Pyrazoloheteroaryl derivatives, their preparation method and their pharmaceutical applications

Abstract

The present disclosure relates to pyrazoloheteroaryl derivatives, their preparation methods, and their pharmaceutical applications. Specifically, the present disclosure relates to pyrazoloheteroaryl derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, particularly their use as ATR kinase inhibitors and in the preparation of medicaments for treating and / or preventing hyperproliferative diseases. The definitions of each group in general formula (I) are as described in the specification. TIFF2023502458000095.tif4136

Description

[Technical Field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to pyrazoloheteroaryl derivatives represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same and their use as therapeutic agents, in particular their use as ATR kinase inhibitors and in the preparation of medicaments for treating and / or preventing hyperproliferative diseases. [Background technology]

[0002] Both normal and tumor cells experience thousands of DNA damage events every day. This makes DNA damage repair crucial for maintaining genome stability and cell survival. Compared with normal cells, tumor cells tolerate greater replication stress, have more endogenous DNA damage, and often exhibit defects in one or more DNA damage repair pathways. This makes tumor cell survival even more dependent on successful DNA damage repair.

[0003] Homologous recombination repair (ATR) is the primary method for repairing DNA double-strand breaks. It replicates the damaged DNA sequence using the homologous sequence of the undamaged sister chromatid as a repair template, resulting in highly accurate DNA repair. This repair process primarily occurs during the G2 and S phases of cells. ATR, a key enzyme in the homologous recombination repair pathway, belongs to the PIKK family. When the ATR / ATRIP complex binds to damaged DNA coated with replication protein A (RPA), ATR becomes activated and phosphorylates downstream proteins, including Chk1 and SMARCAL, thereby regulating various cell cycle checkpoints, causing cell cycle arrest, ensuring the stability of damaged DNA, increasing dNTP concentrations, and promoting DNA damage repair. Repair of DNA damage occurring during the S phase of the cell cycle is primarily achieved through the ATR pathway, suggesting that ATR is crucial for ensuring cell proliferation. Analysis of clinical tumor samples has revealed that ATR expression levels are elevated in many tumor tissues, including gastric, liver, colorectal, ovarian, and pancreatic cancers. Furthermore, high levels of ATR are often associated with poor survival rates in patients with ovarian and pancreatic cancers. This indicates that ATR is an important target for tumor therapy.

[0004] Currently disclosed patent applications for ATR inhibitors include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889, and WO2014140644, among others. Summary of the Invention

[0005] The object of the present disclosure is to provide a compound represented by general formula (I) or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, Ring A is a heteroaryl group; R 1 represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, -NR 4 R 5 , -CONR 4 R 5 , -SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 , -COOR 7 , -SO2R 7 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkoxy group, amino group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally selected from halogen, alkyl group, alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, -NR 4 R 5 , -CONR 4 R 5 , -SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 , -COOR 7 , -SO2R 7 , substituted with one or more substituents selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 2are selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3 are selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 and R 5 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; n is 0, 1, 2 or 3.

[0006] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof has ring A selected from a pyrazolyl group, a pyrrolyl group, and an imidazolyl group.

[0007] In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (I).

[0008] In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or general formula (IV) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, R 1 , R 2 , R 3 and n is as defined in general formula (I).

[0009] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is R 1 are selected from alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0010] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is R 1 is selected from alkyl groups, cycloalkyl groups, and heterocyclyl groups, wherein the alkyl groups are optionally substituted with one or more substituents selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, and the cycloalkyl groups and heterocyclyl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, preferably R 1is a C1-C6 alkyl group or a 3- to 6-membered cycloalkyl group, wherein the C1-C6 alkyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, more preferably R 1 is a C1-C6 alkyl group or a 3- to 6-membered cycloalkyl group, wherein the C1-C6 alkyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one cyano group, and most preferably, R 1 teeth, [ka] is.

[0011] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is R 2 is a hydrogen atom or an alkyl group, preferably an alkyl group, and more preferably C 1-6 It is an alkyl group.

[0012] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is R 2 is an alkyl group.

[0013] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof is R 3 is a hydrogen atom.

[0014] Exemplary compounds of the present disclosure include, but are not limited to: [Table 1]

[0015] [Table 2]

[0016] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or its tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, X is a halogen, preferably Br; G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, R 1 represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, -NR 4 R 5 , -CONR 4 R 5 , -SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 , -COOR 7 , -SO2R 7, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkoxy group, amino group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally selected from halogen, alkyl group, alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, -NR 4 R 5 , -CONR 4 R 5 , -SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 , -COOR 7 , -SO2R 7 , substituted with one or more substituents selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 2 are selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 and R 5 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 7is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0017] Another aspect of the present disclosure relates to a compound represented by general formula (IIIC) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, X and R 1 and R 2 is as defined in general formula (IA).

[0018] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or its tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, R a is an amino protecting group, G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, R 1 represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, -NR 4 R 5 , -CONR 4 R 5 , -SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 , -COOR 7 , -SO2R 7, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkoxy group, amino group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally selected from halogen, alkyl group, alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, -NR 4 R 5 , -CONR 4 R 5 , -SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 , -COOR 7 , -SO2R 7 , substituted with one or more substituents selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 2 are selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3are selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 and R 5 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; n is 0, 1, 2 or 3.

[0019] Another aspect of the present disclosure relates to a compound represented by general formula (IIGA) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, G 1 , G 2 , R 1 , R 2 , R 3 , R a and n is as defined in general formula (IIA).

[0020] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or its tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, R a , R 1 , R 2 , R 3 and n is as defined in general formula (IIA).

[0021] Another aspect of the present disclosure relates to a compound represented by general formula (IIIGA) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: [ka] Among them, R a , R 1 , R 2 , R 3 and n is as defined in general formula (IIIA).

[0022] Exemplary intermediate compounds of the present disclosure include, but are not limited to, the following: [Table 3]

[0023] [Table 4]

[0024] [Table 5]

[0025] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] coupling reaction of a compound of general formula (IA) with a compound of general formula (IB) to obtain a compound of general formula (I); Among them, X is a halogen, preferably Br; R b teeth [ka] and Ring A, G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (I).

[0026] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] coupling reaction of a compound of general formula (IA) with a compound of general formula (IID) to obtain a compound of general formula (II), Among them, X is a halogen, preferably Br; R b teeth [ka] and G 1 , G 2 , R 1 , R 2 , R 3and n is as defined in general formula (II).

[0027] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] coupling reaction of a compound of general formula (IIIC) with a compound of general formula (IID) to obtain a compound of general formula (III), Among them, X is a halogen, preferably Br; R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0028] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] coupling reaction of a compound of general formula (IVC) with a compound of general formula (IID) to obtain a compound of general formula (IV), Among them, X is a halogen, preferably Br; R b teeth [ka] and R 1 , R 2 , R3 and n is as defined in general formula (IV).

[0029] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IIA) or its tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] coupling a compound of general formula (IA) with a compound of general formula (IIB) to obtain a compound of general formula (IIA); Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (II).

[0030] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] removing the amino protecting group from a compound of general formula (IIA) to obtain a compound of general formula (II), Among them, R a is an amino protecting group, G 1 , G 2 , R 1 , R 2 , R3 and n is as defined in general formula (II).

[0031] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIGA) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] a coupling reaction between a compound of general formula (IA) and a compound of general formula (IIGB) to obtain a compound of general formula (IIGA); Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (IIGA).

[0032] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] removing the amino protecting group from a compound of general formula (IIGA) to obtain a compound of general formula (II), Among them, R a is an amino protecting group, G 1 , G 2 , R 1 , R 2 , R3 and n is as defined in general formula (II).

