 20 mL of water and stirred for 10 minutes. 20 mL of ethyl acetate was then added and stirred for another 5 minutes. Extraction was performed three times with ethyl acetate. The organic phases were combined and washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH / DCM = 0% to 5%) to obtain 220 mg of compound 6-2 as a yellow powder (yield: 89.5%).

[0446] Step 2: Preparation of 5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine (6-3)

[0447] In a 50 mL single-necked flask, compound 6-2 (220 mg, 0.79 mmol, 1.0 eq.) was added, along with 44 mg of 20% Pd / C and 35 mL of methanol. The mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through celite, and the filter cake was washed with 4 mL of methanol. The filtrate was concentrated under reduced pressure to afford compound 6-3 (170 mg, yield: 86.7%).

[0448] Step 3: Preparation of 3-amino-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (6)

[0449] Compound A2 (50 mg, 0.16 mmol, 1.0 eq.), compound 6-3 (53 mg, 0.21 mmol, 1.3 eq.), HATU (80 mg, 0.21 mmol, 1.3 eq.), and DIPEA (42 mg, 0.32 mmol, 2.0 eq.) were dissolved in DMF (2.5 mL) and stirred at 25°C for 14 hours. The reaction mixture was added with 2 mL of water and stirred for 10 minutes. Then, 6 mL of water was added and stirring continued for 10 minutes. The mixture was filtered, and the filter cake was rinsed with 2 mL of methanol and then with 2 mL of ethyl acetate. The filter cake was collected and dried to obtain 37 mg of compound 6 as a yellow solid (yield 43%, purity 96%).

[0450] LCMS (ESI) m / z 556, (M+H) + .

[0451] 1H NMR (400MHz, DMSO) δ10.56(s,1H),9.24(s,1H),9.14(s,1H),8.72(s,1H),8.47(d,4H),8.14–7.82(m,5H),7.83(d,2H),4.40(m,1H),4.11( m,1H),3.66(m,5H),3.47(m,2H),3.27(m,3H),3.14(m,3H),2.65(m,5H),2.40(m,5H),2.05(s,1H),1.93(s,6H),1.61(d,2H),1.22(s,6H).

[0452] The following compounds were prepared by referring to the synthesis method of Example 6:

[0453] Example 8: Preparation of 3-amino-N-(4-(4-(ethylcarbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (8)

[0454] Compound A3 (100 mg, 0.18 mmol) and ethylamine hydrochloride (18 mg, 0.22 mmol) were dissolved in DMF (2 ml). HATU (84 mg, 0.22 mmol) and DIPEA (46 mg, 0.36 mmol) were added. The mixture was reacted at room temperature under a nitrogen atmosphere for 3 hours. Water (6 ml) was added dropwise to the reaction solution. A solid precipitated, which was filtered and the filter cake was rinsed with a small amount of water and dried to obtain compound 8 (68 mg, yellow solid, 65% yield).

[0455] LCMS (ESI) m / z 570.3, (M+H) + .

[0456] 1H NMR (400MHz, DMSO) δ10.51(s,1H),9.28(s,1H),9.10(s,1H),8.37(dd,J=18.7,5.8Hz,3H),8.09–7.88(m,4H),7.78(t,J=5.4Hz,1H),3.59(dt,J=13 .5,6.7Hz,1H),3.26–3.18(m,2H),3.05(dd,J=7.1,5.6Hz,4H),2.31–2.2 2(m,1H),1.87–1.77(m,4H),1.20(d,J=6.8Hz,6H),0.99(t,J=7.2Hz,3H).

[0457] The following compounds were prepared according to the synthesis method of Example 8:

[0458] Example 54: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-(4-(methylcarbamoyl)piperidin-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)pyrazole-2-carboxamide (54)

[0459] Step 1: Preparation of 1-(2-hydroxy-5-nitropyridin-4-yl)-N-methylpiperidine-4-carboxamide (54-3)

[0460] 4-Chloro-5-nitropyridin-2-ol (54-1) (200 mg, 1.15 mmol, 1.0 eq.), N-methylpiperidine-4-carboxamide hydrochloride (54-2) (246 mg, 1.37 mmol, 1.2 eq.), and triethylamine (0.48 mL, 3.45 mmol, 3 eq.) were added sequentially to DMF (5 mL) at room temperature. The reaction mixture was stirred at 40°C for 16 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-29%) to afford compound 54-3 (330 mg, 100% yield).

