Pyrazolo heteroaryl derivative, preparation method thereof and application of pyrazolo heteroaryl derivative in medicine

Abstract

The invention relates to a pyrazolo heteroaryl derivative, a preparation method thereof and application of the pyrazolo heteroaryl derivative in medicine. Specifically, the invention relates to a pyrazolo heteroaryl derivative as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, especially application of the derivative as an ATR kinase inhibitor and application of the derivative in preparation of drugs for treating and / or preventing hyperproliferative diseases. The definition of each group in the general formula (I) is the same as that in the specification. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080066108.4, application date November 20, 2020, and invention name “Pyrazoloheteroaryl derivatives, preparation methods and their applications in medicine”. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to a pyrazoloheteroaryl derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and the use thereof as a therapeutic agent, in particular, the use thereof as an ATR kinase inhibitor and the use thereof in the preparation of a drug for treating and / or preventing hyperproliferative diseases. Background Art

[0003] Thousands of DNA damages occur every day in both normal cells and tumor cells. This makes DNA damage repair play a vital role in maintaining genome stability and cell survival. Compared with normal cells, tumor cells are under greater replication pressure, carry more endogenous DNA damage, and often lack one or more DNA damage repair pathways. This makes the survival of tumor cells more dependent on the smooth progress of DNA damage repair.

[0004] Homologous recombination repair is the main repair method for double-strand breaks in DNA. It uses the homologous sequence of the undamaged sister chromatid as a template for repair to replicate the DNA sequence at the damaged site and accurately repair the DNA. This repair method mainly occurs in the G2 and S phases of the cell. ATR is a key enzyme in the homologous recombination repair pathway and belongs to the PIKK family. When the ATR / ATRIP complex binds to the damaged DNA covered with replication protein A (RPA), ATR is activated and regulates various checkpoints of the cell cycle by phosphorylating downstream proteins such as Chk1 and SMARCAL, causing cell cycle arrest; ensuring the stability of damaged DNA; increasing dNTP concentration, and promoting DNA damage to be repaired. The repair of DNA damage that occurs in the S phase of the cell cycle is mainly completed by the ATR pathway, indicating that ATR is very important for ensuring cell proliferation. The analysis results of clinical tumor samples show that increased ATR expression levels have been observed in a variety of tumor tissues, such as gastric cancer, liver cancer, colorectal cancer, ovarian cancer, pancreatic cancer, etc. In addition, in patients with ovarian cancer and pancreatic cancer, high levels of ATR are often accompanied by lower survival rates. This shows that ATR is an important target for tumor treatment.

[0005] The patent applications for ATR inhibitors that have been disclosed include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889 and WO2014140644, etc. Summary of the invention

[0006] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] G 1 and G 2 are the same or different, each independently CH or N, provided that G 1 and G 2 Not at the same time CH;

[0010] Ring A is a heteroaryl group;

[0011] R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0012] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0013] R 3 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0014] 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 hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0015] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0016] R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0017] n is 0, 1, 2 or 3.

[0018] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, pyrrolyl and imidazolyl.

[0019] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is a compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt:

[0020]

[0021] in:

[0022] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (I).

[0023] In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt is a compound represented by the general formula (III) or the general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt:

[0024]

[0025] Where: R 1 , R 2 , R 3 and n are as defined in the general formula (I).

[0026] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein R 1 Selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0027] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein R 1 is selected from alkyl, cycloalkyl and heterocyclic; wherein the alkyl is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl, and the cycloalkyl and heterocyclic are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R 1 C 1- C6 alkyl or 3 to 6 membered cycloalkyl; wherein the C1- C6 alkyl and 3 to 6 membered cycloalkyl are each independently optionally selected from halogen, C 1- C6 alkyl, C 1- C6 alkoxy, C 1- C6 haloalkyl, C 1- C6 hydroxyalkyl, cyano, amino, nitro, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic, 6 to 10-membered aryl and 5 to 10-membered heteroaryl are substituted with one or more substituents; more preferably R 1 C 1- C6 alkyl or 3 to 6 membered cycloalkyl; wherein the C 1- C6 alkyl and 3 to 6 membered cycloalkyl are each independently optionally substituted with a cyano group; most preferably R 1 for

[0028] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein R 2 is a hydrogen atom or an alkyl group; preferably an alkyl group; more preferably C 1-6 alkyl.

[0029] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein R 2 It is an alkyl group.

[0030] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt, wherein R 3 A hydrogen atom.

[0031] Typical compounds of the present disclosure include, but are not limited to:

[0032]

[0033]

[0034]

[0035] Another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0036]

[0037] in:

[0038] X is halogen; preferably Br;

[0039] G 1 and G 2 are the same or different, each independently CH or N, provided that G 1 and G 2 Not at the same time CH;

[0040] R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0041] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0042] R 4 and R 5are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0043] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0044] R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group.

[0045] Another aspect of the present disclosure relates to a compound represented by general formula (IIIC) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0046]

[0047] Where: X, R 1 and R 2 As defined in formula (IA).

[0048] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0049]

[0050] in:

[0051] R a is an amino protecting group;

[0052] G 1 and G 2 are the same or different, each independently CH or N, provided that G 1 and G 2 Not at the same time CH;

[0053] R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7, cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0054] R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0055] R 3 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0056] 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 hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0057] R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0058] R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0059] n is 0, 1, 2 or 3.

[0060] Another aspect of the present disclosure relates to a compound represented by the general formula (IIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0061]

[0062] Where: G 1 , G 2 , R 1 , R 2 , R 3 , R a and n are as defined in formula (IIA).

[0063] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0064]

[0065] Where: R a , R 1 , R 2 , R 3 and n are as defined in formula (IIA).

[0066] Another aspect of the present disclosure relates to a compound represented by the general formula (IIIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof,

[0067]

[0068] Where: R a , R 1 , R 2 , R 3 and n are as defined in formula (IIIA).

[0069] Typical intermediate compounds of the present disclosure include, but are not limited to:

[0070]

[0071]

[0072]

[0073] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0074]

[0075] The compound of general formula (IA) and the compound of general formula (IB) undergo coupling reaction to obtain the compound of general formula (I),

[0076] in:

[0077] X is halogen; preferably Br;

[0078] R b for

[0079] Ring A, G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (I).