[0033] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] coupling reaction of a compound of general formula (IIIC) with a compound of general formula (IIB) to obtain a compound of general formula (IIIA); Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0034] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] removing the amino protecting group from a compound of general formula (IIIA) to obtain a compound of general formula (III), Among them, R a is an amino protecting group, R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0035] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIGA) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] a coupling reaction between a compound of general formula (IIIC) and a compound of general formula (IIGB) to obtain a compound of general formula (IIIGA); Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (IIIG).

[0036] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] removing the amino protecting group from a compound of general formula (IIIGA) to obtain a compound of general formula (III); Among them, R a is an amino protecting group, R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0037] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] removing the amino protecting group from a compound of general formula (IVA) to obtain a compound of general formula (IV), Among them, R a is an amino protecting group, R 1 , R 2 , R 3 and n is as defined in general formula (IV).

[0038] Another aspect of the present disclosure relates to a pharmaceutical composition, comprising a compound represented by general formula (I) according to the present disclosure or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0039] The present disclosure further relates to the use of a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, pharmaceutically acceptable salt, or pharmaceutical composition comprising the same in the preparation of a medicament for inhibiting ATR kinase.

[0040] The present disclosure further relates to the use of a compound of general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, pharmaceutically acceptable salt, or pharmaceutical composition comprising the same in the preparation of a medicament for treating and / or preventing a hyperproliferative disease.

[0041] The present disclosure further relates to the use of a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, pharmaceutically acceptable salt, or pharmaceutical composition comprising the same in the preparation of a medicament for treating and / or preventing tumors.

[0042] The present disclosure further relates to the use of a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, pharmaceutically acceptable salt, or pharmaceutical composition comprising the same in the preparation of a medicament for treating tumors.

[0043] The present disclosure also relates to a method for inhibiting ATR kinase, comprising administering to a patient in need thereof an effective amount of a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture thereof, pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0044] The present disclosure also relates to a method for treating and / or preventing a hyperproliferative disease, comprising administering to a patient in need thereof an effective amount of a compound represented by general formula (I) or its tautomer, meso-isomer, racemate, enantiomer, diastereomer, mixture thereof, pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0045] The present disclosure also relates to a method for treating and / or preventing tumors, comprising administering to a patient in need thereof an effective amount of a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same.

[0046] The present disclosure further relates to a compound of general formula (I) or its tautomers, meso-isomers, racemates, enantiomers, diastereomers, mixtures thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for use as a pharmaceutical, which can be used to treat and / or prevent hyperproliferative diseases, particularly tumors.

[0047] The present disclosure also relates to a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as an ATR kinase inhibitor.

[0048] The present disclosure also relates to a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, pharmaceutically acceptable salt, or pharmaceutical composition containing the same, for use in treating and / or preventing a hyperproliferative disease.

[0049] The present disclosure further relates to a compound represented by general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, pharmaceutically acceptable salt, or pharmaceutical composition containing the same, for use in treating tumors.

[0050] The tumors described herein are selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.

[0051] The active compound can be in a form suitable for administration by any suitable route, preferably in unit dosage form or in a form that the patient can self-administer as a single dose. A unit dosage of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottled drug solution, drug powder, granules, tablet, suppository, reconstituted powder, or liquid formulation.

[0052] The dose of the compound or composition used in the therapeutic methods of the present disclosure will generally vary depending on the severity of the disease, the weight of the patient, and the relative efficacy of the compound, although as a general guideline, a suitable unit dose may be between 0.1 and 1000 mg.

[0053] In addition to the active compound, the pharmaceutical composition according to the present disclosure may contain one or more additives selected from fillers (diluents), adhesives, wetting agents, disintegrants, excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0054] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a visually appealing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing in the manufacture of tablets. These excipients may include inert diluents, granulating agents, disintegrating agents, adhesives, and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a long period of time.

[0055] Oral formulations may be provided in soft gelatin capsules containing the active ingredient mixed with an inert solid diluent, or the active ingredient mixed with a water-soluble carrier or oily solvent.

[0056] Aqueous suspensions contain the active substance and a mixing excipient suitable for preparing an aqueous suspension. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners.

[0057] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil. Oil suspensions may contain thickeners. In order to provide a palatable formulation, the above-mentioned sweeteners and flavoring agents may be added. These compositions can be preserved by adding antioxidants.

[0058] Dispersible powders and granules suitable for preparing aqueous suspensions by the addition of water can contain the active ingredient and a dispersing or wetting agent for mixing, a suspending agent, or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be exemplified above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by adding an antioxidant, such as ascorbic acid.

[0059] The pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain emollients, preservatives, coloring agents, and antioxidants.

[0060] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be infused into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant, cyclical concentration of the compounds of the present disclosure. To maintain such a constant concentration, a continuous intravenous infusion device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 infusion pump.

[0061] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the above-mentioned suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable preparations may be sterile injectable solutions or suspensions prepared in non-toxic parenterally acceptable diluents or solvents. Furthermore, sterile fixed oils can be conveniently used as solvents or suspending media. For this purpose, any suitable fixed oil can be used. Fatty acids can also be used to prepare injectables.

[0062] The compounds of the present disclosure may also be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing a pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, thereby dissolving and releasing the pharmaceutical agent in the rectum.

[0063] As is well known to those skilled in the art, the dosage of a pharmaceutical depends on many factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's physical condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the pharmaceutical, etc. In addition, the optimal treatment method, such as the treatment mode, the daily dose of the compound of general formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment plans.

[0064] Detailed Description of the Invention

[0065] Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0066] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl Examples of alkyl groups include 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, and when substituted, the substituent may be substituted at any available point of attachment, and preferably said substituent is independently and optionally substituted with one or more substituents selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups.

[0067] The term "alkylene group" refers to a saturated, straight- or branched-chain aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of an alkane parent, and is a straight- or branched-chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups 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-), 1,4-butylene (-CHCHCHCHCH-), and the like. An alkylene group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and said substituents are independently and optionally substituted with one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, thiol, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0068] The term "alkenyl group" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, of which alkyl is defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0069] The term "alkynyl group" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, of which alkyl is defined above. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0070] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0071] The term "spirocycloalkyl group" refers to a polycyclic group in which 5- to 20-membered monocyclic rings share one carbon atom (referred to as a spiro atom) and may contain one or more double bonds. It is preferably 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10)-membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include: [ka]

[0072] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and one or more rings may contain one or more double bonds. The group is preferably 6 to 14 members, and more preferably 7 to 10 (e.g., 7, 8, 9, or 10) members. Depending on the number of rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include: [ka] .

[0073] The term "bridged cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and may contain one or more double bonds. It is preferably 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10) members. Depending on the number of rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following: [ka]

[0074] The cycloalkyl ring includes those in which the above-mentioned cycloalkyl group (including monocyclic, spiro, fused, and bridged rings) is fused to an aryl group, heteroaryl group, or heterocycloalkyl ring, and among these, the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples thereof include an indanyl group, a tetrahydronaphthyl group, a benzocyclopentyl group, and a benzocycloheptanyl group, and preferably a benzocyclopentyl group and a tetrahydronaphthyl group.

[0075] The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and preferably said substituent is independently and optionally substituted with one or more substituents selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0076] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is defined as above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently substituted with one or more substituents selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, S, S(O), and S(O)2, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms being carbon. Preferably, the group contains 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms, of which 1 to 3 (e.g., 1, 2, or 3) are heteroatoms; even more preferably, 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups.