[0461] Step 2: Preparation of 1-(5-amino-2-hydroxypyridin-4-yl)-N-methylpiperidine-4-carboxamide (54-4)

[0462] Compound 54-3 (330 mg, 1.2 mmol, 1.0 eq.) and palladium / carbon (10 wt.%, palladium loading) (100 mg) were added sequentially to THF / DMF / H2O (10 mL / 5 mL / 1 mL) at room temperature. The reaction mixture was stirred at 20°C under a hydrogen atmosphere for 16 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-78%) to afford compound 54-4 (130 mg, 43.8% yield).

[0463] Step 3: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-(4-(methylcarbamoyl)piperidin-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)pyrazole-2-carboxamide (54)

[0464] At room temperature, HATU (100 mg, 0.26 mmol, 1.2 eq.) was slowly added to a solution of compound 54-4 (66 mg, 0.26 mmol, 1.2 eq.), compound A2 (73 mg, 0.22 mmol, 1.0 eq.), and DIPEA (0.12 mL, 0.66 mmol, 3.0 eq.) in DMF (2.0 mL). The reaction mixture was stirred at 30°C for 6 hours. The reaction mixture was cooled to room temperature, water (2 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was rinsed with methanol (2 mL) and then with EA (2 mL). The filter cake was collected and dried under reduced pressure to obtain compound 54 (45 mg, 36% yield, 96.7% purity).

[0465] LCMS (ESI) m / z 554.2, (M+H) + .

[0466] 1 H NMR (400MHz, DMSO) δ11.20(s,1H),9.88(s,1H),9.08(s,1H),8.41(d,J=8.3Hz,2H),8.03-7.84(m,4H),7.72(d,J=4.6Hz,1H),5.94(s,1H), 3.59(dt,J=13.9,7.0Hz,1H),3.31-3.28(m,4H),2.62(dd,J=25.1,16.6Hz,3H),2.20(d,J=26.6Hz,1H),1.77(s,4H),1.23(d,J=6.8Hz,6H).

[0467] Example 85: Preparation of 3-amino-N-(5-carbamoyl-4-(4-(methylcarbamoyl)piperidin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (85)

[0468] Compound 56 (60 mg, 0.1 mmol, 1.0 eq) was added to 1 ml of concentrated sulfuric acid and stirred at room temperature for 12 h. The reaction solution was added dropwise to ice water and made alkaline by adding sodium carbonate. The solution was extracted with DCM and water and purified to afford compound 85 (18.7 mg, 100% purity).

[0469] LCMS (ESI) m / z 582.2, (M+H) + .

[0470] 1 H NMR (400MHz, DMSO) δ10.30(s,1H),9.21(s,1H),9.13(s,1H),8.44(d,J=8.4Hz,2H),8.28(s,1H),8.17(s,1H),8.02(d,J=8.5Hz,3H),7.74(s,1H ),7.67(d,J=4.6Hz,1H),3.56(dt,J=13.7,6.8Hz,1H),3.16(d,J=13.0Hz,5H),2.26–2.13(m,1H),1.81(d,J=3.8Hz,4H),1.26(d,J=6.8Hz,7H).

[0471] Example 100: Preparation of 3-amino-N-(5-fluoro-4-(4-(3-(piperidin-1-yl)azetidine-1-carbonyl)phenyl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (100)

[0472] Step 1: Preparation of (3-(piperidin-1-yl)azetidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (100-3)

[0473] HATU (551 mg, 1.45 mmol, 1.2 eq.) was slowly added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100-1) (300 mg, 1.21 mmol, 1.0 eq.), 1-(azetidin-3-yl)piperidine (100-2) (309 mg, 1.45 mmol, 1.2 eq.), and DIPEA (0.9 mL, 4.84 mmol, 4.0 eq.) in DMF (6.0 mL) at room temperature. The reaction mixture was stirred at 30°C for 3 hours. Saturated aqueous sodium bicarbonate (20.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-16%) to obtain compound 100-3 (482 mg, yield 100%).