[0080] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0081]

[0082] The compound of general formula (IA) and the compound of general formula (IID) undergo coupling reaction to obtain the compound of general formula (II),

[0083] in:

[0084] X is halogen; preferably Br;

[0085] R b for

[0086] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0087] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0088]

[0089] The compound of general formula (IIIC) and the compound of general formula (IID) undergo coupling reaction to obtain a compound of general formula (III),

[0090] in:

[0091] X is halogen; preferably Br;

[0092] R b for

[0093] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0094] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0095]

[0096] The compound of general formula (IVC) and the compound of general formula (IID) undergo coupling reaction to obtain the compound of general formula (IV),

[0097] in:

[0098] X is halogen; preferably Br;

[0099] R b for

[0100] R 1 , R 2 , R 3 and n are as defined in the general formula (IV).

[0101] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0102]

[0103] The compound of general formula (IA) and the compound of general formula (IIB) undergo coupling reaction to obtain the compound of general formula (IIA),

[0104] in:

[0105] X is halogen; preferably Br;

[0106] R a is an amino protecting group;

[0107] R b for

[0108] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0109] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0110]

[0111] The compound of general formula (IIA) is deprotected from the amino protecting group to obtain a compound of general formula (II),

[0112] in:

[0113] R a is an amino protecting group;

[0114] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0115] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0116]

[0117] The compound of general formula (IA) and the compound of general formula (IIGB) undergo coupling reaction to obtain a compound of general formula (IIGA),

[0118] in:

[0119] X is halogen; preferably Br;

[0120] R a is an amino protecting group;

[0121] R b for

[0122] G 1 , G 2 , R 1 , R 2 , R3 and n are as defined in the general formula (IIGA).

[0123] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0124]

[0125] The compound of general formula (IIGA) is deprotected from the amino protecting group to obtain a compound of general formula (II),

[0126] in:

[0127] R a is an amino protecting group;

[0128] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0129] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0130]

[0131] The compound of general formula (IIIC) and the compound of general formula (IIB) undergo coupling reaction to obtain the compound of general formula (IIIA),

[0132] in:

[0133] X is halogen; preferably Br;

[0134] R a is an amino protecting group;

[0135] R b for

[0136] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0137] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0138]

[0139] The compound of general formula (IIIA) is deprotected from the amino protecting group to obtain a compound of general formula (III),

[0140] in:

[0141] R a is an amino protecting group;

[0142] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0143] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0144]

[0145] The compound of general formula (IIIC) and the compound of general formula (IIGB) undergo coupling reaction to obtain a compound of general formula (IIIGA),

[0146] in:

[0147] X is halogen; preferably Br;

[0148] R a is an amino protecting group;

[0149] R b for

[0150] R 1 , R 2 , R 3 and n are as defined in Formula (IIIG).

[0151] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0152]

[0153] The compound of general formula (IIIGA) is deprotected from the amino protecting group to obtain a compound of general formula (III),

[0154] in:

[0155] R a is an amino protecting group;

[0156] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0157] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

[0158]

[0159] The compound of general formula (IVA) is deprotected from the amino protecting group to obtain a compound of general formula (IV),

[0160] in:

[0161] R a is an amino protecting group;

[0162] R 1 , R 2 , R 3 and n are as defined in the general formula (IV).

[0163] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound represented by the general formula (I) of the present disclosure or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0164] The present disclosure further relates to the use of the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same in the preparation of a drug for inhibiting ATR kinase.

[0165] The present disclosure further relates to the use of the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same in the preparation of a medicament for treating and / or preventing a hyperproliferative disease.

[0166] The present disclosure further relates to the use of the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a drug for treating and / or preventing tumors.

[0167] The present disclosure further relates to the use of the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt or pharmaceutical composition containing the same in the preparation of a drug for treating tumors.

[0168] The present disclosure also relates to a method for inhibiting ATR kinase, which comprises administering to a patient in need thereof an effective amount of a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0169] 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, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0170] The present disclosure also relates to a method for treating and / or preventing tumors, which comprises administering to a patient in need thereof an effective amount of a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0171] The present disclosure further relates to a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition comprising the same, which is used as a medicament. The medicament can be used to treat and / or prevent hyperproliferative diseases, particularly tumors.

[0172] The present disclosure also relates to a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an ATR kinase inhibitor.

[0173] The present disclosure also relates to a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing hyperproliferative diseases.

[0174] The present disclosure further relates to a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating tumors.

[0175] The tumor described in the present disclosure 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, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.

[0176] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form in which a patient can self-administer a single dose. The unit dosage form of the disclosed compound or composition may be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations.

[0177] The dosage of the compound or composition used in the disclosed treatment methods will generally vary with the severity of the disease, the patient's weight and the relative efficacy of the compound. However, as a general guide, a suitable unit dosage may be 0.1 to 1000 mg.

[0178] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0179] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0180] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0181] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants 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 sweetening agents.

[0182] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0183] Dispersible powders and granules suitable for preparing water suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents illustrate the examples above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0184] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. 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 emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0185] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0186] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0187] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0188] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0189] Detailed description of the invention

[0190] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0191] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (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, 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 having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0192] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which is a straight or branched 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, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0193] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0194] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0195] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 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, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused ring and bridged ring cycloalkyls.

[0196] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0197]

[0198] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0199]

[0200] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0201]

[0202] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, phenylcyclopentyl and benzocycloheptyl, etc.; preferably phenylcyclopentyl and tetrahydronaphthyl.

[0203] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0204] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic radical, aryl, heteroaryl. The term "heterocyclic radical" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, S, S(O) and S(O)2 heteroatoms, but do not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms, of which 1-3 (e.g., 1, 2, or 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spirocyclic, fused, and bridged heterocyclic groups.

[0205] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 monocyclic rings, wherein 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 may contain one or more double bonds. Preferably, it is 6 to 14, more preferably 7 to 10. According to the number of shared spiro atoms between rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, it is a 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0206]

[0207] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms of the polycyclic heterocyclic group with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are selected from nitrogen, oxygen, S, S (O) and S (O) 2 heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radical. Non-limiting examples of fused heterocyclic radical include:

[0208]

[0209] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein 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. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0210]

[0211] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0212]

[0213] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0214] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0215]

[0216] The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0217] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, and 10), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0218]

[0219]

[0220] The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0221] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from a parent ring atom, or two residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0222] The term "amino protecting group" is to protect the amino group with a group that is easily removed in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl. These groups can be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tetrahydropyranyl.

[0223] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0224] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0225] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0226] The term "hydroxy" refers to an -OH group.

[0227] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0228] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0229] The term "amino" refers to -NH2.

[0230] The term "cyano" refers to -CN.

[0231] The term "nitro" refers to -NO2.