[0077] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group in which two 5- to 20-membered monocyclic rings share one atom (referred to as a spiro atom), one or more of which are heteroatoms selected from nitrogen, oxygen, S, S(O), and S(O)2, and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified as monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups, with monospiroheterocyclyl groups and bisspiroheterocyclyl groups being preferred. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups include: [ka]

[0078] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings optionally containing one or more double bonds, one or more ring atoms of which are heteroatoms selected from nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon. Preferably, the group has 6 to 14 members, more preferably 7 to 10 (e.g., 7, 8, 9, or 10) members. Depending on the number of rings, fused heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include: [ka]

[0079] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) and S(O)2, and the remaining ring atoms are carbon. It is preferably 6-14 membered, more preferably 7-10 (e.g., 7, 8, 9 or 10) membered. Depending on the number of rings, bridged heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, and are preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include the following: [ka]

[0080] The heterocyclyl ring includes the above heterocyclyl groups (including monocyclic, spiro heterocycles, fused heterocycles, and bridged heterocycles) fused to an aryl group, heteroaryl group, or cycloalkyl ring, in which the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which include: [ka]

[0081] Heterocyclyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and preferably said substituents are independently and optionally substituted with one or more substituents selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0082] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as a phenyl group or a naphthyl group. The aryl ring includes those in which the aryl ring is fused to a heteroaryl group, heterocyclyl group, or cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, non-limiting examples of which include: [ka]

[0083] The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and preferably said substituent is independently and optionally substituted with one or more substituents selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0084] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 (e.g., 5, 6, 7, 8, 9, and 10) members, more preferably 5 or 6 members, such as furan, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. The heteroaryl ring includes the above heteroaryl groups fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include: [ka]

[0085] Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and preferably said substituents are independently and optionally substituted with one or more substituents selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0086] The cycloalkyl, heterocyclyl, aryl, and heteroaryl groups have one residue derived by removing one hydrogen atom from a parent ring atom, or two residues derived by removing two hydrogen atoms from the same parent ring atom or two different parent ring atoms, i.e., a "divalent cycloalkyl group," a "divalent heterocyclyl group," an "arylene group," or a "heteroarylene group."

[0087] The term "amino-protecting group" refers to an easily removable group that protects an amino group so that the amino group remains unchanged when other sites on the molecule react. Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups can be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, or nitro. The amino-protecting group is preferably a tetrahydropyranyl group.

[0088] The term "cycloalkoxy group" refers to a cycloalkyl-O- group, in which the cycloalkyl group is as defined above.

[0089] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein alkyl group is as defined above.

[0090] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl group is as defined above.

[0091] The term "hydroxy group" refers to an --OH group.

[0092] The term "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, wherein the definition of alkyl group is as defined above.

[0093] The term "halogen" refers to fluorine, chlorine, bromine or iodine

[0094] The term "amino group" refers to -NH2.

[0095] The term "cyano" refers to -CN.

[0096] The term "nitro group" refers to -NO2.

[0097] The term "carbonyl group" refers to C=O.

[0098] The term "carboxy group" refers to -C(O)OH.

[0099] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group) or -C(O)O(cycloalkyl group), where alkyl group and cycloalkyl group are as defined above.

[0100] THP is a tetrahydropyranyl group.

[0101] The compounds of the present disclosure can exist as tautomers. For the purposes of this disclosure, reference to a compound of formula (I) refers to the compound itself, any one of its tautomers, or a mixture of two or more tautomers. For example, reference to a pyrazolyl group should be understood to include any one or a mixture of two tautomers of the following two structures: [ka]

[0102] The compounds of the present disclosure include their isotopic derivatives. The term "isotopic derivative" refers to a compound that differs structurally only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure but in which hydrogen has been replaced by "deuterium" or "tritium" or fluorine has been replaced by 18 F-fluorine labeling ( 18 F isotope) or carbon atoms are replaced by 11 C-, 13 C-, or 14 C-rich carbon ( 11 C-, 13 C- or 14 C-carbon label, 11 C-, 13 C- or 14 Compounds in which the carbon atom is replaced with a C-isotope (C-isotope) are included within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in bioassays, as imaging tracers for in vivo diagnosis of disease, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. The present disclosure includes various deuterated forms of the compound of formula (I). Each available hydrogen atom connected to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compound of formula (I) by referring to relevant literature. When preparing the deuterated form of the compound of formula (I), commercially available deuterated starting materials may be used, or the compound may be synthesized by conventional techniques using deuterated reagents, including, but not limited to, deuterated borane, tritiated borane in tetrahydrofuran, deuterated lithium aluminum, deuterated iodoethane, deuterated iodomethane, and the like.

[0103] "Optionally" or "optionally" means that the thing or circumstance described thereafter may occur, but does not necessarily have to, and the phrase includes cases where the thing or circumstance occurs and cases where it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may be present, but is not necessarily present, and the phrase includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0104] The term "substituted" means that one or more hydrogen atoms, preferably 5 or less, more preferably 1 to 3 hydrogen atoms in the group are independently replaced with a corresponding number of substituents. Of course, substituents are only located at chemically feasible positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino group or hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0105] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert their biological activity.

[0106] A "pharmaceutically acceptable salt" is a salt of a compound according to the present disclosure, which is safe and effective when used in a mammalian body and possesses the desired biological activity.

[0107] The term "therapeutically effective amount" of a pharmaceutical or pharmacologically active agent refers to a sufficient dose of the pharmaceutical or drug to produce the desired effect while being non-toxic. The effective amount is determined by the individual and depends on the age and general condition of the recipient, as well as the type of active substance, but an appropriate effective amount for an individual can be determined by one skilled in the art through routine testing.

[0108] Methods for synthesizing compounds according to the present disclosure

[0109] To achieve the objectives of this disclosure, this disclosure adopts the following technical solutions. Plan 1

[0110] The method for preparing a compound represented by general formula (I) or a salt thereof according to the present disclosure comprises: [ka] a step of coupling a compound of general formula (IA) with a compound of general formula (IB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (I); Among them, X is a halogen, preferably Br; R b teeth [ka] and Ring A, G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (I).

[0111] Plan 2 The method for preparing a compound represented by general formula (II) or a salt thereof according to the present disclosure comprises: [ka] a step of coupling a compound of general formula (IA) with a compound of general formula (IID) under basic conditions in the presence of a catalyst to obtain a compound of general formula (II), Among them, X is a halogen, preferably Br; R b teeth [ka] and G1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (II).

[0112] Plan 3 The method for preparing a compound represented by general formula (II) or a salt thereof according to the present disclosure comprises: [ka] coupling reaction of a compound of general formula (IA) with a compound of general formula (IIB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IIA); removing the amino protecting group from the compound of general formula (IIA) under acidic conditions to obtain a compound of general formula (II), Among them, X is a halogen, preferably Br; R b teeth [ka] and G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (II).

[0113] Plan 4 The method for preparing a compound represented by general formula (II) or a salt thereof according to the present disclosure comprises: [ka] A step of coupling a compound of general formula (IA) with a compound of general formula (IIGB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IIGA); removing the amino protecting group from the compound of general formula (IIGA) under acidic conditions to obtain a compound of general formula (II), Among them, X is a halogen, preferably Br; R b teeth [ka] and G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in general formula (II).

[0114] Plan 5 The method for preparing a compound represented by general formula (III) or a salt thereof according to the present disclosure comprises: [ka] a step of coupling a compound of general formula (IIIC) with a compound of general formula (IID) under basic conditions in the presence of a catalyst to obtain a compound of general formula (III), Among them, X is a halogen, preferably Br; R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0115] Plan 6 The method for preparing a compound represented by general formula (III) or a salt thereof according to the present disclosure comprises: [ka] coupling reaction of a compound of general formula (IIIC) with a compound of general formula (IIB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IIIA); removing the amino protecting group from the compound of general formula (IIIA) under acidic conditions to obtain a compound of general formula (III), Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0116] Plan 7 The method for preparing a compound represented by general formula (III) or a salt thereof according to the present disclosure comprises: [ka] A step of coupling a compound of general formula (IIIC) with a compound of general formula (IIGB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IIIGA); removing the amino protecting group from the compound of general formula (IIIGA) under acidic conditions to obtain a compound of general formula (III), Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (III).

[0117] Plan 8 The method for preparing a compound represented by general formula (IV) or a salt thereof according to the present disclosure comprises: [ka] coupling reaction of a compound of general formula (IVC) with a compound of general formula (IID) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IV); Among them, X is a halogen, preferably Br; R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (IV).