[0474] Step 2: Preparation of (4-(3-amino-5-fluoropyridin-4-yl)phenyl)(3-(piperidin-1-yl)azetidin-1-yl)methanone (100-4)

[0475] Compound 100-3 (30 mg, 0.158 mmol, 1.0 eq.), compound A1 (59 mg, 0.158 mmol, 1.0 eq.), Pd(dppf)Cl2 (13 mg, 0.016 mmol, 0.1 eq.), and potassium acetate (46.5 mg, 0.474 mmol, 3 eq.) were added sequentially to dioxane / H2O (1.2 mL / 0.3 mL) at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-32%) to afford compound 100-4 (63 mg, 100% yield).

[0476] Step 3: Preparation of 3-amino-N-(5-fluoro-4-(4-(3-(piperidin-1-yl)azetidine-1-carbonyl)phenyl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (100)

[0477] At room temperature, HATU (81 mg, 0.213 mmol, 1.2 eq.) was slowly added to a solution of compound 100-4 (63 mg, 0.178 mmol, 1.0 eq.), compound A2 (68.5 mg, 0.213 mmol, 1.2 eq.), and DIPEA (0.1 mL, 0.534 mmol, 3.0 eq.) in DMF (2 mL). The reaction was stirred at 25°C for 16 hours. Saturated aqueous sodium bicarbonate (10.0 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-32%) to afford compound 100 (35 mg, 29.9% yield, 98.2% purity).

[0478] LCMS (ESI) m / z 658.2 (M+H) + .

[0479] 1 H NMR (400MHz, DMSO) δ10.05(s,1H),9.39(s,1H),9.02(s,1H),8.61(s,1H),7.94–7.85(m,8H),7.71(d,J=7.9Hz,2H),4 .31-4.05(m,2H),3.58-3.49(m,1H),3.28-2.99(m,3H),2.52-1.95(m,4H),1.61-1.37(m,6H),1.23(d,J=6.8Hz,6H).

[0480] The following compounds were prepared by referring to the synthetic method of Example 100:

[0481] Example 101: Preparation of 3-amino-N-(3,5-difluoro-2-(4-(methylcarbamoyl)piperidin-1-yl)phenyl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (101)

[0482] Step 1: Preparation of 1-(2,4-difluoro-6-nitrophenyl)-N-methylpiperidine-4-carboxamide (101-3)

[0483] At room temperature, 2-bromo-1,5-difluoro-3-nitrobenzene (101-1) (160 mg, 0.67 mmol, 1.2 eq.), compound 54-2 (100 mg, 0.56 mmol, 1.0 eq.), Pd2(dba)3 (77 mg, 0.08 mmol, 0.15 eq.), xantphos (65 mg, 0.112 mmol, 0.2 eq.), and cesium carbonate (547 mg, 1.68 mmol, 3 eq.) were added sequentially to dioxane (6 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-11%) to afford compound 101-3 (99 mg, 28.5% yield, 48.3% purity).

[0484] Step 2: Preparation of 1-(2-amino-4,6-difluorophenyl)-N-methylpiperidine-4-carboxamide (101-4)

[0485] Compound 101-3 (99 mg, 0.33 mmol, 1.0 eq.), iron powder (93 mg, 1.65 mmol, 5 eq.), and ammonium chloride (176 mg, 3.3 mmol, 10 eq.) were added sequentially to a mixture of methanol and water (6 mL / 1.5 mL) at room temperature. The reaction mixture was stirred at 65°C for 9 hours. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: (dichloromethane:methanol = 4:1) / dichloromethane = 0-12%) to afford compound 101-4 (20 mg, 46.5% yield).

[0486] Step 3: Preparation of 3-amino-N-(3,5-difluoro-2-(4-(methylcarbamoyl)piperidin-1-yl)phenyl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (101)

[0487] HATU (34 mg, 0.089 mmol, 1.2 eq.) was slowly added to a solution of compound 101-4 (20 mg, 0.074 mmol, 1.0 eq.), compound A2 (28.6 mg, 0.089 mmol, 1.2 eq.), and DIPEA (28 mg, 0.22 mmol, 3.0 eq.) in DMF (1 mL) at room temperature. The reaction mixture was stirred at 25°C for 7 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate (5.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1) / dichloromethane=0-5.5%) to give compound 101 (12 mg, yield 28.2%, purity 98.98%).