[0232] The term "carbonyl" refers to C=O.

[0233] The term "carboxy" refers to -C(O)OH.

[0234] The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0235] THP is tetrahydropyranyl.

[0236] The compounds of the present disclosure may exist as tautomers. For the purposes of the present disclosure, reference to a compound of formula (I) refers to the compound itself, or any one of its tautomers itself, or a mixture of two or more tautomers. For example, reference to pyrazolyl is understood to include any one or a mixture of two tautomers of the following two structures,

[0237] The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure, with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The present disclosure includes various deuterated forms of compounds of formula (I). Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, which include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.

[0238] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0239] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0240] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0241] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals and have the desired biological activity.

[0242] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0243] Synthesis method of the disclosed compound

[0244] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0245] Solution 1

[0246] The method for preparing the compound represented by the general formula (I) or a salt thereof disclosed herein comprises the following steps:

[0247]

[0248] The compound of general formula (IA) and the compound of general formula (IB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (I).

[0249] in:

[0250] X is halogen; preferably Br;

[0251] R b for

[0252] Ring A, G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (I).

[0253] Solution 2

[0254] The method for preparing the compound represented by the general formula (II) or a salt thereof disclosed herein comprises the following steps:

[0255]

[0256] The compound of general formula (IA) and the compound of general formula (IID) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (II).

[0257] in:

[0258] X is halogen; preferably Br;

[0259] R b for

[0260] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0261] Option 3

[0262] The method for preparing the compound represented by the general formula (II) or a salt thereof disclosed herein comprises the following steps:

[0263]

[0264] The compound of general formula (IA) and the compound of general formula (IIB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IIA);

[0265] The compound of general formula (IIA) is deprotected from the amino protecting group under acidic conditions to obtain a compound of general formula (II);

[0266] in:

[0267] X is halogen; preferably Br;

[0268] R b for

[0269] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0270] Option 4

[0271] The method for preparing the compound represented by the general formula (II) or a salt thereof disclosed herein comprises the following steps:

[0272]

[0273] The compound of general formula (IA) and the compound of general formula (IIGB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IIGA);

[0274] The compound of general formula (IIGA) is deprotected from the amino protecting group under acidic conditions to obtain a compound of general formula (II);

[0275] in:

[0276] X is halogen; preferably Br;

[0277] R b for

[0278] G 1 , G 2 , R 1 , R 2 , R 3 and n are as defined in the general formula (II).

[0279] Option 5

[0280] The method for preparing the compound represented by the general formula (III) or a salt thereof disclosed herein comprises the following steps:

[0281]

[0282] The compound of general formula (IIIC) and the compound of general formula (IID) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (III).

[0283] in:

[0284] X is halogen; preferably Br;

[0285] R b for

[0286] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0287] Option 6

[0288] The method for preparing the compound represented by the general formula (III) or a salt thereof disclosed herein comprises the following steps:

[0289]

[0290] The compound of general formula (IIIC) and the compound of general formula (IIB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IIIA);

[0291] The compound of general formula (IIIA) is deprotected by removing the amino protecting group under acidic conditions to obtain a compound of general formula (III);

[0292] in:

[0293] X is halogen; preferably Br;

[0294] R a is an amino protecting group;

[0295] R b for

[0296] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0297] Option 7

[0298] The method for preparing the compound represented by the general formula (III) or a salt thereof disclosed herein comprises the following steps:

[0299]

[0300] The compound of general formula (IIIC) and the compound of general formula (IIGB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IIIGA);

[0301] The compound of general formula (IIIGA) is deprotected from the amino protecting group under acidic conditions to obtain a compound of general formula (III);

[0302] in:

[0303] X is halogen; preferably Br;

[0304] R a is an amino protecting group;

[0305] R b for

[0306] R 1 , R 2 , R 3 and n are as defined in the general formula (III).

[0307] Option 8

[0308] The method for preparing the compound represented by the general formula (IV) or a salt thereof disclosed herein comprises the following steps:

[0309]

[0310] The compound of general formula (IVC) and the compound of general formula (IID) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IV).

[0311] in:

[0312] X is halogen; preferably Br;

[0313] R b for

[0314] R 1 , R 2 , R 3 and n are as defined in the general formula (IV).

[0315] Option 9

[0316] The method for preparing the compound represented by the general formula (IV) or a salt thereof disclosed herein comprises the following steps:

[0317]

[0318] The compound of general formula (IVC) and the compound of general formula (IIB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IVA);

[0319] The compound of general formula (IVA) is deprotected by removing the amino protecting group under acidic conditions to obtain a compound of general formula (IV);

[0320] in:

[0321] X is halogen; preferably Br;

[0322] R a is an amino protecting group;

[0323] R b for

[0324] R 1 , R 2 , R 3 and n are as defined in the general formula (IV).

[0325] Plan 10

[0326] The method for preparing the compound represented by the general formula (IV) or a salt thereof disclosed herein comprises the following steps:

[0327]

[0328] The compound of general formula (IVC) and the compound of general formula (IIGB) undergo coupling reaction under alkaline conditions in the presence of a catalyst to obtain a compound of general formula (IVGA);

[0329] The compound of general formula (IVGA) is deprotected by removing the amino protecting group under acidic conditions to obtain a compound of general formula (IV);

[0330] in:

[0331] X is halogen; preferably Br;

[0332] R a is an amino protecting group;

[0333] R b for

[0334] R 1 , R 2 , R 3 and n are as defined in the general formula (IV).

[0335] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyllithium amide, bistrimethylsilyl lithium amide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, and the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide.

[0336] The catalyst described in the above synthesis scheme includes but is not limited to palladium / carbon, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, bis(triphenylphosphine)palladium dichloride (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]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentylferropalladium or tris(dibenzylideneacetone)dipalladium, preferably tetrakistriphenylphosphine palladium or bis(triphenylphosphine)palladium dichloride (II).

[0337] The reagents providing acidic conditions in the above synthesis scheme include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl, TMSOTf, preferably trifluoroacetic acid.

[0338] In the above synthesis scheme, the amino protecting group includes but is not limited to tetrahydropyranyl (THP), tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, which may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. Preferably, the amino protecting group is tetrahydropyranyl.

[0339] The above reaction is preferably carried out in a solvent, and the solvent used includes but is 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

[0340] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0341] Example

[0342] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0343] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0344] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0345] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0346] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0347] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0348] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0349] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0350] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0351] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0352] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0353] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0354] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0355] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0356] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0357] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0358] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0359] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0360] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0361] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of eluent for column chromatography used for purifying the compound and the developing solvent system for thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0362] THP is tetrahydropyranyl.