[0118] Plan 9 The method for preparing a compound represented by general formula (IV) or a salt thereof according to the present disclosure comprises: [ka] A step in which a compound of general formula (IVC) and a compound of general formula (IIB) undergo a coupling reaction under basic conditions in the presence of a catalyst to obtain a compound of general formula (IVA); removing the amino protecting group from the compound of general formula (IVA) under acidic conditions to obtain a compound of general formula (IV), Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (IV).

[0119] Plan 10 The method for preparing a compound represented by general formula (IV) or a salt thereof according to the present disclosure comprises: [ka] A step of coupling a compound of general formula (IVC) with a compound of general formula (IIGB) under basic conditions in the presence of a catalyst to obtain a compound of general formula (IVGA); removing the amino protecting group from the compound of general formula (IVGA) under acidic conditions to obtain a compound of general formula (IV), Among them, X is a halogen, preferably Br; R a is an amino protecting group, R b teeth [ka] and R 1 , R 2 , R 3 and n is as defined in general formula (IV).

[0120] In the above synthesis methods, reagents that provide basic conditions include organic bases and inorganic bases, the organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and sodium n-butoxide, and the inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0121] The catalysts used in the above synthesis methods include, but are not limited to, palladium / carbon, tetrakis(triphenylphosphine)palladium, palladium dichloride, palladium acetate, bis(triphenylphosphine)dichloropalladium(II), bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, 1,1'-bis(dibenzylphosphorus)dichlorodipentylironpalladium, or tris(dibenzylideneacetone)dipalladium, and preferably tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)dichloropalladium(II).

[0122] In the above synthesis schemes, reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, a solution of hydrogen chloride in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, MeSiCl, and TMSOTf, and preferably trifluoroacetic acid.

[0123] In the above synthesis schemes, the amino protecting group includes, but is not limited to, tetrahydropyranyl (THP), tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, which can be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, and nitro groups, with tetrahydropyranyl being preferred.

[0124] The reaction is preferably carried out in a solvent, and solvents used include, but are not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, or N,N-dimethylformamide. DETAILED DESCRIPTION OF THE INVENTION

[0125] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. [Example]

[0126] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The NMR was measured using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard.

[0127] For MS measurements, liquid chromatograph mass spectrometers Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0128] For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 are used.

[0129] For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD is used.

[0130] For preparative high performance liquid chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 are used.

[0131] For chiral separation, a preparative chromatograph Shimadzu LC-20AP is used.

[0132] As a CombiFlash high-speed preparative chromatograph, Combiflash Rf200 (TELEDYNE ISCO) is used.

[0133] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography. The silica gel plate specifications for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and those for separating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0134] Silica gel column chromatography generally uses 200-300 mesh silica gel manufactured by Yantai Yellow Sea Silica Gel Co., Ltd. as a carrier.

[0135] Kinase mean inhibition rate and IC 50 The values ​​are measured using a microplate reader NovoStar (manufactured by BMG, Germany).

[0136] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0137] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0138] The argon or nitrogen atmosphere means that an argon or nitrogen balloon with a capacity of about 1 L is connected to the reaction flask.

[0139] The hydrogen atmosphere means that a hydrogen balloon with a capacity of about 1 L is connected to the reaction flask.

[0140] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenator and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenator are used.

[0141] The hydrogenation reaction is generally carried out by evacuating the reactor and injecting hydrogen, and repeating this procedure three times.

[0142] For microwave reactions, a CEM Discover-S 908860 microwave reactor is used.

[0143] In the examples, unless otherwise specified, the solutions are aqueous solutions.

[0144] In the examples, unless otherwise specified, the reaction temperature is room temperature, ie, 20°C to 30°C.

[0145] In the examples, the reaction process was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system of column chromatography used to purify the compound, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system, and the volume ratio of the solvents was adjusted according to the polarity of the compound, but may also be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0146] THP is a tetrahydropyranyl group.

[0147] Example 1 (R)-2-Methyl-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 1 [ka]

[0148] Step 1 (R,E)-1-Methyl-4-((1-(3-methylmorpholine)ethylidene)amino)-1H-pyrazole-5-carboxylate methyl ester 1c The compound (R)-1-(3-methylmorpholine)ethan-1-one 1b (2.5 g, 17.7 mmol, prepared by the method disclosed in the patent application "WO2016020320A1, page 86, Example Intermediate-1") was dissolved in 1,2-dichloroethane, and cooled in ice water under argon gas protection. Phosphorus oxychloride (7.4 g, 48.3 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 minutes. The compound 4-amino-1-methyl-1H-pyrazole-5-methyl formate 1a (2.5 g, 16.1 mmol, Jiangsu Aikang Bio) was added, and the mixture was heated to 80°C and reacted with stirring for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (200 mL), cooled in ice water, and neutralized to pH 8-9 by dropwise addition of saturated sodium bicarbonate solution. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography using eluent system C to obtain the title compound 1c (4.8 g) in a 94% yield. MS m / z (ESI): 281.2 [M+1].

[0149] Step 2 (R)-1-Methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-ol 1d Compound 1c (2.6 g, 9.3 mmol) was dissolved in tetrahydrofuran (20 mL), cooled in ice water, and lithium bis(trimethylsilyl)amide (27.8 mL, 1 M tetrahydrofuran solution, 27.8 mmol) was slowly added and reacted at 0° C. for 1 hour. Methanol (10 mL) was added to quench the reaction, and the mixture was purified by silica gel column chromatography using eluent system A to give the title compound 1d (400 mg) in a 55.8% yield. MS m / z (ESI): 249.0 [M+1].

[0150] Step 3 (R)-4-(7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 1e Compound 1d (400 mg, 1.6 mmol) was dissolved in 3.0 mL of phosphorus oxychloride, heated to 90 °C, and stirred for 2.0 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (50 mL), cooled in ice water, and neutralized to pH 8-9 with saturated sodium bicarbonate solution. The mixture was stirred for 0.5 hours, allowed to stand, and the layers were separated. The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography using eluent system C to obtain the title compound 1e (240 mg) in 56% yield. MS m / z (ESI): 267.0 [M+1].

[0151] Step 4 (R)-2-methyl-2-(1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 1g Compound 1e (240 mg, 0.91 mmol) and compound isobutyronitrile 1f (620 mg, 8.9 mmol, Shanghai Bide) were dissolved in 30 mL of tetrahydrofuran and cooled in a dry ice acetone bath under a nitrogen atmosphere. Lithium bis(trimethylsilyl)amide (8.9 mL, 1 M tetrahydrofuran solution, 8.9 mmol) was added dropwise and stirred at low temperature for 0.5 hours. The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to quench the reaction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to obtain the title compound 1g (200 mg) in a 74% yield. MS m / z (ESI): 300.1 [M+1].

[0152] Step 5 (R)-2-(3-Bromo-1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 1h 1g (200 mg, 0.67 mmol) was dissolved in 5 mL of 1,4-dioxane, sodium hydroxide solution (0.66 mL, 2 M solution, 1.32 mmol) was added, and the mixture was cooled with ice water. Liquid bromine (427 mg, 2.67 mmol) was added and stirred at low temperature for 10 min. The mixture was allowed to warm to room temperature and react with stirring for 1 h. The mixture was diluted with ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography using eluent system C to give the title compound 1h (140 mg) in 55% yield. MS m / z (ESI): 377.9 [M+1].

[0153] Step 6 2-Methyl-2-(1-methyl-5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 1i 1h (20 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.015 mmol), sodium carbonate (11 mg, 0.10 mmol), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29 mg, 0.10 mmol, Shanghai Bide) were dissolved in 4 mL of ethylene glycol dimethyl ether, 1 mL of water was added, and the mixture was heated to 120°C in a microwave oven under an argon atmosphere for 1 hour. The reaction mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system C to obtain the title compound 1i (20 mg) in a yield of 84%. MS m / z (ESI): 450.1 [M+1].