[0488] LCMS (ESI) m / z 573.2, (M+H) + .

[0489] 1 H NMR (400MHz, DMSO) δ10.92 (s, 1H), 9.09 (s, 1H), 8.36 (d, J = 8.4Hz, 2H), 8.27(d,J=11.0Hz,1H),8.07(d,J=8.2Hz,3H),7.79(t,J=9.0Hz,1H),7.13–6.97(m,1H),3.56–3.37(m,1H ),3.19-2.99(m,4H),2.65(d,J=4.5Hz,3H),2.35-2.24(m,1H),1.93-1.78(m,4H),1.23(d,J=6.8Hz,6H).

[0490] Example 111: Preparation of 3-amino-N-(5-(aminomethyl)-4-(4-(methylcarbamoyl)piperidin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (111)

[0491] To a solution of compound 56 (90 mg, 0.16 mmol, 1.0 eq) in aqueous ammonia-methanol (6 ml) was added Raney nickel (188 mg, 1.89 mmol, 20.0 eq), and the mixture was allowed to react at room temperature for 48 h. The reaction solution was purified by preparative HPLC (mobile phase: water / acetonitrile = 100% to 70% / 30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL / min) to obtain compound 111 (19.2 mg, 22% yield).

[0492] LCMS (ESI) m / z 567, (M+H) + .

[0493] 1 H NMR (400MHz, DMSO) δ10.39(s,1H),9.08(d,J=5.1Hz,1H),8.87(s,1H),8.49–8.38(m,3H),8.34(s,1H),7.96(d,J=8.5Hz,4H),7.71 –7.59(m,1H),4.29(d,J=5.5Hz,1H),3.87(s,2H),3.60–3.45(m,2H),3.17(s,5H),2.19(s,2H),1.76(s,5H),1.22(d,J=6.8Hz,6H).

[0494] Biological tests

[0495] Test Example 1: ATR in vitro enzymatic activity inhibition experiment

[0496] Compounds were evaluated for their inhibitory activity against ATR kinase (Eurofins-14-953M) using HTRF detection, using GST-tagged p53 protein (Eurofins-14-952M) as a substrate. Compounds (0-10,000 nM) and ATR kinase were diluted in 1x kinase assay buffer (cisbio) containing 1.25 mM MnCl2, 50 nM SEB, and 1 mM DTT. Compounds were mixed with 30 ng of ATR kinase per well and incubated at room temperature for 15 minutes. The reaction was initiated by adding 500 nM p53 and 3.91 μM ATP in a total of 10 μL. The reaction was continued at room temperature for 90 minutes, followed by the addition of 10 μL of detection solution containing Mab Anti-phospho P53-Eu cryptate (cisbio-61P08KAZ) and Mab Anti-GST-d2 (cisbio-61GSTDLB) and incubated at room temperature for 1 hour. HTRF signals were collected using a Tecan spark multifunctional microplate reader at 620 nm and 665 nm wavelengths for calculating the IC values ​​of the compounds for ATR kinase inhibition. 50 Table 1 reports the ATR enzyme activity inhibition results of each compound.

[0497] Table 1 IC of the compounds of the present invention for inhibiting ATR kinase 50 value

[0498] Conclusion: In the ATR enzyme activity inhibition experiment, the compounds of the present invention showed strong inhibitory activity.

[0499] Test Example 2: Inhibitory effect of the compounds of the present invention on 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells) cell proliferation

[0500] 22RV1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) and MDA-MB-436 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were seeded into 96-well plates at a density of 5000 per well. The next day, the compound was diluted 4-fold from 10000nM in 8 gradients, and the compound was added to the corresponding wells of the 96-well plate and cultured in a 37°C incubator for 72 hours. The cell plate was equilibrated to room temperature, and then 50uL of CellTiter-Glo solution was added to each well. After reacting at room temperature for 10 minutes, the chemiluminescence signal was read on a biotek H1 multifunctional microplate reader, and the results were analyzed using xlfit software to calculate the inhibitory efficiency of the compound on the viability of 22RV1 and MDA-MB-436 cells. Table 2 reports the results of the compound's inhibition of cell proliferation on 22RV1 and MDA-MB-436 cells.