[0363] Example 1

[0364] (R)-2-methyl-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1

[0365]

[0366]

[0367] first step

[0368] (R,E)-1-methyl-4-((1-(3-methylmorpholino)ethylidene)amino)-1H-pyrazole-5-carboxylic acid methyl ester 1c

[0369] Compound (R)-1-(3-methylmorpholine)ethan-1-one 1b (2.5 g, 17.7 mmol, prepared by the method disclosed in the patent application "Intermediate-1 in the example on page 86 of the specification of WO2016020320A1") was dissolved in 1,2-dichloroethane, protected by argon, and cooled in ice water. 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. Compound 4-amino-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester 1a (2.5 g, 16.1 mmol, Jiangsu Aikon Biotechnology) was added, and the mixture was heated to 80°C and stirred for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Dichloromethane (200 mL) was added to the residue to dilute it, and the mixture was placed in ice water to cool. Saturated sodium bicarbonate solution was added dropwise to neutralize it to pH 8-9. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography with eluent system C to give the title compound 1c (4.8 g). Yield: 94%.

[0370] MS m / z(ESI):281.2[M+1].

[0371] Step 2

[0372] (R)-1-Methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-ol 1d

[0373] 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 purified by silica gel column chromatography with eluent system A to obtain the title compound 1d (400 mg), with a yield of 55.8%.

[0374] MS m / z(ESI):249.0[M+1].

[0375] Step 3

[0376] (R)-4-(7-Chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 1e

[0377] 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 solution was cooled to room temperature and concentrated under reduced pressure. Dichloromethane (50 mL) was added to the obtained residue for dilution, placed in ice water for cooling, and saturated sodium bicarbonate solution was added to neutralize to pH = 8-9. The reaction was stirred for 0.5 hours, and the liquid was separated by standing. 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 with eluent system C to obtain the title compound 1e (240 mg), yield: 56%. MS m / z (ESI): 267.0 [M+1].

[0378] Step 4

[0379] (R)-2-Methyl-2-(1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1g

[0380] Compound 1e (240 mg, 0.91 mmol) and compound isobutyronitrile 1f (620 mg, 8.9 mmol, Shanghai Bidex) 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. The mixture was stirred at low temperature for 0.5 hour, and the mixture was naturally heated 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 with eluent system C to obtain the title compound 1g (200 mg) in a yield of 74%.

[0381] MS m / z(ESI):300.1[M+1].

[0382] Step 5

[0383] (R)-2-(3-Bromo-1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 1h

[0384] Dissolve 1g (200mg, 0.67mmol) in 5mL of 1,4-dioxane, add sodium hydroxide solution (0.66mL, 2M solution, 1.32mmol), cool with ice water, add liquid bromine (427mg, 2.67mmol), stir at low temperature for 10 minutes, naturally warm to room temperature and stir to react for 1 hour. Add ethyl acetate to dilute, wash the organic phase with saturated sodium thiosulfate solution, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography with eluent system C to obtain the title compound 1h (140mg), yield: 55%.

[0385] MS m / z(ESI):377.9[M+1].

[0386] Step 6

[0387] 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)propionitrile 1i

[0388] 1h (20 mg, 0.05 mmol), tetrakistriphenylphosphine 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 Bid) were dissolved in 4 mL of ethylene glycol dimethyl ether, 1 mL of water was added, and microwave heating was performed at 120°C under argon atmosphere for 1 hour. The reaction solution was cooled to room temperature, 20 mL of water was added, and ethyl acetate was extracted (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 title compound 1i (20 mg) was purified by silica gel column chromatography with eluent system C, with a yield of 84%.

[0389] MS m / z(ESI):450.1[M+1].

[0390] Step 7

[0391] (R)-2-methyl-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1

[0392] 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 completed, the mixture was stirred and reacted for 4 hours. The reaction solution was concentrated under reduced pressure, 7 M ammonia methanol solution was added dropwise to adjust the pH to 8-9, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 1 (7.0 mg), with a yield of 43%.

[0393] MS m / z(ESI):366.0[M+1].

[0394] 1 H NMR (400MHz, CD3OD): δ7.58(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).

[0395] Example 2

[0396] (R)-1-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 2

[0397]

[0398] first step

[0399] (R)-1-(1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 2a

[0400] Dissolve 1e (86 mg, 0.32 mmol), cyclopropanenitrile (65 mg, 0.97 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (40 mg, 0.06 mmol) in 2 mL of tetrahydrofuran, add bistrimethylsilylamide lithium (1.0 mL, 1 M tetrahydrofuran solution, 1.0 mmol) under argon atmosphere, seal and heat to 80°C, stir and react for 1 hour, and cool the reaction solution to room temperature. Add 20 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system C to obtain the title compound 2a (80 mg), yield: 84%.

[0401] MS m / z(ESI):298.3[M+1].

[0402] Step 2

[0403] (R)-1-(3-Bromo-1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 2b

[0404] Dissolve 2a (30 mg, 0.1 mmol) in 5 mL of 1,4-dioxane, add sodium hydroxide solution (0.1 mL, 2M solution, 0.2 mmol), cool with ice water, add liquid bromine (64 mg, 0.4 mmol), stir at low temperature for 10 minutes, naturally warm to room temperature and stir to react for 1 hour. Add 20 mL of ethyl acetate to dilute, wash the organic phase with saturated sodium thiosulfate solution, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system C to obtain the title compound 2b (30 mg), yield: 80%.

[0405] MS m / z(ESI):376.4[M+1].

[0406] Step 3

[0407] 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)cyclopropanenitrile 2c

[0408] 2b (30 mg, 0.08 mmol), tetrakistriphenylphosphine 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, and 1.0 mL of water was added. The mixture was heated to 120°C under argon atmosphere and stirred for 1 hour. The reaction solution 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 with eluent system C to obtain the title compound 2c (30 mg) with a yield of 84%.

[0409] MS m / z(ESI):448.3[M+1].

[0410] Step 4

[0411] (R)-1-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 2

[0412] 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 completed, the mixture was stirred and reacted for 4 hours. The reaction solution was concentrated under reduced pressure, and 7 M ammonia methanol solution was added dropwise to adjust the pH to 8-9, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 2 (13.5 mg), with a yield of 55%.

[0413] MS m / z(ESI):364.3[M+1].

[0414] 1 H NMR (400MHz, CD3OD): δ7.58(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).