[0154] Step 7 (R)-2-Methyl-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 1 Compound 1i (20 mg, 0.04 mmol) was dissolved in 5 mL of dichloromethane and 5 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M ammonia-methanol solution dropwise. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give the title compound 1 (7.0 mg) in 43% yield. MS m / z (ESI): 366.0 [M+1]. 1H NMR (400 MHz, CD3OD):δ 7.58 (s, 1H), 7.03 (s, 1H), 6.86 (s, 1H), 4.39 (s, 4H), 4.04 - 3.82 (m, 2H), 3.74 (s, 2H), 3.58 (td, 1H), 3.26 (dd, 1H), 1.88 (d, 6H), 1.19 (d, 3H).

[0155] Example 2 (R)-1-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 2 [ka]

[0156] Step 1 (R)-1-(1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 2a 1e (86 mg, 0.32 mmol), cyclopropanecarbonitrile (65 mg, 0.97 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (40 mg, 0.06 mmol) were dissolved in 2 mL of tetrahydrofuran. Under an argon atmosphere, lithium bis(trimethylsilyl)amide (1.0 mL, 1 M tetrahydrofuran solution, 1.0 mmol) was added. The mixture was sealed and heated to 80 °C. The mixture was stirred for 1 h and then cooled to room temperature. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 2a (80 mg) in 84% yield. MS m / z (ESI): 298.3 [M+1].

[0157] Step 2 (R)-1-(3-Bromo-1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 2b 2a (30 mg, 0.1 mmol) was dissolved in 5 mL of 1,4-dioxane, sodium hydroxide solution (0.1 mL, 2 M solution, 0.2 mmol) was added, and the mixture was cooled with ice water. Liquid bromine (64 mg, 0.4 mmol) was added and stirred at low temperature for 10 min. The mixture was allowed to warm to room temperature and react with stirring for 1 h. The mixture was diluted with 20 mL of ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 2b (30 mg) in 80% yield. MS m / z (ESI): 376.4 [M+1].

[0158] Step 3 1-(1-methyl-5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 2c 2b (30 mg, 0.08 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 0.08 mmol), sodium carbonate (17 mg, 0.16 mmol), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44 mg, 0.16 mmol) were dissolved in 4.0 mL of ethylene glycol dimethyl ether, 1.0 mL of water was added, and the mixture was heated to 120°C in a microwave under an argon gas atmosphere and stirred for 1 hour. The reaction mixture was then cooled to room temperature. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 2c (30 mg) in a yield of 84%. MS m / z (ESI): 448.3 [M+1].

[0159] Step 4 (R)-1-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 2 Compound 2c (30 mg, 0.07 mmol) was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M ammonia in methanol. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 2 (13.5 mg) in 55% yield. MS m / z (ESI): 364.3 [M+1]. 1H NMR (400 MHz, CD3OD):δ 7.58 (d, 1H), 7.01 (d , 1H), 6.93 (s, 1H), 4.40 (d, 1H), 4.38 (s, 3H), 3.95 (dd, 2H), 3.79-3.68 (m, 2H), 3.57 (td, 1H), 3.30-3.25 (m, 1H), 1.92-1.80 (m, 2H), 1.72 - 1.58 (m, 2H), 1.18 (d, 3H).

[0160] Example 3 (R)-3-Methyl-4-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine 3 [ka]

[0161] Step 1 (R)-3-Methyl-4-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine 3a 1e (250 mg, 0.94 mmol), bis(triphenylphosphine)dichloropalladium (66 mg, 0.09 mmol), potassium carbonate (260 mg, 1.8 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (390 mg, 1.87 mmol) were dissolved in 8.0 mL of ethylene glycol dimethyl ether (EDTA). 2.0 mL of water was added and the mixture was heated to 120 °C in a microwave oven under argon gas for 2 h. The reaction mixture was then cooled to room temperature. The mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 3a (290 mg) in 99% yield. MS m / z (ESI): 313.2 [M+1].

[0162] Step 2 (R)-4-(3-Bromo-1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 3b 3a (300 mg, 0.97 mmol) was dissolved in 5 mL of N,N-dimethylformamide and cooled in ice water. N-bromosuccinimide (205 mg, 1.2 mmol) was added and stirred at low temperature for 10 min. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with 20 mL of ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography using eluent system C to give the title compound 3b (115 mg) in 30% yield. MS m / z (ESI): 391.1 [M+1].

[0163] Step 3 (3R)-3-Methyl-4-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine 3c 3b (35 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), sodium carbonate (19 mg, 0.18 mmol), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.18 mmol) were dissolved in 5.0 mL of ethylene glycol dimethyl ether, 1 mL of water was added, and the mixture was heated to 120 °C in a microwave oven under argon gas atmosphere for 1 h. The mixture was then cooled. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 3c (20 mg) in 48% yield. MS m / z (ESI): 463.4 [M+1].

[0164] Step 4 (R)-3-Methyl-4-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine 3 Compound 3c (60 mg, 0.13 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added dropwise, and the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M ammonia in methanol. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give the title compound 3 (20 mg) in 40.7% yield. MS m / z (ESI): 379.2 [M+1]. 1H NMR (400 MHz, CD3OD):δ 7.58 (d, 1H), 7.57 (d , 1H), 7.03 (d, 1H), 6.90 (s, 1H), 6.48 (d, 1H), 4.38 (d, 1H), 4.02-3.88 (m, 2H), 3.72 (s, 2H), 3.65 (s, 3H), 3.57 (td, 1H), 3.50 (s, 3H), 3.27-3.22 (m, 1H), 1.19 (d, 3H).

[0165] Example 4 (R)-2-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 4 [ka]

[0166] Step 1 Methyl 1-ethyl-4-nitro-1H-pyrazole-5-carboxylate 4b The compound 1-ethyl-4-nitro-1H-pyrazole-5-methyl formate 4a (5 g, 25.1 mmol, Shanghai BiDe) was dissolved in 100 mL of methanol, and 10% palladium on carbon (1 g) was added. The mixture was purged with hydrogen gas three times and stirred for 14 h. The filtrate was filtered and concentrated under reduced pressure to give the crude title compound 4b (4.2 g). The product was used directly in the next step without further purification. MS m / z (ESI): 170.1 [M+1].

[0167] Step 2 (R,E)-1-Ethyl-4-((1-(3-methylmorpholine)ethylidene)amino)-1H-pyrazole-5-carboxylate methyl ester 4c 1b (3.3 g, 23.0 mmol) was dissolved in 1,2-dichloroethane and cooled in ice-water under an argon atmosphere. Phosphorus oxychloride (5.4 g, 35.2 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. 4b (2.5 g, 16.1 mmol) was added and the mixture was heated to 80 °C with stirring for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (200 mL), cooled in ice-water, and neutralized to pH 8-9 by the dropwise addition of saturated sodium bicarbonate solution. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography using eluent system C to give the title compound 4c (2.3 g) in 66.1% yield. MS m / z (ESI): 295.2 [M+1].

[0168] Step 3 (R)-1-Ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-ol 4d 4c (1 g, 3.39 mmol) was dissolved in tetrahydrofuran (20 mL), cooled in ice water, and lithium bis(trimethylsilyl)amide (10 mL, 1 M tetrahydrofuran solution, 10 mmol) was slowly added and reacted at 0° C. for 1 hour. Methanol (10 mL) was added to quench the reaction, and the mixture was purified by silica gel column chromatography using eluent system A to give the title compound 4d (250 mg) in a yield of 28.1%. MS m / z (ESI): 263.1 [M+1].