[0501] Table 2 IC inhibition of cell proliferation of 22RV1 and MDA-MB-436 cells by the compounds of the present invention 50 value

[0502] Conclusion: The compounds of the present invention have good cell proliferation inhibitory activity against 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells).

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in: R 1 is selected from hydrogen, alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkoxy, halohydroxyalkyl, alkenyl, and alkynyl; Or, R 1 for in: L is selected from a bond, alkylene, alkenylene, alkynylene, -C(O)-, -S(O)-, -S(O)2-, -C(O)NH-, -S(O)NH-, -S(O)2NH-, -C(O)O-; Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclyl, and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with one or more Q groups; Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c (O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-C(O)NR c (CH2) q NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c (O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c is substituted by one or more substituents; R 2 Selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy substituted by one or more substituents of alkyl, haloalkoxy, hydroxyalkyl, alkenyl, or alkynyl; Or, R 1 and R 2 The nitrogen atom to which it is attached forms a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2) q NR a R b is substituted by one or more substituents; R 3 Selected from alkyl, haloalkyl or cycloalkyl; Each R 4 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkoxy, halohydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in; Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R d and R e each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, and haloalkyl; R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1, 2, or 3; p is 0, 1, or 2; q is an integer from 0 to 6.

2. The compound of general formula (I) according to claim 1, or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R 1 for in: L is selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, -C(O)-, -S(O)-, -S(O)2-, -C(O)NH-, -S(O)NH-, -S(O)2NH-, -C(O)O-; preferably, a bond, an alkylene group, -C(O)-; Ring A is selected from aryl, heteroaryl, preferably C 6-10 Aryl or 5-10 membered heteroaryl; the aryl or heteroaryl is optionally substituted with one or more Q groups; Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro alkyl, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-C(O)NR c (CH2) q NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c is substituted by one or more substituents; R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in; Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R d and R e each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, and haloalkyl; R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p is 0, 1, or 2; q is an integer from 0 to 6.

3. The compound of general formula (I) according to claim 1 or 2, or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which is a compound of general formula (II) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in: L is selected from a bond, an alkylene group, -C(O)-; preferably a bond; X1, X2, X3, X4 are each independently selected from CH or N; Q1 is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、-(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR a R b 、-(CH2) q R c 、-(CH2) q OR c 、 -(CH2) q C(O)R c 、-(CH2) q C(O)OR c 、-(CH2) q OC(O)R c 、-(CH2) q C(O)NR a R b 、-C(O)NR c (CH2) q NR a R b 、-(CH2) q S(O) p R c 、-(CH2) q S(O) p NR a R b 、-NR c C(O)NR a R b 、-(CH2) q NR a C(O)R c 、-(CH2) q NR a C(O)OR c or -(CH2) q NR a S(O) p R c is substituted by one or more substituents; Each Q2 is independently selected from hydrogen, halogen, alkyl, haloalkyl, -(CH2) q C(O)NR a R b , the alkyl group is optionally further NR a R b replace; R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in; Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R d and R e each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, and haloalkyl; R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, or 2; R 2 、R 3 、R 4 , m, p, q as defined in claim 1.

4. The compound of general formula (I) according to claim 3, or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: Q1 is -NR a R b ; R a and R b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR d (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f is substituted by one or more substituents in; Or, R a and R b Together with the nitrogen atom to which it is attached, it forms a 4-10 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、-(CH2) q R f 、-(CH2) q OR f 、-(CH2) q C(O)R f 、-(CH2) q C(O)OR f 、-(CH2) q OC(O)R f 、-(CH2) q C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-(CH2) q S(O) p R f 、-(CH2) q S(O) p NR d R e 、-NR d C(O)NR d R e 、-(CH2) q NR d C(O)R f 、-(CH2) q NR d C(O)OR f or -(CH2) q NR d S(O) p R f wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R d and R e Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl; Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic group are optionally further substituted by one or more groups selected from halogen, alkyl, haloalkyl; R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p is 1 or 2; q is an integer of 0-6, preferably an integer of 1-6, more preferably an integer of 1-4.