[0415] Example 3

[0416] (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

[0417]

[0418] first step

[0419] (R)-3-Methyl-4-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine 3a

[0420] 1e (250 mg, 0.94 mmol), bistriphenylphosphine palladium dichloride (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, and 2.0 mL of water was added. The mixture was heated to 120°C in a microwave oven under an argon atmosphere for 2 hours, and the reaction solution was cooled to room temperature. 20 mL of water was added for dilution, 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 with eluent system C to obtain the title compound 3a (290 mg) with a yield of 99%.

[0421] MS m / z(ESI):313.2[M+1].

[0422] Step 2

[0423] (R)-4-(3-bromo-1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 3b

[0424] 3a (300 mg, 0.97 mmol) was dissolved in 5 mL of N,N-dimethylformamide, cooled in ice water, and N-bromosuccinimide (205 mg, 1.2 mmol) was added. The mixture was stirred at low temperature for 10 minutes, and then naturally heated to room temperature and stirred for 1 hour. 20 mL of ethyl acetate was added to dilute the mixture, 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 title compound 3b (115 mg) was purified by silica gel column chromatography with eluent system C, with a yield of 30%.

[0425] MS m / z(ESI):391.1[M+1].

[0426] Step 3

[0427] (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

[0428] 3b (35 mg, 0.09 mmol), tetrakistriphenylphosphine 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, microwave heating was performed at 120°C under argon atmosphere for 1 hour, and the mixture was cooled. 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 with eluent system C to obtain the title compound 3c (20 mg) in a yield of 48%.

[0429] MS m / z(ESI):463.4[M+1].

[0430] Step 4

[0431] (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

[0432] Compound 3c (60 mg, 0.13 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 and reacted for 4 hours. The reaction solution was concentrated under reduced pressure, 7 M ammonia methanol solution was added dropwise to adjust the pH to 8-9, and concentrated under reduced pressure. The title compound 3 (20 mg) was purified by silica gel column chromatography using eluent system A, with a yield of 40.7%.

[0433] MS m / z(ESI):379.2[M+1].

[0434] 1H NMR (400MHz, CD3OD): δ7.58(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).

[0435] Example 4

[0436] (R)-2-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile

[0437]

[0438]

[0439] first step

[0440] 1-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid methyl ester 4b

[0441] Compound 1-ethyl-4-nitro-1H-pyrazole-5-carboxylic acid methyl ester 4a (5 g, 25.1 mmol, Shanghai Bidex) was dissolved in 100 mL of methanol, 10% palladium / carbon (1 g) was added, hydrogen was replaced three times, and the reaction was stirred for 14 hours. Filtered, the filtrate was concentrated under reduced pressure to obtain the crude title compound 4b (4.2 g), which was directly used in the next step without purification.

[0442] MS m / z(ESI):170.1[M+1].

[0443] Step 2

[0444] (R,E)-1-ethyl-4-((1-(3-methylmorpholino)ethylidene)amino)-1H-pyrazole-5-carboxylic acid methyl ester 4c

[0445] 1b (3.3 g, 23.0 mmol) was dissolved in 1,2-dichloroethane, cooled in ice water under argon atmosphere, phosphorus oxychloride (5.4 g, 35.2 mmol) was slowly added dropwise, stirred at room temperature for 30 minutes after the addition, 4b (2.5 g, 16.1 mmol) was added, heated to 80°C and stirred for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure, and dichloromethane (200 mL) was added to the residue to dilute it, cooled in ice water, and saturated sodium bicarbonate solution was added dropwise to neutralize it to pH=8-9. 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 with eluent system C to obtain the title compound 4c (2.3 g) with a yield of 66.1%.

[0446] MS m / z(ESI):295.2[M+1].

[0447] Step 3

[0448] (R)-1-Ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-ol 4d

[0449] 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 the mixture was 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 with eluent system A to obtain the title compound 4d (250 mg), with a yield of 28.1%.

[0450] MS m / z(ESI):263.1[M+1].

[0451] Step 4

[0452] (R)-4-(7-Chloro-1-ethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 4e

[0453] 4d (250 mg, 0.95 mmol) was dissolved in 2.0 mL of phosphorus oxychloride, heated to 90°C and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Dichloromethane (50 mL) was added to the obtained residue for dilution, placed in ice water for cooling, and saturated sodium bicarbonate solution was added to neutralize to pH = 8-9. The reaction was stirred for 0.5 hours, and the mixture was allowed to stand for separation. 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 with eluent system C to obtain the title compound 4e (120 mg) with a yield of 42.5%.

[0454] MS m / z(ESI):281.3[M+1].

[0455] Step 5

[0456] (R)-2-(1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4g

[0457] Compound 4e (120 mg, 0.43 mmol) and compound 1f (295 mg, 4.3 mmol, Shanghai Bidex) were dissolved in 30 mL of tetrahydrofuran and cooled in a dry ice acetone bath under an argon atmosphere. Lithium bis(trimethylsilyl)amide (1.7 mL, 1 M tetrahydrofuran solution, 1.7 mmol) was added dropwise. The mixture was stirred at low temperature for 0.5 hour, and the mixture was naturally heated 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 with eluent system C to obtain the title compound 4g (95 mg) with a yield of 74%.

[0458] MS m / z(ESI):314.1[M+1].

[0459] Step 6

[0460] (R)-2-(3-Bromo-1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4h

[0461] 4g (95mg, 0.67mmol) was dissolved in 5mL of 1,4-dioxane, sodium hydroxide solution (0.3mL, 2M solution, 0.6mmol) was added, ice water was cooled, liquid bromine (194mg, 1.2mmol) was added, and the mixture was stirred at low temperature for 10 minutes, and the mixture was naturally heated to room temperature and stirred for 1 hour. Ethyl acetate was added for dilution, 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 with eluent system C to obtain the title compound 4h (41mg), with a yield of 34%.

[0462] MS m / z(ESI):392.1[M+1].

[0463] Step 7

[0464] 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-methylpropionitrile 4i

[0465] 4h (40 mg, 0.1 mmol), tetrakistriphenylphosphine 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 Bid) were dissolved in 4 mL of dioxane, 1 mL of water was added, and microwave heating was performed at 120°C under argon atmosphere for 1 hour. The reaction solution was cooled to room temperature, 20 mL of water was added, and ethyl acetate was extracted (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 with eluent system C to obtain the title compound 4i (40 mg) with a yield of 85%.

[0466] MS m / z(ESI):464.1[M+1].