[0169] Step 4 (R)-4-(7-chloro-1-ethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 4e 4d (250 mg, 0.95 mmol) was dissolved in 2.0 mL of phosphorus oxychloride and heated to 90 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (50 mL), cooled in ice water, and neutralized to pH 8-9 with saturated sodium bicarbonate solution. The mixture was stirred for 0.5 h, allowed to stand, and the layers were separated. The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography using eluent system C to give the title compound 4e (120 mg) in 42.5% yield. MS m / z (ESI): 281.3 [M+1].

[0170] Step 5 (R)-2-(1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 4g Compound 4e (120 mg, 0.43 mmol) and compound 1f (295 mg, 4.3 mmol, Shanghai Bide) were dissolved in 30 mL of tetrahydrofuran. The mixture was cooled in a dry ice acetone bath under an argon gas atmosphere. Lithium bis(trimethylsilyl)amide (1.7 mL, 1 M tetrahydrofuran solution, 1.7 mmol) was added dropwise and stirred at low temperature for 0.5 hours. The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to quench the reaction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 4g (95 mg) in a 74% yield. MS m / z (ESI): 314.1 [M+1].

[0171] Step 6 (R)-2-(3-Bromo-1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 4h 4g (95 mg, 0.67 mmol) was dissolved in 5 mL of 1,4-dioxane, sodium hydroxide solution (0.3 mL, 2 M solution, 0.6 mmol) was added, and the mixture was cooled with ice water. Liquid bromine (194 mg, 1.2 mmol) was added and stirred at low temperature for 10 minutes. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 4h (41 mg) in 34% yield. MS m / z (ESI): 392.1 [M+1].

[0172] Step 7 2-(1-Ethyl-5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 4i 4h (40 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol), sodium carbonate (32 mg, 0.3 mmol), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32 mg, 0.20 mmol, Shanghai Bide) were dissolved in 4 mL of dioxane, 1 mL of water was added, and the mixture was heated to 120 °C in a microwave oven under an argon atmosphere for 1 h. The reaction mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were concentrated under reduced pressure, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 4i (40 mg) in 85% yield. MS m / z (ESI): 464.1 [M+1].

[0173] Step 8 (R)-2-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 4 Compound 4i (20 mg, 0.04 mmol) was dissolved in 5 mL of dichloromethane and 5 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M ammonia in methanol. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give the title compound 4 (15 mg) in 45% yield. MS m / z (ESI): 380.2 [M+1]. 1 H NMR (400 MHz, CD3OD):δ 7.57 (s, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 4.66-4.64 (m, 2H), 4.39-4.38 (m, 1H), 3.97-3.91 (m, 2H), 3.74 (s, 2H), 3.58-3.57 (m, 1H), 3.28-3.27 (m, 1H), 1.86 (d, 6H), 1.46(t, 3H),1.18 (d, 3H).

[0174] Example 5 (R)-1-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 5 [ka]

[0175] Step 1 (R)-1-(1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 5a 4e (500 mg, 1.78 mmol), cyclopropanecarbonitrile (239 mg, 3.56 mmol), tris(dibenzylideneacetone)dipalladium (162 mg, 0.18 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (222 mg, 0.36 mmol) were dissolved in 2 mL of tetrahydrofuran, and lithium bis(trimethylsilyl)amide (5.3 mL, 1 M tetrahydrofuran solution, 5.3 mmol) was added under an argon gas atmosphere. The mixture was sealed and heated to 80°C and reacted with stirring for 1 hour. The reaction solution was then cooled to room temperature. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 5a (360 mg) in a yield of 64.9%. MS m / z (ESI): 312.2 [M+1].

[0176] Step 2 (R)-1-(3-Bromo-1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 5b 5a (377 mg, 1.2 mmol) was dissolved in 5 mL of tetrahydrofuran, cooled with ice water, and N-bromosuccinimide (215 mg, 1.2 mmol) was added. The mixture was stirred at low temperature for 10 minutes, then allowed to warm to room temperature and react for 2 hours with stirring. 20 mL of ethyl acetate was added for dilution. The organic phase was washed with saturated sodium thiosulfate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 5b (100 mg) in 21% yield. MS m / z (ESI): 390.3 [M+1].

[0177] Step 3 (R)-1-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanecarbonitrile 5 5b (100 mg, 0.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium·dichloromethane complex (43 mg, 0.05 mmol), sodium carbonate (81 mg, 0.78 mmol), and (1H-pyrazol-3-yl)boronic acid (43 mg, 0.38 mmol, Shanghai Bide) were dissolved in 4.0 mL of dioxane, 1.0 mL of water was added, and the mixture was stirred under argon at 100 °C for 2 h. The reaction mixture was then cooled to room temperature. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 5 (10 mg) in 10% yield. 1 H NMR (400 MHz, CD3OD):δ 7.82 (s, 1H), 7.04-7.12 (m, 2H), 4.84-4.82 (m, 2H), 4.51-4.50 (m, 1H), 4.09-4.05 (m, 2H), 3.86-3.85 (m, 2H), 3.69-3.66 (m, 1H), 3.43-3.42 (m, 1H), 1.97 (d, 2H), 1.80-1.78(m, 2H), 1.67(t, 3H),1.32 (d, 3H).

[0178] Example 6 (R)-2-Methyl-2-(5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 6 [ka]

[0179] Step 1 Methyl 1-benzyl-4-nitro-1H-pyrazole-5-carboxylate 6b Methyl 4-nitro-1H-pyrazole-3-carboxylate 6a (2 g, 11.69 mmol, Meryer) was dissolved in 30 mL of N,N-dimethylformamide, and potassium carbonate (1.75 g, 12.66 mmol) and benzyl bromide (2.04 g, 11.93 mmol) were added. The mixture was stirred at room temperature for 17 h. 80 mL of ethyl acetate was added to the reaction mixture, which was washed with water (30 mL × 3), saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 6b (710 mg) in 23.3% yield. MS m / z (ESI): 262.0 [M+1].

[0180] Step 2 Methyl 4-amino-1-benzyl-1H-pyrazole-5-carboxylate 6c Compound 6b (710 mg, 2.72 mmol) was dissolved in 20 mL of absolute ethanol, and iron powder (1.52 g, 27.22 mmol) and ammonium chloride (1.46 g, 27.29 mmol) were added. The reaction mixture was heated to reflux and stirred for 17 hours. The reaction mixture was cooled to room temperature and filtered through a Buchner funnel containing a layer of diatomaceous earth. The solid was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 6c (650 mg, containing the transesterification product of ethanol) in 100% yield. MS m / z (ESI): 232.2 [M+1],246.2[M+1].

[0181] Step 3 (R)-1-(4-amino-1-benzyl-1H-pyrazol-5-yl)-3-(3-methylmorpholinyl)propane-1,3-dione 6d Lithium bis(trimethylsilyl)amide (11.29 mL, 1 M tetrahydrofuran solution, 11.29 mmol) was placed in a three-neck flask. The reaction mixture was cooled to an internal temperature of -10°C to 0°C under a nitrogen atmosphere. A 2-methyltetrahydrofuran solution of 1b (0.65 g, 4.54 mmol, 1.6 mL) was added dropwise and allowed to react for 40 minutes while maintaining the temperature. A 2-methyltetrahydrofuran solution of 6c (0.65 g, 2.81 mmol, 2.6 mL) was then added dropwise and allowed to react for 1 hour while maintaining the temperature. The reaction mixture was added with 10 mL of water, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 6d (440 mg) in 45.7% yield. MS m / z (ESI): 343.2 [M+1].

[0182] Step 4 (R)-1-Benzyl-7-chloro-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridine 6e Compound 6d (0.44 g, 1.29 mmol) was dissolved in 5 mL of acetonitrile, and N,N-diisopropylethylamine (0.5 g, 3.87 mmol) was added. The reaction mixture was cooled to an internal temperature of -5°C to 0°C. Phosphorus oxychloride (0.79 g, 5.15 mmol) was added dropwise, and the mixture was incubated for 1.5 hours, then heated to 65°C and incubated for 4 hours. The reaction mixture was cooled to room temperature and poured into 20 mL of saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 6e (180 mg) in 40.8% yield. MS m / z (ESI): 343.1 [M+1].