5. A compound of formula (I) according to any one of claims 1 to 4, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof; which is a compound of formula (III) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: X1, X2, X3, X4 are each independently selected from CH or N; preferably, X1 is N and X2, X3, X4 are CH, or X2 is N and X1, X3, X4 are CH, or X1, X2, X3, X4 are all CH; Y is selected from NR 5 , CR 5 R 6 or SO2; R 5 Selected from hydrogen, halogen, amino, oxo, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、C(O)R f 、C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e 、-S(O) p R f 、-S(O) p NR d R e 、-NR d C(O)R f ; the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents in a haloalkyl group; R 6 Selected from hydrogen, halogen, amino and C 1-6 alkyl; Or, R 5 and R 6 The carbon atom to which it is attached forms a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, or heteroaryl; R d and R e Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl; Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic group are optionally further substituted by one or more groups selected from halogen, alkyl, haloalkyl; R f selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p is 1 or 2; q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2; n is 0, 1, or 2; s is 1 or 2; preferably 1; t is 1 or 2; preferably 1; R 2 、R 3 、R 4 , m as defined in claim 1; Q2 as defined in claim 3.

6. A compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIIA) or (IIIB), or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: X1 and X2 are each independently selected from CH or N; Y1 is selected from N or CR 6 ; R 6 Selected from hydrogen, halogen, amino and C 1-6 alkyl; R 7 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further selected from halogen, hydroxyl, thiol, C 1-6 Alkyl, C 1-6 substituted by one or more substituents of a haloalkyl group or a 3- to 6-membered heterocyclic group; R 8 Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkyl halide; Or, R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, preferably a 6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, wherein the C 3-6 Cycloalkyl, 3-8 membered heterocyclic group may be further selected from halogen, C 1-6 Alkyl, C 1-6 substituted with one or more haloalkyl groups; R d and R e are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocyclyl are optionally further substituted with one or more substituents selected from halogen; Or, R d and R e Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group The cyclic group is optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents of a haloalkyl group; R 10 Selected from C 1-6 Alkyl, C 1-6 alkyl halide; q is an integer from 1 to 4, preferably 1 or 2; n is 0, 1, or 2; R 2 、R 3 、R 4 , m as defined in claim 1; Q2 as defined in claim 3.

7. A compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIIC) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: X1 and X2 are each independently selected from CH or N; Y2 is selected from NR 11 , CR 11 R 12 , SO2; R 12 Selected from hydrogen, halogen, amino and C 1-6 alkyl; R 11 Selected from hydrogen, halogen, oxo, thio, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) q NR d R e 、-C(O)NR d R e 、-S(O) p NR d R e and -NR d C(O)R f is substituted by one or more substituents; said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 substituted by one or more substituents in a haloalkyl group; Or, R 11 and R 12 The carbon atom to which it is attached forms a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 substituted by one or more substituents of cycloalkyl, 3-8 membered heterocyclic group, aryl, or heteroaryl; R d and R e are each independently selected from hydrogen and C 1-6 alkyl; R f Selected from C 1-6 alkyl; p is 1 or 2; q is an integer from 0 to 4, preferably an integer from 0 to 2; R 2 、R 3 、R 4 , m as defined in claim 1; Q2, n as defined in claim 3.

8. The compound of general formula (I) according to any one of claims 1 to 3, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Q1 is selected from NR a R b ; R a Selected from hydrogen and C 1-6 alkyl; R b Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further selected from -NR d R e 、-NR d C(O)R f 、-C(O)NR d R e substituted by a substituent; R d and R e are each independently selected from hydrogen and C 1-6 alkyl; or R d and R e Together with the nitrogen atom to which it is attached, it forms a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally further selected from halogen, amino, oxo, C 1-6 substituted by an alkyl substituent; R f Selected from C 1-6 alkyl.