[0467] Step 8

[0468] (R)-2-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile

[0469] 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 completed, the mixture was stirred and reacted for 4 hours. The reaction solution was concentrated under reduced pressure, 7 M ammonia methanol solution was added dropwise to adjust the pH to 8-9, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to obtain the title compound 4 (15 mg), with a yield of 45%.

[0470] MS m / z(ESI):380.2[M+1].

[0471] 1 H NMR (400MHz, CD3OD): δ7.57(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).

[0472] Example 5

[0473] (R)-1-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 5

[0474]

[0475] first step

[0476] (R)-1-(1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 5a

[0477] 4e (500 mg, 1.78 mmol), cyclopropanenitrile (239 mg, 3.56 mmol), tris(dibenzylideneacetone)dipalladium (162 mg, 0.18 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (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 argon atmosphere, and the mixture was heated to 80°C with stirring for 1 hour, and the reaction solution was cooled to room temperature. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), and 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 with eluent system C to obtain the title compound 5a (360 mg) with a yield of 64.9%.

[0478] MS m / z(ESI):312.2[M+1].

[0479] Step 2

[0480] (R)-1-(3-Bromo-1-ethyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 5b

[0481] 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, and then naturally warmed to room temperature and stirred for 2 hours. 20 mL of ethyl acetate was added to dilute the mixture, and the organic phase was washed with a saturated sodium thiosulfate solution, a 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 with eluent system C to obtain the title compound 5b (100 mg) with a yield of 21%.

[0482] MS m / z(ESI):390.3[M+1].

[0483] Step 3 (R)-1-(1-ethyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropanenitrile 5

[0484] 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)boric acid (43 mg, 0.38 mmol, Shanghai Bidex) were dissolved in 4.0 mL of dioxane, 1.0 mL of water was added, and the mixture was stirred at 100°C for 2 hours under argon atmosphere. The reaction solution 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, 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 with eluent system A to obtain the title compound 5 (10 mg) with a yield of 10%.

[0485] 1 H NMR (400MHz, CD3OD): δ7.82(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).

[0486] Example 6

[0487] (R)-2-methyl-2-(5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile

[0488]

[0489]

[0490] first step

[0491] 1-Benzyl-4-nitro-1H-pyrazole-5-carboxylic acid methyl ester 6b

[0492] 4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester 6a (2 g, 11.69 mmol, Myrel) was dissolved in 30 mL of N,N-dimethylformamide, potassium carbonate (1.75 g, 12.66 mmol) and benzyl bromide (2.04 g, 11.93 mmol) were added, and stirred at room temperature for 17 hours. 80 mL of ethyl acetate was added to the reaction solution, washed with water (30 mL×3), washed with 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 with eluent system C to obtain the title compound 6b (710 mg), with a yield of 23.3%.

[0493] MS m / z(ESI):262.0[M+1].

[0494] Step 2

[0495] 4-Amino-1-benzyl-1H-pyrazole-5-carboxylic acid methyl ester 6c

[0496] Compound 6b (710 mg, 2.72 mmol) was dissolved in 20 mL of anhydrous ethanol, and iron powder (1.52 g, 27.22 mmol) and ammonium chloride (1.46 g, 27.29 mmol) were added. The reaction solution was heated to reflux and stirred for 17 hours. The reaction solution was cooled to room temperature and filtered through a Buchner funnel pre-painted with a layer of diatomaceous earth. The solid was washed with ethyl acetate, and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 6c (650 mg, containing ethanol transesterification products), yield: 100%.

[0497] MS m / z(ESI):232.2[M+1], 246.2[M+1].

[0498] Step 3

[0499] (R)-1-(4-amino-1-benzyl-1H-pyrazol-5-yl)-3-(3-methylmorpholinyl)propane-1,3-dione 6d

[0500] Lithium bis(trimethylsilyl)amide (11.29 mL, 1M tetrahydrofuran solution, 11.29 mmol) was placed in a three-necked flask. Under nitrogen atmosphere, the reaction solution was cooled to an internal temperature between -10°C and 0°C, and a 2-methyltetrahydrofuran solution of 1b (0.65 g, 4.54 mmol, 1.6 mL) was added dropwise, and the reaction was kept warm for 40 minutes. A 2-methyltetrahydrofuran solution of 6c (0.65 g, 2.81 mmol, 2.6 mL) was then added dropwise, and the reaction was kept warm for 1 hour. 10 mL of water was added to the reaction solution, 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 with eluent system C to obtain the title compound 6d (440 mg), with a yield of 45.7%.

[0501] MS m / z(ESI):343.2[M+1].

[0502] Step 4

[0503] (R)-1-Benzyl-7-chloro-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridine 6e

[0504] 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 solution was cooled to an internal temperature between -5°C and 0°C. Phosphorus oxychloride (0.79 g, 5.15 mmol) was added dropwise, and the temperature was kept for 1.5 hours, and then the temperature was raised to 65°C for 4 hours. The reaction solution was cooled to room temperature, poured into 20 mL of saturated sodium carbonate solution, extracted with ethyl acetate (20 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 with eluent system C to obtain the title compound 6e (180 mg) with a yield of 40.8%.

[0505] MS m / z(ESI):343.1[M+1].

[0506] Step 5

[0507] (R)-2-methyl-2-(5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 6g

[0508] 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 below -70°C under a nitrogen atmosphere. Lithium bis(trimethylsilyl)amide (3.15 mL, 1 M tetrahydrofuran solution, 3.15 mmol) was added dropwise, and the mixture was kept warm for 30 minutes, and then warmed to room temperature 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 with eluent system C to obtain the title compound 6g (80 mg), with a yield of 53.3%.

[0509] MS m / z(ESI):286.2[M+1].

[0510] Step 6

[0511] (R)-2-(3-Bromo-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 6h

[0512] 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 obtain the title compound 6h (40 mg), with a yield of 39.2%.

[0513] MS m / z(ESI):364.1[M+1].

[0514] Step 7

[0515] 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)propionitrile 6j

[0516] 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 Bid) 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 atmosphere was replaced with nitrogen three times. Then, bis(triphenylphosphine)palladium(II)dichloride (16 mg, 22.8 umol) was added, and the atmosphere was replaced with nitrogen three times. Under a nitrogen atmosphere, the external temperature was raised to 85°C and stirred for 1 hour. The reaction solution was cooled to room temperature, 10 mL of water was added, 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 with eluent system C to give the title compound 6j (25 mg). Yield: 52.3%.

[0517] MS m / z(ESI):436.3[M+1].