[0183] Step 5 (R)-2-Methyl-2-(5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 6g Compound 6e (180 mg, 0.53 mmol) and isobutyronitrile 6f (218 mg, 3.15 mmol) were dissolved in 5 mL of tetrahydrofuran and cooled to an internal temperature of -70 °C or below under a nitrogen atmosphere. Lithium bis(trimethylsilyl)amide (3.15 mL, 1 M tetrahydrofuran solution, 3.15 mmol) was added dropwise and allowed to react for 30 minutes, then warmed to room temperature and allowed to react for 1 hour. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to obtain the title compound 6g (80 mg) in 53.3% yield. MS m / z (ESI): 286.2 [M+1].

[0184] Step 6 (R)-2-(3-Bromo-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropanenitrile 6h Compound 6g (80 mg, 0.28 mmol) was dissolved in 2 mL of tetrahydrofuran, N-bromosuccinimide (50 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 10 mL of saturated sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 6h (40 mg) in 39.2% yield. MS m / z (ESI): 364.1 [M+1].

[0185] Step 7 2-Methyl-2-(5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 6j Compound 6h (40 mg, 0.11 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 6i (61 mg, 0.22 mmol, Shanghai BiDe), and sodium carbonate (24 mg, 0.22 mmol) were placed in a three-necked flask, 2 mL of 1,4-dioxane and 0.5 mL of water were added, and the mixture was purged with nitrogen gas three times. Then, bis(triphenylphosphine)dichloropalladium(II) (16 mg, 22.8 umol) was added, and the mixture was purged with nitrogen gas three times. The mixture was heated to 85°C under a nitrogen atmosphere and stirred for 1 hour. The reaction mixture was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to obtain the title compound 6j (25 mg) in a yield of 52.3%. MS m / z (ESI): 436.3 [M+1].

[0186] Step 8 2-Methyl-2-(5-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propanenitrile 6 Compound 6j (22 mg, 50.51 μmol) was dissolved in 3 mL of isopropanol, trifluoroacetic acid (404 mg, 3.54 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 10 mL of saturated sodium bicarbonate solution and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography using developing solvent system C to give the title compound 6 (5 mg) in a 28.2% yield. MS m / z (ESI): 352.1 [M+1]. 1H NMR (500 MHz, CDCl3):δ 7.77 (s, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 4.42-4.43 (d, 1H), 4.14-4.11 (m, 1H), 4.01-3.98 (m, 1H), 3.88-3.89(m, 2H), 3.74-3.67(m, 1H),3.44-3.42 (m, 1H), 2.00 (s, 6H), 1.36-1.35(d, 3H).

[0187] Control Example 1 (Example 7) (R)-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propan-2-ol 7 [ka]

[0188] Step 1 (R)-1-Methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl-trifluoromethanesulfonate 7a Compound 1d (500 mg, 2.0 mmol) was dissolved in 5.0 mL of dichloromethane, and N,N-diisopropylethylamine (520 mg, 4.0 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (790 mg, 2.2 mmol) were added and stirred for 2.0 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system C to give the title compound 7a (600 mg) in 78.3% yield. MS m / z (ESI): 381.3[M+1].

[0189] Step 2 (R)-1-Methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate methyl ester 7b Compound 7a (400 mg, 1.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium·dichloromethane complex (178 mg, 0.21 mmol, Shanghai Bide), and triethylamine (210 mg, 2.09 mmol) were dissolved in 8 mL of methanol and stirred at 65 °C under a carbon monoxide atmosphere for 15 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 7b (90 mg) in 29.5% yield. MS m / z (ESI): 291.1[M+1].

[0190] Step 3 (R)-3-Bromo-1-methyl-5-(3-methylmorpholine)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate methyl ester 7c Compound 7b (90 mg, 0.31 mmol) was dissolved in 5 mL of tetrahydrofuran, N-bromosuccinimide (110 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 10 mL of saturated sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 7c (180 mg), which was used directly in the next step without further purification. MS m / z (ESI): 369.1[M+1].

[0191] Step 4 1-methyl-5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate methyl ester 7d 7c (180 mg, 0.316 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium·dichloromethane complex (30 mg, 0.032 mmol), sodium carbonate (83 mg, 0.783 mmol), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (176 mg, 0.632 mmol, Shanghai Bide) were dissolved in 4 mL of dioxane, and 1 mL of water was added. The mixture was heated to 120 °C in a microwave oven under an argon atmosphere for 1 h. The reaction mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to give the title compound 7d (45 mg) in a yield of 32.3%. MS m / z (ESI): 441.2[M+1].

[0192] Step 5 2-(1-methyl-5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propan-2-ol 7e Compound 7d (45 mg, 0.102 mmol) was dissolved in 5 mL of tetrahydrofuran, and a 1 M solution of methylmagnesium bromide in tetrahydrofuran (36 mg, 0.301 mmol, Shanghai BiDe) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred for 2 hours. 10 mL of saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 7e (40 mg) in 88.9% yield. MS m / z (ESI): 441.6[M+1].

[0193] Step 6 (R)-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propan-2-ol 7 Compound 7e (40 mg, 90 μmol) was dissolved in 3 mL of methanol, and a solution of hydrochloric acid in dioxane (1 mL, 4 N) was added and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography using developing solvent system C to give the title compound 7 (10 mg) in a 30.9% yield. MS m / z (ESI): 357.6 [M+1]. 1 H NMR (400 MHz, CD3OD): δ 7.68 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H), 4.50- 4.42 (m, 2H), 4.21 (s, 3H), 4.10-3.99 (m, 4H), 3.84 (d, 2H), 3.68 (td, 2H), 1.28 (d, 6H).

[0194] Test example: Biological evaluation Test Example 1: Inhibitory effect of the compound according to the present disclosure on the ATR enzyme. The following method is for measuring the inhibitory effect of the compounds according to the present disclosure on the ATR enzyme. The experimental method is briefly described as follows:

[0195] 1. Experimental materials and equipment 1. ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M) 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M) 3. 384-well plate (Thermo Scientific, 267462) 4. U-bottom 96-well plate (Corning, 3795) 5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE) 6. Anti-GST antibody binding to d2 (cisbio, 61GSTDLF) 7. ATP solution (Promega, V916B) 8. EDTA (Thermo Scientific, AM9260G) 9. HEPES (Gibco, 15630-080) 10. Microplate reader (BMG, PHERAsta)

[0196] 2. Experimental Procedure 1 nM ATR enzyme, 50 nM P53 protein, 7.435 μM ATP, and various concentrations of small molecule compounds (initial concentration 1 μM, diluted 3-fold to 11 concentrations) were incubated in a mixing chamber for 2 hours. A stop solution (12.5 mM HEPES, 250 mM EDTA) was added and mixed uniformly. 0.42 ng / well of europium cryptate-labeled anti-phosphorylated P53 protein antibody and 25 ng / well of d2-binding anti-GST antibody were then added. After overnight incubation at room temperature, fluorescence signals were detected at 620 nm and 665 nm using a PHERAstar™. Data were processed using GraphPad software.

[0197] 3. Experimental Data The inhibitory activity of the compounds according to the present disclosure against the ATR enzyme can be measured by the above test, and the measured IC 50 The values ​​are shown in Table 1. [Table 6] Conclusion: Compared with Control Example 1, the compounds according to the present disclosure have superior inhibitory activity against the ATR enzyme.