9. The compound of any one of claims 1 to 3, wherein the compound is a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and the compound is a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: in: X1 and X2 are each independently selected from CH or N; Y3, Y4, Y5, and Y6 are each independently selected from CH or N, preferably all CH, or one of them is N and the others are CH, or two of them are N and the others are CH; Each R 13a are each independently selected from hydrogen, halogen, C 1-6 Alkyl; s is 0, 1, 2, 3 or 4, preferably 0, 1 or 2; R 13b Selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, -C(O)NR d R e 、-C(O)NR f (CH2) q NR d R e ; R d and R e are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; or R d and R e Together with the nitrogen atom to which it is connected, it forms a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is is further selected from halogen, amino, oxo, C 1-6 substituted by an alkyl group or a 5-6-membered heterocyclic group; R f Selected from hydrogen and C 1-6 alkyl; q is an integer from 1 to 4, preferably 1 or 2; R 2 、R 3 、R 4 , m as defined in claim 1; Q2, n as defined in claim 3.

10. The compound of general formula (I) according to any one of claims 1 to 3, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Q1 is selected from 8-10 membered fused heterocyclic groups, preferably It is optionally further selected from C 1-6 Alkyl and C 1-6 The alkyl group is substituted by a haloalkyl substituent.

11. The compound of general formula (I) according to claim 1 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in: R 1 for L is selected from a bond, an alkylene group or -C(O)-; Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, preferably phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, quinolinyl, quinoxalinyl, quinazolinyl, pyridopyrrolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl; which are optionally substituted with one or more Q groups; Q is selected from halogen, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) q NR a R b ; R a and R b are each independently selected from hydrogen and C 1-6 alkyl; q is an integer of 0-4, preferably an integer of 0-2.

12. A compound of the general formula (I) according to any one of claims 1 to 11, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, R 2 Selected from hydrogen and C 1-6 alkyl.

13. The compound of general formula (I) according to claim 1 or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R 1 and R 2 Together with the nitrogen atom to which it is connected, it forms a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, preferably an 8-10 membered heterocyclic group, more preferably It is optionally further selected from halogen, amino, cyano, hydroxy, mercapto, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) q NR a R b is substituted by one or more substituents; q is an integer from 1 to 4, preferably 1 or 2; R a and R b Each independently selected from hydrogen or C 1-6 alkyl.

14. A compound of the general formula (I) according to any one of claims 1 to 13, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl.

15. A compound of the general formula (I) according to any one of claims 1 to 14, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R 4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl; m is 0 or 1.

16. The compound of general formula (I) according to any one of claims 3 to 10, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each Q2 is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, cyano, (CH2) q C(O)NR a R b 、C 1-6 Halogenated alkyl, the C 1-6 The alkyl group is optionally further substituted with NR a R b replace; R a and R b Each independently selected from hydrogen or C 1-6 alkyl; q is an integer from 0 to 6; n is an integer of 0 to 4, preferably an integer of 0 to 2.

17. A compound of formula (I) according to any one of claims 1 to 16, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:

18. A method for preparing a compound represented by general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of: Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IB) to obtain a compound of general formula (I); The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP, triethylamine, or DIPEA; The condensing agent is preferably EDCI, DCC, CDI, HOBt, HOAT, HATU, TBTU, HBTU, PyBOP; Where: R 1 、R 2 、R 3 、R 4 , m as defined in claim 1.

19. A method for preparing a compound represented by general formula (IIIA) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of: Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IIIAa) undergoes a condensation reaction with the compound of general formula (IIIAb) to obtain a compound represented by general formula (IIIA); The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP, triethylamine, or DIPEA; The condensing agent is preferably EDCI, DCC, CDI, HOBt, HOAT, HATU, TBTU, HBTU, PyBOP; Where: R 2 、R 3 、R 4 、R 7 、R 8 , X1, X2, Y1, Q2, m, n are as defined in claim 6.

20. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

21. Use of a compound of formula (I) according to any one of claims 1 to 17 or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of an ATR kinase inhibitor.

22. Use of a compound of formula (I) according to any one of claims 1 to 17, or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for treating an ATR kinase-mediated disease, preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

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