[0518] Step 8

[0519] 2-Methyl-2-(5-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile

[0520] Compound 6j (22 mg, 50.51 umol) 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 solution was poured into 10 mL of saturated sodium bicarbonate solution, concentrated under reduced pressure, 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 a developing solvent system C to obtain the title compound 6 (5 mg), with a yield of 28.2%.

[0521] MS m / z(ESI):352.1[M+1].

[0522] 1 H NMR (500MHz, CDCl3): δ7.77(s,1H),7.18(s,1H),6.93(s,1H),4.42-4.43(d,1H),4.14-4.11(m,1H),4.0 1-3.98(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).

[0523] Comparative Example 1 (Example 7)

[0524] (R)-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propan-2-ol 7

[0525]

[0526] first step

[0527] (R)-1-Methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridin-7-yl trifluoromethanesulfonate 7a

[0528] 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 solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 7a (600 mg), with a yield of 78.3%.

[0529] MS m / z(ESI):381.3[M+1].

[0530] Step 2

[0531] (R)-1-methyl-5-(3-methylmorpholinyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid methyl ester 7b

[0532] Compound 7a (400 mg, 1.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (178 mg, 0.21 mmol, Shanghai Bidex) and triethylamine (210 mg, 2.09 mmol) were dissolved in 8 mL of methanol and stirred at 65 °C for 15 hours under a carbon monoxide atmosphere. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 7b (90 mg) in a yield of 29.5%.

[0533] MS m / z(ESI):291.1[M+1].

[0534] Step 3

[0535] (R)-3-Bromo-1-methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid methyl ester 7c

[0536] 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 obtain a crude title compound 7c (180 mg), which was used directly in the next step without purification.

[0537] MS m / z(ESI):369.1[M+1].

[0538] Step 4

[0539] 1-Methyl-5-((R)-3-methylmorpholinyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid methyl ester 7d

[0540] 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 Bid) were dissolved in 4 mL of dioxane, 1 mL of water was added, and the reaction was heated to 120°C in a microwave under an argon atmosphere for 1 hour. The reaction solution was cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and 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 with eluent system C to give the title compound 7d (45 mg). Yield: 32.3%.

[0541] MS m / z(ESI):441.2[M+1].

[0542] Step 5

[0543] 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

[0544] 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 Bidex) was added dropwise in an ice bath. After addition, the mixture was stirred for 2 hours. 10 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7e (40 mg), with a yield of 88.9%. MS m / z (ESI): 441.6 [M+1].

[0545] Step 6 (R)-2-(1-methyl-5-(3-methylmorpholinyl)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propane-2-

[0546] Alcohol 7

[0547] Compound 7e (40 mg, 90 umol) was dissolved in 3 mL of methanol, and dioxane hydrochloride solution (1 mL, 4 N) was added, and stirred at room temperature for 30 minutes. The residue was concentrated under reduced pressure and purified by thin layer chromatography using developing solvent system C to obtain the title compound 7 (10 mg), with a yield of 30.9%.

[0548] MS m / z (ESI): 357.6 [M+1].

[0549] 1 H NMR (400MHz, CD3OD): δ7.68(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).

[0550] Test example:

[0551] Biological evaluation

[0552] Test Example 1: Inhibitory effect of the disclosed compounds on ATR enzyme.

[0553] The following method is used to determine the inhibitory effect of the disclosed compounds on the ATR enzyme. The experimental method is briefly described as follows:

[0554] 1. Experimental Materials and Instruments

[0555] 1.ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M)

[0556] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

[0557] 3. 384-well plate (Thermo Scientific, 267462)

[0558] 4. U-bottom 96-well plate (Corning, 3795)

[0559] 5. Labeling of europium cryptate anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)

[0560] 6. Anti-GST antibody linked to D2 (Cisbio, 61GSTDLF)

[0561] 7. ATP solution (Promega, V916B)

[0562] 8.EDTA (Thermo Scientific, AM9260G)

[0563] 9.HEPES (Gibco, 15630-080)

[0564] 10. Microplate reader (BMG, PHERAsta)

[0565] 2. Experimental steps

[0566] ATR enzyme 1nM, P53 protein 50nM, 7.435μM ATP and small molecule compounds of different concentrations (first concentration 1μM, 3-fold gradient dilution 11 concentrations) were mixed and incubated at room temperature for 2 hours, then the stop solution (12.5mM HEPES, 250mM EDTA) was added and mixed, and then 0.42ng / well of europium-labeled cryptate anti-phosphorylated P53 protein antibody and 25ng / well of linked d2 anti-GST antibody were added. After incubation at room temperature overnight, the 620nm and 665nm fluorescence signals were detected with PHERAstar. The data were processed using GraphPad software.

[0567] 3. Experimental Data

[0568] The inhibitory activity of the disclosed compounds on ATR enzyme can be determined by the above test, and the measured IC 50 See Table 1 for values.

[0569] Table 1 IC of the compounds disclosed herein for ATR enzyme inhibition 50 .

[0570] Example No. <![CDATA[IC 50 / nM]]> Maximum inhibition rate (%) 1 3 100 2 9 100 3 15 100 4 6 100 5 8 100 6 3 100 Comparative Example 1 73 97

[0571] Conclusion: Compared with Control Example 1, the compounds disclosed herein have better inhibitory activity against ATR enzyme.

[0572] Test Example 2: Cell Proliferation Experiment

[0573] The following method detects the intracellular ATP content according to IC 50 The inhibitory effect of the disclosed compounds on the proliferation of LoVo cells was evaluated. The experimental method is briefly described as follows:

[0574] 1. Experimental Materials and Instruments

[0575] 1. LoVo, human colon cancer tumor cells (Nanjing Kebai, CBP60032)

[0576] 2. Fetal bovine serum (FBS) (GIBCO, 10091-148)

[0577] 3. F-12K culture medium (Gibco, 21127030)

[0578] 4. CellTite-Glo reagent (Promega, G7573)

[0579] 5.96-well cell culture plate (corning, 3903)

[0580] 6. Pancreatin (Invitrogen, 25200-072)

[0581] 7. Microplate reader (BMG, PHERAstar)

[0582] 8. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0583] 2. Experimental steps

[0584] LoVo cells were cultured in F-12K medium containing 10% FBS and passaged 2-3 times a week at a passage ratio of 1:3 or 1:5. During passage, the cells were digested with trypsin and transferred to a centrifuge tube. Centrifuged at 1200 rpm for 3 minutes, the 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 at a density of 3.88×10 4 cells / ml, only 100 μL of complete culture medium was added to the periphery of the 96-well plate, and the culture plate was cultured in an incubator for 24 hours (37° C., 5% CO 2 ).