[0198] Test Example 2: Cell proliferation experiment The following method detects intracellular ATP content and determines IC 50 The inhibitory effect of the compounds according to the present disclosure on LoVo cell proliferation is evaluated based on the magnitude of the . The experimental method is briefly described as follows:

[0199] 1. Experimental materials and equipment 1. LoVo, human colon cancer tumor cells (Nanjing Kebai, CBP60032) 2. Fetal bovine serum (FBS) (GIBCO, 10091-148) 3. F-12K medium (Gibco, 21127030) 4. CellTite-Glo Reagent (Promega, G7573) 5. 96-well cell culture plate (Corning, 3903) 6. Pancreatin (Invitrogen, 25200-072) 7. Microplate reader (BMG, PHERAstar) 8. Cell counter (Shanghai Ruiyi Biological Technology Co., Ltd., IC1000)

[0200] 2. Experimental Procedure LoVo cells were cultured in 10% FBS-containing F-12K medium and passaged 2-3 times a week at a passage ratio of 1:3 or 1:5. During passage, cells were digested with pancreatin, transferred to a centrifuge tube, and centrifuged at 1200 rpm for 3 minutes. The remaining supernatant medium was discarded, and fresh medium was added to resuspend the cells. 90 μL of the cell suspension was added to a 96-well cell culture plate, and the cells were cultured at a density of 3.88 × 10 4 100 μL of complete medium was added to the periphery of the 96-well plate. The culture plate was cultured in an incubator (37°C, 5% CO2) for 24 hours.

[0201] The test sample was diluted to 2 mM with DMSO and then serially diluted three-fold to 10 concentrations, with blank and control wells. 5 μL of the test compound solution prepared at the gradient concentrations was added to 95 μL of fresh medium. 10 μL of the above-mentioned drug-containing medium solution was then added to the culture plate. The culture plate was incubated in an incubator (37°C, 5% CO2) for 3 days. 50 μL of CellTiter-Glo reagent was added to each well of a 96-well cell culture plate and left in the dark at room temperature for 5-10 minutes. Chemiluminescence signal values ​​were read using a PHERAstar, and the data were processed using GraphPad software.

[0202] 3. Experimental Data The inhibitory activity of the compounds according to the present disclosure against LoVo cell proliferation can be measured by the above test, and the measured IC 50 The values ​​are shown in Table 2. [Table 7] Conclusion: Compared with Control Example 1, the compounds of the present disclosure have a better inhibitory effect on LoVo cell proliferation.

[0203] Pharmacokinetic evaluation Test Example 3: Pharmacokinetic test of the compound according to the present disclosure

[0204] 1. Summary Rats were used as test animals, and the plasma drug concentrations at different time points after intragastric administration of the compounds of Example 1, Example 2, and Example 3 were measured by LC / MS / MS. The pharmacokinetic behavior of the compounds according to the present disclosure in rats was studied, and the pharmacokinetic characteristics were evaluated.

[0205] 2. Test plan 2.1 Study Drugs The compound of Example 1, the compound of Example 2 and the compound of Example 3.

[0206] 2.2 Test animals Twelve healthy adult SD rats, half male and half female, purchased from Weitong Lihua Laboratory Animal Co., Ltd., were divided into three groups on average, with four rats per group.

[0207] 2.3 Pharmaceutical Combinations A certain amount of the drug was weighed and mixed with 5% DMSO, 5% Tween 80 and 90% saline to prepare a colorless, transparent solution.

[0208] 2.4 Administration SD rats were fasted overnight and then intragastrically administered with a dose of 2 mg / kg and a volume of 10.0 mL / kg.

[0209] 3, operation The compound of Example 1, the compound of Example 2, and the compound of Example 3 were intragastrically administered to rats, and 0.2 mL of blood was collected from the orbit before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and the collected blood was placed in an EDTA-K2kk anticoagulant test tube. The plasma was centrifuged at 11,000 rpm at 4°C for 5 minutes, stored at -20°C, and fed to rats 2 hours after administration.

[0210] The content of the test compound in rat plasma after intragastric administration of different concentrations of pharmaceuticals was measured: 25 μL of rat plasma was collected at each time point after administration, and 50 μL of internal standard solution and 175 μL of acetonitrile were added. The mixture was vortex-mixed for 5 minutes and centrifuged for 10 minutes (4000 rpm). 1 μL of the supernatant was then taken from the plasma sample and analyzed by LC / MS / MS.

[0211] 4. Pharmacokinetic parameter results [Table 8] Conclusion: The compounds of the present disclosure have good pharmacokinetic absorption and significant pharmacokinetic advantages. Furthermore, the present invention includes the following aspects. [Aspect 1] A compound represented by general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof:

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Claims

1. A compound represented by general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, Ring A is a 5- to 10-membered heteroaryl group; R 1 teeth, 【Chemistry 2】 and R 2 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; R 3 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; n is 0, 1, 2 or 3.

2. 2. A compound represented by general formula (I) according to claim 1, wherein ring A is selected from a pyrazolyl group, a pyrrolyl group, and an imidazolyl group, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. A compound represented by general formula (I) according to claim 1 or 2, which is a compound represented by general formula (II) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: 【Transformation 3】 [In the formula, G 1 , G 2 , R 1 , R 2 and R 3 is as defined in claim 1, n is 0, 1 or 2].

4. R 2 is a hydrogen atom or C 1 ~C 6 A compound represented by general formula (I) according to any one of claims 1 to 3, wherein the compound is an alkyl group, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. R 2 But C 1 ~C 6 alkyl group and / or R 3 is a hydrogen atom, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. A compound represented by general formula (I) according to claim 1, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, selected from any one of the following compounds: 【Chemistry 4】

7. A compound represented by general formula (IA) or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: 【Transformation 5】 [In the formula, X is a halogen, preferably Br; G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, R 1 teeth, 【Transformation 6】 and R 2 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group.

8. A compound represented by general formula (IIA) or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: 【Transformation 7】 [In the formula, R a is a tetrahydropyranyl group, G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, R 1 teeth, 【Transformation 8】 and R 2 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; R 3 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; n is 0, 1 or 2.

9. A compound represented by general formula (IIGA) or its tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof: 【Chemistry 9】 [In the formula, R a is a tetrahydropyranyl group, G 1 and G 2 are identical or different and each independently represents C-H or N; G 1 and G 2 is not simultaneously CH, R 1 is C 1 ~C 6 alkyl groups and 3- to 12-membered cycloalkyl groups, wherein said C 1 ~C 6 the alkyl group and the 3- to 12-membered cycloalkyl group are each independently substituted with one or more cyano groups; R 2 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; R 3 is a hydrogen atom, halogen, C 1 ~C 6 Alkyl group, C 2 ~C 6 Alkenyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, C 1 ~C 6 Haloalkoxy group, hydroxy group, C 1 ~C 6 is selected from a hydroxyalkyl group, a cyano group, an amino group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group, wherein said C 1 ~C 6 Alkyl group, C 1 ~C 6 The alkoxy group, the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocyclyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently optionally selected from halogen, C 1 ~C 6 Alkyl group, C 1 ~C 6 Alkoxy group, C 1 ~C 6 Haloalkyl group, hydroxy group, C 1 ~C 6 substituted with one or more substituents selected from a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; n is 0, 1 or 2.

10. The following compounds or their tautomers, meso-isomers, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof: 【Chemistry 10】

11. A method for preparing a compound represented by general formula (I) according to claim 1 or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 11】 coupling reaction of a compound of general formula (IA) with a compound of general formula (IB) to obtain a compound of general formula (I); where: X is a halogen, preferably Br; R b teeth 【Chemistry 12】 and Ring A, G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in claim 1; method.

12. A method for preparing a compound represented by general formula (II) according to claim 3, or a tautomer, meso form, racemic form, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 13】 removing the amino protecting group from a compound of general formula (IIA) to obtain a compound of general formula (II), wherein R a is an amino protecting group, G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in claim 3; method. 【Request Item 13】 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 6, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound according to claim 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. 15. The pharmaceutical composition of claim 14 for inhibiting ATR kinase.

16. 15. A pharmaceutical composition according to claim 14 for treating and / or preventing a hyperproliferative disease, comprising: The disease is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.

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