[0585] The sample to be tested was diluted to 2mM with DMSO, and diluted 3 times in sequence to 10 concentrations, and blank and control wells were set. Take 5μL of the compound solution to be tested prepared in gradient concentrations and add it to 95μL of fresh culture medium. Then add 10μL of the above-mentioned drug-containing culture medium solution to the culture plate. Incubate the culture plate in an incubator for 3 days (37°C, 5% CO2). In a 96-well cell culture plate, 50μL of CellTiter-Glo reagent was added to each well, placed in the dark at room temperature for 5-10min, and the chemiluminescent signal value was read in PHERAstar, and the data was processed using GraphPad software.

[0586] 3. Experimental Data

[0587] The inhibitory activity of the disclosed compounds on LoVo cell proliferation can be determined by the above test, and the measured IC 50 See Table 2 for values.

[0588] Table 2 IC of the compounds disclosed herein on the inhibition of LoVo cell proliferation 50 .

[0589] Example No. <![CDATA[IC 50 / nM]]> Maximum inhibition rate (%) 1 43 93 2 75 90 3 124 87 4 64 89 5 100 93 6 55 95 Comparative Example 1 316 92

[0590] Conclusion: Compared with Control Example 1, the compounds disclosed herein have a better inhibitory effect on LoVo cell proliferation.

[0591] Pharmacokinetic evaluation

[0592] Test Example 3: Pharmacokinetic Test of the Disclosed Compounds

[0593] 1. Summary

[0594] Rats were used as test animals, and the drug concentrations in plasma at different times after oral administration of the compounds of Example 1, Example 2, and Example 3 were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in rats was studied, and their pharmacokinetic characteristics were evaluated.

[0595] 2. Experimental plan

[0596] 2.1 Trial Drugs

[0597] The compound of Example 1, the compound of Example 2 and the compound of Example 3.

[0598] 2.2 Experimental animals

[0599] Twelve healthy adult SD rats, half male and half female, were equally divided into 3 groups, 4 rats in each group, purchased from Weitonglihua Experimental Animal Co., Ltd.

[0600] 2.3 Drug preparation

[0601] Weigh a certain amount of drug, add 5% DMSO, 5% Tween 80 and 90% saline to prepare a colorless clear solution.

[0602] 2.4 Administration

[0603] SD rats were fasted overnight and then gavaged with the drug. The dosage was 2 mg / kg and the administration volume was 10.0 mL / kg.

[0604] 3. Operation

[0605] Rats were intragastrically administered with the compounds of Example 1, Example 2, and Example 3, and 0.2 mL of blood was collected from the eye sockets before and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2kk anticoagulant tube and centrifuged at 4°C and 11,000 rpm for 5 minutes to separate the plasma, which was stored at -20°C and fed 2 hours after administration.

[0606] Determine the content of the test compound in rat plasma after oral administration of different concentrations of the drug: take 25 μL of rat plasma at each time after administration, add 50 μL of internal standard solution and 175 μL of acetonitrile, vortex mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 1 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[0607] 4. Pharmacokinetic parameter results

[0608] Table 3 The pharmacokinetic parameters of the disclosed compounds are as follows:

[0609]

[0610] Conclusion: The compounds disclosed herein have good pharmacokinetic absorption and have obvious pharmacokinetic advantages.

Claims

1. A compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof: in: G 1 and G 2 are the same or different, each independently CH or N, provided that G 1 and G 2 Not at the same time CH; Ring A is a heteroaryl group; R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; R 3 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; 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 hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; n is 0, 1, 2 or 3.

2. A compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

3. The compound of the general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, pyrrolyl and imidazolyl.

4. A compound of the general formula (I) according to claim 1 or 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in claim 1.

5. A compound of the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (III) or general formula (IV), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: in: R 1 , R 2 , R 3 and n is as defined in claim 1.

6. A compound according to any one of the general formula (I) of claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; and / or R 2 is a hydrogen atom or an alkyl group; preferably an alkyl group.

7. A compound according to any one of the general formula (I) of claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

8. A compound of the general formula (I) according to any one of claims 1 to 7, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

9. A compound represented by the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, in: X is halogen; preferably Br; G 1 and G 2 are the same or different, each independently CH or N, provided that G 1 and G 2 Not at the same time CH; R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; 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 hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group.

10. A compound represented by the general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, in: R a is an amino protecting group; G 1 and G 2 are the same or different, each independently CH or N, provided that G 1 and G 2 Not at the same time CH; R 1 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclic radical, aryl and heteroaryl; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR 4 R 5 、-CONR 4 R 5 、-SO2NR 4 R 5 , -R 6 N-CO-NR 4 R 5 、-COOR 7 、-SO2R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; R 3 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; 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 hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; n is 0, 1, 2 or 3.

11. A compound represented by the general formula (IIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, in: G 1 , G 2 , R 1 , R 2 , R 3 , R a and n is as defined in claim 10.

12. The compound of the general formula (IA) according to claim 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

13. The compound represented by the general formula (IIA) according to claim 10 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:

14. The compound represented by the general formula (IIGA) according to claim 11 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

15. A method for preparing the compound of general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IA) and the compound of general formula (IB) undergo coupling reaction to obtain the compound of general formula (I), in: X is halogen; preferably Br; R b for Ring A, G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in claim 1.

16. A method for preparing the compound represented by the general formula (IIA) according to claim 10 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IA) and the compound of general formula (IIB) undergo coupling reaction to obtain the compound of general formula (IIA), in: X is halogen; preferably Br; R a is an amino protecting group; R b for G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in claim 10.

17. A method for preparing a compound represented by the general formula (IIGA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IA) and the compound of general formula (IIGB) undergo coupling reaction to obtain a compound of general formula (IIGA), in: X is halogen; preferably Br; R a is an amino protecting group; R b for G 1 , G 2 , R 1 , R 2 , R 3 and n is as defined in claim 11.

18. A method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IIA) or the compound of general formula (IIGA) is deprotected from the amino protecting group 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.

19. A pharmaceutical composition comprising a compound of the general formula (I) according to any one of claims 1 to 8 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of a compound of general formula (I) according to any one of claims 1 to 8 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting ATR kinase.

21. Use of a compound of general formula (I) according to any one of claims 1 to 8 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing a hyperproliferative disease.

22. Use of a compound of the general formula (I) according to any one of claims 1 to 8 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing tumors.

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